Early Outcomes of Stereotactic Body Radiotherapy for Localized Prostate Cancer: A Retrospective Analysis

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Early Outcomes of Stereotactic Body Radiotherapy for Localized Prostate Cancer: A Retrospective Analysis

Author(s)
Eashwer Reddy, MD
Inamul Haque, PhD
John Park, MD
Dunia T. Khaled, MD

Prostate cancer is the most common cancer in US males, with an estimated 313,780 new cases and 35,770 deaths in 2025.1 Several treatment options are available for localized prostate cancer that have similar outcomes, including active surveillance for low-risk cancers, surgery, or radiotherapy.2,3 Conventional fractionation radiotherapy (CFRT) with 40 to 45 fractions over 8 to 9 weeks has been used for decades. Over the past 2 decades, moderate hypofractionation schedules with 2.4 to 3.4 Gy per fraction over 20 to 28 fractions have become standard, as many noninferiority randomized clinical trials (RCTs) such as CHHiP (UK),4 PROFIT (Canada and Europe),5 NRG Oncology RTOG 0415 (US),6 HYPRO (Netherlands),7,8 and HYPO-RT-PC (Sweden and Denmark),9 have shown the noninferiority of moderately hypofractionated radiotherapy compared with CFRT. Notably, most of these noninferiority studies primarily included patients with low- or intermediate-risk prostate cancer, except for the HYPO-RT-PC trial,9 which also included patients with intermediate- and high-risk prostate cancer.

These noninferiority studies, along with technological advances in radiotherapy, such as intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and image-guided radiotherapy (IGRT), paved the path to ultrahypofractionated stereotactic body radiotherapy (SBRT) that is delivered in 5 fractions of ≥ 6 Gy. This high dose per fraction may have a radiobiologic advantage over conventional fractionation. The relatively low a/ß ratio of prostate cancer, estimated to be between 1 and 2, suggests that tumor cells may be particularly sensitive to the high doses per fraction delivered in SBRT.10-13 Compared with CFRT, SBRT-induced tumor cell death may also be mediated through different pathways; this pathway appears to be generated in a dose-dependent manner, particularly with doses > 8 Gy per fraction.14,15 Additionally, the higher a/ß ratio for the surrounding organs at risk, such as the bladder and rectum, theoretically allows for an improved therapeutic ratio window that maximizes tumor control while minimizing damage to healthy tissues.

A substantial body of evidence from prospective studies and meta-analyses supports the use of SBRT for localized prostate cancer. HYPO-RT-PC, a significant phase 3 noninferiority study, enrolled 1200 patients with intermediate (89%) and high-risk (11%) prostate cancer randomized between 2 arms, including CFRT to 78 Gy in 39 fractions and SBRT to 42.7 Gy in 7 fractions, treated 3 days weekly. After a median follow-up of 60 months, the estimated 5-year biochemical relapse-free survival rate was 84% in both groups.9 This trial was notable because it was the first randomized study to demonstrate that SBRT was noninferior to CFRT in intermediate- and high-risk prostate cancer patients. Another pivotal phase 3 trial, the PACE-B study, enrolled 874 patients to compare SBRT (36.25 Gy to the prostate gland, with a secondary dose of 40 Gy to the gross tumor volume where applicable, in 5 fractions) with CFRT (78 Gy in 39 fractions) and moderately hypofractionated radiotherapy (HFRT) (62 Gy in 20 fractions) in patients with low- or intermediate-risk prostate cancer. With a 74-month median follow-up, the study reported 5-year biochemical free rates of 94.6% for CFRT and 95.8% for SBRT, confirming the noninferiority of SBRT to CFRT.15

SBRT offers short, effective, and convenient treatment to many patients with localized prostate cancer. While previous guidelines were more restrictive, the March 2026 National Comprehensive Cancer Network (NCCN) guidelines now list SBRT as a preferred treatment modality for high-risk prostate cancer.16

Given the growing body of evidence supporting the efficacy and safety of SBRT, we implemented an SBRT program in 2014 at a tertiary care center for veterans. This retrospective study was undertaken to evaluate the early efficacy and toxicity of SBRT in patients with localized prostate cancer treated at our institution, including patients across all risk stratifications.

METHODS

We identified 242 patients diagnosed with prostate cancer who underwent SBRT treatment between November 2014 and October 2024 at Overland Park Veterans Affairs Radiation Oncology Clinic. For the final analysis, 46 patients with < 2 years of follow-up and 22 patients who died from causes other than prostate cancer were excluded, resulting in a cohort of 174 patients with ≥ 24-month follow-up.

Treatment

Patients eligible for staging underwent imaging according to NCCN guidelines, including computed tomography (CT) of the abdomen and pelvis, bone scintigraphy, or, in recent years, prostate-specific membrane antigen positron emission tomography, primarily used for unfavorable intermediate-risk (UIR) and high-risk (HR) cancers. Patients with a negative staging work-up for nodal or skeletal disease were included. Prior to planning the CT simulation, patients were given bowel preparation instructions, including a low-fiber and low-gas-producing diet, simethicone, and enemas, the night before and morning of the simulation. Patients were instructed to arrive with a comfortably full bladder, having not voided for 2 to 3 hours prior to the procedure. At Kansas City Veterans Affairs Medical Center (KCVAMC), SBRT treatment was generally restricted to patients with a baseline American Urological Association symptom score of 15 to 20 out of 35 and a prostate gland size < 80 mL to minimize the risk of acute urinary toxicity. We did not use intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast agents for planning CT simulation.

Patients were placed in a supine position, and a vacuum bag was used for immobilization. Following the CT simulation, the images were transferred to the Eclipse treatment planning system. The clinical target volume (CTV) encompassed the prostate and the proximal 1.0 cm of the seminal vesicles for Gleason score (GS) 1 to 2, and the entire seminal vesicle was included for GS 3 to 5, which is consistent with KCVAMC practice and established safety protocols. The planning target volume (PTV) was created by uniformly expanding the CTV by 5 to 7 mm, except for the posterior margin, which was limited to 3 to 5 mm. When elective nodal radiotherapy was planned for HR prostate cancer, the pelvic field for CT simulation started at the L-2 upper border, with the lower border extending to the lesser trochanter. The pelvic nodes were delineated per Radiation Therapy Oncology Group (RTOG) guidelines.17 The CTV nodes (CTVn), including common iliac, external and internal iliac nodes, obturator, and presacral nodes, were created by uniformly expanding the CTVn by 2 to 3 mm. Slice-by-slice corrections were made to avoid bowel overlap in these patients.

The use of androgen deprivation therapy (ADT) for a duration of 6 to 24 months was prescribed for patients with UIR or HR prostate cancer per NCCN guidelines.16 The prescribed dose to the PTV was 36.25 to 40 Gy (40 Gy was mostly used as a boost to the dominant lesion) in 5 fractions, with each fraction ranging from 7.25 to 8 Gy. For elective nodal radiotherapy in patients at HR, the prescribed dose was 25 Gy in 5 fractions. All patients were planned for VMAT, which aims to deliver ≥ 95% of the prescription dose to 95% of the PTV. Once the physician approved the treatment plan and physics quality assessment was completed, treatments commenced on an every-other-day schedule. Patients received the same bowel preparation instructions for each treatment as for the planning CT simulation. Daily treatment accuracy was confirmed via daily 3-dimensional cone-beam CT (CBCT) for IGRT. No fiducials or hydrogel rectal spacers were used.

Follow-up Schedule and Toxicity Assessment

Follow-up assessments were conducted 4 to 6 weeks after radiation therapy and then repeated every 6 months for 2 to 5 years, and annually thereafter. At each follow-up visit, patients were evaluated for genitourinary (GU) and gastrointestinal (GI) toxicity, according to RTOG toxicity criteria. Prostate-specific antigen (PSA) levels were monitored; in patients receiving ADT, testosterone levels were also checked.

Statistical Analysis

Biochemical failure was defined using the Phoenix definition (nadir PSA + 2 ng/mL). Differences between dose cohorts were assessed using the log-rank test for survival outcomes and X2 testing for categorical variables. GU and GI toxicities were summarized as cumulative incidences of RTOG grade ≥ II events. Statistical significance was set at P < .05.

RESULTS

One hundred seventy-four patients were included in the retrospective review. Patients had a median follow-up of 45 months (range, 24-111) (Figure). The median age at treatment was 74 years (range, 51-88), and the median pretreatment PSA level was 11.9 ng/mL (range, 0.6-69.5). Twenty-six patients (14.9%) had a GS 1, 77 (44.3%) had GS 2, 41 (23.6%) had GS 3, 18 (10.3%) had GS 4, and 12 (6.9%) had GS 5. Fifty-one patients (29.3%) received elective pelvic nodal radiotherapy, and 93 patients (53.4%) received ADT (Table 1).

0526FED-AVAHO-SBRT_F1
FIGURE. Patient Selection Flowchart
0526FED-AVAHO-SBRT_T1

At 24 months follow-up, 6 patients (3.4%) had biochemical failures. One patient died from metastatic prostate cancer, and 5 patients are living with biochemical failure (Table 2). The actuarial 5-year overall survival (OS) rate was 99.4%, and the 5-year disease-free survival (DFS) rate was 96.6%. We performed a subanalysis comparing outcomes of the 36.25 Gy vs 40 Gy SBRT cohorts. There was no statistically significant difference in DFS, OS, or the cumulative incidence of grade II/III toxicity between patients treated with 40 Gy vs 36.25 Gy. Outcomes stratified by NCCN risk groups (low, intermediate, high/very high) are detailed in Table 3. As expected, DFS was slightly lower in the high-risk group, but overall disease control remained high across all stratifications.

0526FED-AVAHO-SBRT_T20526FED-AVAHO-SBRT_T3

The cumulative incidence of RTOG grade II and higher GU toxicity was 28.2% (Table 4). This included 46 patients (26.4%) with grade II GU toxicity and 2 patients (1.2%) who developed grade III GU complications (1 requiring self-catheterization and another a suprapubic catheter for urinary retention). One patient (0.6%) treated with a 40 Gy dose regimen experienced a grade IV GU complication in the form of a rectovesical fistula necessitating surgical intervention.

0526FED-AVAHO-SBRT_T4

The cumulative incidence of RTOG grade II or higher GI toxicity was 3.4%, and no grade III or IV gastrointestinal toxicities were observed during the follow-up period. Importantly, intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast were not routinely used in this cohort of patients.

The high rates of actuarial 5-year DFS and OS observed suggest a favorable initial response to the SBRT regimen employed at KCVAMC. However, given the potential for late recurrence in patients with prostate cancer, longer follow-up is essential to determine the durability of these outcomes. The observed GU toxicity rate of 28.2% for grade II and higher events warrants careful consideration and compares with other published data on SBRT for prostate cancer.15 The occurrence of a grade IV rectovesical fistula, although rare, is a notable adverse event that warrants discussion in the context of the treatment approach. The low incidence of grade II or higher GI toxicity is an encouraging finding, particularly given that hydrogel rectal spacers are not routinely used to minimize rectal exposure.

DISCUSSION

The primary objective of this retrospective study was to evaluate the outcomes of SBRT for patients with localized prostate cancer treated at KCVAMC and to compare these results with those reported in the literature. Our findings demonstrate promising intermediate-term efficacy, with an estimated 5-year DFS of 96.6% and OS of 99.4% at a median follow-up of 45 months. Furthermore, the observed toxicity profile appears acceptable, with a cumulative grade II and higher GU toxicity rate of 28.2% and a grade II or higher GI toxicity rate of 3.4%. Notably, these outcomes were achieved without the routine use of intraprostatic fiducials or hydrogel rectal spacers.

Two pivotal randomized phase 3 trials have established the noninferiority of ultrahypofractionated radiotherapy (UHRT) with SBRT over conventional fractionation. The HYPO-RT-PC trial compared SBRT (42.7 Gy in 7 fractions) with conventional fractionation (78 Gy in 39 fractions) in intermediate- and high-risk patients with prostate cancer and reported a 5-year biochemical relapse-free survival of 84% in both arms.9 The PACE-B trial, which included patients at low- and intermediate-risk, compared SBRT (36.25 Gy in 5 fractions) with conventional or moderate HFRT and reported a 5-year biochemical control rate of 95.8% in the SBRT arm and 94.6% in the control arm.15

A comprehensive review and meta-analysis of 7 phase 3 studies involving 6795 patients compared different radiotherapy regimens, namely, UHRT, HFRT, and CFRT, and reported that after 5 years, the DFS rates were 85.1% for CFRT, 86% for HFRT, and 85% for UHRT, with no significant difference in toxicity among the 3 different treatment approaches.18 This suggests that shorter, more intense radiotherapy schedules (UHRT and HFRT) may be as effective and safe as traditional, longer courses of radiation.

There are multiple published nonrandomized prospective trials in which thousands of patients with extreme hypofractionation have been treated with different doses, fractions, and techniques. While heterogeneity and limited long-term follow-up in the existing evidence are acknowledged, these data suggest that prostate SBRT provides appropriate biochemical control with few high-grade toxicities, supporting its ongoing global use and justifying further prospective investigations. Comparative data are shown in Table 5. Several ongoing studies are evaluating noninferiority, superiority, and cost-effectiveness using different methodologies (Table 6).9,15,19-24

0526FED-AVAHO-SBRT_T50526FED-AVAHO-SBRT_T6

This study’s efficacy outcomes, particularly the high DFS rate, are consistent with the findings from these landmark trials, suggesting that the SBRT regimen used at KCVAMC is effective in achieving early disease control despite 17.2% of patients having high-risk disease. The GU toxicity observed in this study, with a 28.2% rate of grade II or higher events, is also comparable with the 26.9% reported in the 5-fraction SBRT arm of the PACE-B trial, which had a longer median follow-up of 74 months.15 It is important to note that a portion of these grade II events occurred in patients who were already on a blockers for pre-existing lower urinary tract symptoms before starting radiotherapy, which may inflate the observed cumulative acute toxicity score.

A critical comparison is how SBRT toxicity aligns with moderate hypofractionation (eg, 60 Gy in 20 fractions or 70 Gy in 28 fractions as reported by others).4,6 Our observed grade III and higher GU toxicity rate (1.7%) and grade III and higher GI toxicity rate (0%) are highly favorable when compared with historical moderate hypofractionation data, which typically report grade III GU toxicity in the range of 2% to 3% and grade III GI toxicity around 1% to 2%. This suggests that despite the higher dose per fraction, SBRT does not necessarily lead to increased severe acute toxicity, potentially offering a superior therapeutic ratio for GI and GU sparing.

However, the occurrence of a grade IV rectovesical fistula in 1 patient (0.6%)—who received the 40 Gy dose—was a serious complication that warrants careful consideration. This rare, but severe, complication in the higher dose cohort underscores the potential for increased organ-at-risk toxicity, particularly in the absence of a hydrogel rectal spacer, which is designed to mitigate high-dose rectal exposure. While the overall rate of significant GU toxicity remains low, this event highlights the potential risks associated with SBRT. Hydrogel rectal spacers are designed to increase the distance between the prostate and the rectum, which can reduce the rectal radiation dose and potentially mitigate the risk of such fistulas. The low rate of grade II or worse GI toxicity (3.4%) in our study is noteworthy, especially considering that hydrogel spacers were not routinely used. This finding aligns with the 2.5% GI toxicity rate reported in the SBRT arm of the PACE-B trial, suggesting that careful treatment planning and delivery techniques, such as VMAT-IMRT and daily CBCT for IGRT, may contribute to minimizing GI toxicity even without the use of rectal spacers.15 The exclusive use of 3-dimensional CBCT for IGRT in our study, without the use of fiducial markers, suggests that accurate target localization can be achieved with this approach, contributing to the observed efficacy and reduced toxicity.

Strengths and Limitations

This study’s retrospective, single-center design may have introduced selection bias. The median follow-up of 45 months, while substantial, is still relatively short for assessing very late toxicities and long-term oncologic outcomes in prostate cancer, which is known for late recurrences. Additionally, the lack of a direct comparison group within KCVAMC limits the ability to definitively attribute the observed outcomes solely to SBRT treatment. However, the strengths of this study include the inclusion of a consecutive series of veteran patients with localized prostate cancer across all risk categories, providing a real-world perspective on SBRT outcomes in a diverse patient population. Furthermore, the detailed assessment of efficacy and toxicity via standardized RTOG criteria enhances the comparability of our findings with those of other published prospective studies, despite the retrospective nature of the data.

CONCLUSIONS

This single-institution retrospective analysis revealed that short-term SBRT (36.25 to 40 Gy in 5 fractions), with a minimum follow-up of 24 months and a median follow-up of 45 months, for localized prostate cancer, including patients at HR, is associated with promising early efficacy and acceptable toxicity, even in the absence of routine fiducial or hydrogel spacer use. The favorable actuarial 5-year DFS and OS rates, coupled with a manageable toxicity profile, suggest that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer. However, a longer follow-up is necessary to confirm these findings and fully characterize the long-term efficacy and toxicity of this SBRT regimen. Nevertheless, the results contribute to the growing body of evidence suggesting that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer.

