Neil Osterweil

For patients with myelodysplastic syndrome, gene sequencing of bone marrow samples early after bone marrow transplant with curative intent may provide important prognostic information.

Among 86 patients with myelodysplastic syndrome (MDS), higher maximum variant allele frequency of residual disease–associated mutations at 30 days posttransplantation was significantly associated with disease progression and lower rates of progression-free survival (PFS) at 1 year, reported Eric J. Duncavage, MD, from Washington University in St. Louis, and his colleagues.

“Although this exploratory study has limitations, our results suggest that sequencing-based detection of tumor cells and measurable residual disease after allogeneic hematopoietic stem cell transplantation has prognostic significance for patients with MDS,” they wrote in the New England Journal of Medicine.

Risk of progression was significantly higher among patients who had undergone reduced-intensity conditioning prior to hematopoietic stem cell transplants (HSCT) than among patients who had undergone myeloablative conditioning regimens.

To get a better handle on the significance of molecular predictors of disease progression after HSCT, the authors used enhanced exome sequencing to evaluate paired samples of bone marrow and control DNA from normal skin, and error-corrected sequencing to identify somatic single-nucleotide variant mutations in posttransplant samples.

They detected at least one validated somatic mutation in the pretransplant samples from 86 of 90 patients. Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after transplantation. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the authors explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not have progression (P less than .001).

In all, 53.1% of patients with one or more mutations with a variant allele frequency of at least 0.5% at 30 days had disease progression within a year, compared with 13% of patients who did not have the mutations, even after adjustment for the type of conditioning regimen. The hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P less than .001).

The association between the presence of one or more mutations with a variant allele frequency of at least 0.5% with increased risk of disease progression was also seen at 100 days, even after adjustment for conditioning regimen (66.7% vs. 0%; HR, 6.52; P less than .001). In multivariable analysis controlling for prognostic scores, maximum variant allele frequency at 30 days, TP53 mutation status and conditioning regimen, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than fourfold risk of progression, including when the revised International Prognostic Scoring System score and conditioning regimen were considered as covariates. (HR, 4.48; P less than .001),

A separate multivariable analysis of PFS controlling for maximum variant allele frequency at day 30, conditioning regimen, age at transplantation, and type of MDS showed that mutations were associated with a more than twofold risk of progression or death (HR, 2.39; P = .002).

This analysis also showed that secondary acute myeloid leukemia was associated with worse PFS, compared with primary MDS (HR, 2.24; P = .001).

The investigators acknowledged that the high-coverage exome sequencing technique used for the study is not routinely available in the clinic. To control for this, they also looked at their data using a subset of genes that are usually included in gene sequencing panels for MDS and AML.

“Although we identified fewer patients with mutations with the use of this approach than with enhanced exome sequencing, the prognostic value of detection of measurable residual disease was still highly clinically significant,” they wrote.

The study was supported by grants from the Leukemia and Lymphoma Society, Edward P. Evans Foundation, National Cancer Institute, National Institutes of Health, Gabrielle’s Angel Foundation, and the Lottie Caroline Hardy Trust. Dr. Duncavage disclosed personal fees from AbbVie and Cofactor Genomics. The majority of coauthors reported nothing to disclose.

SOURCE: Duncavage EJ et al. N Engl J Med 2018;379:1028-41.

For patients with myelodysplastic syndrome, gene sequencing of bone marrow samples early after bone marrow transplant with curative intent may provide important prognostic information.

Among 86 patients with myelodysplastic syndrome (MDS), higher maximum variant allele frequency of residual disease–associated mutations at 30 days posttransplantation was significantly associated with disease progression and lower rates of progression-free survival (PFS) at 1 year, reported Eric J. Duncavage, MD, from Washington University in St. Louis, and his colleagues.

“Although this exploratory study has limitations, our results suggest that sequencing-based detection of tumor cells and measurable residual disease after allogeneic hematopoietic stem cell transplantation has prognostic significance for patients with MDS,” they wrote in the New England Journal of Medicine.

Risk of progression was significantly higher among patients who had undergone reduced-intensity conditioning prior to hematopoietic stem cell transplants (HSCT) than among patients who had undergone myeloablative conditioning regimens.

To get a better handle on the significance of molecular predictors of disease progression after HSCT, the authors used enhanced exome sequencing to evaluate paired samples of bone marrow and control DNA from normal skin, and error-corrected sequencing to identify somatic single-nucleotide variant mutations in posttransplant samples.

They detected at least one validated somatic mutation in the pretransplant samples from 86 of 90 patients. Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after transplantation. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the authors explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not have progression (P less than .001).

In all, 53.1% of patients with one or more mutations with a variant allele frequency of at least 0.5% at 30 days had disease progression within a year, compared with 13% of patients who did not have the mutations, even after adjustment for the type of conditioning regimen. The hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P less than .001).

The association between the presence of one or more mutations with a variant allele frequency of at least 0.5% with increased risk of disease progression was also seen at 100 days, even after adjustment for conditioning regimen (66.7% vs. 0%; HR, 6.52; P less than .001). In multivariable analysis controlling for prognostic scores, maximum variant allele frequency at 30 days, TP53 mutation status and conditioning regimen, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than fourfold risk of progression, including when the revised International Prognostic Scoring System score and conditioning regimen were considered as covariates. (HR, 4.48; P less than .001),

A separate multivariable analysis of PFS controlling for maximum variant allele frequency at day 30, conditioning regimen, age at transplantation, and type of MDS showed that mutations were associated with a more than twofold risk of progression or death (HR, 2.39; P = .002).

This analysis also showed that secondary acute myeloid leukemia was associated with worse PFS, compared with primary MDS (HR, 2.24; P = .001).

The investigators acknowledged that the high-coverage exome sequencing technique used for the study is not routinely available in the clinic. To control for this, they also looked at their data using a subset of genes that are usually included in gene sequencing panels for MDS and AML.

“Although we identified fewer patients with mutations with the use of this approach than with enhanced exome sequencing, the prognostic value of detection of measurable residual disease was still highly clinically significant,” they wrote.

The study was supported by grants from the Leukemia and Lymphoma Society, Edward P. Evans Foundation, National Cancer Institute, National Institutes of Health, Gabrielle’s Angel Foundation, and the Lottie Caroline Hardy Trust. Dr. Duncavage disclosed personal fees from AbbVie and Cofactor Genomics. The majority of coauthors reported nothing to disclose.

SOURCE: Duncavage EJ et al. N Engl J Med 2018;379:1028-41.

For patients with myelodysplastic syndrome, gene sequencing of bone marrow samples early after bone marrow transplant with curative intent may provide important prognostic information.

Among 86 patients with myelodysplastic syndrome (MDS), higher maximum variant allele frequency of residual disease–associated mutations at 30 days posttransplantation was significantly associated with disease progression and lower rates of progression-free survival (PFS) at 1 year, reported Eric J. Duncavage, MD, from Washington University in St. Louis, and his colleagues.

“Although this exploratory study has limitations, our results suggest that sequencing-based detection of tumor cells and measurable residual disease after allogeneic hematopoietic stem cell transplantation has prognostic significance for patients with MDS,” they wrote in the New England Journal of Medicine.

Risk of progression was significantly higher among patients who had undergone reduced-intensity conditioning prior to hematopoietic stem cell transplants (HSCT) than among patients who had undergone myeloablative conditioning regimens.

To get a better handle on the significance of molecular predictors of disease progression after HSCT, the authors used enhanced exome sequencing to evaluate paired samples of bone marrow and control DNA from normal skin, and error-corrected sequencing to identify somatic single-nucleotide variant mutations in posttransplant samples.

They detected at least one validated somatic mutation in the pretransplant samples from 86 of 90 patients. Of the 86 patients, 32 had at least one mutation with a maximum variant allele frequency of at least 0.5% detected 30 days after transplantation. The frequency is equivalent to 1 heterozygous mutant cell per 100 cells, the authors explained.

Patients who experienced disease progression had mutations with a median maximum variant allele frequency of 0.9%, compared with 0% for patients who did not have progression (P less than .001).

In all, 53.1% of patients with one or more mutations with a variant allele frequency of at least 0.5% at 30 days had disease progression within a year, compared with 13% of patients who did not have the mutations, even after adjustment for the type of conditioning regimen. The hazard ratio (HR) for disease progression in the patients with mutations was 3.86 (P less than .001).

The association between the presence of one or more mutations with a variant allele frequency of at least 0.5% with increased risk of disease progression was also seen at 100 days, even after adjustment for conditioning regimen (66.7% vs. 0%; HR, 6.52; P less than .001). In multivariable analysis controlling for prognostic scores, maximum variant allele frequency at 30 days, TP53 mutation status and conditioning regimen, the presence of a mutation with at least 0.5% variant allele frequency was associated with a more than fourfold risk of progression, including when the revised International Prognostic Scoring System score and conditioning regimen were considered as covariates. (HR, 4.48; P less than .001),

A separate multivariable analysis of PFS controlling for maximum variant allele frequency at day 30, conditioning regimen, age at transplantation, and type of MDS showed that mutations were associated with a more than twofold risk of progression or death (HR, 2.39; P = .002).

This analysis also showed that secondary acute myeloid leukemia was associated with worse PFS, compared with primary MDS (HR, 2.24; P = .001).

The investigators acknowledged that the high-coverage exome sequencing technique used for the study is not routinely available in the clinic. To control for this, they also looked at their data using a subset of genes that are usually included in gene sequencing panels for MDS and AML.

“Although we identified fewer patients with mutations with the use of this approach than with enhanced exome sequencing, the prognostic value of detection of measurable residual disease was still highly clinically significant,” they wrote.

The study was supported by grants from the Leukemia and Lymphoma Society, Edward P. Evans Foundation, National Cancer Institute, National Institutes of Health, Gabrielle’s Angel Foundation, and the Lottie Caroline Hardy Trust. Dr. Duncavage disclosed personal fees from AbbVie and Cofactor Genomics. The majority of coauthors reported nothing to disclose.

SOURCE: Duncavage EJ et al. N Engl J Med 2018;379:1028-41.

Outcomes for women with operable HER2-positive breast cancer were similar whether they received standard combination chemotherapy with either concurrent or sequential paclitaxel/trastuzumab, long-term results of the phase 3, randomized American College of Surgeons Oncology Group Z1041 trial showed.

Among 280 women with HER-2 positive breast cancer followed for a median of 5.1 years, there were no significant differences in either pathological complete response rates (pCR), disease-free survival (DFS), or overall survival with either concurrent or sequential therapy, wrote Aman U. Buzdar, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

“A previous publication of this study’s primary analysis reported that breast pCR in patients treated with paclitaxel and trastuzumab followed by FEC [fluorouracil, epirubicin, cyclophosphamide] and trastuzumab did not differ significantly from that of patients receiving FEC followed by paclitaxel and trastuzumab. We now report the findings concerning the secondary outcomes, that is, with a median follow-up of approximately 5 years, DFS is similar among the two treatment arms,” they wrote in JAMA Oncology.