References
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  11. Dasu A. Is the alpha/beta value for prostate tumours low enough to be safely used in clinical trials? Clin Oncol (R Coll Radiol). 2007;19:289-301. doi:10.1016/j.clon.2007.02.007
  12. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300:1155-1159. doi:10.1126/science.1082504
  13. Gulliford S, Hall E, Dearnaley D. Hypofractionation trials and radiobiology of prostate cancer. Oncoscience. 2017;4:27-28. doi:10.18632/oncoscience.347
  14. Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response. Cancer Cell. 2005;8:89-91. doi:10.1016/j.ccr.2005.07.014
  15. van As N, Griffin C, Tree A, et al. Phase 3 Trial of stereotactic body radiotherapy in localized prostate cancer. N Engl J Med. Oct 17 2024;391:1413-1425. doi:10.1056/NEJMoa2403365
  16. National Comprehensive Cancer Network. NCCN Guidelines Version 5. 2026 Prostate Cancer. Accessed March 24, 2026. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
  17. Lawton CA, Michalski J, El-Naqa I, et al. RTOG GU radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2009;74:383-387. doi:10.1016/j.ijrobp.2008.08.002
  18. Lehrer EJ, Kishan AU, Yu JB, et al. Ultrahypofractionated versus hypofractionated and conventionally fractionated radiation therapy for localized prostate cancer: a systematic review and meta-analysis of phase III randomized trials. Radiother Oncol. 2020;148:235-242. doi:10.1016/j.radonc.2020.04.037
  19. De Cooman B, Debacker T, Adams T, et al. Stereotactic body radiotherapy (SBRT) as a treatment for localized prostate cancer: a retrospective analysis. Radiat Oncol. 2025;20:25. doi:10.1186/s13014-025-02598-8
  20. Fuller DB, Falchook AD, Crabtree T, et al. Phase 2 multicenter trial of heterogeneous-dosing stereotactic body radiotherapy for low- and intermediate-risk prostate cancer: 5-year outcomes. Eur Urol Oncol. 2018;1:540-547. doi:10.1016/j.euo.2018.06.013
  21. Jackson WC, Silva J, Hartman HE, et al. Stereotactic body radiation therapy for localized prostate cancer: a systematic review and meta-analysis of over 6,000 patients treated on prospective studies. Int J Radiat Oncol Biol Phys. 2019;104:778-789. doi:10.1016/j.ijrobp.2019.03.051
  22. Meier RM, Bloch DA, Cotrutz C, et al. Multicenter trial of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer: survival and toxicity endpoints. nt J Radiat Oncol Biol Phys. 2018;102:296-303. doi:10.1016/j.ijrobp.2018.05.040
  23. Quon HC, Ong A, Cheung P, et al. Once-weekly versus every-other-day stereotactic body radiotherapy in patients with prostate cancer (PATRIOT): a phase 2 randomized trial. Radiother Oncol. 2018;127:206-212. doi:10.1016/j.radonc.2018.02.029
  24. Zelefsky MJ, Kollmeier M, McBride S, et al. Five-year outcomes of a phase 1 dose-escalation study using stereotactic body radiosurgery for patients with low-risk and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2019;104:42-49. doi:10.1016/j.ijrobp.2018.12.045
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0526FED AVAHO SBRT.pdf
Author and Disclosure Information

Eashwer Reddy, MDa; Inamul Haque, PhDa,b,c; John Park, MDd; Dunia T. Khaled, MDc

Author affiliations
aKansas City Veterans Affairs Medical Center, Missouri
bKansas City Kansas Community College
cUniversity of Kansas Medical Center, Kansas City
dNorth Kansas City Hospital, Missouri

Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Ethics and consent The Kansas City Veterans Affairs Medical Center Research and Development Committee and Institutional Review Board reviewed and approved the study (IRBNet ID#1578727).

Funding This study was supported partly by the Veterans Affairs Cancer Clinical Research Network Grant, Genitourinary Precision Oncology Program, and the Midwest Veterans’ Biomedical Research Foundation.

Acknowledgments The authors thank all the patients who participated in this study, as well as the research team for their direct or indirect contributions in the completion of this study. We also thank the staff of the Research and Development Office at the Kansas City VA Medical Center (KCVAMC) and the Overland Park VA Radiation Oncology Clinic. This material is the result of work supported by resources and the use of facilities at KCVAMC.

Correspondence: Eashwer Reddy (eashwer.reddy@va.gov)

Fed Pract. 2026;43(suppl 2). Published online May 15. doi:10.12788/fp.0706

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Federal Practitioner - 43(suppl 2)
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Topics
Oncology
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Author(s)
Eashwer Reddy, MD
Inamul Haque, PhD
John Park, MD
Dunia T. Khaled, MD
Author(s)
Eashwer Reddy, MD
Inamul Haque, PhD
John Park, MD
Dunia T. Khaled, MD
Author and Disclosure Information

Eashwer Reddy, MDa; Inamul Haque, PhDa,b,c; John Park, MDd; Dunia T. Khaled, MDc

Author affiliations
aKansas City Veterans Affairs Medical Center, Missouri
bKansas City Kansas Community College
cUniversity of Kansas Medical Center, Kansas City
dNorth Kansas City Hospital, Missouri

Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Ethics and consent The Kansas City Veterans Affairs Medical Center Research and Development Committee and Institutional Review Board reviewed and approved the study (IRBNet ID#1578727).

Funding This study was supported partly by the Veterans Affairs Cancer Clinical Research Network Grant, Genitourinary Precision Oncology Program, and the Midwest Veterans’ Biomedical Research Foundation.

Acknowledgments The authors thank all the patients who participated in this study, as well as the research team for their direct or indirect contributions in the completion of this study. We also thank the staff of the Research and Development Office at the Kansas City VA Medical Center (KCVAMC) and the Overland Park VA Radiation Oncology Clinic. This material is the result of work supported by resources and the use of facilities at KCVAMC.

Correspondence: Eashwer Reddy (eashwer.reddy@va.gov)

Fed Pract. 2026;43(suppl 2). Published online May 15. doi:10.12788/fp.0706

Author and Disclosure Information

Eashwer Reddy, MDa; Inamul Haque, PhDa,b,c; John Park, MDd; Dunia T. Khaled, MDc

Author affiliations
aKansas City Veterans Affairs Medical Center, Missouri
bKansas City Kansas Community College
cUniversity of Kansas Medical Center, Kansas City
dNorth Kansas City Hospital, Missouri

Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Ethics and consent The Kansas City Veterans Affairs Medical Center Research and Development Committee and Institutional Review Board reviewed and approved the study (IRBNet ID#1578727).

Funding This study was supported partly by the Veterans Affairs Cancer Clinical Research Network Grant, Genitourinary Precision Oncology Program, and the Midwest Veterans’ Biomedical Research Foundation.

Acknowledgments The authors thank all the patients who participated in this study, as well as the research team for their direct or indirect contributions in the completion of this study. We also thank the staff of the Research and Development Office at the Kansas City VA Medical Center (KCVAMC) and the Overland Park VA Radiation Oncology Clinic. This material is the result of work supported by resources and the use of facilities at KCVAMC.

Correspondence: Eashwer Reddy (eashwer.reddy@va.gov)

Fed Pract. 2026;43(suppl 2). Published online May 15. doi:10.12788/fp.0706

Article PDF
0526FED AVAHO SBRT.pdf
Article PDF
0526FED AVAHO SBRT.pdf

Prostate cancer is the most common cancer in US males, with an estimated 313,780 new cases and 35,770 deaths in 2025.1 Several treatment options are available for localized prostate cancer that have similar outcomes, including active surveillance for low-risk cancers, surgery, or radiotherapy.2,3 Conventional fractionation radiotherapy (CFRT) with 40 to 45 fractions over 8 to 9 weeks has been used for decades. Over the past 2 decades, moderate hypofractionation schedules with 2.4 to 3.4 Gy per fraction over 20 to 28 fractions have become standard, as many noninferiority randomized clinical trials (RCTs) such as CHHiP (UK),4 PROFIT (Canada and Europe),5 NRG Oncology RTOG 0415 (US),6 HYPRO (Netherlands),7,8 and HYPO-RT-PC (Sweden and Denmark),9 have shown the noninferiority of moderately hypofractionated radiotherapy compared with CFRT. Notably, most of these noninferiority studies primarily included patients with low- or intermediate-risk prostate cancer, except for the HYPO-RT-PC trial,9 which also included patients with intermediate- and high-risk prostate cancer.

These noninferiority studies, along with technological advances in radiotherapy, such as intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and image-guided radiotherapy (IGRT), paved the path to ultrahypofractionated stereotactic body radiotherapy (SBRT) that is delivered in 5 fractions of ≥ 6 Gy. This high dose per fraction may have a radiobiologic advantage over conventional fractionation. The relatively low a/ß ratio of prostate cancer, estimated to be between 1 and 2, suggests that tumor cells may be particularly sensitive to the high doses per fraction delivered in SBRT.10-13 Compared with CFRT, SBRT-induced tumor cell death may also be mediated through different pathways; this pathway appears to be generated in a dose-dependent manner, particularly with doses > 8 Gy per fraction.14,15 Additionally, the higher a/ß ratio for the surrounding organs at risk, such as the bladder and rectum, theoretically allows for an improved therapeutic ratio window that maximizes tumor control while minimizing damage to healthy tissues.

A substantial body of evidence from prospective studies and meta-analyses supports the use of SBRT for localized prostate cancer. HYPO-RT-PC, a significant phase 3 noninferiority study, enrolled 1200 patients with intermediate (89%) and high-risk (11%) prostate cancer randomized between 2 arms, including CFRT to 78 Gy in 39 fractions and SBRT to 42.7 Gy in 7 fractions, treated 3 days weekly. After a median follow-up of 60 months, the estimated 5-year biochemical relapse-free survival rate was 84% in both groups.9 This trial was notable because it was the first randomized study to demonstrate that SBRT was noninferior to CFRT in intermediate- and high-risk prostate cancer patients. Another pivotal phase 3 trial, the PACE-B study, enrolled 874 patients to compare SBRT (36.25 Gy to the prostate gland, with a secondary dose of 40 Gy to the gross tumor volume where applicable, in 5 fractions) with CFRT (78 Gy in 39 fractions) and moderately hypofractionated radiotherapy (HFRT) (62 Gy in 20 fractions) in patients with low- or intermediate-risk prostate cancer. With a 74-month median follow-up, the study reported 5-year biochemical free rates of 94.6% for CFRT and 95.8% for SBRT, confirming the noninferiority of SBRT to CFRT.15

SBRT offers short, effective, and convenient treatment to many patients with localized prostate cancer. While previous guidelines were more restrictive, the March 2026 National Comprehensive Cancer Network (NCCN) guidelines now list SBRT as a preferred treatment modality for high-risk prostate cancer.16

Given the growing body of evidence supporting the efficacy and safety of SBRT, we implemented an SBRT program in 2014 at a tertiary care center for veterans. This retrospective study was undertaken to evaluate the early efficacy and toxicity of SBRT in patients with localized prostate cancer treated at our institution, including patients across all risk stratifications.

METHODS

We identified 242 patients diagnosed with prostate cancer who underwent SBRT treatment between November 2014 and October 2024 at Overland Park Veterans Affairs Radiation Oncology Clinic. For the final analysis, 46 patients with < 2 years of follow-up and 22 patients who died from causes other than prostate cancer were excluded, resulting in a cohort of 174 patients with ≥ 24-month follow-up.

Treatment

Patients eligible for staging underwent imaging according to NCCN guidelines, including computed tomography (CT) of the abdomen and pelvis, bone scintigraphy, or, in recent years, prostate-specific membrane antigen positron emission tomography, primarily used for unfavorable intermediate-risk (UIR) and high-risk (HR) cancers. Patients with a negative staging work-up for nodal or skeletal disease were included. Prior to planning the CT simulation, patients were given bowel preparation instructions, including a low-fiber and low-gas-producing diet, simethicone, and enemas, the night before and morning of the simulation. Patients were instructed to arrive with a comfortably full bladder, having not voided for 2 to 3 hours prior to the procedure. At Kansas City Veterans Affairs Medical Center (KCVAMC), SBRT treatment was generally restricted to patients with a baseline American Urological Association symptom score of 15 to 20 out of 35 and a prostate gland size < 80 mL to minimize the risk of acute urinary toxicity. We did not use intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast agents for planning CT simulation.

Patients were placed in a supine position, and a vacuum bag was used for immobilization. Following the CT simulation, the images were transferred to the Eclipse treatment planning system. The clinical target volume (CTV) encompassed the prostate and the proximal 1.0 cm of the seminal vesicles for Gleason score (GS) 1 to 2, and the entire seminal vesicle was included for GS 3 to 5, which is consistent with KCVAMC practice and established safety protocols. The planning target volume (PTV) was created by uniformly expanding the CTV by 5 to 7 mm, except for the posterior margin, which was limited to 3 to 5 mm. When elective nodal radiotherapy was planned for HR prostate cancer, the pelvic field for CT simulation started at the L-2 upper border, with the lower border extending to the lesser trochanter. The pelvic nodes were delineated per Radiation Therapy Oncology Group (RTOG) guidelines.17 The CTV nodes (CTVn), including common iliac, external and internal iliac nodes, obturator, and presacral nodes, were created by uniformly expanding the CTVn by 2 to 3 mm. Slice-by-slice corrections were made to avoid bowel overlap in these patients.

The use of androgen deprivation therapy (ADT) for a duration of 6 to 24 months was prescribed for patients with UIR or HR prostate cancer per NCCN guidelines.16 The prescribed dose to the PTV was 36.25 to 40 Gy (40 Gy was mostly used as a boost to the dominant lesion) in 5 fractions, with each fraction ranging from 7.25 to 8 Gy. For elective nodal radiotherapy in patients at HR, the prescribed dose was 25 Gy in 5 fractions. All patients were planned for VMAT, which aims to deliver ≥ 95% of the prescription dose to 95% of the PTV. Once the physician approved the treatment plan and physics quality assessment was completed, treatments commenced on an every-other-day schedule. Patients received the same bowel preparation instructions for each treatment as for the planning CT simulation. Daily treatment accuracy was confirmed via daily 3-dimensional cone-beam CT (CBCT) for IGRT. No fiducials or hydrogel rectal spacers were used.

Follow-up Schedule and Toxicity Assessment

Follow-up assessments were conducted 4 to 6 weeks after radiation therapy and then repeated every 6 months for 2 to 5 years, and annually thereafter. At each follow-up visit, patients were evaluated for genitourinary (GU) and gastrointestinal (GI) toxicity, according to RTOG toxicity criteria. Prostate-specific antigen (PSA) levels were monitored; in patients receiving ADT, testosterone levels were also checked.

Statistical Analysis

Biochemical failure was defined using the Phoenix definition (nadir PSA + 2 ng/mL). Differences between dose cohorts were assessed using the log-rank test for survival outcomes and X2 testing for categorical variables. GU and GI toxicities were summarized as cumulative incidences of RTOG grade ≥ II events. Statistical significance was set at P < .05.

RESULTS

One hundred seventy-four patients were included in the retrospective review. Patients had a median follow-up of 45 months (range, 24-111) (Figure). The median age at treatment was 74 years (range, 51-88), and the median pretreatment PSA level was 11.9 ng/mL (range, 0.6-69.5). Twenty-six patients (14.9%) had a GS 1, 77 (44.3%) had GS 2, 41 (23.6%) had GS 3, 18 (10.3%) had GS 4, and 12 (6.9%) had GS 5. Fifty-one patients (29.3%) received elective pelvic nodal radiotherapy, and 93 patients (53.4%) received ADT (Table 1).

0526FED-AVAHO-SBRT_F1
FIGURE. Patient Selection Flowchart
0526FED-AVAHO-SBRT_T1

At 24 months follow-up, 6 patients (3.4%) had biochemical failures. One patient died from metastatic prostate cancer, and 5 patients are living with biochemical failure (Table 2). The actuarial 5-year overall survival (OS) rate was 99.4%, and the 5-year disease-free survival (DFS) rate was 96.6%. We performed a subanalysis comparing outcomes of the 36.25 Gy vs 40 Gy SBRT cohorts. There was no statistically significant difference in DFS, OS, or the cumulative incidence of grade II/III toxicity between patients treated with 40 Gy vs 36.25 Gy. Outcomes stratified by NCCN risk groups (low, intermediate, high/very high) are detailed in Table 3. As expected, DFS was slightly lower in the high-risk group, but overall disease control remained high across all stratifications.

0526FED-AVAHO-SBRT_T20526FED-AVAHO-SBRT_T3

The cumulative incidence of RTOG grade II and higher GU toxicity was 28.2% (Table 4). This included 46 patients (26.4%) with grade II GU toxicity and 2 patients (1.2%) who developed grade III GU complications (1 requiring self-catheterization and another a suprapubic catheter for urinary retention). One patient (0.6%) treated with a 40 Gy dose regimen experienced a grade IV GU complication in the form of a rectovesical fistula necessitating surgical intervention.

0526FED-AVAHO-SBRT_T4

The cumulative incidence of RTOG grade II or higher GI toxicity was 3.4%, and no grade III or IV gastrointestinal toxicities were observed during the follow-up period. Importantly, intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast were not routinely used in this cohort of patients.

The high rates of actuarial 5-year DFS and OS observed suggest a favorable initial response to the SBRT regimen employed at KCVAMC. However, given the potential for late recurrence in patients with prostate cancer, longer follow-up is essential to determine the durability of these outcomes. The observed GU toxicity rate of 28.2% for grade II and higher events warrants careful consideration and compares with other published data on SBRT for prostate cancer.15 The occurrence of a grade IV rectovesical fistula, although rare, is a notable adverse event that warrants discussion in the context of the treatment approach. The low incidence of grade II or higher GI toxicity is an encouraging finding, particularly given that hydrogel rectal spacers are not routinely used to minimize rectal exposure.

DISCUSSION

The primary objective of this retrospective study was to evaluate the outcomes of SBRT for patients with localized prostate cancer treated at KCVAMC and to compare these results with those reported in the literature. Our findings demonstrate promising intermediate-term efficacy, with an estimated 5-year DFS of 96.6% and OS of 99.4% at a median follow-up of 45 months. Furthermore, the observed toxicity profile appears acceptable, with a cumulative grade II and higher GU toxicity rate of 28.2% and a grade II or higher GI toxicity rate of 3.4%. Notably, these outcomes were achieved without the routine use of intraprostatic fiducials or hydrogel rectal spacers.

Two pivotal randomized phase 3 trials have established the noninferiority of ultrahypofractionated radiotherapy (UHRT) with SBRT over conventional fractionation. The HYPO-RT-PC trial compared SBRT (42.7 Gy in 7 fractions) with conventional fractionation (78 Gy in 39 fractions) in intermediate- and high-risk patients with prostate cancer and reported a 5-year biochemical relapse-free survival of 84% in both arms.9 The PACE-B trial, which included patients at low- and intermediate-risk, compared SBRT (36.25 Gy in 5 fractions) with conventional or moderate HFRT and reported a 5-year biochemical control rate of 95.8% in the SBRT arm and 94.6% in the control arm.15

A comprehensive review and meta-analysis of 7 phase 3 studies involving 6795 patients compared different radiotherapy regimens, namely, UHRT, HFRT, and CFRT, and reported that after 5 years, the DFS rates were 85.1% for CFRT, 86% for HFRT, and 85% for UHRT, with no significant difference in toxicity among the 3 different treatment approaches.18 This suggests that shorter, more intense radiotherapy schedules (UHRT and HFRT) may be as effective and safe as traditional, longer courses of radiation.

There are multiple published nonrandomized prospective trials in which thousands of patients with extreme hypofractionation have been treated with different doses, fractions, and techniques. While heterogeneity and limited long-term follow-up in the existing evidence are acknowledged, these data suggest that prostate SBRT provides appropriate biochemical control with few high-grade toxicities, supporting its ongoing global use and justifying further prospective investigations. Comparative data are shown in Table 5. Several ongoing studies are evaluating noninferiority, superiority, and cost-effectiveness using different methodologies (Table 6).9,15,19-24

0526FED-AVAHO-SBRT_T50526FED-AVAHO-SBRT_T6

This study’s efficacy outcomes, particularly the high DFS rate, are consistent with the findings from these landmark trials, suggesting that the SBRT regimen used at KCVAMC is effective in achieving early disease control despite 17.2% of patients having high-risk disease. The GU toxicity observed in this study, with a 28.2% rate of grade II or higher events, is also comparable with the 26.9% reported in the 5-fraction SBRT arm of the PACE-B trial, which had a longer median follow-up of 74 months.15 It is important to note that a portion of these grade II events occurred in patients who were already on a blockers for pre-existing lower urinary tract symptoms before starting radiotherapy, which may inflate the observed cumulative acute toxicity score.

A critical comparison is how SBRT toxicity aligns with moderate hypofractionation (eg, 60 Gy in 20 fractions or 70 Gy in 28 fractions as reported by others).4,6 Our observed grade III and higher GU toxicity rate (1.7%) and grade III and higher GI toxicity rate (0%) are highly favorable when compared with historical moderate hypofractionation data, which typically report grade III GU toxicity in the range of 2% to 3% and grade III GI toxicity around 1% to 2%. This suggests that despite the higher dose per fraction, SBRT does not necessarily lead to increased severe acute toxicity, potentially offering a superior therapeutic ratio for GI and GU sparing.

However, the occurrence of a grade IV rectovesical fistula in 1 patient (0.6%)—who received the 40 Gy dose—was a serious complication that warrants careful consideration. This rare, but severe, complication in the higher dose cohort underscores the potential for increased organ-at-risk toxicity, particularly in the absence of a hydrogel rectal spacer, which is designed to mitigate high-dose rectal exposure. While the overall rate of significant GU toxicity remains low, this event highlights the potential risks associated with SBRT. Hydrogel rectal spacers are designed to increase the distance between the prostate and the rectum, which can reduce the rectal radiation dose and potentially mitigate the risk of such fistulas. The low rate of grade II or worse GI toxicity (3.4%) in our study is noteworthy, especially considering that hydrogel spacers were not routinely used. This finding aligns with the 2.5% GI toxicity rate reported in the SBRT arm of the PACE-B trial, suggesting that careful treatment planning and delivery techniques, such as VMAT-IMRT and daily CBCT for IGRT, may contribute to minimizing GI toxicity even without the use of rectal spacers.15 The exclusive use of 3-dimensional CBCT for IGRT in our study, without the use of fiducial markers, suggests that accurate target localization can be achieved with this approach, contributing to the observed efficacy and reduced toxicity.

Strengths and Limitations

This study’s retrospective, single-center design may have introduced selection bias. The median follow-up of 45 months, while substantial, is still relatively short for assessing very late toxicities and long-term oncologic outcomes in prostate cancer, which is known for late recurrences. Additionally, the lack of a direct comparison group within KCVAMC limits the ability to definitively attribute the observed outcomes solely to SBRT treatment. However, the strengths of this study include the inclusion of a consecutive series of veteran patients with localized prostate cancer across all risk categories, providing a real-world perspective on SBRT outcomes in a diverse patient population. Furthermore, the detailed assessment of efficacy and toxicity via standardized RTOG criteria enhances the comparability of our findings with those of other published prospective studies, despite the retrospective nature of the data.

CONCLUSIONS

This single-institution retrospective analysis revealed that short-term SBRT (36.25 to 40 Gy in 5 fractions), with a minimum follow-up of 24 months and a median follow-up of 45 months, for localized prostate cancer, including patients at HR, is associated with promising early efficacy and acceptable toxicity, even in the absence of routine fiducial or hydrogel spacer use. The favorable actuarial 5-year DFS and OS rates, coupled with a manageable toxicity profile, suggest that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer. However, a longer follow-up is necessary to confirm these findings and fully characterize the long-term efficacy and toxicity of this SBRT regimen. Nevertheless, the results contribute to the growing body of evidence suggesting that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer.

Prostate cancer is the most common cancer in US males, with an estimated 313,780 new cases and 35,770 deaths in 2025.1 Several treatment options are available for localized prostate cancer that have similar outcomes, including active surveillance for low-risk cancers, surgery, or radiotherapy.2,3 Conventional fractionation radiotherapy (CFRT) with 40 to 45 fractions over 8 to 9 weeks has been used for decades. Over the past 2 decades, moderate hypofractionation schedules with 2.4 to 3.4 Gy per fraction over 20 to 28 fractions have become standard, as many noninferiority randomized clinical trials (RCTs) such as CHHiP (UK),4 PROFIT (Canada and Europe),5 NRG Oncology RTOG 0415 (US),6 HYPRO (Netherlands),7,8 and HYPO-RT-PC (Sweden and Denmark),9 have shown the noninferiority of moderately hypofractionated radiotherapy compared with CFRT. Notably, most of these noninferiority studies primarily included patients with low- or intermediate-risk prostate cancer, except for the HYPO-RT-PC trial,9 which also included patients with intermediate- and high-risk prostate cancer.

These noninferiority studies, along with technological advances in radiotherapy, such as intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and image-guided radiotherapy (IGRT), paved the path to ultrahypofractionated stereotactic body radiotherapy (SBRT) that is delivered in 5 fractions of ≥ 6 Gy. This high dose per fraction may have a radiobiologic advantage over conventional fractionation. The relatively low a/ß ratio of prostate cancer, estimated to be between 1 and 2, suggests that tumor cells may be particularly sensitive to the high doses per fraction delivered in SBRT.10-13 Compared with CFRT, SBRT-induced tumor cell death may also be mediated through different pathways; this pathway appears to be generated in a dose-dependent manner, particularly with doses > 8 Gy per fraction.14,15 Additionally, the higher a/ß ratio for the surrounding organs at risk, such as the bladder and rectum, theoretically allows for an improved therapeutic ratio window that maximizes tumor control while minimizing damage to healthy tissues.

A substantial body of evidence from prospective studies and meta-analyses supports the use of SBRT for localized prostate cancer. HYPO-RT-PC, a significant phase 3 noninferiority study, enrolled 1200 patients with intermediate (89%) and high-risk (11%) prostate cancer randomized between 2 arms, including CFRT to 78 Gy in 39 fractions and SBRT to 42.7 Gy in 7 fractions, treated 3 days weekly. After a median follow-up of 60 months, the estimated 5-year biochemical relapse-free survival rate was 84% in both groups.9 This trial was notable because it was the first randomized study to demonstrate that SBRT was noninferior to CFRT in intermediate- and high-risk prostate cancer patients. Another pivotal phase 3 trial, the PACE-B study, enrolled 874 patients to compare SBRT (36.25 Gy to the prostate gland, with a secondary dose of 40 Gy to the gross tumor volume where applicable, in 5 fractions) with CFRT (78 Gy in 39 fractions) and moderately hypofractionated radiotherapy (HFRT) (62 Gy in 20 fractions) in patients with low- or intermediate-risk prostate cancer. With a 74-month median follow-up, the study reported 5-year biochemical free rates of 94.6% for CFRT and 95.8% for SBRT, confirming the noninferiority of SBRT to CFRT.15

SBRT offers short, effective, and convenient treatment to many patients with localized prostate cancer. While previous guidelines were more restrictive, the March 2026 National Comprehensive Cancer Network (NCCN) guidelines now list SBRT as a preferred treatment modality for high-risk prostate cancer.16

Given the growing body of evidence supporting the efficacy and safety of SBRT, we implemented an SBRT program in 2014 at a tertiary care center for veterans. This retrospective study was undertaken to evaluate the early efficacy and toxicity of SBRT in patients with localized prostate cancer treated at our institution, including patients across all risk stratifications.

METHODS

We identified 242 patients diagnosed with prostate cancer who underwent SBRT treatment between November 2014 and October 2024 at Overland Park Veterans Affairs Radiation Oncology Clinic. For the final analysis, 46 patients with < 2 years of follow-up and 22 patients who died from causes other than prostate cancer were excluded, resulting in a cohort of 174 patients with ≥ 24-month follow-up.

Treatment

Patients eligible for staging underwent imaging according to NCCN guidelines, including computed tomography (CT) of the abdomen and pelvis, bone scintigraphy, or, in recent years, prostate-specific membrane antigen positron emission tomography, primarily used for unfavorable intermediate-risk (UIR) and high-risk (HR) cancers. Patients with a negative staging work-up for nodal or skeletal disease were included. Prior to planning the CT simulation, patients were given bowel preparation instructions, including a low-fiber and low-gas-producing diet, simethicone, and enemas, the night before and morning of the simulation. Patients were instructed to arrive with a comfortably full bladder, having not voided for 2 to 3 hours prior to the procedure. At Kansas City Veterans Affairs Medical Center (KCVAMC), SBRT treatment was generally restricted to patients with a baseline American Urological Association symptom score of 15 to 20 out of 35 and a prostate gland size < 80 mL to minimize the risk of acute urinary toxicity. We did not use intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast agents for planning CT simulation.

Patients were placed in a supine position, and a vacuum bag was used for immobilization. Following the CT simulation, the images were transferred to the Eclipse treatment planning system. The clinical target volume (CTV) encompassed the prostate and the proximal 1.0 cm of the seminal vesicles for Gleason score (GS) 1 to 2, and the entire seminal vesicle was included for GS 3 to 5, which is consistent with KCVAMC practice and established safety protocols. The planning target volume (PTV) was created by uniformly expanding the CTV by 5 to 7 mm, except for the posterior margin, which was limited to 3 to 5 mm. When elective nodal radiotherapy was planned for HR prostate cancer, the pelvic field for CT simulation started at the L-2 upper border, with the lower border extending to the lesser trochanter. The pelvic nodes were delineated per Radiation Therapy Oncology Group (RTOG) guidelines.17 The CTV nodes (CTVn), including common iliac, external and internal iliac nodes, obturator, and presacral nodes, were created by uniformly expanding the CTVn by 2 to 3 mm. Slice-by-slice corrections were made to avoid bowel overlap in these patients.

The use of androgen deprivation therapy (ADT) for a duration of 6 to 24 months was prescribed for patients with UIR or HR prostate cancer per NCCN guidelines.16 The prescribed dose to the PTV was 36.25 to 40 Gy (40 Gy was mostly used as a boost to the dominant lesion) in 5 fractions, with each fraction ranging from 7.25 to 8 Gy. For elective nodal radiotherapy in patients at HR, the prescribed dose was 25 Gy in 5 fractions. All patients were planned for VMAT, which aims to deliver ≥ 95% of the prescription dose to 95% of the PTV. Once the physician approved the treatment plan and physics quality assessment was completed, treatments commenced on an every-other-day schedule. Patients received the same bowel preparation instructions for each treatment as for the planning CT simulation. Daily treatment accuracy was confirmed via daily 3-dimensional cone-beam CT (CBCT) for IGRT. No fiducials or hydrogel rectal spacers were used.

Follow-up Schedule and Toxicity Assessment

Follow-up assessments were conducted 4 to 6 weeks after radiation therapy and then repeated every 6 months for 2 to 5 years, and annually thereafter. At each follow-up visit, patients were evaluated for genitourinary (GU) and gastrointestinal (GI) toxicity, according to RTOG toxicity criteria. Prostate-specific antigen (PSA) levels were monitored; in patients receiving ADT, testosterone levels were also checked.

Statistical Analysis

Biochemical failure was defined using the Phoenix definition (nadir PSA + 2 ng/mL). Differences between dose cohorts were assessed using the log-rank test for survival outcomes and X2 testing for categorical variables. GU and GI toxicities were summarized as cumulative incidences of RTOG grade ≥ II events. Statistical significance was set at P < .05.

RESULTS

One hundred seventy-four patients were included in the retrospective review. Patients had a median follow-up of 45 months (range, 24-111) (Figure). The median age at treatment was 74 years (range, 51-88), and the median pretreatment PSA level was 11.9 ng/mL (range, 0.6-69.5). Twenty-six patients (14.9%) had a GS 1, 77 (44.3%) had GS 2, 41 (23.6%) had GS 3, 18 (10.3%) had GS 4, and 12 (6.9%) had GS 5. Fifty-one patients (29.3%) received elective pelvic nodal radiotherapy, and 93 patients (53.4%) received ADT (Table 1).

0526FED-AVAHO-SBRT_F1
FIGURE. Patient Selection Flowchart
0526FED-AVAHO-SBRT_T1

At 24 months follow-up, 6 patients (3.4%) had biochemical failures. One patient died from metastatic prostate cancer, and 5 patients are living with biochemical failure (Table 2). The actuarial 5-year overall survival (OS) rate was 99.4%, and the 5-year disease-free survival (DFS) rate was 96.6%. We performed a subanalysis comparing outcomes of the 36.25 Gy vs 40 Gy SBRT cohorts. There was no statistically significant difference in DFS, OS, or the cumulative incidence of grade II/III toxicity between patients treated with 40 Gy vs 36.25 Gy. Outcomes stratified by NCCN risk groups (low, intermediate, high/very high) are detailed in Table 3. As expected, DFS was slightly lower in the high-risk group, but overall disease control remained high across all stratifications.

0526FED-AVAHO-SBRT_T20526FED-AVAHO-SBRT_T3

The cumulative incidence of RTOG grade II and higher GU toxicity was 28.2% (Table 4). This included 46 patients (26.4%) with grade II GU toxicity and 2 patients (1.2%) who developed grade III GU complications (1 requiring self-catheterization and another a suprapubic catheter for urinary retention). One patient (0.6%) treated with a 40 Gy dose regimen experienced a grade IV GU complication in the form of a rectovesical fistula necessitating surgical intervention.

0526FED-AVAHO-SBRT_T4

The cumulative incidence of RTOG grade II or higher GI toxicity was 3.4%, and no grade III or IV gastrointestinal toxicities were observed during the follow-up period. Importantly, intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast were not routinely used in this cohort of patients.

The high rates of actuarial 5-year DFS and OS observed suggest a favorable initial response to the SBRT regimen employed at KCVAMC. However, given the potential for late recurrence in patients with prostate cancer, longer follow-up is essential to determine the durability of these outcomes. The observed GU toxicity rate of 28.2% for grade II and higher events warrants careful consideration and compares with other published data on SBRT for prostate cancer.15 The occurrence of a grade IV rectovesical fistula, although rare, is a notable adverse event that warrants discussion in the context of the treatment approach. The low incidence of grade II or higher GI toxicity is an encouraging finding, particularly given that hydrogel rectal spacers are not routinely used to minimize rectal exposure.

DISCUSSION

The primary objective of this retrospective study was to evaluate the outcomes of SBRT for patients with localized prostate cancer treated at KCVAMC and to compare these results with those reported in the literature. Our findings demonstrate promising intermediate-term efficacy, with an estimated 5-year DFS of 96.6% and OS of 99.4% at a median follow-up of 45 months. Furthermore, the observed toxicity profile appears acceptable, with a cumulative grade II and higher GU toxicity rate of 28.2% and a grade II or higher GI toxicity rate of 3.4%. Notably, these outcomes were achieved without the routine use of intraprostatic fiducials or hydrogel rectal spacers.

Two pivotal randomized phase 3 trials have established the noninferiority of ultrahypofractionated radiotherapy (UHRT) with SBRT over conventional fractionation. The HYPO-RT-PC trial compared SBRT (42.7 Gy in 7 fractions) with conventional fractionation (78 Gy in 39 fractions) in intermediate- and high-risk patients with prostate cancer and reported a 5-year biochemical relapse-free survival of 84% in both arms.9 The PACE-B trial, which included patients at low- and intermediate-risk, compared SBRT (36.25 Gy in 5 fractions) with conventional or moderate HFRT and reported a 5-year biochemical control rate of 95.8% in the SBRT arm and 94.6% in the control arm.15

A comprehensive review and meta-analysis of 7 phase 3 studies involving 6795 patients compared different radiotherapy regimens, namely, UHRT, HFRT, and CFRT, and reported that after 5 years, the DFS rates were 85.1% for CFRT, 86% for HFRT, and 85% for UHRT, with no significant difference in toxicity among the 3 different treatment approaches.18 This suggests that shorter, more intense radiotherapy schedules (UHRT and HFRT) may be as effective and safe as traditional, longer courses of radiation.

There are multiple published nonrandomized prospective trials in which thousands of patients with extreme hypofractionation have been treated with different doses, fractions, and techniques. While heterogeneity and limited long-term follow-up in the existing evidence are acknowledged, these data suggest that prostate SBRT provides appropriate biochemical control with few high-grade toxicities, supporting its ongoing global use and justifying further prospective investigations. Comparative data are shown in Table 5. Several ongoing studies are evaluating noninferiority, superiority, and cost-effectiveness using different methodologies (Table 6).9,15,19-24

0526FED-AVAHO-SBRT_T50526FED-AVAHO-SBRT_T6

This study’s efficacy outcomes, particularly the high DFS rate, are consistent with the findings from these landmark trials, suggesting that the SBRT regimen used at KCVAMC is effective in achieving early disease control despite 17.2% of patients having high-risk disease. The GU toxicity observed in this study, with a 28.2% rate of grade II or higher events, is also comparable with the 26.9% reported in the 5-fraction SBRT arm of the PACE-B trial, which had a longer median follow-up of 74 months.15 It is important to note that a portion of these grade II events occurred in patients who were already on a blockers for pre-existing lower urinary tract symptoms before starting radiotherapy, which may inflate the observed cumulative acute toxicity score.

A critical comparison is how SBRT toxicity aligns with moderate hypofractionation (eg, 60 Gy in 20 fractions or 70 Gy in 28 fractions as reported by others).4,6 Our observed grade III and higher GU toxicity rate (1.7%) and grade III and higher GI toxicity rate (0%) are highly favorable when compared with historical moderate hypofractionation data, which typically report grade III GU toxicity in the range of 2% to 3% and grade III GI toxicity around 1% to 2%. This suggests that despite the higher dose per fraction, SBRT does not necessarily lead to increased severe acute toxicity, potentially offering a superior therapeutic ratio for GI and GU sparing.

However, the occurrence of a grade IV rectovesical fistula in 1 patient (0.6%)—who received the 40 Gy dose—was a serious complication that warrants careful consideration. This rare, but severe, complication in the higher dose cohort underscores the potential for increased organ-at-risk toxicity, particularly in the absence of a hydrogel rectal spacer, which is designed to mitigate high-dose rectal exposure. While the overall rate of significant GU toxicity remains low, this event highlights the potential risks associated with SBRT. Hydrogel rectal spacers are designed to increase the distance between the prostate and the rectum, which can reduce the rectal radiation dose and potentially mitigate the risk of such fistulas. The low rate of grade II or worse GI toxicity (3.4%) in our study is noteworthy, especially considering that hydrogel spacers were not routinely used. This finding aligns with the 2.5% GI toxicity rate reported in the SBRT arm of the PACE-B trial, suggesting that careful treatment planning and delivery techniques, such as VMAT-IMRT and daily CBCT for IGRT, may contribute to minimizing GI toxicity even without the use of rectal spacers.15 The exclusive use of 3-dimensional CBCT for IGRT in our study, without the use of fiducial markers, suggests that accurate target localization can be achieved with this approach, contributing to the observed efficacy and reduced toxicity.