The purpose of the current analysis was to evaluate long-term outcomes associated with the two treatment approaches.

In the trial, conducted at 36 centers in the continental United States and Puerto Rico, 280 women (median age, 50 years; range, 28-76 years) were treated with 500 mg/m² of fluorouracil, 75 mg/m² epirubicin, and 500 mg/m² cyclophosphamide every 3 weeks for 12 weeks with concurrent weekly paclitaxel at 80 mg/m² and trastuzumab at 2 mg/kg – after an initial dose of 4 mg/kg – or the same paclitaxel/trastuzumab combination delivered weekly for 12 weeks, followed by FEC every 3 weeks with weekly trastuzumab for 12 weeks.

Women who also had hormone receptor–positive disease received endocrine therapy. Radiotherapy was delivered at the discretion of the attending physician.

As noted, there were no differences in either DFS rates (adjusted hazard ratio, 1.02; P = .96) or overall survival rates (adjusted HR, 1.17; P = .73) between the trial arms.

The authors concluded that “concurrent administration of trastuzumab with FEC was not found to offer additional clinical benefit and is not warranted.”

The study was supported by grants to participating institutions from the National Cancer Institute. Dr. Buzdar reported no conflicts of interest. Three coauthors reported research support, consulting fees, travel support, and/or other relationships with multiple companies.

SOURCE: Buzdar AU et al. JAMA Oncol. 2018 Sept 6. doi: 10.1001/jamaoncol.2018.3691.

Outcomes for women with operable HER2-positive breast cancer were similar whether they received standard combination chemotherapy with either concurrent or sequential paclitaxel/trastuzumab, long-term results of the phase 3, randomized American College of Surgeons Oncology Group Z1041 trial showed.

Among 280 women with HER-2 positive breast cancer followed for a median of 5.1 years, there were no significant differences in either pathological complete response rates (pCR), disease-free survival (DFS), or overall survival with either concurrent or sequential therapy, wrote Aman U. Buzdar, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

“A previous publication of this study’s primary analysis reported that breast pCR in patients treated with paclitaxel and trastuzumab followed by FEC [fluorouracil, epirubicin, cyclophosphamide] and trastuzumab did not differ significantly from that of patients receiving FEC followed by paclitaxel and trastuzumab. We now report the findings concerning the secondary outcomes, that is, with a median follow-up of approximately 5 years, DFS is similar among the two treatment arms,” they wrote in JAMA Oncology.

The purpose of the current analysis was to evaluate long-term outcomes associated with the two treatment approaches.

In the trial, conducted at 36 centers in the continental United States and Puerto Rico, 280 women (median age, 50 years; range, 28-76 years) were treated with 500 mg/m² of fluorouracil, 75 mg/m² epirubicin, and 500 mg/m² cyclophosphamide every 3 weeks for 12 weeks with concurrent weekly paclitaxel at 80 mg/m² and trastuzumab at 2 mg/kg – after an initial dose of 4 mg/kg – or the same paclitaxel/trastuzumab combination delivered weekly for 12 weeks, followed by FEC every 3 weeks with weekly trastuzumab for 12 weeks.

Women who also had hormone receptor–positive disease received endocrine therapy. Radiotherapy was delivered at the discretion of the attending physician.

As noted, there were no differences in either DFS rates (adjusted hazard ratio, 1.02; P = .96) or overall survival rates (adjusted HR, 1.17; P = .73) between the trial arms.

The authors concluded that “concurrent administration of trastuzumab with FEC was not found to offer additional clinical benefit and is not warranted.”

The study was supported by grants to participating institutions from the National Cancer Institute. Dr. Buzdar reported no conflicts of interest. Three coauthors reported research support, consulting fees, travel support, and/or other relationships with multiple companies.

SOURCE: Buzdar AU et al. JAMA Oncol. 2018 Sept 6. doi: 10.1001/jamaoncol.2018.3691.

Outcomes for women with operable HER2-positive breast cancer were similar whether they received standard combination chemotherapy with either concurrent or sequential paclitaxel/trastuzumab, long-term results of the phase 3, randomized American College of Surgeons Oncology Group Z1041 trial showed.

Among 280 women with HER-2 positive breast cancer followed for a median of 5.1 years, there were no significant differences in either pathological complete response rates (pCR), disease-free survival (DFS), or overall survival with either concurrent or sequential therapy, wrote Aman U. Buzdar, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

“A previous publication of this study’s primary analysis reported that breast pCR in patients treated with paclitaxel and trastuzumab followed by FEC [fluorouracil, epirubicin, cyclophosphamide] and trastuzumab did not differ significantly from that of patients receiving FEC followed by paclitaxel and trastuzumab. We now report the findings concerning the secondary outcomes, that is, with a median follow-up of approximately 5 years, DFS is similar among the two treatment arms,” they wrote in JAMA Oncology.

The purpose of the current analysis was to evaluate long-term outcomes associated with the two treatment approaches.

In the trial, conducted at 36 centers in the continental United States and Puerto Rico, 280 women (median age, 50 years; range, 28-76 years) were treated with 500 mg/m² of fluorouracil, 75 mg/m² epirubicin, and 500 mg/m² cyclophosphamide every 3 weeks for 12 weeks with concurrent weekly paclitaxel at 80 mg/m² and trastuzumab at 2 mg/kg – after an initial dose of 4 mg/kg – or the same paclitaxel/trastuzumab combination delivered weekly for 12 weeks, followed by FEC every 3 weeks with weekly trastuzumab for 12 weeks.

Women who also had hormone receptor–positive disease received endocrine therapy. Radiotherapy was delivered at the discretion of the attending physician.

As noted, there were no differences in either DFS rates (adjusted hazard ratio, 1.02; P = .96) or overall survival rates (adjusted HR, 1.17; P = .73) between the trial arms.

The authors concluded that “concurrent administration of trastuzumab with FEC was not found to offer additional clinical benefit and is not warranted.”

The study was supported by grants to participating institutions from the National Cancer Institute. Dr. Buzdar reported no conflicts of interest. Three coauthors reported research support, consulting fees, travel support, and/or other relationships with multiple companies.

SOURCE: Buzdar AU et al. JAMA Oncol. 2018 Sept 6. doi: 10.1001/jamaoncol.2018.3691.

Green is just as good – make that better – than blue at identifying sentinel lymph nodes in women with cervical and uterine cancers, results of the multicenter FILM (Fluorescence Imaging for Lymphatic Mapping) study indicate.

Among 176 patients randomly assigned to first have lymphatic mapping with indocyanine green fluorescent dye visualized with near infrared imaging followed by isosulfan blue dye visualized with white light, or the two modalities in the reverse order, indocyanine green identified 50% more lymph nodes in both modified intention-to-treat and per-protocol analyses, reported Michael Frumovitz, MD, from the University of Texas MD Anderson Cancer Center in Houston and colleagues.

“Indocyanine green dye with near-infrared imaging identified significantly more sentinel nodes and more bilateral sentinel nodes than did isosulfan blue dye. It also identified all sentinel nodes with metastatic disease, whereas isosulfan blue dye missed a large proportion of them,” they wrote in the Lancet Oncology.

The FILM study was designed to determine whether fluorescent indocyanine green dye would be noninferior to isosulfan blue dye for accurately identifying sentinel lymph nodes in patients with cancer.

Although several single-center retrospective studies have reported on the use of interstitial injection of indocyanine green for lymphatic mapping in various solid tumors, including uterine and cervical cancers, there were no published studies comparing indocyanine green mapping to isosulfan blue mapping, the standard of care, the authors noted.

They enrolled 180 women aged 18 or older with clinical stage I endometrial or cervical cancers who were undergoing curative surgery and randomly assigned them as described above to have lymphatic mapping with each of the imaging modalities assigned in random order.

The patients but not the operators were masked as to the order of randomization.

Of the 180 patients enrolled, 176 received the intervention, and 13 of these patients were excluded because of major protocol violations, leaving 163 for a per-protocol analysis.

In the per-protocol analysis, 517 sentinel nodes were identified in the 163 patients, and of these, 478 (92%) were confirmed to be lymph nodes on pathological examination. This sample included 219 of 238 nodes identified with both blue and green dyes, all seven nodes revealed by blue dye alone, and 252 of 265 nodes identified by only green dye. Seven sentinel lymph nodes that were not identified by either dye were removed because they were enlarged or appeared suspicious on visual inspection.

In total, green dye identified 97% of lymph nodes in the per-protocol population, and blue dye identified 47%, an absolute difference of 50% (P less than .0001).

In the modified intention-to-treat population, which included all 176 patients randomized and treated, 545 nodes were identified, and 513 (94%) were confirmed to be lymph nodes on pathology. In this sample, 229 (92%) of 248 nodes showed both blue and green, nine nodes were blue only, and 266 (95%) of 279 were green only. Nine sentinel lymph nodes that were not revealed by either blue or green were removed for appearing suspicious or enlarged visually.

In total, in the modified-ITT analysis, 495 of 513 (96%) nodes were identified with the green dye and 238 (46%) were identified with the blue dye, again for an absolute difference of 50% (P less than .0001).

Based on the results of the study, the green dye’s maker, Novadaq Technologies, is submitting an application to the Food and Drug Administration for on-label use of interstitial injection of indocyanine green combined with near-infrared imaging for lymphatic mapping.

The study was funded by Novadaq. Dr. Frumovitz reported grants from Novadaq/Stryker during the conduct of the study, as well as personal fees; grants from Navidea; personal fees from Johnson & Johnson; and personal fees from Genentech outside the submitted work. The other authors declared no competing interests.

SOURCE: Frumovitz M et al. Lancet Oncol. 2018 Aug 21. doi: 10.1016/S1470-2045(18)30448-0.

Green is just as good – make that better – than blue at identifying sentinel lymph nodes in women with cervical and uterine cancers, results of the multicenter FILM (Fluorescence Imaging for Lymphatic Mapping) study indicate.

Among 176 patients randomly assigned to first have lymphatic mapping with indocyanine green fluorescent dye visualized with near infrared imaging followed by isosulfan blue dye visualized with white light, or the two modalities in the reverse order, indocyanine green identified 50% more lymph nodes in both modified intention-to-treat and per-protocol analyses, reported Michael Frumovitz, MD, from the University of Texas MD Anderson Cancer Center in Houston and colleagues.

“Indocyanine green dye with near-infrared imaging identified significantly more sentinel nodes and more bilateral sentinel nodes than did isosulfan blue dye. It also identified all sentinel nodes with metastatic disease, whereas isosulfan blue dye missed a large proportion of them,” they wrote in the Lancet Oncology.

The FILM study was designed to determine whether fluorescent indocyanine green dye would be noninferior to isosulfan blue dye for accurately identifying sentinel lymph nodes in patients with cancer.

Although several single-center retrospective studies have reported on the use of interstitial injection of indocyanine green for lymphatic mapping in various solid tumors, including uterine and cervical cancers, there were no published studies comparing indocyanine green mapping to isosulfan blue mapping, the standard of care, the authors noted.