Strengths and Limitations

This study’s retrospective, single-center design may have introduced selection bias. The median follow-up of 45 months, while substantial, is still relatively short for assessing very late toxicities and long-term oncologic outcomes in prostate cancer, which is known for late recurrences. Additionally, the lack of a direct comparison group within KCVAMC limits the ability to definitively attribute the observed outcomes solely to SBRT treatment. However, the strengths of this study include the inclusion of a consecutive series of veteran patients with localized prostate cancer across all risk categories, providing a real-world perspective on SBRT outcomes in a diverse patient population. Furthermore, the detailed assessment of efficacy and toxicity via standardized RTOG criteria enhances the comparability of our findings with those of other published prospective studies, despite the retrospective nature of the data.

CONCLUSIONS

This single-institution retrospective analysis revealed that short-term SBRT (36.25 to 40 Gy in 5 fractions), with a minimum follow-up of 24 months and a median follow-up of 45 months, for localized prostate cancer, including patients at HR, is associated with promising early efficacy and acceptable toxicity, even in the absence of routine fiducial or hydrogel spacer use. The favorable actuarial 5-year DFS and OS rates, coupled with a manageable toxicity profile, suggest that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer. However, a longer follow-up is necessary to confirm these findings and fully characterize the long-term efficacy and toxicity of this SBRT regimen. Nevertheless, the results contribute to the growing body of evidence suggesting that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer.

References
  1. Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025. CA Cancer J Clin. 2025;75:10-45. doi:10.3322/caac.21871
  2. Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med. 2016;375:1425-1437. doi:10.1056/NEJMoa1606221
  3. Hamdy FC, Donovan JL, Lane JA, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016;375:1415-1424. doi:10.1056/NEJMoa1606220
  4. Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17:1047-1060. doi:10.1016/S1470-2045(16)30102-4
  5. Catton CN, Lukka H, Gu CS, et al. Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer. J Clin Oncol. 2017;35:1884-1890. doi:10.1200/JCO.2016.71.7397
  6. Lee WR, Dignam JJ, Amin MB, et al. Long-term analysis of NRG Oncology RTOG 0415: a randomized phase III noninferiority study comparing two fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol. 2024;42:2377-2381. doi:10.1200/JCO.23.02445
  7. de Vries KC, Wortel RC, Oomen-de Hoop E, et al. Hypofractionated versus conventionally fractionated radiation therapy for patients with intermediate- or high-risk, localized, prostate cancer: 7-year outcomes from the randomized, multicenter, open-label, phase 3 HYPRO trial. Int J Radiat Oncol Biol Phys. 2020;106:108-115. doi:10.1016/j.ijrobp.2019.09.007
  8. Incrocci L, Wortel RC, Alemayehu WG, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17:1061-1069. doi:10.1016/S1470-2045(16)30070-5
  9. Widmark A, Gunnlaugsson A, Beckman L, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet. 2019;394:385-395. doi:10.1016/S0140-6736(19)31131-6
  10. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys. 1999;43:1095-101. doi:10.1016/s0360-3016(98)00438-6
  11. Dasu A. Is the alpha/beta value for prostate tumours low enough to be safely used in clinical trials? Clin Oncol (R Coll Radiol). 2007;19:289-301. doi:10.1016/j.clon.2007.02.007
  12. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300:1155-1159. doi:10.1126/science.1082504
  13. Gulliford S, Hall E, Dearnaley D. Hypofractionation trials and radiobiology of prostate cancer. Oncoscience. 2017;4:27-28. doi:10.18632/oncoscience.347
  14. Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response. Cancer Cell. 2005;8:89-91. doi:10.1016/j.ccr.2005.07.014
  15. van As N, Griffin C, Tree A, et al. Phase 3 Trial of stereotactic body radiotherapy in localized prostate cancer. N Engl J Med. Oct 17 2024;391:1413-1425. doi:10.1056/NEJMoa2403365
  16. National Comprehensive Cancer Network. NCCN Guidelines Version 5. 2026 Prostate Cancer. Accessed March 24, 2026. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
  17. Lawton CA, Michalski J, El-Naqa I, et al. RTOG GU radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2009;74:383-387. doi:10.1016/j.ijrobp.2008.08.002
  18. Lehrer EJ, Kishan AU, Yu JB, et al. Ultrahypofractionated versus hypofractionated and conventionally fractionated radiation therapy for localized prostate cancer: a systematic review and meta-analysis of phase III randomized trials. Radiother Oncol. 2020;148:235-242. doi:10.1016/j.radonc.2020.04.037
  19. De Cooman B, Debacker T, Adams T, et al. Stereotactic body radiotherapy (SBRT) as a treatment for localized prostate cancer: a retrospective analysis. Radiat Oncol. 2025;20:25. doi:10.1186/s13014-025-02598-8
  20. Fuller DB, Falchook AD, Crabtree T, et al. Phase 2 multicenter trial of heterogeneous-dosing stereotactic body radiotherapy for low- and intermediate-risk prostate cancer: 5-year outcomes. Eur Urol Oncol. 2018;1:540-547. doi:10.1016/j.euo.2018.06.013
  21. Jackson WC, Silva J, Hartman HE, et al. Stereotactic body radiation therapy for localized prostate cancer: a systematic review and meta-analysis of over 6,000 patients treated on prospective studies. Int J Radiat Oncol Biol Phys. 2019;104:778-789. doi:10.1016/j.ijrobp.2019.03.051
  22. Meier RM, Bloch DA, Cotrutz C, et al. Multicenter trial of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer: survival and toxicity endpoints. nt J Radiat Oncol Biol Phys. 2018;102:296-303. doi:10.1016/j.ijrobp.2018.05.040
  23. Quon HC, Ong A, Cheung P, et al. Once-weekly versus every-other-day stereotactic body radiotherapy in patients with prostate cancer (PATRIOT): a phase 2 randomized trial. Radiother Oncol. 2018;127:206-212. doi:10.1016/j.radonc.2018.02.029
  24. Zelefsky MJ, Kollmeier M, McBride S, et al. Five-year outcomes of a phase 1 dose-escalation study using stereotactic body radiosurgery for patients with low-risk and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2019;104:42-49. doi:10.1016/j.ijrobp.2018.12.045
References
  1. Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025. CA Cancer J Clin. 2025;75:10-45. doi:10.3322/caac.21871
  2. Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med. 2016;375:1425-1437. doi:10.1056/NEJMoa1606221
  3. Hamdy FC, Donovan JL, Lane JA, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016;375:1415-1424. doi:10.1056/NEJMoa1606220
  4. Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17:1047-1060. doi:10.1016/S1470-2045(16)30102-4
  5. Catton CN, Lukka H, Gu CS, et al. Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer. J Clin Oncol. 2017;35:1884-1890. doi:10.1200/JCO.2016.71.7397
  6. Lee WR, Dignam JJ, Amin MB, et al. Long-term analysis of NRG Oncology RTOG 0415: a randomized phase III noninferiority study comparing two fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol. 2024;42:2377-2381. doi:10.1200/JCO.23.02445
  7. de Vries KC, Wortel RC, Oomen-de Hoop E, et al. Hypofractionated versus conventionally fractionated radiation therapy for patients with intermediate- or high-risk, localized, prostate cancer: 7-year outcomes from the randomized, multicenter, open-label, phase 3 HYPRO trial. Int J Radiat Oncol Biol Phys. 2020;106:108-115. doi:10.1016/j.ijrobp.2019.09.007
  8. Incrocci L, Wortel RC, Alemayehu WG, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17:1061-1069. doi:10.1016/S1470-2045(16)30070-5
  9. Widmark A, Gunnlaugsson A, Beckman L, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet. 2019;394:385-395. doi:10.1016/S0140-6736(19)31131-6
  10. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys. 1999;43:1095-101. doi:10.1016/s0360-3016(98)00438-6
  11. Dasu A. Is the alpha/beta value for prostate tumours low enough to be safely used in clinical trials? Clin Oncol (R Coll Radiol). 2007;19:289-301. doi:10.1016/j.clon.2007.02.007
  12. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300:1155-1159. doi:10.1126/science.1082504
  13. Gulliford S, Hall E, Dearnaley D. Hypofractionation trials and radiobiology of prostate cancer. Oncoscience. 2017;4:27-28. doi:10.18632/oncoscience.347
  14. Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response. Cancer Cell. 2005;8:89-91. doi:10.1016/j.ccr.2005.07.014
  15. van As N, Griffin C, Tree A, et al. Phase 3 Trial of stereotactic body radiotherapy in localized prostate cancer. N Engl J Med. Oct 17 2024;391:1413-1425. doi:10.1056/NEJMoa2403365
  16. National Comprehensive Cancer Network. NCCN Guidelines Version 5. 2026 Prostate Cancer. Accessed March 24, 2026. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
  17. Lawton CA, Michalski J, El-Naqa I, et al. RTOG GU radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2009;74:383-387. doi:10.1016/j.ijrobp.2008.08.002
  18. Lehrer EJ, Kishan AU, Yu JB, et al. Ultrahypofractionated versus hypofractionated and conventionally fractionated radiation therapy for localized prostate cancer: a systematic review and meta-analysis of phase III randomized trials. Radiother Oncol. 2020;148:235-242. doi:10.1016/j.radonc.2020.04.037
  19. De Cooman B, Debacker T, Adams T, et al. Stereotactic body radiotherapy (SBRT) as a treatment for localized prostate cancer: a retrospective analysis. Radiat Oncol. 2025;20:25. doi:10.1186/s13014-025-02598-8
  20. Fuller DB, Falchook AD, Crabtree T, et al. Phase 2 multicenter trial of heterogeneous-dosing stereotactic body radiotherapy for low- and intermediate-risk prostate cancer: 5-year outcomes. Eur Urol Oncol. 2018;1:540-547. doi:10.1016/j.euo.2018.06.013
  21. Jackson WC, Silva J, Hartman HE, et al. Stereotactic body radiation therapy for localized prostate cancer: a systematic review and meta-analysis of over 6,000 patients treated on prospective studies. Int J Radiat Oncol Biol Phys. 2019;104:778-789. doi:10.1016/j.ijrobp.2019.03.051
  22. Meier RM, Bloch DA, Cotrutz C, et al. Multicenter trial of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer: survival and toxicity endpoints. nt J Radiat Oncol Biol Phys. 2018;102:296-303. doi:10.1016/j.ijrobp.2018.05.040
  23. Quon HC, Ong A, Cheung P, et al. Once-weekly versus every-other-day stereotactic body radiotherapy in patients with prostate cancer (PATRIOT): a phase 2 randomized trial. Radiother Oncol. 2018;127:206-212. doi:10.1016/j.radonc.2018.02.029
  24. Zelefsky MJ, Kollmeier M, McBride S, et al. Five-year outcomes of a phase 1 dose-escalation study using stereotactic body radiosurgery for patients with low-risk and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2019;104:42-49. doi:10.1016/j.ijrobp.2018.12.045
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Federal Practitioner - 43(suppl 2)
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Early Outcomes of Stereotactic Body Radiotherapy for Localized Prostate Cancer: A Retrospective Analysis

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Early Outcomes of Stereotactic Body Radiotherapy for Localized Prostate Cancer: A Retrospective Analysis

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A Phase II Study With Androgen Deprivation Therapy and Up-Front Radiotherapy in High-Intermediate and High-Risk Prostate Cancer With Stereotactic Body Radiation Therapy to Pelvic Nodes and Concomitant Prostate Boost by Simultaneous Integrated Boost

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Lauren B. Birkeness, MPH
John H. Park, MD
January Fields-Meehan, MD
Linda Verkruyse, MD
Dunia Khaled, MD
Eashwer Reddy, MD

Background

The adoption of Stereotactic Body Radiation Therapy (SBRT) for prostate cancer has allowed treatment to be completed in less than 2 weeks, but has predominantly been given to the prostate only. Currently, very few prospective studies have compared delivery of SBRT versus hypofractionated radiotherapy (HFX) when giving concurrent pelvic radiation. The aim of the study is to evaluate the tolerance and efficacy of pelvic node radiotherapy and SIB to the prostate in prostate patients requiring nodal irradiation.

Methods

A total of 58 patients were irradiated with SBRT and initiated ADT therapy between 2014 and 2023. 57 patients were treated with 7.5 Gy to the prostate and 1 to 7.25 Gy. All patients were treated with 5 Gy x 5 fraction to the pelvis. This group was compared to a preselected historical cohort of 65 HFX patients with 57 of these patients treated with 67.5/50 Gy in 25 fractions, 1 with patient 67.5/45 Gy in 25 fractions, and 6 patients with 60/44-46 Gy in 20 fractions. Patients were evaluated for GU and GI toxicities according to Radiation Therapy Oncology Group Toxicity criteria at one year post radiation therapy.

Results

There were 31 grade 0 (53.4%), 1 grade 1 (1.7%), 25 grade 2 (43.1%), 1 grade 3 (1.7%) events in the SBRT group and 29 GU grade 0 (44.6%), 3 grade 1 (4.6%), and 33 grade 2 (50.8%) GU toxicities in the HFX group with no significant difference between the groups (p=0.464). There were 55 grade 0 (94.8%), 1 grade 1 (1.7%), and 2 grade 2 (3.4%) GI toxicities in the SBRT group and 59 grade 0 (90.8%), 1 grade 1 (1.5%), and 5 grade 2 (7.7%) events in the HFX group with no significant difference between the groups (p=0.381).

Conclusions

This prospective study provides data to support the use of concurrent pelvic radiation with SBRT to the prostate. Our findings suggest there is no difference in toxicity between HFX and 25 Gy pelvic radiation (5 Gy/5 fractions) concurrent with SBRT to the prostate, therefore it appears to be a safe and convenient option for veterans with prostate cancer.

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Federal Practitioner - 41(suppl 4)
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Lauren B. Birkeness, MPH
John H. Park, MD
January Fields-Meehan, MD
Linda Verkruyse, MD
Dunia Khaled, MD
Eashwer Reddy, MD
Author(s)
Lauren B. Birkeness, MPH
John H. Park, MD
January Fields-Meehan, MD
Linda Verkruyse, MD
Dunia Khaled, MD
Eashwer Reddy, MD

Background

The adoption of Stereotactic Body Radiation Therapy (SBRT) for prostate cancer has allowed treatment to be completed in less than 2 weeks, but has predominantly been given to the prostate only. Currently, very few prospective studies have compared delivery of SBRT versus hypofractionated radiotherapy (HFX) when giving concurrent pelvic radiation. The aim of the study is to evaluate the tolerance and efficacy of pelvic node radiotherapy and SIB to the prostate in prostate patients requiring nodal irradiation.

Methods

A total of 58 patients were irradiated with SBRT and initiated ADT therapy between 2014 and 2023. 57 patients were treated with 7.5 Gy to the prostate and 1 to 7.25 Gy. All patients were treated with 5 Gy x 5 fraction to the pelvis. This group was compared to a preselected historical cohort of 65 HFX patients with 57 of these patients treated with 67.5/50 Gy in 25 fractions, 1 with patient 67.5/45 Gy in 25 fractions, and 6 patients with 60/44-46 Gy in 20 fractions. Patients were evaluated for GU and GI toxicities according to Radiation Therapy Oncology Group Toxicity criteria at one year post radiation therapy.

Results

There were 31 grade 0 (53.4%), 1 grade 1 (1.7%), 25 grade 2 (43.1%), 1 grade 3 (1.7%) events in the SBRT group and 29 GU grade 0 (44.6%), 3 grade 1 (4.6%), and 33 grade 2 (50.8%) GU toxicities in the HFX group with no significant difference between the groups (p=0.464). There were 55 grade 0 (94.8%), 1 grade 1 (1.7%), and 2 grade 2 (3.4%) GI toxicities in the SBRT group and 59 grade 0 (90.8%), 1 grade 1 (1.5%), and 5 grade 2 (7.7%) events in the HFX group with no significant difference between the groups (p=0.381).

Conclusions

This prospective study provides data to support the use of concurrent pelvic radiation with SBRT to the prostate. Our findings suggest there is no difference in toxicity between HFX and 25 Gy pelvic radiation (5 Gy/5 fractions) concurrent with SBRT to the prostate, therefore it appears to be a safe and convenient option for veterans with prostate cancer.

Background

The adoption of Stereotactic Body Radiation Therapy (SBRT) for prostate cancer has allowed treatment to be completed in less than 2 weeks, but has predominantly been given to the prostate only. Currently, very few prospective studies have compared delivery of SBRT versus hypofractionated radiotherapy (HFX) when giving concurrent pelvic radiation. The aim of the study is to evaluate the tolerance and efficacy of pelvic node radiotherapy and SIB to the prostate in prostate patients requiring nodal irradiation.

Methods

A total of 58 patients were irradiated with SBRT and initiated ADT therapy between 2014 and 2023. 57 patients were treated with 7.5 Gy to the prostate and 1 to 7.25 Gy. All patients were treated with 5 Gy x 5 fraction to the pelvis. This group was compared to a preselected historical cohort of 65 HFX patients with 57 of these patients treated with 67.5/50 Gy in 25 fractions, 1 with patient 67.5/45 Gy in 25 fractions, and 6 patients with 60/44-46 Gy in 20 fractions. Patients were evaluated for GU and GI toxicities according to Radiation Therapy Oncology Group Toxicity criteria at one year post radiation therapy.

Results

There were 31 grade 0 (53.4%), 1 grade 1 (1.7%), 25 grade 2 (43.1%), 1 grade 3 (1.7%) events in the SBRT group and 29 GU grade 0 (44.6%), 3 grade 1 (4.6%), and 33 grade 2 (50.8%) GU toxicities in the HFX group with no significant difference between the groups (p=0.464). There were 55 grade 0 (94.8%), 1 grade 1 (1.7%), and 2 grade 2 (3.4%) GI toxicities in the SBRT group and 59 grade 0 (90.8%), 1 grade 1 (1.5%), and 5 grade 2 (7.7%) events in the HFX group with no significant difference between the groups (p=0.381).

Conclusions

This prospective study provides data to support the use of concurrent pelvic radiation with SBRT to the prostate. Our findings suggest there is no difference in toxicity between HFX and 25 Gy pelvic radiation (5 Gy/5 fractions) concurrent with SBRT to the prostate, therefore it appears to be a safe and convenient option for veterans with prostate cancer.

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Factors Associated with Radiation Toxicity and Survival in Patients with Presumed Early-Stage Non-Small Cell Lung Cancer Receiving Empiric Stereotactic Ablative Radiotherapy

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Author(s)
John Park, MD
Curtis Whiting, MD
Eashwer Reddy, MD
Sushant Govindan, MD
Chao Huang, MD
Sonia M. Castillo, MD

Stereotactic ablative radiotherapy (SABR) has become the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC). Many patients are unable to undergo a biopsy safely because of poor pulmonary function or underlying emphysema and are then empirically treated with radiotherapy if they meet criteria. In these patients, local control can be achieved with SABR with minimal toxicity.1 Considering that median overall survival (OS) among patients with untreated stage I NSCLC has been reported to be as low as 9 months, early treatment with SABR could lead to increased survival of 29 to 60 months.2-4

The RTOG 0236 trial showed a median OS of 48 months and the randomized phase III CHISEL trial showed a median OS of 60 months; however, these survival data were reported in patients who were able to safely undergo a biopsy and had confirmed NSCLC.4,5 For patients without a diagnosis confirmed by biopsy and who are treated with empiric SABR, patient factors that influence radiation toxicity and OS are not well defined.

It is not clear if empiric radiation benefits survival or if treatment causes decline in lung function, considering that underlying chronic lung disease precludes these patients from biopsy. The purpose of this study was to evaluate the factors associated with radiation toxicity with empiric SABR and to evaluate OS in this population without a biopsy-confirmed diagnosis.

Methods

This was a single center retrospective review of patients treated at the radiation oncology department at the Kansas City Veterans Affairs Medical Center from August 2014 to February 2019. Data were collected on 69 patients with pulmonary nodules identified by chest computed tomography (CT) and/or positron emission tomography (PET)-CT that were highly suspicious for primary NSCLC.

These patients were presented at a multidisciplinary meeting that involved pulmonologists, oncologists, radiation oncologists, and thoracic surgeons. Patients were deemed to be poor candidates for biopsy because of severe underlying emphysema, which would put them at high risk for pneumothorax with a percutaneous needle biopsy, or were unable to tolerate general anesthesia for navigational bronchoscopy or surgical biopsy because of poor lung function. These patients were diagnosed with presumed stage I NSCLC using the criteria: minimum of 2 sequential CT scans with enlarging nodule; absence of metastases on PET-CT; the single nodule had to be fluorodeoxyglucose avid with a minimum standardized uptake value of 2.5, and absence of clinical history or physical examination consistent with small cell lung cancer or infection.

After a consensus was reached that patients met these criteria, individuals were referred for empiric SABR. Follow-up visits were at 1 month, 3 months, and every 6 months. Variables analyzed included: patient demographics, pre- and posttreatment pulmonary function tests (PFT) when available, pre-treatment oxygen use, tumor size and location (peripheral, central, or ultra-central), radiation doses, and grade of toxicity as defined by Human and Health Services Common Terminology Criteria for Adverse Events version 5.0 (dyspnea and cough both counted as pulmonary toxicity): acute ≤ 90 days and late > 90 days (Table 1).



SPSS versions 24 and 26 were used for statistical analysis. Median and range were obtained for continuous variables with a normal distribution. Kaplan-Meier log-rank testing was used to analyze OS. χ2 and Mann-Whitney U tests were used to analyze association between independent variables and OS. Analysis of significant findings were repeated with operable patients excluded for further analysis.

Results

The median follow-up was 18 months (range, 1 to 54). The median age was 71 years (range, 59 to 95) (Table 2). Most patients (97.1%) were male. The majority of patients (79.4%) had a 0 or 1 for the Eastern Cooperative Oncology group performance status, indicating fully active or restricted in physically strenuous activity but ambulatory and able to perform light work. All patients were either current or former smokers with an average pack-year history of 69.4. Only 11.6% of patients had operable disease, but received empiric SABR because they declined surgery. Four patients did not have pretreatment spirometry available and 37 did not have pretreatment diffusing capacity for carbon monoxide (DLCO) data.

 

 

Most patients had a pretreatment forced expiratory volume during the first seconds (FEV1) value and DLCO < 60% of predicted (60% and 84% of the patients, respectively). The median tumor diameter was 2 cm. Of the 68.2% of patients who did not have chronic hypoxemic respiratory failure before SABR, 16% developed a new requirement for supplemental oxygen. Sixty-two tumors (89.9%) were peripheral. There were 4 local recurrences (5.7%), 10 regional (different lobe and nodal) failures (14.3%), and 15 distant metastases (21.4%).

Nineteen of 67 patients (26.3%) had acute toxicity of which 9 had acute grade ≥ 2 toxicity; information regarding toxicity was missing on 2 patients. Thirty-two of 65 (49.9%) patients had late toxicity of which 20 (30.8%) had late grade ≥ 2 toxicity. The main factor associated with development of acute toxicity was pretreatment oxygendependence (P = .047). This was not significant when comparing only inoperable patients. Twenty patients (29.9%) developed some type of acute toxicity; pulmonary toxicity was most common (22.4%) (Table 3). All patients with acute toxicity also developed late toxicity except for 1 who died before 3 months. Predominantly, the deaths in our sample were from causes other than the malignancy or treatment, such as sepsis, deconditioning after a fall, cardiovascular complications, etc. Acute toxicity of grade ≥ 2 was significantly associated with late toxicity (P < .001 for both) in both operable and inoperable patients (P < .001).



Development of any acute toxicity grade ≥ 2 was significantly associated with oxygendependence at baseline (P = .003), central location (P < .001), and new oxygen requirement (P = .02). Only central tumor location was found to be significant (P = .001) within the inoperable cohort. There were no significant differences in outcome based on pulmonary function testing (FEV1, forced vital capacity, or DLCO) or the analyzed PFT subgroups (FEV1 < 1.0 L, FEV1 < 1.5 L, FEV1 < 30%, and FEV1 < 35%).



At the time of data collection, 30 patients were deceased (43.5%). There was a statistically significant association between OS and operability (P = .03; Table 4, Figure 1). Decreased OS was significantly associated with acute toxicity (P = .001) and acute toxicity grade ≥ 2 (P = .005; Figures 2 and 3). For the inoperable patients, both acute toxicity (P < .001) and acute toxicity grade ≥ 2 (P = .026) remained significant.

Discussion

SABR is an effective treatment for inoperable early-stage NSCLC, however its therapeutic ratio in a more frail population who cannot withstand biopsy is not well established. Additionally, the prevalence of benign disease in patients with solitary pulmonary nodules can be between 9% and 21%.6 Haidar and colleagues looked at 55 patients who received empiric SABR and found a median OS of 30.2 months with an 8.7% risk of local failure, 13% risk of regional failure with 8.7% acute toxicity, and 13% chronic toxicity.7 Data from Harkenrider and colleagues (n = 34) revealed similar results with a 2-year OS of 85%, local control of 97.1%, and regional control of 80%. The authors noted no grade ≥ 3 acute toxicities and an incidence of grade ≥ 3 late toxicities of 8.8%.1 These findings are concordant with our study results, confirming the safety and efficacy of SABR. Furthermore, a National Cancer Database analysis of observation vs empiric SABR found an OS of 10.1 months and 29 months respectively, with a hazard ratio of 0.64 (P < .001).3 Additionally, Fischer-Valuck and colleagues (n = 88) compared biopsy confirmed vs unbiopsied patients treated with SABR and found no difference in the 3-year local progression-free survival (93.1% vs 94.1%), regional lymph node metastasis and distant metastases free survival (92.5% vs 87.4%), or OS (59.9% vs 58.9%).8 With a median OS of ≤ 1 year for untreated stage I NSCLC,these studies support treating patients with empiric SABR.4

Other researchers have sought parameters to identify patients for whom radiation therapy would be too toxic. Guckenberger and colleagues aimed to establish a lower limit of pretreatment PFT to exclude patients and found only a 7% incidence of grade ≥ 2 adverse effects and toxicity did not increase with lower pulmonary function.9 They concluded that SABR was safe even for patients with poor pulmonary function. Other institutions have confirmed such findings and have been unable to find a cut-off PFT to exclude patients from empiric SABR.10,11 An analysis from the RTOG 0236 trial also noted that poor baseline PFT could not predict pulmonary toxicity or survival. Additionally, the study demonstrated only minimal decreases in patients’ FEV1 (5.8%) and DLCO (6%) at 2 years.12

 

 


Our study sought to identify a cut-off on FEV1 or DLCO that could be associated with increased toxicity. We also evaluated the incidence of acute toxicities grade ≥ 2 by stratifying patients according to FEV1 into subgroups: FEV1 < 1.0 L, FEV1 < 1.5 L, FEV1 < 30% of predicted and FEV1 < 35% of predicted. However, similar to other studies, we did not find any value that was significantly associated with increased toxicity that could preclude empiric SABR. One possible reason is that no treatment is offered for patients with extremely poor lung function as deemed by clinical judgement, therefore data on these patients is unavailable. In contradiction to other studies, our study found that oxygen dependence before treatment was significantly associated with development of acute toxicities. The exact mechanism for this association is unknown and could not be elucidated by baseline PFT. One possible explanation is that SABR could lead to oxygen free radical generation. In addition, our study indicated that those who developed acute toxicities had worse OS.

Limitations

Our study is limited by caveats of a retrospective study and its small sample size, but is in line with the reported literature (ranging from 33 to 88 patients).1,7,8 Another limitation is that data on pretreatment DLCO was missing in 37 patients and the lack of statistical robustness in terms of the smaller inoperable cohort, which limits the analyses of these factors in regards to anticipated morbidity from SABR. Also, given this is data collected from the US Department of Veterans Affairs, only 3% of our sample was female.

Conclusions

Empiric SABR for patients with presumed early-stage NSCLC appears to be safe and might positively impact OS. Development of any acute toxicity grade ≥ 2 was significantly associated with dependence on supplemental oxygen before treatment, central tumor location, and development of new oxygen requirement. No association was found in patients with poor pulmonary function before treatment because we could not find a FEV1 or DLCO cutoff that could preclude patients from empiric SABR. Considering the poor survival of untreated early-stage NSCLC, coupled with the efficacy and safety of empiric SABR for those with presumed disease, definitive SABR should be offered selectively within this patient population.

Acknowledgments

Drs. Park, Whiting and Castillo contributed to data collection. Drs. Park, Govindan and Castillo contributed to the statistical analysis and writing the first draft and final manuscript. Drs. Park, Govindan, Huang, and Reddy contributed to the discussion section.

References

1. Harkenrider MM, Bertke MH, Dunlap NE. Stereotactic body radiation therapy for unbiopsied early-stage lung cancer: a multi-institutional analysis. Am J Clin Oncol. 2014;37(4):337-342. doi:10.1097/COC.0b013e318277d822

2. Raz DJ, Zell JA, Ou SH, Gandara DR, Anton-Culver H, Jablons DM. Natural history of stage I non-small cell lung cancer: implications for early detection. Chest. 2007;132(1):193-199. doi:10.1378/chest.06-3096

3. Nanda RH, Liu Y, Gillespie TW, et al. Stereotactic body radiation therapy versus no treatment for early stage non-small cell lung cancer in medically inoperable elderly patients: a National Cancer Data Base analysis. Cancer. 2015;121(23):4222-4230. doi:10.1002/cncr.29640

4. Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol. 2019;20(4):494-503. doi:10.1016/S1470-2045(18)30896-9

5. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303(11):1070-1076. doi:10.1001/jama.2010.261

6. Smith MA, Battafarano RJ, Meyers BF, Zoole JB, Cooper JD, Patterson GA. Prevalence of benign disease in patients undergoing resection for suspected lung cancer. Ann Thorac Surg. 2006;81(5):1824-1828. doi:10.1016/j.athoracsur.2005.11.010

7. Haidar YM, Rahn DA 3rd, Nath S, et al. Comparison of outcomes following stereotactic body radiotherapy for nonsmall cell lung cancer in patients with and without pathological confirmation. Ther Adv Respir Dis. 2014;8(1):3-12. doi:10.1177/1753465813512545

8. Fischer-Valuck BW, Boggs H, Katz S, Durci M, Acharya S, Rosen LR. Comparison of stereotactic body radiation therapy for biopsy-proven versus radiographically diagnosed early-stage non-small lung cancer: a single-institution experience. Tumori. 2015;101(3):287-293. doi:10.5301/tj.5000279

9. Guckenberger M, Kestin LL, Hope AJ, et al. Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body radiotherapy for early-stage non-small cell lung cancer? J Thorac Oncol. 2012;7:542-551. doi:10.1097/JTO.0b013e31824165d7

10. Wang J, Cao J, Yuan S, et al. Poor baseline pulmonary function may not increase the risk of radiation-induced lung toxicity. Int J Radiat Oncol Biol Phys. 2013;85(3):798-804. doi:10.1016/j.ijrobp.2012.06.040

11. Henderson M, McGarry R, Yiannoutsos C, et al. Baseline pulmonary function as a predictor for survival and decline in pulmonary function over time in patients undergoing stereotactic body radiotherapy for the treatment of stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2008;72(2):404-409. doi:10.1016/j.ijrobp.2007.12.051

12. Stanic S, Paulus R, Timmerman RD, et al. No clinically significant changes in pulmonary function following stereotactic body radiation therapy for early- stage peripheral non-small cell lung cancer: an analysis of RTOG 0236. Int J Radiat Oncol Biol Phys. 2014;88(5):1092-1099. doi:10.1016/j.ijrobp.2013.12.050

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John Park is a Radiation Oncologist; Eashwer Reddy is the Section Chief of Radiation Oncology; Sushant Govindan is a Pulmonology and Critical Care Physician; Chao Huang is the Section Chief of Hematology/Medical Oncology; and Sonia Castillo is a Pulmonology and Critical Care Physician, all at the Kansas City VA Medical Center in Missouri. Curtis Whiting is a Pulmonology and Critical Care Physician at Our Lady of the Lake Regional Medical Center in Baton Rouge, Louisiana. John Park is a clinical Assistant Professor and Eashwer Reddy is a Clincal Professor at the University of Missouri in Kansas City. Sushant Govindan is an Assistant Professor, Chao Huang is a Professor, and Sonia Castillo is a Clinical Assistant Professor, all at University of Kansas Medical Center in Kansas City, Kansas.
Corrrespondence: John Park (john.park@va.gov)

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

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Author(s)
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Author(s)
John Park, MD
Curtis Whiting, MD
Eashwer Reddy, MD
Sushant Govindan, MD
Chao Huang, MD
Sonia M. Castillo, MD
Author and Disclosure Information

John Park is a Radiation Oncologist; Eashwer Reddy is the Section Chief of Radiation Oncology; Sushant Govindan is a Pulmonology and Critical Care Physician; Chao Huang is the Section Chief of Hematology/Medical Oncology; and Sonia Castillo is a Pulmonology and Critical Care Physician, all at the Kansas City VA Medical Center in Missouri. Curtis Whiting is a Pulmonology and Critical Care Physician at Our Lady of the Lake Regional Medical Center in Baton Rouge, Louisiana. John Park is a clinical Assistant Professor and Eashwer Reddy is a Clincal Professor at the University of Missouri in Kansas City. Sushant Govindan is an Assistant Professor, Chao Huang is a Professor, and Sonia Castillo is a Clinical Assistant Professor, all at University of Kansas Medical Center in Kansas City, Kansas.
Corrrespondence: John Park (john.park@va.gov)

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Author and Disclosure Information

John Park is a Radiation Oncologist; Eashwer Reddy is the Section Chief of Radiation Oncology; Sushant Govindan is a Pulmonology and Critical Care Physician; Chao Huang is the Section Chief of Hematology/Medical Oncology; and Sonia Castillo is a Pulmonology and Critical Care Physician, all at the Kansas City VA Medical Center in Missouri. Curtis Whiting is a Pulmonology and Critical Care Physician at Our Lady of the Lake Regional Medical Center in Baton Rouge, Louisiana. John Park is a clinical Assistant Professor and Eashwer Reddy is a Clincal Professor at the University of Missouri in Kansas City. Sushant Govindan is an Assistant Professor, Chao Huang is a Professor, and Sonia Castillo is a Clinical Assistant Professor, all at University of Kansas Medical Center in Kansas City, Kansas.
Corrrespondence: John Park (john.park@va.gov)

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Article PDF
0521fed_avaho_radiotherapy.pdf
Article PDF
0521fed_avaho_radiotherapy.pdf

Stereotactic ablative radiotherapy (SABR) has become the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC). Many patients are unable to undergo a biopsy safely because of poor pulmonary function or underlying emphysema and are then empirically treated with radiotherapy if they meet criteria. In these patients, local control can be achieved with SABR with minimal toxicity.1 Considering that median overall survival (OS) among patients with untreated stage I NSCLC has been reported to be as low as 9 months, early treatment with SABR could lead to increased survival of 29 to 60 months.2-4

The RTOG 0236 trial showed a median OS of 48 months and the randomized phase III CHISEL trial showed a median OS of 60 months; however, these survival data were reported in patients who were able to safely undergo a biopsy and had confirmed NSCLC.4,5 For patients without a diagnosis confirmed by biopsy and who are treated with empiric SABR, patient factors that influence radiation toxicity and OS are not well defined.

It is not clear if empiric radiation benefits survival or if treatment causes decline in lung function, considering that underlying chronic lung disease precludes these patients from biopsy. The purpose of this study was to evaluate the factors associated with radiation toxicity with empiric SABR and to evaluate OS in this population without a biopsy-confirmed diagnosis.

Methods

This was a single center retrospective review of patients treated at the radiation oncology department at the Kansas City Veterans Affairs Medical Center from August 2014 to February 2019. Data were collected on 69 patients with pulmonary nodules identified by chest computed tomography (CT) and/or positron emission tomography (PET)-CT that were highly suspicious for primary NSCLC.

These patients were presented at a multidisciplinary meeting that involved pulmonologists, oncologists, radiation oncologists, and thoracic surgeons. Patients were deemed to be poor candidates for biopsy because of severe underlying emphysema, which would put them at high risk for pneumothorax with a percutaneous needle biopsy, or were unable to tolerate general anesthesia for navigational bronchoscopy or surgical biopsy because of poor lung function. These patients were diagnosed with presumed stage I NSCLC using the criteria: minimum of 2 sequential CT scans with enlarging nodule; absence of metastases on PET-CT; the single nodule had to be fluorodeoxyglucose avid with a minimum standardized uptake value of 2.5, and absence of clinical history or physical examination consistent with small cell lung cancer or infection.