They enrolled 180 women aged 18 or older with clinical stage I endometrial or cervical cancers who were undergoing curative surgery and randomly assigned them as described above to have lymphatic mapping with each of the imaging modalities assigned in random order.

The patients but not the operators were masked as to the order of randomization.

Of the 180 patients enrolled, 176 received the intervention, and 13 of these patients were excluded because of major protocol violations, leaving 163 for a per-protocol analysis.

In the per-protocol analysis, 517 sentinel nodes were identified in the 163 patients, and of these, 478 (92%) were confirmed to be lymph nodes on pathological examination. This sample included 219 of 238 nodes identified with both blue and green dyes, all seven nodes revealed by blue dye alone, and 252 of 265 nodes identified by only green dye. Seven sentinel lymph nodes that were not identified by either dye were removed because they were enlarged or appeared suspicious on visual inspection.

In total, green dye identified 97% of lymph nodes in the per-protocol population, and blue dye identified 47%, an absolute difference of 50% (P less than .0001).

In the modified intention-to-treat population, which included all 176 patients randomized and treated, 545 nodes were identified, and 513 (94%) were confirmed to be lymph nodes on pathology. In this sample, 229 (92%) of 248 nodes showed both blue and green, nine nodes were blue only, and 266 (95%) of 279 were green only. Nine sentinel lymph nodes that were not revealed by either blue or green were removed for appearing suspicious or enlarged visually.

In total, in the modified-ITT analysis, 495 of 513 (96%) nodes were identified with the green dye and 238 (46%) were identified with the blue dye, again for an absolute difference of 50% (P less than .0001).

Based on the results of the study, the green dye’s maker, Novadaq Technologies, is submitting an application to the Food and Drug Administration for on-label use of interstitial injection of indocyanine green combined with near-infrared imaging for lymphatic mapping.

The study was funded by Novadaq. Dr. Frumovitz reported grants from Novadaq/Stryker during the conduct of the study, as well as personal fees; grants from Navidea; personal fees from Johnson & Johnson; and personal fees from Genentech outside the submitted work. The other authors declared no competing interests.

SOURCE: Frumovitz M et al. Lancet Oncol. 2018 Aug 21. doi: 10.1016/S1470-2045(18)30448-0.

Green is just as good – make that better – than blue at identifying sentinel lymph nodes in women with cervical and uterine cancers, results of the multicenter FILM (Fluorescence Imaging for Lymphatic Mapping) study indicate.

Among 176 patients randomly assigned to first have lymphatic mapping with indocyanine green fluorescent dye visualized with near infrared imaging followed by isosulfan blue dye visualized with white light, or the two modalities in the reverse order, indocyanine green identified 50% more lymph nodes in both modified intention-to-treat and per-protocol analyses, reported Michael Frumovitz, MD, from the University of Texas MD Anderson Cancer Center in Houston and colleagues.

“Indocyanine green dye with near-infrared imaging identified significantly more sentinel nodes and more bilateral sentinel nodes than did isosulfan blue dye. It also identified all sentinel nodes with metastatic disease, whereas isosulfan blue dye missed a large proportion of them,” they wrote in the Lancet Oncology.

The FILM study was designed to determine whether fluorescent indocyanine green dye would be noninferior to isosulfan blue dye for accurately identifying sentinel lymph nodes in patients with cancer.

Although several single-center retrospective studies have reported on the use of interstitial injection of indocyanine green for lymphatic mapping in various solid tumors, including uterine and cervical cancers, there were no published studies comparing indocyanine green mapping to isosulfan blue mapping, the standard of care, the authors noted.

They enrolled 180 women aged 18 or older with clinical stage I endometrial or cervical cancers who were undergoing curative surgery and randomly assigned them as described above to have lymphatic mapping with each of the imaging modalities assigned in random order.

The patients but not the operators were masked as to the order of randomization.

Of the 180 patients enrolled, 176 received the intervention, and 13 of these patients were excluded because of major protocol violations, leaving 163 for a per-protocol analysis.

In the per-protocol analysis, 517 sentinel nodes were identified in the 163 patients, and of these, 478 (92%) were confirmed to be lymph nodes on pathological examination. This sample included 219 of 238 nodes identified with both blue and green dyes, all seven nodes revealed by blue dye alone, and 252 of 265 nodes identified by only green dye. Seven sentinel lymph nodes that were not identified by either dye were removed because they were enlarged or appeared suspicious on visual inspection.

In total, green dye identified 97% of lymph nodes in the per-protocol population, and blue dye identified 47%, an absolute difference of 50% (P less than .0001).

In the modified intention-to-treat population, which included all 176 patients randomized and treated, 545 nodes were identified, and 513 (94%) were confirmed to be lymph nodes on pathology. In this sample, 229 (92%) of 248 nodes showed both blue and green, nine nodes were blue only, and 266 (95%) of 279 were green only. Nine sentinel lymph nodes that were not revealed by either blue or green were removed for appearing suspicious or enlarged visually.

In total, in the modified-ITT analysis, 495 of 513 (96%) nodes were identified with the green dye and 238 (46%) were identified with the blue dye, again for an absolute difference of 50% (P less than .0001).

Based on the results of the study, the green dye’s maker, Novadaq Technologies, is submitting an application to the Food and Drug Administration for on-label use of interstitial injection of indocyanine green combined with near-infrared imaging for lymphatic mapping.

The study was funded by Novadaq. Dr. Frumovitz reported grants from Novadaq/Stryker during the conduct of the study, as well as personal fees; grants from Navidea; personal fees from Johnson & Johnson; and personal fees from Genentech outside the submitted work. The other authors declared no competing interests.

SOURCE: Frumovitz M et al. Lancet Oncol. 2018 Aug 21. doi: 10.1016/S1470-2045(18)30448-0.

The European Society for Medical Oncology (ESMO) has published a proposed scale that would rank molecular targets for various cancers by how well they can be treated with new or emerging drugs.

The ESMO Scale of Clinical Actionability for Molecular Targets is designed to “harmonize and standardize the reporting and interpretation of clinically relevant genomics data,” according to Joaquin Mateo, MD, PhD, from the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and his fellow members of the ESMO Translational Research and Precision Medicine Working Group.

“A major challenge for oncologists in the clinic is to distinguish between findings that represent proven clinical value or potential value based on preliminary clinical or preclinical evidence from hypothetical gene-drug matches and findings that are currently irrelevant for clinical practice,” they wrote in Annals of Oncology.

The scale groups targets into one of six tiers based on levels of evidence ranging from the gold standard of prospective, randomized clinical trials to targets for which there are no evidence and only hypothetical actionability. The primary goal is to help oncologists assign priority to potential targets when they review results of gene-sequencing panels for individual patients, according to the developers.

Briefly, the six tiers are:

Tier I includes targets that are agreed to be suitable for routine use and a recommended specific drug when a specific molecular alteration is detected. Examples include trastuzumab for human epidermal growth factor receptor 2 (HER2)–positive breast cancer, and inhibitors of epidermal growth factor receptor (EGFR) in patients with non–small cell lung cancer positive for EGFR mutations.

Tier II includes “investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed.” This tier includes agents that work in the phosphatidylinostiol 3-kinase pathway.

Tier III is similar to Tier II, in that it includes investigational targets that define a patient population with proven benefit from a targeted therapy, but in this case the target is detected in a different tumor type that has not previously been studied. For example, the targeted agent vemurafenib (Zelboraf), which extends survival of patients with metastatic melanomas carrying the BRAF V600E mutation, has only limited activity against BRAF-mutated colorectal cancers.

Tier IV includes targets with preclinical evidence of actionability.

Tier V includes targets with “evidence of relevant antitumor activity, not resulting in clinical meaningful benefit as single treatment but supporting development of cotargeting approaches.” The authors cite the example of PIK3CA inhibitors in patients with estrogen receptor–positive, HER2-negative breast cancers who also have PIK3CA activating mutations. In clinical trials, this strategy led to objective responses but not change outcomes.

The final tier is not Tier VI, as might be expected, but Tier X, with the X in this case being the unknown – that is, alterations/mutations for which there is neither preclinical nor clinical evidence to support their hypothetical use as a drug target.

“This clinical benefit–centered classification system offers a common language for all the actors involved in clinical cancer drug development. Its implementation in sequencing reports, tumor boards, and scientific communication can enable precise treatment decisions and facilitate discussions with patients about novel therapeutic options,” Dr. Mateo and his associates wrote in their conclusion.

The development process was supported by ESMO. Multiple coauthors reported financial relationships with various companies as well as grants/support from other foundations or charities.

SOURCE: Mateo J et al. Ann Oncol. 2018 Aug 21. doi: 10.1093/annonc/mdy263.

The European Society for Medical Oncology (ESMO) has published a proposed scale that would rank molecular targets for various cancers by how well they can be treated with new or emerging drugs.

The ESMO Scale of Clinical Actionability for Molecular Targets is designed to “harmonize and standardize the reporting and interpretation of clinically relevant genomics data,” according to Joaquin Mateo, MD, PhD, from the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and his fellow members of the ESMO Translational Research and Precision Medicine Working Group.

“A major challenge for oncologists in the clinic is to distinguish between findings that represent proven clinical value or potential value based on preliminary clinical or preclinical evidence from hypothetical gene-drug matches and findings that are currently irrelevant for clinical practice,” they wrote in Annals of Oncology.

The scale groups targets into one of six tiers based on levels of evidence ranging from the gold standard of prospective, randomized clinical trials to targets for which there are no evidence and only hypothetical actionability. The primary goal is to help oncologists assign priority to potential targets when they review results of gene-sequencing panels for individual patients, according to the developers.

Briefly, the six tiers are:

Tier I includes targets that are agreed to be suitable for routine use and a recommended specific drug when a specific molecular alteration is detected. Examples include trastuzumab for human epidermal growth factor receptor 2 (HER2)–positive breast cancer, and inhibitors of epidermal growth factor receptor (EGFR) in patients with non–small cell lung cancer positive for EGFR mutations.

Tier II includes “investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed.” This tier includes agents that work in the phosphatidylinostiol 3-kinase pathway.

Tier III is similar to Tier II, in that it includes investigational targets that define a patient population with proven benefit from a targeted therapy, but in this case the target is detected in a different tumor type that has not previously been studied. For example, the targeted agent vemurafenib (Zelboraf), which extends survival of patients with metastatic melanomas carrying the BRAF V600E mutation, has only limited activity against BRAF-mutated colorectal cancers.

Tier IV includes targets with preclinical evidence of actionability.

Tier V includes targets with “evidence of relevant antitumor activity, not resulting in clinical meaningful benefit as single treatment but supporting development of cotargeting approaches.” The authors cite the example of PIK3CA inhibitors in patients with estrogen receptor–positive, HER2-negative breast cancers who also have PIK3CA activating mutations. In clinical trials, this strategy led to objective responses but not change outcomes.

The final tier is not Tier VI, as might be expected, but Tier X, with the X in this case being the unknown – that is, alterations/mutations for which there is neither preclinical nor clinical evidence to support their hypothetical use as a drug target.

“This clinical benefit–centered classification system offers a common language for all the actors involved in clinical cancer drug development. Its implementation in sequencing reports, tumor boards, and scientific communication can enable precise treatment decisions and facilitate discussions with patients about novel therapeutic options,” Dr. Mateo and his associates wrote in their conclusion.

The development process was supported by ESMO. Multiple coauthors reported financial relationships with various companies as well as grants/support from other foundations or charities.

SOURCE: Mateo J et al. Ann Oncol. 2018 Aug 21. doi: 10.1093/annonc/mdy263.

The European Society for Medical Oncology (ESMO) has published a proposed scale that would rank molecular targets for various cancers by how well they can be treated with new or emerging drugs.

The ESMO Scale of Clinical Actionability for Molecular Targets is designed to “harmonize and standardize the reporting and interpretation of clinically relevant genomics data,” according to Joaquin Mateo, MD, PhD, from the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and his fellow members of the ESMO Translational Research and Precision Medicine Working Group.

“A major challenge for oncologists in the clinic is to distinguish between findings that represent proven clinical value or potential value based on preliminary clinical or preclinical evidence from hypothetical gene-drug matches and findings that are currently irrelevant for clinical practice,” they wrote in Annals of Oncology.

The scale groups targets into one of six tiers based on levels of evidence ranging from the gold standard of prospective, randomized clinical trials to targets for which there are no evidence and only hypothetical actionability. The primary goal is to help oncologists assign priority to potential targets when they review results of gene-sequencing panels for individual patients, according to the developers.

Briefly, the six tiers are:

Tier I includes targets that are agreed to be suitable for routine use and a recommended specific drug when a specific molecular alteration is detected. Examples include trastuzumab for human epidermal growth factor receptor 2 (HER2)–positive breast cancer, and inhibitors of epidermal growth factor receptor (EGFR) in patients with non–small cell lung cancer positive for EGFR mutations.

Tier II includes “investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed.” This tier includes agents that work in the phosphatidylinostiol 3-kinase pathway.

Tier III is similar to Tier II, in that it includes investigational targets that define a patient population with proven benefit from a targeted therapy, but in this case the target is detected in a different tumor type that has not previously been studied. For example, the targeted agent vemurafenib (Zelboraf), which extends survival of patients with metastatic melanomas carrying the BRAF V600E mutation, has only limited activity against BRAF-mutated colorectal cancers.

Tier IV includes targets with preclinical evidence of actionability.

Tier V includes targets with “evidence of relevant antitumor activity, not resulting in clinical meaningful benefit as single treatment but supporting development of cotargeting approaches.” The authors cite the example of PIK3CA inhibitors in patients with estrogen receptor–positive, HER2-negative breast cancers who also have PIK3CA activating mutations. In clinical trials, this strategy led to objective responses but not change outcomes.

The final tier is not Tier VI, as might be expected, but Tier X, with the X in this case being the unknown – that is, alterations/mutations for which there is neither preclinical nor clinical evidence to support their hypothetical use as a drug target.

“This clinical benefit–centered classification system offers a common language for all the actors involved in clinical cancer drug development. Its implementation in sequencing reports, tumor boards, and scientific communication can enable precise treatment decisions and facilitate discussions with patients about novel therapeutic options,” Dr. Mateo and his associates wrote in their conclusion.

The development process was supported by ESMO. Multiple coauthors reported financial relationships with various companies as well as grants/support from other foundations or charities.

SOURCE: Mateo J et al. Ann Oncol. 2018 Aug 21. doi: 10.1093/annonc/mdy263.

Men who undergo MRI of the prostate around the time of a low-risk prostate cancer diagnosis are nearly twice as likely to be managed with active surveillance as are men who do not get MRI, investigators found.

roobcio/Thinkstock.com

The findings suggest that MRI at the time of diagnosis can enhance patient and physician confidence in the decision to choose active surveillance (AS) over immediate surgery or radiation therapy in men with low-risk disease, according to Michael S. Leapman, MD, and his colleagues from Yale University, New Haven, Conn.

“Despite initial high costs associated with obtaining and interpreting MRI studies of the prostate, economic modeling studies imply that MRI would be cost effective if it resulted in increased utilization of AS for low- and very-low-risk PCa [prostate cancer]. The association identified in our study between MRI use and initial observation may serve as an informative basis for examining strategies to improve the quality of PCa care with the anticipated growing use of this technology,” they wrote in Urology.

Although active surveillance is increasingly accepted as an initial management strategy for patients with low-risk (Gleason score 6 or less) localized prostate cancer, the majority of patients with low-risk disease still receive definitive treatment.

“Although longitudinal studies support the safety of AS, uncertainty about the possibility of underestimating an indvidual’s risk of harboring aggressive disease remains a strong motivator to treat,” Dr. Leapman and his associates noted.

To see whether MRI of the prostate may have an effect on the use of active surveillance in men with low-risk disease, the investigators reviewed records from the Surveillance, Epidemiology and End Results (SEER) Medicare database to identify men diagnosed with low-risk prostate cancer during 2010-2013.

They looked at the association between MRI and patient management (ascertained by claims) and evaluated clinical and demographic factors associated with the receipt of MRI.

They identified 8,144 patients with low-risk prostate cancer during the study period, of whom 495 (6.1%) had undergone MRI scans. They found that the use of MRI in patients with low-risk cancer increased from 3.4% in 2010 to 10.5% in 2013.

MRI was performed significantly more frequently among 3,060 patients who were managed with observation, with 265 (8.7%) receiving scans, compared with 230 (4.5%) of the 5,084 patients who underwent treatment within a year of diagnosis.

In multivariable analysis that controlled for demographics, factors significantly associated with increased likelihood of undergoing observation versus definitive therapy included MRI, white vs. nonwhite race, later years of diagnosis, higher income status (by ZIP code), unmarried vs. married, treatment region (more common in the West and Midwest versus Northeast or South), and in referral regions with higher population density of urologists.

In a propensity score–matched analysis designed to smooth out potential confounders, the investigators found that receipt of MRI around the time of diagnosis was associated with a significantly higher likelihood of active surveillance, with an odds ratio of 1.90 (95% confidence interval, 1.56-2.32).

“Efforts to facilitate observational approaches for low-risk PCa are highly valuable to improving the quality of cancer care. Because the use of prostate MRI has grown, and is likely to continue expanding, the cost-effectiveness of MRI-driven pathways are increasingly relevant to the sustainability of the practice,” the authors wrote.

SOURCE: Leapman MS et al. Urology. 2018 Aug 11. doi: 10.1016/j.urology.2018.07.041.

Men who undergo MRI of the prostate around the time of a low-risk prostate cancer diagnosis are nearly twice as likely to be managed with active surveillance as are men who do not get MRI, investigators found.

roobcio/Thinkstock.com

The findings suggest that MRI at the time of diagnosis can enhance patient and physician confidence in the decision to choose active surveillance (AS) over immediate surgery or radiation therapy in men with low-risk disease, according to Michael S. Leapman, MD, and his colleagues from Yale University, New Haven, Conn.

“Despite initial high costs associated with obtaining and interpreting MRI studies of the prostate, economic modeling studies imply that MRI would be cost effective if it resulted in increased utilization of AS for low- and very-low-risk PCa [prostate cancer]. The association identified in our study between MRI use and initial observation may serve as an informative basis for examining strategies to improve the quality of PCa care with the anticipated growing use of this technology,” they wrote in Urology.

Although active surveillance is increasingly accepted as an initial management strategy for patients with low-risk (Gleason score 6 or less) localized prostate cancer, the majority of patients with low-risk disease still receive definitive treatment.

“Although longitudinal studies support the safety of AS, uncertainty about the possibility of underestimating an indvidual’s risk of harboring aggressive disease remains a strong motivator to treat,” Dr. Leapman and his associates noted.

To see whether MRI of the prostate may have an effect on the use of active surveillance in men with low-risk disease, the investigators reviewed records from the Surveillance, Epidemiology and End Results (SEER) Medicare database to identify men diagnosed with low-risk prostate cancer during 2010-2013.

They looked at the association between MRI and patient management (ascertained by claims) and evaluated clinical and demographic factors associated with the receipt of MRI.

They identified 8,144 patients with low-risk prostate cancer during the study period, of whom 495 (6.1%) had undergone MRI scans. They found that the use of MRI in patients with low-risk cancer increased from 3.4% in 2010 to 10.5% in 2013.

MRI was performed significantly more frequently among 3,060 patients who were managed with observation, with 265 (8.7%) receiving scans, compared with 230 (4.5%) of the 5,084 patients who underwent treatment within a year of diagnosis.

In multivariable analysis that controlled for demographics, factors significantly associated with increased likelihood of undergoing observation versus definitive therapy included MRI, white vs. nonwhite race, later years of diagnosis, higher income status (by ZIP code), unmarried vs. married, treatment region (more common in the West and Midwest versus Northeast or South), and in referral regions with higher population density of urologists.

In a propensity score–matched analysis designed to smooth out potential confounders, the investigators found that receipt of MRI around the time of diagnosis was associated with a significantly higher likelihood of active surveillance, with an odds ratio of 1.90 (95% confidence interval, 1.56-2.32).

“Efforts to facilitate observational approaches for low-risk PCa are highly valuable to improving the quality of cancer care. Because the use of prostate MRI has grown, and is likely to continue expanding, the cost-effectiveness of MRI-driven pathways are increasingly relevant to the sustainability of the practice,” the authors wrote.

SOURCE: Leapman MS et al. Urology. 2018 Aug 11. doi: 10.1016/j.urology.2018.07.041.

Men who undergo MRI of the prostate around the time of a low-risk prostate cancer diagnosis are nearly twice as likely to be managed with active surveillance as are men who do not get MRI, investigators found.

roobcio/Thinkstock.com

The findings suggest that MRI at the time of diagnosis can enhance patient and physician confidence in the decision to choose active surveillance (AS) over immediate surgery or radiation therapy in men with low-risk disease, according to Michael S. Leapman, MD, and his colleagues from Yale University, New Haven, Conn.

“Despite initial high costs associated with obtaining and interpreting MRI studies of the prostate, economic modeling studies imply that MRI would be cost effective if it resulted in increased utilization of AS for low- and very-low-risk PCa [prostate cancer]. The association identified in our study between MRI use and initial observation may serve as an informative basis for examining strategies to improve the quality of PCa care with the anticipated growing use of this technology,” they wrote in Urology.

Although active surveillance is increasingly accepted as an initial management strategy for patients with low-risk (Gleason score 6 or less) localized prostate cancer, the majority of patients with low-risk disease still receive definitive treatment.

“Although longitudinal studies support the safety of AS, uncertainty about the possibility of underestimating an indvidual’s risk of harboring aggressive disease remains a strong motivator to treat,” Dr. Leapman and his associates noted.

To see whether MRI of the prostate may have an effect on the use of active surveillance in men with low-risk disease, the investigators reviewed records from the Surveillance, Epidemiology and End Results (SEER) Medicare database to identify men diagnosed with low-risk prostate cancer during 2010-2013.