After a consensus was reached that patients met these criteria, individuals were referred for empiric SABR. Follow-up visits were at 1 month, 3 months, and every 6 months. Variables analyzed included: patient demographics, pre- and posttreatment pulmonary function tests (PFT) when available, pre-treatment oxygen use, tumor size and location (peripheral, central, or ultra-central), radiation doses, and grade of toxicity as defined by Human and Health Services Common Terminology Criteria for Adverse Events version 5.0 (dyspnea and cough both counted as pulmonary toxicity): acute ≤ 90 days and late > 90 days (Table 1).



SPSS versions 24 and 26 were used for statistical analysis. Median and range were obtained for continuous variables with a normal distribution. Kaplan-Meier log-rank testing was used to analyze OS. χ2 and Mann-Whitney U tests were used to analyze association between independent variables and OS. Analysis of significant findings were repeated with operable patients excluded for further analysis.

Results

The median follow-up was 18 months (range, 1 to 54). The median age was 71 years (range, 59 to 95) (Table 2). Most patients (97.1%) were male. The majority of patients (79.4%) had a 0 or 1 for the Eastern Cooperative Oncology group performance status, indicating fully active or restricted in physically strenuous activity but ambulatory and able to perform light work. All patients were either current or former smokers with an average pack-year history of 69.4. Only 11.6% of patients had operable disease, but received empiric SABR because they declined surgery. Four patients did not have pretreatment spirometry available and 37 did not have pretreatment diffusing capacity for carbon monoxide (DLCO) data.

 

 

Most patients had a pretreatment forced expiratory volume during the first seconds (FEV1) value and DLCO < 60% of predicted (60% and 84% of the patients, respectively). The median tumor diameter was 2 cm. Of the 68.2% of patients who did not have chronic hypoxemic respiratory failure before SABR, 16% developed a new requirement for supplemental oxygen. Sixty-two tumors (89.9%) were peripheral. There were 4 local recurrences (5.7%), 10 regional (different lobe and nodal) failures (14.3%), and 15 distant metastases (21.4%).

Nineteen of 67 patients (26.3%) had acute toxicity of which 9 had acute grade ≥ 2 toxicity; information regarding toxicity was missing on 2 patients. Thirty-two of 65 (49.9%) patients had late toxicity of which 20 (30.8%) had late grade ≥ 2 toxicity. The main factor associated with development of acute toxicity was pretreatment oxygendependence (P = .047). This was not significant when comparing only inoperable patients. Twenty patients (29.9%) developed some type of acute toxicity; pulmonary toxicity was most common (22.4%) (Table 3). All patients with acute toxicity also developed late toxicity except for 1 who died before 3 months. Predominantly, the deaths in our sample were from causes other than the malignancy or treatment, such as sepsis, deconditioning after a fall, cardiovascular complications, etc. Acute toxicity of grade ≥ 2 was significantly associated with late toxicity (P < .001 for both) in both operable and inoperable patients (P < .001).



Development of any acute toxicity grade ≥ 2 was significantly associated with oxygendependence at baseline (P = .003), central location (P < .001), and new oxygen requirement (P = .02). Only central tumor location was found to be significant (P = .001) within the inoperable cohort. There were no significant differences in outcome based on pulmonary function testing (FEV1, forced vital capacity, or DLCO) or the analyzed PFT subgroups (FEV1 < 1.0 L, FEV1 < 1.5 L, FEV1 < 30%, and FEV1 < 35%).



At the time of data collection, 30 patients were deceased (43.5%). There was a statistically significant association between OS and operability (P = .03; Table 4, Figure 1). Decreased OS was significantly associated with acute toxicity (P = .001) and acute toxicity grade ≥ 2 (P = .005; Figures 2 and 3). For the inoperable patients, both acute toxicity (P < .001) and acute toxicity grade ≥ 2 (P = .026) remained significant.

Discussion

SABR is an effective treatment for inoperable early-stage NSCLC, however its therapeutic ratio in a more frail population who cannot withstand biopsy is not well established. Additionally, the prevalence of benign disease in patients with solitary pulmonary nodules can be between 9% and 21%.6 Haidar and colleagues looked at 55 patients who received empiric SABR and found a median OS of 30.2 months with an 8.7% risk of local failure, 13% risk of regional failure with 8.7% acute toxicity, and 13% chronic toxicity.7 Data from Harkenrider and colleagues (n = 34) revealed similar results with a 2-year OS of 85%, local control of 97.1%, and regional control of 80%. The authors noted no grade ≥ 3 acute toxicities and an incidence of grade ≥ 3 late toxicities of 8.8%.1 These findings are concordant with our study results, confirming the safety and efficacy of SABR. Furthermore, a National Cancer Database analysis of observation vs empiric SABR found an OS of 10.1 months and 29 months respectively, with a hazard ratio of 0.64 (P < .001).3 Additionally, Fischer-Valuck and colleagues (n = 88) compared biopsy confirmed vs unbiopsied patients treated with SABR and found no difference in the 3-year local progression-free survival (93.1% vs 94.1%), regional lymph node metastasis and distant metastases free survival (92.5% vs 87.4%), or OS (59.9% vs 58.9%).8 With a median OS of ≤ 1 year for untreated stage I NSCLC,these studies support treating patients with empiric SABR.4

Other researchers have sought parameters to identify patients for whom radiation therapy would be too toxic. Guckenberger and colleagues aimed to establish a lower limit of pretreatment PFT to exclude patients and found only a 7% incidence of grade ≥ 2 adverse effects and toxicity did not increase with lower pulmonary function.9 They concluded that SABR was safe even for patients with poor pulmonary function. Other institutions have confirmed such findings and have been unable to find a cut-off PFT to exclude patients from empiric SABR.10,11 An analysis from the RTOG 0236 trial also noted that poor baseline PFT could not predict pulmonary toxicity or survival. Additionally, the study demonstrated only minimal decreases in patients’ FEV1 (5.8%) and DLCO (6%) at 2 years.12

 

 


Our study sought to identify a cut-off on FEV1 or DLCO that could be associated with increased toxicity. We also evaluated the incidence of acute toxicities grade ≥ 2 by stratifying patients according to FEV1 into subgroups: FEV1 < 1.0 L, FEV1 < 1.5 L, FEV1 < 30% of predicted and FEV1 < 35% of predicted. However, similar to other studies, we did not find any value that was significantly associated with increased toxicity that could preclude empiric SABR. One possible reason is that no treatment is offered for patients with extremely poor lung function as deemed by clinical judgement, therefore data on these patients is unavailable. In contradiction to other studies, our study found that oxygen dependence before treatment was significantly associated with development of acute toxicities. The exact mechanism for this association is unknown and could not be elucidated by baseline PFT. One possible explanation is that SABR could lead to oxygen free radical generation. In addition, our study indicated that those who developed acute toxicities had worse OS.

Limitations

Our study is limited by caveats of a retrospective study and its small sample size, but is in line with the reported literature (ranging from 33 to 88 patients).1,7,8 Another limitation is that data on pretreatment DLCO was missing in 37 patients and the lack of statistical robustness in terms of the smaller inoperable cohort, which limits the analyses of these factors in regards to anticipated morbidity from SABR. Also, given this is data collected from the US Department of Veterans Affairs, only 3% of our sample was female.

Conclusions

Empiric SABR for patients with presumed early-stage NSCLC appears to be safe and might positively impact OS. Development of any acute toxicity grade ≥ 2 was significantly associated with dependence on supplemental oxygen before treatment, central tumor location, and development of new oxygen requirement. No association was found in patients with poor pulmonary function before treatment because we could not find a FEV1 or DLCO cutoff that could preclude patients from empiric SABR. Considering the poor survival of untreated early-stage NSCLC, coupled with the efficacy and safety of empiric SABR for those with presumed disease, definitive SABR should be offered selectively within this patient population.

Acknowledgments

Drs. Park, Whiting and Castillo contributed to data collection. Drs. Park, Govindan and Castillo contributed to the statistical analysis and writing the first draft and final manuscript. Drs. Park, Govindan, Huang, and Reddy contributed to the discussion section.

Stereotactic ablative radiotherapy (SABR) has become the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC). Many patients are unable to undergo a biopsy safely because of poor pulmonary function or underlying emphysema and are then empirically treated with radiotherapy if they meet criteria. In these patients, local control can be achieved with SABR with minimal toxicity.1 Considering that median overall survival (OS) among patients with untreated stage I NSCLC has been reported to be as low as 9 months, early treatment with SABR could lead to increased survival of 29 to 60 months.2-4

The RTOG 0236 trial showed a median OS of 48 months and the randomized phase III CHISEL trial showed a median OS of 60 months; however, these survival data were reported in patients who were able to safely undergo a biopsy and had confirmed NSCLC.4,5 For patients without a diagnosis confirmed by biopsy and who are treated with empiric SABR, patient factors that influence radiation toxicity and OS are not well defined.

It is not clear if empiric radiation benefits survival or if treatment causes decline in lung function, considering that underlying chronic lung disease precludes these patients from biopsy. The purpose of this study was to evaluate the factors associated with radiation toxicity with empiric SABR and to evaluate OS in this population without a biopsy-confirmed diagnosis.

Methods

This was a single center retrospective review of patients treated at the radiation oncology department at the Kansas City Veterans Affairs Medical Center from August 2014 to February 2019. Data were collected on 69 patients with pulmonary nodules identified by chest computed tomography (CT) and/or positron emission tomography (PET)-CT that were highly suspicious for primary NSCLC.

These patients were presented at a multidisciplinary meeting that involved pulmonologists, oncologists, radiation oncologists, and thoracic surgeons. Patients were deemed to be poor candidates for biopsy because of severe underlying emphysema, which would put them at high risk for pneumothorax with a percutaneous needle biopsy, or were unable to tolerate general anesthesia for navigational bronchoscopy or surgical biopsy because of poor lung function. These patients were diagnosed with presumed stage I NSCLC using the criteria: minimum of 2 sequential CT scans with enlarging nodule; absence of metastases on PET-CT; the single nodule had to be fluorodeoxyglucose avid with a minimum standardized uptake value of 2.5, and absence of clinical history or physical examination consistent with small cell lung cancer or infection.

After a consensus was reached that patients met these criteria, individuals were referred for empiric SABR. Follow-up visits were at 1 month, 3 months, and every 6 months. Variables analyzed included: patient demographics, pre- and posttreatment pulmonary function tests (PFT) when available, pre-treatment oxygen use, tumor size and location (peripheral, central, or ultra-central), radiation doses, and grade of toxicity as defined by Human and Health Services Common Terminology Criteria for Adverse Events version 5.0 (dyspnea and cough both counted as pulmonary toxicity): acute ≤ 90 days and late > 90 days (Table 1).



SPSS versions 24 and 26 were used for statistical analysis. Median and range were obtained for continuous variables with a normal distribution. Kaplan-Meier log-rank testing was used to analyze OS. χ2 and Mann-Whitney U tests were used to analyze association between independent variables and OS. Analysis of significant findings were repeated with operable patients excluded for further analysis.

Results

The median follow-up was 18 months (range, 1 to 54). The median age was 71 years (range, 59 to 95) (Table 2). Most patients (97.1%) were male. The majority of patients (79.4%) had a 0 or 1 for the Eastern Cooperative Oncology group performance status, indicating fully active or restricted in physically strenuous activity but ambulatory and able to perform light work. All patients were either current or former smokers with an average pack-year history of 69.4. Only 11.6% of patients had operable disease, but received empiric SABR because they declined surgery. Four patients did not have pretreatment spirometry available and 37 did not have pretreatment diffusing capacity for carbon monoxide (DLCO) data.

 

 

Most patients had a pretreatment forced expiratory volume during the first seconds (FEV1) value and DLCO < 60% of predicted (60% and 84% of the patients, respectively). The median tumor diameter was 2 cm. Of the 68.2% of patients who did not have chronic hypoxemic respiratory failure before SABR, 16% developed a new requirement for supplemental oxygen. Sixty-two tumors (89.9%) were peripheral. There were 4 local recurrences (5.7%), 10 regional (different lobe and nodal) failures (14.3%), and 15 distant metastases (21.4%).

Nineteen of 67 patients (26.3%) had acute toxicity of which 9 had acute grade ≥ 2 toxicity; information regarding toxicity was missing on 2 patients. Thirty-two of 65 (49.9%) patients had late toxicity of which 20 (30.8%) had late grade ≥ 2 toxicity. The main factor associated with development of acute toxicity was pretreatment oxygendependence (P = .047). This was not significant when comparing only inoperable patients. Twenty patients (29.9%) developed some type of acute toxicity; pulmonary toxicity was most common (22.4%) (Table 3). All patients with acute toxicity also developed late toxicity except for 1 who died before 3 months. Predominantly, the deaths in our sample were from causes other than the malignancy or treatment, such as sepsis, deconditioning after a fall, cardiovascular complications, etc. Acute toxicity of grade ≥ 2 was significantly associated with late toxicity (P < .001 for both) in both operable and inoperable patients (P < .001).



Development of any acute toxicity grade ≥ 2 was significantly associated with oxygendependence at baseline (P = .003), central location (P < .001), and new oxygen requirement (P = .02). Only central tumor location was found to be significant (P = .001) within the inoperable cohort. There were no significant differences in outcome based on pulmonary function testing (FEV1, forced vital capacity, or DLCO) or the analyzed PFT subgroups (FEV1 < 1.0 L, FEV1 < 1.5 L, FEV1 < 30%, and FEV1 < 35%).



At the time of data collection, 30 patients were deceased (43.5%). There was a statistically significant association between OS and operability (P = .03; Table 4, Figure 1). Decreased OS was significantly associated with acute toxicity (P = .001) and acute toxicity grade ≥ 2 (P = .005; Figures 2 and 3). For the inoperable patients, both acute toxicity (P < .001) and acute toxicity grade ≥ 2 (P = .026) remained significant.

Discussion

SABR is an effective treatment for inoperable early-stage NSCLC, however its therapeutic ratio in a more frail population who cannot withstand biopsy is not well established. Additionally, the prevalence of benign disease in patients with solitary pulmonary nodules can be between 9% and 21%.6 Haidar and colleagues looked at 55 patients who received empiric SABR and found a median OS of 30.2 months with an 8.7% risk of local failure, 13% risk of regional failure with 8.7% acute toxicity, and 13% chronic toxicity.7 Data from Harkenrider and colleagues (n = 34) revealed similar results with a 2-year OS of 85%, local control of 97.1%, and regional control of 80%. The authors noted no grade ≥ 3 acute toxicities and an incidence of grade ≥ 3 late toxicities of 8.8%.1 These findings are concordant with our study results, confirming the safety and efficacy of SABR. Furthermore, a National Cancer Database analysis of observation vs empiric SABR found an OS of 10.1 months and 29 months respectively, with a hazard ratio of 0.64 (P < .001).3 Additionally, Fischer-Valuck and colleagues (n = 88) compared biopsy confirmed vs unbiopsied patients treated with SABR and found no difference in the 3-year local progression-free survival (93.1% vs 94.1%), regional lymph node metastasis and distant metastases free survival (92.5% vs 87.4%), or OS (59.9% vs 58.9%).8 With a median OS of ≤ 1 year for untreated stage I NSCLC,these studies support treating patients with empiric SABR.4

Other researchers have sought parameters to identify patients for whom radiation therapy would be too toxic. Guckenberger and colleagues aimed to establish a lower limit of pretreatment PFT to exclude patients and found only a 7% incidence of grade ≥ 2 adverse effects and toxicity did not increase with lower pulmonary function.9 They concluded that SABR was safe even for patients with poor pulmonary function. Other institutions have confirmed such findings and have been unable to find a cut-off PFT to exclude patients from empiric SABR.10,11 An analysis from the RTOG 0236 trial also noted that poor baseline PFT could not predict pulmonary toxicity or survival. Additionally, the study demonstrated only minimal decreases in patients’ FEV1 (5.8%) and DLCO (6%) at 2 years.12

 

 


Our study sought to identify a cut-off on FEV1 or DLCO that could be associated with increased toxicity. We also evaluated the incidence of acute toxicities grade ≥ 2 by stratifying patients according to FEV1 into subgroups: FEV1 < 1.0 L, FEV1 < 1.5 L, FEV1 < 30% of predicted and FEV1 < 35% of predicted. However, similar to other studies, we did not find any value that was significantly associated with increased toxicity that could preclude empiric SABR. One possible reason is that no treatment is offered for patients with extremely poor lung function as deemed by clinical judgement, therefore data on these patients is unavailable. In contradiction to other studies, our study found that oxygen dependence before treatment was significantly associated with development of acute toxicities. The exact mechanism for this association is unknown and could not be elucidated by baseline PFT. One possible explanation is that SABR could lead to oxygen free radical generation. In addition, our study indicated that those who developed acute toxicities had worse OS.

Limitations

Our study is limited by caveats of a retrospective study and its small sample size, but is in line with the reported literature (ranging from 33 to 88 patients).1,7,8 Another limitation is that data on pretreatment DLCO was missing in 37 patients and the lack of statistical robustness in terms of the smaller inoperable cohort, which limits the analyses of these factors in regards to anticipated morbidity from SABR. Also, given this is data collected from the US Department of Veterans Affairs, only 3% of our sample was female.

Conclusions

Empiric SABR for patients with presumed early-stage NSCLC appears to be safe and might positively impact OS. Development of any acute toxicity grade ≥ 2 was significantly associated with dependence on supplemental oxygen before treatment, central tumor location, and development of new oxygen requirement. No association was found in patients with poor pulmonary function before treatment because we could not find a FEV1 or DLCO cutoff that could preclude patients from empiric SABR. Considering the poor survival of untreated early-stage NSCLC, coupled with the efficacy and safety of empiric SABR for those with presumed disease, definitive SABR should be offered selectively within this patient population.

Acknowledgments

Drs. Park, Whiting and Castillo contributed to data collection. Drs. Park, Govindan and Castillo contributed to the statistical analysis and writing the first draft and final manuscript. Drs. Park, Govindan, Huang, and Reddy contributed to the discussion section.