They looked at the association between MRI and patient management (ascertained by claims) and evaluated clinical and demographic factors associated with the receipt of MRI.

They identified 8,144 patients with low-risk prostate cancer during the study period, of whom 495 (6.1%) had undergone MRI scans. They found that the use of MRI in patients with low-risk cancer increased from 3.4% in 2010 to 10.5% in 2013.

MRI was performed significantly more frequently among 3,060 patients who were managed with observation, with 265 (8.7%) receiving scans, compared with 230 (4.5%) of the 5,084 patients who underwent treatment within a year of diagnosis.

In multivariable analysis that controlled for demographics, factors significantly associated with increased likelihood of undergoing observation versus definitive therapy included MRI, white vs. nonwhite race, later years of diagnosis, higher income status (by ZIP code), unmarried vs. married, treatment region (more common in the West and Midwest versus Northeast or South), and in referral regions with higher population density of urologists.

In a propensity score–matched analysis designed to smooth out potential confounders, the investigators found that receipt of MRI around the time of diagnosis was associated with a significantly higher likelihood of active surveillance, with an odds ratio of 1.90 (95% confidence interval, 1.56-2.32).

“Efforts to facilitate observational approaches for low-risk PCa are highly valuable to improving the quality of cancer care. Because the use of prostate MRI has grown, and is likely to continue expanding, the cost-effectiveness of MRI-driven pathways are increasingly relevant to the sustainability of the practice,” the authors wrote.

SOURCE: Leapman MS et al. Urology. 2018 Aug 11. doi: 10.1016/j.urology.2018.07.041.

Once again, a study has shown that when it comes to managing patients with serious advanced malignancies – in this case, metastatic renal cell carcinoma – experience matters.

A review of data on 41,836 patients with metastatic renal cell carcinoma (mRCC) treated at 1,222 facilities (TFs) showed that across all cohorts, including patients with known liver and lung metastases who received systemic therapies, treatment-center volume was significantly associated with longer survival, reported Daniel M. Geynisman, MD of Fox Chase Cancer Center in Philadelphia, and his colleagues.

“These findings may help define the optimal treatment environment for the management of patients with mRCC. The improved survival outcomes at higher-volume TFs should also be a call to improve mRCC management at lower-volume facilities. Given the negative externalities of care regionalization, focus should shift toward policies that help equalize mRCC management at lower-volume TFs by expanding treatment options, clinical trial access, and specialized resource availability,” the researchers wrote. Their report is in European Urology.

The investigators noted that several studies have demonstrated that patients with localized RCC treated at high-volume centers had better postoperative outcomes and few complications following surgery for renal cancer, but whether treatment volume makes a difference for patients with metastatic disease was less clear.

To get a better understanding of the association between case volume and outcomes for patients with advanced RCC, the investigators searched the National Cancer Database for information on all U.S. patients with mRCC from 2004 through 2013 for whom survival data were available.

To confirm the association with volume, they created five cohorts with increasingly restrictive inclusion criteria, as follows:

• Cohort A: All patients with survival data (41,836 patients).
• Cohort B: Patients with mRCC who received active treatment of any kind (27,557).
• Cohort C: Patients treated with systemic therapy with or without primary surgery (19,138).
• Cohort D: Patients treated with systemic therapy at the reporting facility (12,000).
• Cohort E: Patients with known sites of metastases (4,933).

The investigators also conducted sensitivity analyses on subcohorts of patients who did not receive nephrectomies in cohorts C, D, and E.

They found in a multivariable analysis that increased volume, measured as cases per year, was associated with reduced overall mortality across all cohorts.

For example, in cohort A, the hazard ratio (HR) for overall mortality for TFs caring for a mean of 5 patients per year was 0.92, compared with 0.84 for centers with 10 cases per year, and 0.74 for TFs caring for a mean of 20 patients per year (P less than .001). Similarly, the respective HRs for patients in cohort E were 0.88, 0.79, and 0.72 (P less than .001).

The overall probability of mortality was also significantly lower in higher-volume centers for those patients in cohorts C, D, and E who did not undergo nephrectomy.

The investigators acknowledged that the study was limited by the retrospective nature of the database information, and by the absence of data on treatment regimens used at specific facilities, which may explain mechanisms of the effects they observed.

The investigators did not specify a study funding source. Dr. Geynisman reported having no conflicts of interest.

SOURCE: Joshi SS et al. Eur Urol. 2018 Sep;74[3]:387-93.

Once again, a study has shown that when it comes to managing patients with serious advanced malignancies – in this case, metastatic renal cell carcinoma – experience matters.

A review of data on 41,836 patients with metastatic renal cell carcinoma (mRCC) treated at 1,222 facilities (TFs) showed that across all cohorts, including patients with known liver and lung metastases who received systemic therapies, treatment-center volume was significantly associated with longer survival, reported Daniel M. Geynisman, MD of Fox Chase Cancer Center in Philadelphia, and his colleagues.

“These findings may help define the optimal treatment environment for the management of patients with mRCC. The improved survival outcomes at higher-volume TFs should also be a call to improve mRCC management at lower-volume facilities. Given the negative externalities of care regionalization, focus should shift toward policies that help equalize mRCC management at lower-volume TFs by expanding treatment options, clinical trial access, and specialized resource availability,” the researchers wrote. Their report is in European Urology.

The investigators noted that several studies have demonstrated that patients with localized RCC treated at high-volume centers had better postoperative outcomes and few complications following surgery for renal cancer, but whether treatment volume makes a difference for patients with metastatic disease was less clear.

To get a better understanding of the association between case volume and outcomes for patients with advanced RCC, the investigators searched the National Cancer Database for information on all U.S. patients with mRCC from 2004 through 2013 for whom survival data were available.

To confirm the association with volume, they created five cohorts with increasingly restrictive inclusion criteria, as follows:

• Cohort A: All patients with survival data (41,836 patients).
• Cohort B: Patients with mRCC who received active treatment of any kind (27,557).
• Cohort C: Patients treated with systemic therapy with or without primary surgery (19,138).
• Cohort D: Patients treated with systemic therapy at the reporting facility (12,000).
• Cohort E: Patients with known sites of metastases (4,933).

The investigators also conducted sensitivity analyses on subcohorts of patients who did not receive nephrectomies in cohorts C, D, and E.

They found in a multivariable analysis that increased volume, measured as cases per year, was associated with reduced overall mortality across all cohorts.

For example, in cohort A, the hazard ratio (HR) for overall mortality for TFs caring for a mean of 5 patients per year was 0.92, compared with 0.84 for centers with 10 cases per year, and 0.74 for TFs caring for a mean of 20 patients per year (P less than .001). Similarly, the respective HRs for patients in cohort E were 0.88, 0.79, and 0.72 (P less than .001).

The overall probability of mortality was also significantly lower in higher-volume centers for those patients in cohorts C, D, and E who did not undergo nephrectomy.

The investigators acknowledged that the study was limited by the retrospective nature of the database information, and by the absence of data on treatment regimens used at specific facilities, which may explain mechanisms of the effects they observed.

The investigators did not specify a study funding source. Dr. Geynisman reported having no conflicts of interest.

SOURCE: Joshi SS et al. Eur Urol. 2018 Sep;74[3]:387-93.

Once again, a study has shown that when it comes to managing patients with serious advanced malignancies – in this case, metastatic renal cell carcinoma – experience matters.

A review of data on 41,836 patients with metastatic renal cell carcinoma (mRCC) treated at 1,222 facilities (TFs) showed that across all cohorts, including patients with known liver and lung metastases who received systemic therapies, treatment-center volume was significantly associated with longer survival, reported Daniel M. Geynisman, MD of Fox Chase Cancer Center in Philadelphia, and his colleagues.

“These findings may help define the optimal treatment environment for the management of patients with mRCC. The improved survival outcomes at higher-volume TFs should also be a call to improve mRCC management at lower-volume facilities. Given the negative externalities of care regionalization, focus should shift toward policies that help equalize mRCC management at lower-volume TFs by expanding treatment options, clinical trial access, and specialized resource availability,” the researchers wrote. Their report is in European Urology.

The investigators noted that several studies have demonstrated that patients with localized RCC treated at high-volume centers had better postoperative outcomes and few complications following surgery for renal cancer, but whether treatment volume makes a difference for patients with metastatic disease was less clear.

To get a better understanding of the association between case volume and outcomes for patients with advanced RCC, the investigators searched the National Cancer Database for information on all U.S. patients with mRCC from 2004 through 2013 for whom survival data were available.

To confirm the association with volume, they created five cohorts with increasingly restrictive inclusion criteria, as follows:

• Cohort A: All patients with survival data (41,836 patients).
• Cohort B: Patients with mRCC who received active treatment of any kind (27,557).
• Cohort C: Patients treated with systemic therapy with or without primary surgery (19,138).
• Cohort D: Patients treated with systemic therapy at the reporting facility (12,000).
• Cohort E: Patients with known sites of metastases (4,933).

The investigators also conducted sensitivity analyses on subcohorts of patients who did not receive nephrectomies in cohorts C, D, and E.

They found in a multivariable analysis that increased volume, measured as cases per year, was associated with reduced overall mortality across all cohorts.

For example, in cohort A, the hazard ratio (HR) for overall mortality for TFs caring for a mean of 5 patients per year was 0.92, compared with 0.84 for centers with 10 cases per year, and 0.74 for TFs caring for a mean of 20 patients per year (P less than .001). Similarly, the respective HRs for patients in cohort E were 0.88, 0.79, and 0.72 (P less than .001).

The overall probability of mortality was also significantly lower in higher-volume centers for those patients in cohorts C, D, and E who did not undergo nephrectomy.

The investigators acknowledged that the study was limited by the retrospective nature of the database information, and by the absence of data on treatment regimens used at specific facilities, which may explain mechanisms of the effects they observed.

The investigators did not specify a study funding source. Dr. Geynisman reported having no conflicts of interest.

SOURCE: Joshi SS et al. Eur Urol. 2018 Sep;74[3]:387-93.

In patients with muscle-invasive bladder cancer, a dose-dense neoadjuvant chemotherapy regimen followed by cystectomy was associated with a higher rate of complete responses, compared with standard gemcitabine-platinum neoadjuvant chemotherapy and cystectomy, results of a retrospective analysis indicate.

Among 1,113 patients who underwent neoadjuvant chemotherapy (NAC) and cystectomy, a regimen of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) was associated with a nearly threefold greater likelihood that patients would have a complete response, compared with gemcitabine and cisplatin, reported Scott M. Gilbert, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and colleagues.

“We also found that ddMVAC was associated with longer survival intervals and a lower risk of death than the other treatments examined, although those findings did not reach statistical significance, indicating that larger comparative studies are needed to definitively answer questions regarding survival,” they wrote in JAMA Oncology.

The investigators noted that, despite clear evidence of a survival benefit associated with neoadjuvant chemotherapy followed by cystectomy, compared with cystectomy alone in patients with muscle-invasive bladder cancer, “the rates of adoption and routine use of NAC have been modest.”

Gemcitabine and cisplatin have become the de facto standard of care because of favorable toxicity profile and response rates comparable to those seen with ddMVAC. Yet there are few studies comparing disease control and survival outcomes for different neoadjuvant chemotherapy regimens, they noted, which prompted the current study.

The investigators conducted a cross-sectional analysis of data on 1,113 patients with bladder cancer treated with cystectomy at their center from January 2007 through May 2017. They compared rates of downstaging, complete responses, and overall survival with ddMVAC, compared with gemcitabine combined with either cisplatin or carboplatin, other neoadjuvant combinations (including etoposide- fluorouracil- and paclitaxel-based regimens) or no neoadjuvant chemotherapy.

Of the 1,113 patients, 824 had disease stage T2 or greater, and of this group, 332 had received neoadjuvant chemotherapy.

They found that ddMVAC was associated with a 52.2% downstaging rate, compared with 41.3% for gemcitabine-cisplatin, and 27% for gemcitabine-carboplatin. Respective pathologic complete response rates were 41.3%, 24.5%, and 9.4% (P less than .001).

Downstaging rates for patients treated with other regimens and patients who did not receive neoadjuvant chemotherapy were 42% and 25.7%, respectively. Complete response rates (downstaging to pT0N0) were 24% and 10.7%.

In a multivariable logistic regression model controlling for age, comorbidities, sex, clinical stage, and chemotherapy regimen, ddMVAC was associated with a significantly higher likelihood of pathologic complete response, with an odds ratio of 2.67 (P less than .001). Similarly, a propensity-score model weighted for clinical and demographic characteristics showed an OR for complete response with ddMVAC of 1.52 (P = .05).

The 2-year Kaplan-Meier survival probability estimate for ddMVAC was 73.3%, compared with 62% for gemcitabine-cisplatin and 34.8% for gemcitabine-carboplatin (P = .002).

Regardless of chemotherapy type, a complete pathologic response was a significant predictor for overall survival (P less than .001).

Although ddMVAC showed a trend toward better overall survival in both logistic regression and propensity score models, neither reached statistical significance.

The authors did not report survival results for patients who did not receive neoadjuvant chemotherapy.

The investigators acknowledged that the study is limited by its nonrandomized design and the relatively small sample of patients treated with ddMVAC (46 patients).

The study was supported in part by a National Cancer Institute grant to the H. Lee Moffitt Cancer Center. The authors reported having no conflicts of interest.

SOURCE: Peyton CC et al. JAMA Oncology. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3542.
 

In patients with muscle-invasive bladder cancer, a dose-dense neoadjuvant chemotherapy regimen followed by cystectomy was associated with a higher rate of complete responses, compared with standard gemcitabine-platinum neoadjuvant chemotherapy and cystectomy, results of a retrospective analysis indicate.

Among 1,113 patients who underwent neoadjuvant chemotherapy (NAC) and cystectomy, a regimen of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) was associated with a nearly threefold greater likelihood that patients would have a complete response, compared with gemcitabine and cisplatin, reported Scott M. Gilbert, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and colleagues.

“We also found that ddMVAC was associated with longer survival intervals and a lower risk of death than the other treatments examined, although those findings did not reach statistical significance, indicating that larger comparative studies are needed to definitively answer questions regarding survival,” they wrote in JAMA Oncology.

The investigators noted that, despite clear evidence of a survival benefit associated with neoadjuvant chemotherapy followed by cystectomy, compared with cystectomy alone in patients with muscle-invasive bladder cancer, “the rates of adoption and routine use of NAC have been modest.”

Gemcitabine and cisplatin have become the de facto standard of care because of favorable toxicity profile and response rates comparable to those seen with ddMVAC. Yet there are few studies comparing disease control and survival outcomes for different neoadjuvant chemotherapy regimens, they noted, which prompted the current study.

The investigators conducted a cross-sectional analysis of data on 1,113 patients with bladder cancer treated with cystectomy at their center from January 2007 through May 2017. They compared rates of downstaging, complete responses, and overall survival with ddMVAC, compared with gemcitabine combined with either cisplatin or carboplatin, other neoadjuvant combinations (including etoposide- fluorouracil- and paclitaxel-based regimens) or no neoadjuvant chemotherapy.

Of the 1,113 patients, 824 had disease stage T2 or greater, and of this group, 332 had received neoadjuvant chemotherapy.

They found that ddMVAC was associated with a 52.2% downstaging rate, compared with 41.3% for gemcitabine-cisplatin, and 27% for gemcitabine-carboplatin. Respective pathologic complete response rates were 41.3%, 24.5%, and 9.4% (P less than .001).

Downstaging rates for patients treated with other regimens and patients who did not receive neoadjuvant chemotherapy were 42% and 25.7%, respectively. Complete response rates (downstaging to pT0N0) were 24% and 10.7%.

In a multivariable logistic regression model controlling for age, comorbidities, sex, clinical stage, and chemotherapy regimen, ddMVAC was associated with a significantly higher likelihood of pathologic complete response, with an odds ratio of 2.67 (P less than .001). Similarly, a propensity-score model weighted for clinical and demographic characteristics showed an OR for complete response with ddMVAC of 1.52 (P = .05).

The 2-year Kaplan-Meier survival probability estimate for ddMVAC was 73.3%, compared with 62% for gemcitabine-cisplatin and 34.8% for gemcitabine-carboplatin (P = .002).

Regardless of chemotherapy type, a complete pathologic response was a significant predictor for overall survival (P less than .001).

Although ddMVAC showed a trend toward better overall survival in both logistic regression and propensity score models, neither reached statistical significance.

The authors did not report survival results for patients who did not receive neoadjuvant chemotherapy.

The investigators acknowledged that the study is limited by its nonrandomized design and the relatively small sample of patients treated with ddMVAC (46 patients).

The study was supported in part by a National Cancer Institute grant to the H. Lee Moffitt Cancer Center. The authors reported having no conflicts of interest.

SOURCE: Peyton CC et al. JAMA Oncology. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3542.
 

In patients with muscle-invasive bladder cancer, a dose-dense neoadjuvant chemotherapy regimen followed by cystectomy was associated with a higher rate of complete responses, compared with standard gemcitabine-platinum neoadjuvant chemotherapy and cystectomy, results of a retrospective analysis indicate.

Among 1,113 patients who underwent neoadjuvant chemotherapy (NAC) and cystectomy, a regimen of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) was associated with a nearly threefold greater likelihood that patients would have a complete response, compared with gemcitabine and cisplatin, reported Scott M. Gilbert, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and colleagues.

“We also found that ddMVAC was associated with longer survival intervals and a lower risk of death than the other treatments examined, although those findings did not reach statistical significance, indicating that larger comparative studies are needed to definitively answer questions regarding survival,” they wrote in JAMA Oncology.

The investigators noted that, despite clear evidence of a survival benefit associated with neoadjuvant chemotherapy followed by cystectomy, compared with cystectomy alone in patients with muscle-invasive bladder cancer, “the rates of adoption and routine use of NAC have been modest.”

Gemcitabine and cisplatin have become the de facto standard of care because of favorable toxicity profile and response rates comparable to those seen with ddMVAC. Yet there are few studies comparing disease control and survival outcomes for different neoadjuvant chemotherapy regimens, they noted, which prompted the current study.

The investigators conducted a cross-sectional analysis of data on 1,113 patients with bladder cancer treated with cystectomy at their center from January 2007 through May 2017. They compared rates of downstaging, complete responses, and overall survival with ddMVAC, compared with gemcitabine combined with either cisplatin or carboplatin, other neoadjuvant combinations (including etoposide- fluorouracil- and paclitaxel-based regimens) or no neoadjuvant chemotherapy.

Of the 1,113 patients, 824 had disease stage T2 or greater, and of this group, 332 had received neoadjuvant chemotherapy.

They found that ddMVAC was associated with a 52.2% downstaging rate, compared with 41.3% for gemcitabine-cisplatin, and 27% for gemcitabine-carboplatin. Respective pathologic complete response rates were 41.3%, 24.5%, and 9.4% (P less than .001).

Downstaging rates for patients treated with other regimens and patients who did not receive neoadjuvant chemotherapy were 42% and 25.7%, respectively. Complete response rates (downstaging to pT0N0) were 24% and 10.7%.

In a multivariable logistic regression model controlling for age, comorbidities, sex, clinical stage, and chemotherapy regimen, ddMVAC was associated with a significantly higher likelihood of pathologic complete response, with an odds ratio of 2.67 (P less than .001). Similarly, a propensity-score model weighted for clinical and demographic characteristics showed an OR for complete response with ddMVAC of 1.52 (P = .05).

The 2-year Kaplan-Meier survival probability estimate for ddMVAC was 73.3%, compared with 62% for gemcitabine-cisplatin and 34.8% for gemcitabine-carboplatin (P = .002).

Regardless of chemotherapy type, a complete pathologic response was a significant predictor for overall survival (P less than .001).

Although ddMVAC showed a trend toward better overall survival in both logistic regression and propensity score models, neither reached statistical significance.

The authors did not report survival results for patients who did not receive neoadjuvant chemotherapy.

The investigators acknowledged that the study is limited by its nonrandomized design and the relatively small sample of patients treated with ddMVAC (46 patients).

The study was supported in part by a National Cancer Institute grant to the H. Lee Moffitt Cancer Center. The authors reported having no conflicts of interest.

SOURCE: Peyton CC et al. JAMA Oncology. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3542.
 

The combination of nanoparticle albumin-bound (nab)-paclitaxel and gemcitabine may be comparable in efficacy and safety to other chemotherapy combinations as first-line therapy for advanced or metastatic cholangiocarcinoma, but a phase 2 clinical trial failed to prove that hypothesis.

Among 74 patients with cholangiocarcinoma (CCA) treated with nab-paclitaxel and gemcitabine in a multicenter study, the 6-month progression-free survival (PFS) rate was 61%, which was lower than the 70% or higher rate required to confirm the trial’s primary endpoint, reported Vaibhav Sahai, MBBS, MS, of the University of Michigan in Ann Arbor, and his colleagues.

“Although the trial did not meet its primary efficacy endpoint, the PFS and OS [overall survival] were comparable to those of the gemcitabine plus cisplatin and gemcitabine plus oxaliplatin regimens in the ABC-02 and BINGO trials, respectively. As such, we conclude that combination nab-P and gemcitabine therapy is well tolerated and may be considered as an alternative regimen to current therapeutic approaches in advanced CCA,” they wrote. The report is in JAMA Oncology.

Recent evidence has suggested that nab-paclitaxel may potentiate the activity of gemcitabine by inhibiting cytidine deaminase, a gemcitabine-metabolizing enzyme, thereby allowing active metabolites of gemcitabine to accumulate in tumors, the author noted.

To see whether this observed synergy could translate into clinical benefit, they conducted a trial with 74 patients from 23 community and academic centers in the United States and Europe. The median patient age was 62 (range 36-87) years.