References

1. Harkenrider MM, Bertke MH, Dunlap NE. Stereotactic body radiation therapy for unbiopsied early-stage lung cancer: a multi-institutional analysis. Am J Clin Oncol. 2014;37(4):337-342. doi:10.1097/COC.0b013e318277d822

2. Raz DJ, Zell JA, Ou SH, Gandara DR, Anton-Culver H, Jablons DM. Natural history of stage I non-small cell lung cancer: implications for early detection. Chest. 2007;132(1):193-199. doi:10.1378/chest.06-3096

3. Nanda RH, Liu Y, Gillespie TW, et al. Stereotactic body radiation therapy versus no treatment for early stage non-small cell lung cancer in medically inoperable elderly patients: a National Cancer Data Base analysis. Cancer. 2015;121(23):4222-4230. doi:10.1002/cncr.29640

4. Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol. 2019;20(4):494-503. doi:10.1016/S1470-2045(18)30896-9

5. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303(11):1070-1076. doi:10.1001/jama.2010.261

6. Smith MA, Battafarano RJ, Meyers BF, Zoole JB, Cooper JD, Patterson GA. Prevalence of benign disease in patients undergoing resection for suspected lung cancer. Ann Thorac Surg. 2006;81(5):1824-1828. doi:10.1016/j.athoracsur.2005.11.010

7. Haidar YM, Rahn DA 3rd, Nath S, et al. Comparison of outcomes following stereotactic body radiotherapy for nonsmall cell lung cancer in patients with and without pathological confirmation. Ther Adv Respir Dis. 2014;8(1):3-12. doi:10.1177/1753465813512545

8. Fischer-Valuck BW, Boggs H, Katz S, Durci M, Acharya S, Rosen LR. Comparison of stereotactic body radiation therapy for biopsy-proven versus radiographically diagnosed early-stage non-small lung cancer: a single-institution experience. Tumori. 2015;101(3):287-293. doi:10.5301/tj.5000279

9. Guckenberger M, Kestin LL, Hope AJ, et al. Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body radiotherapy for early-stage non-small cell lung cancer? J Thorac Oncol. 2012;7:542-551. doi:10.1097/JTO.0b013e31824165d7

10. Wang J, Cao J, Yuan S, et al. Poor baseline pulmonary function may not increase the risk of radiation-induced lung toxicity. Int J Radiat Oncol Biol Phys. 2013;85(3):798-804. doi:10.1016/j.ijrobp.2012.06.040

11. Henderson M, McGarry R, Yiannoutsos C, et al. Baseline pulmonary function as a predictor for survival and decline in pulmonary function over time in patients undergoing stereotactic body radiotherapy for the treatment of stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2008;72(2):404-409. doi:10.1016/j.ijrobp.2007.12.051

12. Stanic S, Paulus R, Timmerman RD, et al. No clinically significant changes in pulmonary function following stereotactic body radiation therapy for early- stage peripheral non-small cell lung cancer: an analysis of RTOG 0236. Int J Radiat Oncol Biol Phys. 2014;88(5):1092-1099. doi:10.1016/j.ijrobp.2013.12.050

References

1. Harkenrider MM, Bertke MH, Dunlap NE. Stereotactic body radiation therapy for unbiopsied early-stage lung cancer: a multi-institutional analysis. Am J Clin Oncol. 2014;37(4):337-342. doi:10.1097/COC.0b013e318277d822

2. Raz DJ, Zell JA, Ou SH, Gandara DR, Anton-Culver H, Jablons DM. Natural history of stage I non-small cell lung cancer: implications for early detection. Chest. 2007;132(1):193-199. doi:10.1378/chest.06-3096

3. Nanda RH, Liu Y, Gillespie TW, et al. Stereotactic body radiation therapy versus no treatment for early stage non-small cell lung cancer in medically inoperable elderly patients: a National Cancer Data Base analysis. Cancer. 2015;121(23):4222-4230. doi:10.1002/cncr.29640

4. Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol. 2019;20(4):494-503. doi:10.1016/S1470-2045(18)30896-9

5. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303(11):1070-1076. doi:10.1001/jama.2010.261

6. Smith MA, Battafarano RJ, Meyers BF, Zoole JB, Cooper JD, Patterson GA. Prevalence of benign disease in patients undergoing resection for suspected lung cancer. Ann Thorac Surg. 2006;81(5):1824-1828. doi:10.1016/j.athoracsur.2005.11.010

7. Haidar YM, Rahn DA 3rd, Nath S, et al. Comparison of outcomes following stereotactic body radiotherapy for nonsmall cell lung cancer in patients with and without pathological confirmation. Ther Adv Respir Dis. 2014;8(1):3-12. doi:10.1177/1753465813512545

8. Fischer-Valuck BW, Boggs H, Katz S, Durci M, Acharya S, Rosen LR. Comparison of stereotactic body radiation therapy for biopsy-proven versus radiographically diagnosed early-stage non-small lung cancer: a single-institution experience. Tumori. 2015;101(3):287-293. doi:10.5301/tj.5000279

9. Guckenberger M, Kestin LL, Hope AJ, et al. Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body radiotherapy for early-stage non-small cell lung cancer? J Thorac Oncol. 2012;7:542-551. doi:10.1097/JTO.0b013e31824165d7

10. Wang J, Cao J, Yuan S, et al. Poor baseline pulmonary function may not increase the risk of radiation-induced lung toxicity. Int J Radiat Oncol Biol Phys. 2013;85(3):798-804. doi:10.1016/j.ijrobp.2012.06.040

11. Henderson M, McGarry R, Yiannoutsos C, et al. Baseline pulmonary function as a predictor for survival and decline in pulmonary function over time in patients undergoing stereotactic body radiotherapy for the treatment of stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2008;72(2):404-409. doi:10.1016/j.ijrobp.2007.12.051

12. Stanic S, Paulus R, Timmerman RD, et al. No clinically significant changes in pulmonary function following stereotactic body radiation therapy for early- stage peripheral non-small cell lung cancer: an analysis of RTOG 0236. Int J Radiat Oncol Biol Phys. 2014;88(5):1092-1099. doi:10.1016/j.ijrobp.2013.12.050

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Positivity Rates in Oropharyngeal and Nonoropharyngeal Head and Neck Cancer in the VA

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Article
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Rates of HPV positivity of the p16 biomarker in veterans were similar to those of patients with oropharyngeal head and neck tumors in the general population, but differed from general population patients with non-oropharyngeal squamous cell carcinoma.
Author(s)
John Park, MD
Veronica McPike, RN, MSN
Suman Kambhampati, MD
Chao Huang, MD
January Fields-Meehan, MD
Linda Verkruyse, MD, PhD
Ace Allen, MD
Eashwer Reddy, MD

Head and neck cancer (HNC) continues to be a major health issue with an estimated 51,540 cases in the US in 2018, making it the eighth most common cancer among men with an estimated 4% of all new cancer diagnoses.1 Over the past decade, human papillomavirus (HPV) has emerged as a major prognostic factor for survival in squamous cell carcinomas of the oropharynx. Patients who are HPV-positive (HPV+) have a much higher survival rate than patients who have HPV-negative (HPV-) cancers of the oropharynx. The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual has 2 distinct stagings for HPV+ and HPV- oropharyngeal tumors using p16-positivity (p16+) as a surrogate marker.2

Squamous cell carcinomas of the oropharynx that are HPV+ have about half the risk of death of HPV- tumors, are highly responsive to treatment, and are more often seen in younger and healthier patients with little to no tobacco use.2,3 As such, there also is a movement to de-escalate HPV+ oropharyngeal cancers with multiple trials by either replacing cytotoxic chemotherapy with a targeted agent (cisplatin vs cetuximab in RTOG 1016) or reducing the radiation dose (ECOG 1308, NRG HN002, Quarterback, and OPTIMA trials).3

The focus of many epidemiologic studies has been in the HNC general population. A recent epidemiologic analysis of the HNC general population found a p16 positivity rate of 60% in oropharyngeal squamous cell carcinomas (OPSCC) and 10% in nonoropharyngeal squamous cell carcinomas (NOPSCC).4 There has been a lack of studies focusing on the US Department of Veterans Administration (VA) population. The VA HNC population consists mostly of older white male smokers; whereas the rise of OPSCC in the general population consists primarily of males aged < 60 years often with little or no tobacco use.5 Furthermore, the importance of p16 positivity in NOPSCC also may be prognostic.6 Population data on this subset in the VA are lacking as well.This study’s purpose is to analyze the p16 positivity rate in both the OPSCC and NOPSCC in the VA population. Elucidation of epidemiologic factors that are associated with these groups may bring to light important differences between the VA and general HNC populations.

Methods

A review of the Kansas City VA Medical Center database for patients with HNC was performed from 2011 to 2017. The review consisted of 183 patient records (second primaries were scored separately), and 123 were deemed eligible for the study. Epidemiologic data were collected, including site, OPSCC vs NOPSCC, age, race, education level, tobacco use, alcohol use, TNM stage, and marital status (Table). 

Gender was not included because there was only 1 female patient in the cohort. Four subgroups based on site and p16 status (OPSCC p16+, OPSCC p16-, NOPSCC p16+, and NOPSCC p16-) were further analyzed. Appropriate statistical analysis (chi-square test, analysis of variance, and Kruskal-Wallis test) with IBM SPSS 24.0 (Armonk, NY) was used to find differences (P < .05) among the means of the 4 subgroups.

Results

There were 55 (44%) patients with OPSCC and 68 patients with NOPSCC (56%). Of the 68 patients with NOPSCC, 48 (70%) were primary tumors from the larynx, 12 (18%) from the oral cavity, 4 (6%) from the hypopharynx, 2 from the nasopharynx (3%), and 2 (3%) were unknown primaries. In the OPSCC group, 41 patients were p16+ (75%) and 14 p16- (25%). In the NOPSCC group, 20 patients were p16+ (29%) and 48 were p16- (71%). There was a statistically significant difference seen in tobacco use, TNM stage, and marital status. Alcohol use trended toward significance.

The NOPSCC p16+ group had the greatest mean pack-year use (57). The lowest was in the OPSCC p16+ group (29). The OPSCC p16+ group had 37% never smokers compared with ≤ 10% for the other groups. Both the OPSCC and NOPSCC p16- groups had much more alcohol use per week than that of the p16+ groups. The differences in marital status included a lower rate of never married individuals in the p16+ group and a higher rate of marriage in the NOPSCC p16- group. The T stage distribution within the OPSCC groups was similar, but NOPSCC groups saw more T1 lesions in the NOPSCC p16- group (42% p16- vs 18% p16+). Conversely, more T4 lesions were found in the NOPSCC p16+ patients (7% p16- vs 29% p16+). More advanced nodal staging was seen in both OPSCC groups with 78% N2 or N3 in the p16+ group and 82% in the p16- group. The NOPSCC p16+ group had 55% N0 or N1 patients, and the p16- group had 60%. In terms of overall stage, the OPSCC groups had a similar distribution with predominantly stage IVA/B presentation (74% p16+ and 82% p16-), whereas the NOPSCC groups had only 58% (p16+) and 35% (p16-) at presentation.

Discussion

The overall HPV positivity rate in the general population of patients with HNC has been reported as between 57% and 72% for OPSCC and between 1.3% and 7% for NOPSCC.6 One study, however, examined the p16 positivity rate in NOPSCC patients enrolled in major trials (RTOG 0129, 0234, and 0522 studies) and found that up to 19.3% of NOPSCC patients had p16 positivity.6 Even with the near 20% rate in those aforementioned trials that are above the reported norm, the current study found that nearly 30% of its VA population had p16+ NOPSCC. It has been shown that regardless of site, HPV-driven head and neck tumors share a similar gene expression and DNA methylation profiles (nonkeratinizing, basaloid histopathologic features, and lack of TP53 or CDKN2A alterations).5 p16+ NOPSCC has a different immune microenvironment with less lymphocyte infiltration, and there is some debate in the literature about the effects on tumor outcomes for NOPSCC cancer.5

In the aforementioned RTOG trials, p16- NOPSCC had worse outcomes compared with those of p16+ NOPSCC.6 This result is in contrast to the Danish Head and Neck Cancer Group (DAHANCA) and the combined Johns Hopkins University (JHU) and University of California, San Francisco (UCSF) data that found no difference between p16+ NOPSCC or p16- NOPSCC.7,8 In regards to race, this study did not find any differences. Another UCSF and JHU study showed lower p16+ rates in African American patients with OPSCC, but no distinction between race in the NOPSCC group. This result is consistent with the data in the current study as the distribution of race was no different among the 4 groups; however, this study's cohort was 90% white, 10% African American, and only < 1% Native American.4 This study's cohort population also was consistent with HPV-positive tumors presenting with earlier T, but higher N staging.9

Smoking is known to decrease survival in HPV-positive HNC, with the RTOG 0129 study separating head and neck tumors into low, medium, and high risk, based on HPV status, smoking, and stage.10 Although the average smoking pack-years in the current study’s OPC p16+ group was high at 29 pack-years, there was still a significant number of nonsmokers in that same group (37%). The University of Michigan conducted a study that had a similar profile of patients with an average age of 56.5 and 32.4% never smokers in their p16+ OPSCC cohort; thus, the VA p16+ OPSCC group in this study may be similar to the general population's p16+ OPSCC group.11 Nonmonogamous relationships also have been shown to be a risk factor for HPV positivity, and there was a difference in marital status (assuming it was a surrogate for monogamy) between the 4 groups; however, in contrast, the p16+ group in the current study had a high number of married patients, 45% in OPC p16+ group, and may not have been a good surrogate for monogamy in this VA population.

Limitations

Limitations of this study include all the caveats that come with a retrospective study, such as confounding variables, unbalanced groups, and selection bias. A detailed sexual history was not included, although it is well known that sexual activity is linked with oral HPV positivity.12 Human papillomavirus positivity based on p16 immunohistochemical analysis also was used as a surrogate marker for HPV instead of DNA in situ hybridization. The data also may be skewed due to the study patient’s being predominantly white and male: Both groups have a higher predilection for HPV-driven HNCs.13

Conclusion

The proportion of p16+ VA OPSCC cases was similar to that of the general population at 75% with 37% never smokers, but the percentage in NOPSCC was higher at 29% with only 10% never smokers. The p16+ NOPSCC also presented with more T4 lesions and a higher overall stage compared with p16- NOPSCC. Further studies are needed to compare these subgroups in the VA and in the general HNC populations.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.

2. Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122-137.

3. Mirghani H, Blanchard P. Treatment de-escalation for HPV-driven oropharyngeal cancer: where do we stand? Clin Transl Radiat Oncol. 2017;8:4-11.

4. D’Souza G, Westra WH, Wang SJ, et al. Differences in the prevalence of human papillomavirus (HPV) in head and neck squamous cell cancers by sex, race, anatomic tumor site, and HPV detection method. JAMA Oncol. 2017;3(2):169-177.

5. Chakravarthy A, Henderson S, Thirdborough SM, et al. Human papillomavirus drives tumor development throughout the head and neck: improved prognosis is associated with an immune response largely restricted to the oropharynx. J Clin Oncol. 2016;34(34):4132-4141.

6. Chung CH, Zhang Q, Kong CS, et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol. 2014;32(35):3930-3938.

7. Lassen P, Primdahl H, Johansen J, et al; Danish Head and Neck Cancer Group (DAHANCA). Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. Radiother Oncol. 2014;113(3):310-316.

8. Fakhry C, Westra WH, Wang SJ, et al. The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer. Cancer. 2017;123(9):1566-1575.

9. Elrefaey S, Massaro MA, Chiocca S, Chiesa F, Ansarin M. HPV in oropharyngeal cancer: the basics to know in clinical practice. Acta Otorhinolaryngol Ital. 2014;34(5):299-309.

10. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35.

11. Maxwell, JH, Kumar B, Feng FY, et al. Tobacco use in HPV-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res. 2010;16(4):1226-1235.

12. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307(7):693-703.

13. Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol. 2014;50(6):565-574.

Author and Disclosure Information

Dr. Park, Dr. Kambhampati, Dr. Fields-Meehan, and Dr. Verkruyse are Attending Physicians; Dr. Huang is the Section Chief of the Hematology/Oncology Division; and Dr. Reddy is the Section Chief of Radiation Oncology, all at Kansas City VAMC in Missouri. Mrs. McPike is a Nurse Practitioner, and Dr. Allen is an Attending Physician, both at the VA Eastern Kansas Health Care System Topeka campus. Dr. Park is a Clinical Assistant Professor, and Dr. Reddy is a Clinical Professor, both in the Department of Radiology at the University of Missouri, Kansas City. Dr. Huang and Dr. Kambhampati are Associate Professors, Medical Oncology at the University of Kansas School of Medicine in Kansas City.
Correspondence: Dr. Park (john.park@va.gov)

Author disclosures
Suman Kambhampati is an employee of Takeda Pharma-ceuticals. All other authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

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Veronica McPike, RN, MSN
Suman Kambhampati, MD
Chao Huang, MD
January Fields-Meehan, MD
Linda Verkruyse, MD, PhD
Ace Allen, MD
Eashwer Reddy, MD
Author(s)
John Park, MD
Veronica McPike, RN, MSN
Suman Kambhampati, MD
Chao Huang, MD
January Fields-Meehan, MD
Linda Verkruyse, MD, PhD
Ace Allen, MD
Eashwer Reddy, MD
Author and Disclosure Information

Dr. Park, Dr. Kambhampati, Dr. Fields-Meehan, and Dr. Verkruyse are Attending Physicians; Dr. Huang is the Section Chief of the Hematology/Oncology Division; and Dr. Reddy is the Section Chief of Radiation Oncology, all at Kansas City VAMC in Missouri. Mrs. McPike is a Nurse Practitioner, and Dr. Allen is an Attending Physician, both at the VA Eastern Kansas Health Care System Topeka campus. Dr. Park is a Clinical Assistant Professor, and Dr. Reddy is a Clinical Professor, both in the Department of Radiology at the University of Missouri, Kansas City. Dr. Huang and Dr. Kambhampati are Associate Professors, Medical Oncology at the University of Kansas School of Medicine in Kansas City.
Correspondence: Dr. Park (john.park@va.gov)

Author disclosures
Suman Kambhampati is an employee of Takeda Pharma-ceuticals. All other authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Author and Disclosure Information

Dr. Park, Dr. Kambhampati, Dr. Fields-Meehan, and Dr. Verkruyse are Attending Physicians; Dr. Huang is the Section Chief of the Hematology/Oncology Division; and Dr. Reddy is the Section Chief of Radiation Oncology, all at Kansas City VAMC in Missouri. Mrs. McPike is a Nurse Practitioner, and Dr. Allen is an Attending Physician, both at the VA Eastern Kansas Health Care System Topeka campus. Dr. Park is a Clinical Assistant Professor, and Dr. Reddy is a Clinical Professor, both in the Department of Radiology at the University of Missouri, Kansas City. Dr. Huang and Dr. Kambhampati are Associate Professors, Medical Oncology at the University of Kansas School of Medicine in Kansas City.
Correspondence: Dr. Park (john.park@va.gov)

Author disclosures
Suman Kambhampati is an employee of Takeda Pharma-ceuticals. All other authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Rates of HPV positivity of the p16 biomarker in veterans were similar to those of patients with oropharyngeal head and neck tumors in the general population, but differed from general population patients with non-oropharyngeal squamous cell carcinoma.
Rates of HPV positivity of the p16 biomarker in veterans were similar to those of patients with oropharyngeal head and neck tumors in the general population, but differed from general population patients with non-oropharyngeal squamous cell carcinoma.

Head and neck cancer (HNC) continues to be a major health issue with an estimated 51,540 cases in the US in 2018, making it the eighth most common cancer among men with an estimated 4% of all new cancer diagnoses.1 Over the past decade, human papillomavirus (HPV) has emerged as a major prognostic factor for survival in squamous cell carcinomas of the oropharynx. Patients who are HPV-positive (HPV+) have a much higher survival rate than patients who have HPV-negative (HPV-) cancers of the oropharynx. The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual has 2 distinct stagings for HPV+ and HPV- oropharyngeal tumors using p16-positivity (p16+) as a surrogate marker.2

Squamous cell carcinomas of the oropharynx that are HPV+ have about half the risk of death of HPV- tumors, are highly responsive to treatment, and are more often seen in younger and healthier patients with little to no tobacco use.2,3 As such, there also is a movement to de-escalate HPV+ oropharyngeal cancers with multiple trials by either replacing cytotoxic chemotherapy with a targeted agent (cisplatin vs cetuximab in RTOG 1016) or reducing the radiation dose (ECOG 1308, NRG HN002, Quarterback, and OPTIMA trials).3

The focus of many epidemiologic studies has been in the HNC general population. A recent epidemiologic analysis of the HNC general population found a p16 positivity rate of 60% in oropharyngeal squamous cell carcinomas (OPSCC) and 10% in nonoropharyngeal squamous cell carcinomas (NOPSCC).4 There has been a lack of studies focusing on the US Department of Veterans Administration (VA) population. The VA HNC population consists mostly of older white male smokers; whereas the rise of OPSCC in the general population consists primarily of males aged < 60 years often with little or no tobacco use.5 Furthermore, the importance of p16 positivity in NOPSCC also may be prognostic.6 Population data on this subset in the VA are lacking as well.This study’s purpose is to analyze the p16 positivity rate in both the OPSCC and NOPSCC in the VA population. Elucidation of epidemiologic factors that are associated with these groups may bring to light important differences between the VA and general HNC populations.

Methods

A review of the Kansas City VA Medical Center database for patients with HNC was performed from 2011 to 2017. The review consisted of 183 patient records (second primaries were scored separately), and 123 were deemed eligible for the study. Epidemiologic data were collected, including site, OPSCC vs NOPSCC, age, race, education level, tobacco use, alcohol use, TNM stage, and marital status (Table). 

Gender was not included because there was only 1 female patient in the cohort. Four subgroups based on site and p16 status (OPSCC p16+, OPSCC p16-, NOPSCC p16+, and NOPSCC p16-) were further analyzed. Appropriate statistical analysis (chi-square test, analysis of variance, and Kruskal-Wallis test) with IBM SPSS 24.0 (Armonk, NY) was used to find differences (P < .05) among the means of the 4 subgroups.

Results

There were 55 (44%) patients with OPSCC and 68 patients with NOPSCC (56%). Of the 68 patients with NOPSCC, 48 (70%) were primary tumors from the larynx, 12 (18%) from the oral cavity, 4 (6%) from the hypopharynx, 2 from the nasopharynx (3%), and 2 (3%) were unknown primaries. In the OPSCC group, 41 patients were p16+ (75%) and 14 p16- (25%). In the NOPSCC group, 20 patients were p16+ (29%) and 48 were p16- (71%). There was a statistically significant difference seen in tobacco use, TNM stage, and marital status. Alcohol use trended toward significance.

The NOPSCC p16+ group had the greatest mean pack-year use (57). The lowest was in the OPSCC p16+ group (29). The OPSCC p16+ group had 37% never smokers compared with ≤ 10% for the other groups. Both the OPSCC and NOPSCC p16- groups had much more alcohol use per week than that of the p16+ groups. The differences in marital status included a lower rate of never married individuals in the p16+ group and a higher rate of marriage in the NOPSCC p16- group. The T stage distribution within the OPSCC groups was similar, but NOPSCC groups saw more T1 lesions in the NOPSCC p16- group (42% p16- vs 18% p16+). Conversely, more T4 lesions were found in the NOPSCC p16+ patients (7% p16- vs 29% p16+). More advanced nodal staging was seen in both OPSCC groups with 78% N2 or N3 in the p16+ group and 82% in the p16- group. The NOPSCC p16+ group had 55% N0 or N1 patients, and the p16- group had 60%. In terms of overall stage, the OPSCC groups had a similar distribution with predominantly stage IVA/B presentation (74% p16+ and 82% p16-), whereas the NOPSCC groups had only 58% (p16+) and 35% (p16-) at presentation.

Discussion

The overall HPV positivity rate in the general population of patients with HNC has been reported as between 57% and 72% for OPSCC and between 1.3% and 7% for NOPSCC.6 One study, however, examined the p16 positivity rate in NOPSCC patients enrolled in major trials (RTOG 0129, 0234, and 0522 studies) and found that up to 19.3% of NOPSCC patients had p16 positivity.6 Even with the near 20% rate in those aforementioned trials that are above the reported norm, the current study found that nearly 30% of its VA population had p16+ NOPSCC. It has been shown that regardless of site, HPV-driven head and neck tumors share a similar gene expression and DNA methylation profiles (nonkeratinizing, basaloid histopathologic features, and lack of TP53 or CDKN2A alterations).5 p16+ NOPSCC has a different immune microenvironment with less lymphocyte infiltration, and there is some debate in the literature about the effects on tumor outcomes for NOPSCC cancer.5

In the aforementioned RTOG trials, p16- NOPSCC had worse outcomes compared with those of p16+ NOPSCC.6 This result is in contrast to the Danish Head and Neck Cancer Group (DAHANCA) and the combined Johns Hopkins University (JHU) and University of California, San Francisco (UCSF) data that found no difference between p16+ NOPSCC or p16- NOPSCC.7,8 In regards to race, this study did not find any differences. Another UCSF and JHU study showed lower p16+ rates in African American patients with OPSCC, but no distinction between race in the NOPSCC group. This result is consistent with the data in the current study as the distribution of race was no different among the 4 groups; however, this study's cohort was 90% white, 10% African American, and only < 1% Native American.4 This study's cohort population also was consistent with HPV-positive tumors presenting with earlier T, but higher N staging.9

Smoking is known to decrease survival in HPV-positive HNC, with the RTOG 0129 study separating head and neck tumors into low, medium, and high risk, based on HPV status, smoking, and stage.10 Although the average smoking pack-years in the current study’s OPC p16+ group was high at 29 pack-years, there was still a significant number of nonsmokers in that same group (37%). The University of Michigan conducted a study that had a similar profile of patients with an average age of 56.5 and 32.4% never smokers in their p16+ OPSCC cohort; thus, the VA p16+ OPSCC group in this study may be similar to the general population's p16+ OPSCC group.11 Nonmonogamous relationships also have been shown to be a risk factor for HPV positivity, and there was a difference in marital status (assuming it was a surrogate for monogamy) between the 4 groups; however, in contrast, the p16+ group in the current study had a high number of married patients, 45% in OPC p16+ group, and may not have been a good surrogate for monogamy in this VA population.

Limitations

Limitations of this study include all the caveats that come with a retrospective study, such as confounding variables, unbalanced groups, and selection bias. A detailed sexual history was not included, although it is well known that sexual activity is linked with oral HPV positivity.12 Human papillomavirus positivity based on p16 immunohistochemical analysis also was used as a surrogate marker for HPV instead of DNA in situ hybridization. The data also may be skewed due to the study patient’s being predominantly white and male: Both groups have a higher predilection for HPV-driven HNCs.13

Conclusion

The proportion of p16+ VA OPSCC cases was similar to that of the general population at 75% with 37% never smokers, but the percentage in NOPSCC was higher at 29% with only 10% never smokers. The p16+ NOPSCC also presented with more T4 lesions and a higher overall stage compared with p16- NOPSCC. Further studies are needed to compare these subgroups in the VA and in the general HNC populations.

Head and neck cancer (HNC) continues to be a major health issue with an estimated 51,540 cases in the US in 2018, making it the eighth most common cancer among men with an estimated 4% of all new cancer diagnoses.1 Over the past decade, human papillomavirus (HPV) has emerged as a major prognostic factor for survival in squamous cell carcinomas of the oropharynx. Patients who are HPV-positive (HPV+) have a much higher survival rate than patients who have HPV-negative (HPV-) cancers of the oropharynx. The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual has 2 distinct stagings for HPV+ and HPV- oropharyngeal tumors using p16-positivity (p16+) as a surrogate marker.2

Squamous cell carcinomas of the oropharynx that are HPV+ have about half the risk of death of HPV- tumors, are highly responsive to treatment, and are more often seen in younger and healthier patients with little to no tobacco use.2,3 As such, there also is a movement to de-escalate HPV+ oropharyngeal cancers with multiple trials by either replacing cytotoxic chemotherapy with a targeted agent (cisplatin vs cetuximab in RTOG 1016) or reducing the radiation dose (ECOG 1308, NRG HN002, Quarterback, and OPTIMA trials).3

The focus of many epidemiologic studies has been in the HNC general population. A recent epidemiologic analysis of the HNC general population found a p16 positivity rate of 60% in oropharyngeal squamous cell carcinomas (OPSCC) and 10% in nonoropharyngeal squamous cell carcinomas (NOPSCC).4 There has been a lack of studies focusing on the US Department of Veterans Administration (VA) population. The VA HNC population consists mostly of older white male smokers; whereas the rise of OPSCC in the general population consists primarily of males aged < 60 years often with little or no tobacco use.5 Furthermore, the importance of p16 positivity in NOPSCC also may be prognostic.6 Population data on this subset in the VA are lacking as well.This study’s purpose is to analyze the p16 positivity rate in both the OPSCC and NOPSCC in the VA population. Elucidation of epidemiologic factors that are associated with these groups may bring to light important differences between the VA and general HNC populations.

Methods

A review of the Kansas City VA Medical Center database for patients with HNC was performed from 2011 to 2017. The review consisted of 183 patient records (second primaries were scored separately), and 123 were deemed eligible for the study. Epidemiologic data were collected, including site, OPSCC vs NOPSCC, age, race, education level, tobacco use, alcohol use, TNM stage, and marital status (Table). 

Gender was not included because there was only 1 female patient in the cohort. Four subgroups based on site and p16 status (OPSCC p16+, OPSCC p16-, NOPSCC p16+, and NOPSCC p16-) were further analyzed. Appropriate statistical analysis (chi-square test, analysis of variance, and Kruskal-Wallis test) with IBM SPSS 24.0 (Armonk, NY) was used to find differences (P < .05) among the means of the 4 subgroups.

Results

There were 55 (44%) patients with OPSCC and 68 patients with NOPSCC (56%). Of the 68 patients with NOPSCC, 48 (70%) were primary tumors from the larynx, 12 (18%) from the oral cavity, 4 (6%) from the hypopharynx, 2 from the nasopharynx (3%), and 2 (3%) were unknown primaries. In the OPSCC group, 41 patients were p16+ (75%) and 14 p16- (25%). In the NOPSCC group, 20 patients were p16+ (29%) and 48 were p16- (71%). There was a statistically significant difference seen in tobacco use, TNM stage, and marital status. Alcohol use trended toward significance.

The NOPSCC p16+ group had the greatest mean pack-year use (57). The lowest was in the OPSCC p16+ group (29). The OPSCC p16+ group had 37% never smokers compared with ≤ 10% for the other groups. Both the OPSCC and NOPSCC p16- groups had much more alcohol use per week than that of the p16+ groups. The differences in marital status included a lower rate of never married individuals in the p16+ group and a higher rate of marriage in the NOPSCC p16- group. The T stage distribution within the OPSCC groups was similar, but NOPSCC groups saw more T1 lesions in the NOPSCC p16- group (42% p16- vs 18% p16+). Conversely, more T4 lesions were found in the NOPSCC p16+ patients (7% p16- vs 29% p16+). More advanced nodal staging was seen in both OPSCC groups with 78% N2 or N3 in the p16+ group and 82% in the p16- group. The NOPSCC p16+ group had 55% N0 or N1 patients, and the p16- group had 60%. In terms of overall stage, the OPSCC groups had a similar distribution with predominantly stage IVA/B presentation (74% p16+ and 82% p16-), whereas the NOPSCC groups had only 58% (p16+) and 35% (p16-) at presentation.

Discussion

The overall HPV positivity rate in the general population of patients with HNC has been reported as between 57% and 72% for OPSCC and between 1.3% and 7% for NOPSCC.6 One study, however, examined the p16 positivity rate in NOPSCC patients enrolled in major trials (RTOG 0129, 0234, and 0522 studies) and found that up to 19.3% of NOPSCC patients had p16 positivity.6 Even with the near 20% rate in those aforementioned trials that are above the reported norm, the current study found that nearly 30% of its VA population had p16+ NOPSCC. It has been shown that regardless of site, HPV-driven head and neck tumors share a similar gene expression and DNA methylation profiles (nonkeratinizing, basaloid histopathologic features, and lack of TP53 or CDKN2A alterations).5 p16+ NOPSCC has a different immune microenvironment with less lymphocyte infiltration, and there is some debate in the literature about the effects on tumor outcomes for NOPSCC cancer.5

In the aforementioned RTOG trials, p16- NOPSCC had worse outcomes compared with those of p16+ NOPSCC.6 This result is in contrast to the Danish Head and Neck Cancer Group (DAHANCA) and the combined Johns Hopkins University (JHU) and University of California, San Francisco (UCSF) data that found no difference between p16+ NOPSCC or p16- NOPSCC.7,8 In regards to race, this study did not find any differences. Another UCSF and JHU study showed lower p16+ rates in African American patients with OPSCC, but no distinction between race in the NOPSCC group. This result is consistent with the data in the current study as the distribution of race was no different among the 4 groups; however, this study's cohort was 90% white, 10% African American, and only < 1% Native American.4 This study's cohort population also was consistent with HPV-positive tumors presenting with earlier T, but higher N staging.9

Smoking is known to decrease survival in HPV-positive HNC, with the RTOG 0129 study separating head and neck tumors into low, medium, and high risk, based on HPV status, smoking, and stage.10 Although the average smoking pack-years in the current study’s OPC p16+ group was high at 29 pack-years, there was still a significant number of nonsmokers in that same group (37%). The University of Michigan conducted a study that had a similar profile of patients with an average age of 56.5 and 32.4% never smokers in their p16+ OPSCC cohort; thus, the VA p16+ OPSCC group in this study may be similar to the general population's p16+ OPSCC group.11 Nonmonogamous relationships also have been shown to be a risk factor for HPV positivity, and there was a difference in marital status (assuming it was a surrogate for monogamy) between the 4 groups; however, in contrast, the p16+ group in the current study had a high number of married patients, 45% in OPC p16+ group, and may not have been a good surrogate for monogamy in this VA population.

Limitations

Limitations of this study include all the caveats that come with a retrospective study, such as confounding variables, unbalanced groups, and selection bias. A detailed sexual history was not included, although it is well known that sexual activity is linked with oral HPV positivity.12 Human papillomavirus positivity based on p16 immunohistochemical analysis also was used as a surrogate marker for HPV instead of DNA in situ hybridization. The data also may be skewed due to the study patient’s being predominantly white and male: Both groups have a higher predilection for HPV-driven HNCs.13

Conclusion

The proportion of p16+ VA OPSCC cases was similar to that of the general population at 75% with 37% never smokers, but the percentage in NOPSCC was higher at 29% with only 10% never smokers. The p16+ NOPSCC also presented with more T4 lesions and a higher overall stage compared with p16- NOPSCC. Further studies are needed to compare these subgroups in the VA and in the general HNC populations.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.

2. Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122-137.

3. Mirghani H, Blanchard P. Treatment de-escalation for HPV-driven oropharyngeal cancer: where do we stand? Clin Transl Radiat Oncol. 2017;8:4-11.

4. D’Souza G, Westra WH, Wang SJ, et al. Differences in the prevalence of human papillomavirus (HPV) in head and neck squamous cell cancers by sex, race, anatomic tumor site, and HPV detection method. JAMA Oncol. 2017;3(2):169-177.

5. Chakravarthy A, Henderson S, Thirdborough SM, et al. Human papillomavirus drives tumor development throughout the head and neck: improved prognosis is associated with an immune response largely restricted to the oropharynx. J Clin Oncol. 2016;34(34):4132-4141.

6. Chung CH, Zhang Q, Kong CS, et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol. 2014;32(35):3930-3938.

7. Lassen P, Primdahl H, Johansen J, et al; Danish Head and Neck Cancer Group (DAHANCA). Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. Radiother Oncol. 2014;113(3):310-316.

8. Fakhry C, Westra WH, Wang SJ, et al. The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer. Cancer. 2017;123(9):1566-1575.

9. Elrefaey S, Massaro MA, Chiocca S, Chiesa F, Ansarin M. HPV in oropharyngeal cancer: the basics to know in clinical practice. Acta Otorhinolaryngol Ital. 2014;34(5):299-309.

10. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35.

11. Maxwell, JH, Kumar B, Feng FY, et al. Tobacco use in HPV-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res. 2010;16(4):1226-1235.

12. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307(7):693-703.

13. Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol. 2014;50(6):565-574.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.

2. Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122-137.

3. Mirghani H, Blanchard P. Treatment de-escalation for HPV-driven oropharyngeal cancer: where do we stand? Clin Transl Radiat Oncol. 2017;8:4-11.

4. D’Souza G, Westra WH, Wang SJ, et al. Differences in the prevalence of human papillomavirus (HPV) in head and neck squamous cell cancers by sex, race, anatomic tumor site, and HPV detection method. JAMA Oncol. 2017;3(2):169-177.

5. Chakravarthy A, Henderson S, Thirdborough SM, et al. Human papillomavirus drives tumor development throughout the head and neck: improved prognosis is associated with an immune response largely restricted to the oropharynx. J Clin Oncol. 2016;34(34):4132-4141.

6. Chung CH, Zhang Q, Kong CS, et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol. 2014;32(35):3930-3938.

7. Lassen P, Primdahl H, Johansen J, et al; Danish Head and Neck Cancer Group (DAHANCA). Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. Radiother Oncol. 2014;113(3):310-316.

8. Fakhry C, Westra WH, Wang SJ, et al. The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer. Cancer. 2017;123(9):1566-1575.

9. Elrefaey S, Massaro MA, Chiocca S, Chiesa F, Ansarin M. HPV in oropharyngeal cancer: the basics to know in clinical practice. Acta Otorhinolaryngol Ital. 2014;34(5):299-309.

10. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35.

11. Maxwell, JH, Kumar B, Feng FY, et al. Tobacco use in HPV-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res. 2010;16(4):1226-1235.

12. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307(7):693-703.

13. Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol. 2014;50(6):565-574.

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