The patients received a median of six treatment cycles and were followed for a median of 10.2 months. Treatment consisted of intravenous nab-paclitaxel at a dose of 125mg/m², followed by gemcitabine 1,000 mg/m², on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxicity.

The investigators explained the statistical design of the trial as follows:

“At completion, the trial required more than 43 of 67 evaluable patients to be alive and progression free at 6 months to conclude that the 6-month PFS rate was at least 70% (vs. a null hypothesis of 55%) based on historical data from the Advanced Biliary Cancer (ABC)–02 and BINGO (Gemcitabine and Oxaliplatin With or Without Cetuximab in Advanced Biliary-Tract Cancer) trials.”

As noted, the 6-month PFS rate in evaluable patients was 61%, which was not sufficient to either prove the alternative hypothesis or reject the null hypothesis.

Median PFS was 7.7 months, median time to progression was 7.7 months, and median overall survival was 12.4 months.

The confirmed best overall response rate was 30%, and the disease control rate was 66%.

In all, 72 of the 74 patients had a treatment-related adverse event, including fatigue in 52 patients, neutropenia in 50, and peripheral neuropathy in 41.

Grade 3 or greater adverse events occurred in 61 patients, with neutropenia in 32 patients as the most common treatment-related hematologic event, and grade 3 or greater fatigue in 10 patients as the most common nonhematologic event of grade 3 or greater.

“On the basis of the adverse event profile, nab-P plus gemcitabine treatment may be considered for patients who are not otherwise considered candidates for cisplatin-based therapy, specifically those with renal dysfunction,” the investigators wrote.

SOURCE: Sahai V et al. JAMA Oncol. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3277.

The combination of nanoparticle albumin-bound (nab)-paclitaxel and gemcitabine may be comparable in efficacy and safety to other chemotherapy combinations as first-line therapy for advanced or metastatic cholangiocarcinoma, but a phase 2 clinical trial failed to prove that hypothesis.

Among 74 patients with cholangiocarcinoma (CCA) treated with nab-paclitaxel and gemcitabine in a multicenter study, the 6-month progression-free survival (PFS) rate was 61%, which was lower than the 70% or higher rate required to confirm the trial’s primary endpoint, reported Vaibhav Sahai, MBBS, MS, of the University of Michigan in Ann Arbor, and his colleagues.

“Although the trial did not meet its primary efficacy endpoint, the PFS and OS [overall survival] were comparable to those of the gemcitabine plus cisplatin and gemcitabine plus oxaliplatin regimens in the ABC-02 and BINGO trials, respectively. As such, we conclude that combination nab-P and gemcitabine therapy is well tolerated and may be considered as an alternative regimen to current therapeutic approaches in advanced CCA,” they wrote. The report is in JAMA Oncology.

Recent evidence has suggested that nab-paclitaxel may potentiate the activity of gemcitabine by inhibiting cytidine deaminase, a gemcitabine-metabolizing enzyme, thereby allowing active metabolites of gemcitabine to accumulate in tumors, the author noted.

To see whether this observed synergy could translate into clinical benefit, they conducted a trial with 74 patients from 23 community and academic centers in the United States and Europe. The median patient age was 62 (range 36-87) years.

The patients received a median of six treatment cycles and were followed for a median of 10.2 months. Treatment consisted of intravenous nab-paclitaxel at a dose of 125mg/m², followed by gemcitabine 1,000 mg/m², on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxicity.

The investigators explained the statistical design of the trial as follows:

“At completion, the trial required more than 43 of 67 evaluable patients to be alive and progression free at 6 months to conclude that the 6-month PFS rate was at least 70% (vs. a null hypothesis of 55%) based on historical data from the Advanced Biliary Cancer (ABC)–02 and BINGO (Gemcitabine and Oxaliplatin With or Without Cetuximab in Advanced Biliary-Tract Cancer) trials.”

As noted, the 6-month PFS rate in evaluable patients was 61%, which was not sufficient to either prove the alternative hypothesis or reject the null hypothesis.

Median PFS was 7.7 months, median time to progression was 7.7 months, and median overall survival was 12.4 months.

The confirmed best overall response rate was 30%, and the disease control rate was 66%.

In all, 72 of the 74 patients had a treatment-related adverse event, including fatigue in 52 patients, neutropenia in 50, and peripheral neuropathy in 41.

Grade 3 or greater adverse events occurred in 61 patients, with neutropenia in 32 patients as the most common treatment-related hematologic event, and grade 3 or greater fatigue in 10 patients as the most common nonhematologic event of grade 3 or greater.

“On the basis of the adverse event profile, nab-P plus gemcitabine treatment may be considered for patients who are not otherwise considered candidates for cisplatin-based therapy, specifically those with renal dysfunction,” the investigators wrote.

SOURCE: Sahai V et al. JAMA Oncol. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3277.

The combination of nanoparticle albumin-bound (nab)-paclitaxel and gemcitabine may be comparable in efficacy and safety to other chemotherapy combinations as first-line therapy for advanced or metastatic cholangiocarcinoma, but a phase 2 clinical trial failed to prove that hypothesis.

Among 74 patients with cholangiocarcinoma (CCA) treated with nab-paclitaxel and gemcitabine in a multicenter study, the 6-month progression-free survival (PFS) rate was 61%, which was lower than the 70% or higher rate required to confirm the trial’s primary endpoint, reported Vaibhav Sahai, MBBS, MS, of the University of Michigan in Ann Arbor, and his colleagues.

“Although the trial did not meet its primary efficacy endpoint, the PFS and OS [overall survival] were comparable to those of the gemcitabine plus cisplatin and gemcitabine plus oxaliplatin regimens in the ABC-02 and BINGO trials, respectively. As such, we conclude that combination nab-P and gemcitabine therapy is well tolerated and may be considered as an alternative regimen to current therapeutic approaches in advanced CCA,” they wrote. The report is in JAMA Oncology.

Recent evidence has suggested that nab-paclitaxel may potentiate the activity of gemcitabine by inhibiting cytidine deaminase, a gemcitabine-metabolizing enzyme, thereby allowing active metabolites of gemcitabine to accumulate in tumors, the author noted.

To see whether this observed synergy could translate into clinical benefit, they conducted a trial with 74 patients from 23 community and academic centers in the United States and Europe. The median patient age was 62 (range 36-87) years.

The patients received a median of six treatment cycles and were followed for a median of 10.2 months. Treatment consisted of intravenous nab-paclitaxel at a dose of 125mg/m², followed by gemcitabine 1,000 mg/m², on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxicity.

The investigators explained the statistical design of the trial as follows:

“At completion, the trial required more than 43 of 67 evaluable patients to be alive and progression free at 6 months to conclude that the 6-month PFS rate was at least 70% (vs. a null hypothesis of 55%) based on historical data from the Advanced Biliary Cancer (ABC)–02 and BINGO (Gemcitabine and Oxaliplatin With or Without Cetuximab in Advanced Biliary-Tract Cancer) trials.”

As noted, the 6-month PFS rate in evaluable patients was 61%, which was not sufficient to either prove the alternative hypothesis or reject the null hypothesis.

Median PFS was 7.7 months, median time to progression was 7.7 months, and median overall survival was 12.4 months.

The confirmed best overall response rate was 30%, and the disease control rate was 66%.

In all, 72 of the 74 patients had a treatment-related adverse event, including fatigue in 52 patients, neutropenia in 50, and peripheral neuropathy in 41.

Grade 3 or greater adverse events occurred in 61 patients, with neutropenia in 32 patients as the most common treatment-related hematologic event, and grade 3 or greater fatigue in 10 patients as the most common nonhematologic event of grade 3 or greater.

“On the basis of the adverse event profile, nab-P plus gemcitabine treatment may be considered for patients who are not otherwise considered candidates for cisplatin-based therapy, specifically those with renal dysfunction,” the investigators wrote.

SOURCE: Sahai V et al. JAMA Oncol. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3277.

An investigational antibody-drug conjugate labeled SGN-CD70A showed signs of efficacy against relapsed or refractory non-Hodgkin lymphomas in a phase 1 trial, but its future is clouded by a high incidence of treatment-associated thrombocytopenia, investigators reported.

Among 20 patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and other histologies, SGN-CD70A was associated with one complete remission (CR) and three partial remissions (PR), two of which were ongoing at nearly 43 weeks of follow-up.

However, 15 of the 20 patients (75%) had treatment-related thrombocytopenias, and 13 of these adverse events (AEs) were grade 3 or greater in severity, reported Tycel Phillips, MD, of the University of Michigan, Ann Arbor, and his colleagues.

Notwithstanding the antibody-drug conjugate’s apparent efficacy in this early trial, “the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term of response with limited drug exposure. Given that we are currently unable to mitigate this AE, the rationale for further investigation of SGN-CD70A remains limited and is, therefore, not planned,” they wrote in the journal Investigational New Drugs.

SGN-CD70A consists of an antibody directed against the plasma membrane protein CD70, a protease-cleavable linker, and a DNA-crosslinking pyrrolobenzodiazepine dimer drug. Its mechanism of action is via double-strand DNA breaks in CD70-positive cells that eventually cause programmed cell death.

Dr. Phillips and his colleagues reported on the high-risk non-Hodgkin lymphoma cohort in the phase 1 trial. The cohort included nine patients with DLBCL, five with mantle cell lymphoma, two with transformed DLBCL, one with T- cell/histocyte–rich large B cell lymphoma, and three with unspecified NHL histologies.

The patients had undergone a median of 3.5 prior lines of systemic therapy, and all had relatively good performance status, with Eastern Cooperative Oncology Group scores of 0 or 1.

Patients were started on intravenous SGN-CD70A at a dose of 8 mcg/kg on day 1 of each 3-week cycle, with a planned dose escalation to 200 mcg/kg, The protocol was amended to dosing every 6 weeks, however, after the investigators observed prolonged thrombocytopenias in some patients. A total of 12 patients were treated every 3 weeks, and 8 were treated every 6 weeks.

The most common treatment-related AEs were thrombocytopenias, which occurred in three-quarters of all patients, and were largely grade 3 or greater in severity. Other treatment-related AEs of grade 3 or greater occurring in more than one patient include neutropenia in six patients; anemia in five patients; and congestive heart failure, Clostridium difficile infections, dyspnea, and decreased forced expiratory volume in two patients each.

Other common AEs were nausea and fatigue.

The investigators noted that the cause of the deep and durable thrombocytopenias could not be determined, despite assessment of known biomarkers for this complication.

The duration of the thrombocytopenia and the fact that some of the few responses that did occur were also durable after the end of treatment suggest that the dimer drug, the cytotoxic “payload” of the antibody-drug conjugate, was responsible for the effects they observed, the authors said.

The study was funded by Seattle Genetics. Dr. Phillips reported advisory board membership with the company, and four of the coauthors are employees of the company with equity interests.

SOURCE: Phillips T et al. Invest New Drugs. 2018 Aug 22. doi: 10.1007/s10637-018-0655-0.

An investigational antibody-drug conjugate labeled SGN-CD70A showed signs of efficacy against relapsed or refractory non-Hodgkin lymphomas in a phase 1 trial, but its future is clouded by a high incidence of treatment-associated thrombocytopenia, investigators reported.

Among 20 patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and other histologies, SGN-CD70A was associated with one complete remission (CR) and three partial remissions (PR), two of which were ongoing at nearly 43 weeks of follow-up.

However, 15 of the 20 patients (75%) had treatment-related thrombocytopenias, and 13 of these adverse events (AEs) were grade 3 or greater in severity, reported Tycel Phillips, MD, of the University of Michigan, Ann Arbor, and his colleagues.

Notwithstanding the antibody-drug conjugate’s apparent efficacy in this early trial, “the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term of response with limited drug exposure. Given that we are currently unable to mitigate this AE, the rationale for further investigation of SGN-CD70A remains limited and is, therefore, not planned,” they wrote in the journal Investigational New Drugs.

SGN-CD70A consists of an antibody directed against the plasma membrane protein CD70, a protease-cleavable linker, and a DNA-crosslinking pyrrolobenzodiazepine dimer drug. Its mechanism of action is via double-strand DNA breaks in CD70-positive cells that eventually cause programmed cell death.

Dr. Phillips and his colleagues reported on the high-risk non-Hodgkin lymphoma cohort in the phase 1 trial. The cohort included nine patients with DLBCL, five with mantle cell lymphoma, two with transformed DLBCL, one with T- cell/histocyte–rich large B cell lymphoma, and three with unspecified NHL histologies.

The patients had undergone a median of 3.5 prior lines of systemic therapy, and all had relatively good performance status, with Eastern Cooperative Oncology Group scores of 0 or 1.

Patients were started on intravenous SGN-CD70A at a dose of 8 mcg/kg on day 1 of each 3-week cycle, with a planned dose escalation to 200 mcg/kg, The protocol was amended to dosing every 6 weeks, however, after the investigators observed prolonged thrombocytopenias in some patients. A total of 12 patients were treated every 3 weeks, and 8 were treated every 6 weeks.

The most common treatment-related AEs were thrombocytopenias, which occurred in three-quarters of all patients, and were largely grade 3 or greater in severity. Other treatment-related AEs of grade 3 or greater occurring in more than one patient include neutropenia in six patients; anemia in five patients; and congestive heart failure, Clostridium difficile infections, dyspnea, and decreased forced expiratory volume in two patients each.

Other common AEs were nausea and fatigue.

The investigators noted that the cause of the deep and durable thrombocytopenias could not be determined, despite assessment of known biomarkers for this complication.

The duration of the thrombocytopenia and the fact that some of the few responses that did occur were also durable after the end of treatment suggest that the dimer drug, the cytotoxic “payload” of the antibody-drug conjugate, was responsible for the effects they observed, the authors said.

The study was funded by Seattle Genetics. Dr. Phillips reported advisory board membership with the company, and four of the coauthors are employees of the company with equity interests.

SOURCE: Phillips T et al. Invest New Drugs. 2018 Aug 22. doi: 10.1007/s10637-018-0655-0.

An investigational antibody-drug conjugate labeled SGN-CD70A showed signs of efficacy against relapsed or refractory non-Hodgkin lymphomas in a phase 1 trial, but its future is clouded by a high incidence of treatment-associated thrombocytopenia, investigators reported.

Among 20 patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and other histologies, SGN-CD70A was associated with one complete remission (CR) and three partial remissions (PR), two of which were ongoing at nearly 43 weeks of follow-up.

However, 15 of the 20 patients (75%) had treatment-related thrombocytopenias, and 13 of these adverse events (AEs) were grade 3 or greater in severity, reported Tycel Phillips, MD, of the University of Michigan, Ann Arbor, and his colleagues.

Notwithstanding the antibody-drug conjugate’s apparent efficacy in this early trial, “the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term of response with limited drug exposure. Given that we are currently unable to mitigate this AE, the rationale for further investigation of SGN-CD70A remains limited and is, therefore, not planned,” they wrote in the journal Investigational New Drugs.

SGN-CD70A consists of an antibody directed against the plasma membrane protein CD70, a protease-cleavable linker, and a DNA-crosslinking pyrrolobenzodiazepine dimer drug. Its mechanism of action is via double-strand DNA breaks in CD70-positive cells that eventually cause programmed cell death.

Dr. Phillips and his colleagues reported on the high-risk non-Hodgkin lymphoma cohort in the phase 1 trial. The cohort included nine patients with DLBCL, five with mantle cell lymphoma, two with transformed DLBCL, one with T- cell/histocyte–rich large B cell lymphoma, and three with unspecified NHL histologies.

The patients had undergone a median of 3.5 prior lines of systemic therapy, and all had relatively good performance status, with Eastern Cooperative Oncology Group scores of 0 or 1.

Patients were started on intravenous SGN-CD70A at a dose of 8 mcg/kg on day 1 of each 3-week cycle, with a planned dose escalation to 200 mcg/kg, The protocol was amended to dosing every 6 weeks, however, after the investigators observed prolonged thrombocytopenias in some patients. A total of 12 patients were treated every 3 weeks, and 8 were treated every 6 weeks.

The most common treatment-related AEs were thrombocytopenias, which occurred in three-quarters of all patients, and were largely grade 3 or greater in severity. Other treatment-related AEs of grade 3 or greater occurring in more than one patient include neutropenia in six patients; anemia in five patients; and congestive heart failure, Clostridium difficile infections, dyspnea, and decreased forced expiratory volume in two patients each.

Other common AEs were nausea and fatigue.

The investigators noted that the cause of the deep and durable thrombocytopenias could not be determined, despite assessment of known biomarkers for this complication.

The duration of the thrombocytopenia and the fact that some of the few responses that did occur were also durable after the end of treatment suggest that the dimer drug, the cytotoxic “payload” of the antibody-drug conjugate, was responsible for the effects they observed, the authors said.

The study was funded by Seattle Genetics. Dr. Phillips reported advisory board membership with the company, and four of the coauthors are employees of the company with equity interests.

SOURCE: Phillips T et al. Invest New Drugs. 2018 Aug 22. doi: 10.1007/s10637-018-0655-0.

CHICAGO – Single-agent lurbinectedin (PM1183, Zepsyre) showed “encouraging” activity against advanced Ewing’s Sarcoma in previously treated adults, results of a phase 2 study indicated.

Among 28 adults with Ewing’s sarcoma (ES) that had relapsed after up to two prior lines of therapy, treatment with lurbinectedin was associated with five partial responses and six cases of stable disease, reported Vivek Subbiah, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“Treatment in combination with other agents is warranted in this patient population,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

Lurbinectedin’s mechanism of action is through blocking DNA transcription and inducing DNA double-strand breaks, which leads to programmed cell death.

“Moreover, in sarcomas associated with translocations, such as ES, in which the translocation produces a fusion protein that acts as a deregulated transcription factor, lurbinectedin might interfere with the binding of this protein to specific DNA promoters and thus with the synthesis of downstream proteins,” the investigators wrote.

This agent is being investigated against ES as part of a phase 2 basket trial, which is testing the drug against a variety of malignancies. The ES cohort in this study included 15 adults who had received up to two prior chemotherapy regimens. The trial rules called for recruitment of a minimum of 10 more patients if at least one of the first 15 had a confirmed response. There were two responses among the 15 patients, leading to an expansion cohort with 13 patients, for a total of 28 in the current analysis.

The median patient age was 33 years (range, 18-74 years). The majority of patients had good performance status, with Eastern Cooperative Oncology Group scores of 0 (11 patients) or 1 (15 patients); one patient had an ECOG PS score of 2, and one had unknown status.

All but one patient had received a minimum of two prior lines of therapy.

The patients were treated with lurbinectedin 3.2 mg/m² in a 1-hour infusion on day 1 of every 21-day cycle, with the longest duration of therapy out to 14 cycles.

Among 25 evaluable patients, eight had tumor shrinkage, ranging from less than 5% (two patients) to more than 45% (four patients).

Median progression-free survival (PFS) was 2.7 months. The 4-month PFS rate was 42.9%, and the 6-month rates was 21.4%.

A total of 11 patients had some clinical benefit, including five partial responses and six cases of stable disease.

Grade 3 or 4 treatment-related adverse events included febrile neutropenia (two events grade 3 and two grade 4), anemia (five events, all grade 3), neutropenia (five grade 3 and 10 grade 4), thrombocytopenia (four grade 3 events), and elevated alanine aminotransferase levels (two grade 3 events).

Myelosuppression was transient and manageable with granulocyte colony-stimulating factor, the investigators said.

The study was supported by PharmaMar. Dr. Subbiah disclosed travel, accommodations, and/or expenses from the company and from Bayer; a consulting or advisory role with MedImmune; and institutional research funding from PharmaMar and multiple other companies.

SOURCE: Subbiah V et al. ASCO 2018, Abstract 11519.

CHICAGO – Single-agent lurbinectedin (PM1183, Zepsyre) showed “encouraging” activity against advanced Ewing’s Sarcoma in previously treated adults, results of a phase 2 study indicated.

Among 28 adults with Ewing’s sarcoma (ES) that had relapsed after up to two prior lines of therapy, treatment with lurbinectedin was associated with five partial responses and six cases of stable disease, reported Vivek Subbiah, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“Treatment in combination with other agents is warranted in this patient population,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

Lurbinectedin’s mechanism of action is through blocking DNA transcription and inducing DNA double-strand breaks, which leads to programmed cell death.

“Moreover, in sarcomas associated with translocations, such as ES, in which the translocation produces a fusion protein that acts as a deregulated transcription factor, lurbinectedin might interfere with the binding of this protein to specific DNA promoters and thus with the synthesis of downstream proteins,” the investigators wrote.

This agent is being investigated against ES as part of a phase 2 basket trial, which is testing the drug against a variety of malignancies. The ES cohort in this study included 15 adults who had received up to two prior chemotherapy regimens. The trial rules called for recruitment of a minimum of 10 more patients if at least one of the first 15 had a confirmed response. There were two responses among the 15 patients, leading to an expansion cohort with 13 patients, for a total of 28 in the current analysis.

The median patient age was 33 years (range, 18-74 years). The majority of patients had good performance status, with Eastern Cooperative Oncology Group scores of 0 (11 patients) or 1 (15 patients); one patient had an ECOG PS score of 2, and one had unknown status.

All but one patient had received a minimum of two prior lines of therapy.

The patients were treated with lurbinectedin 3.2 mg/m² in a 1-hour infusion on day 1 of every 21-day cycle, with the longest duration of therapy out to 14 cycles.

Among 25 evaluable patients, eight had tumor shrinkage, ranging from less than 5% (two patients) to more than 45% (four patients).

Median progression-free survival (PFS) was 2.7 months. The 4-month PFS rate was 42.9%, and the 6-month rates was 21.4%.

A total of 11 patients had some clinical benefit, including five partial responses and six cases of stable disease.

Grade 3 or 4 treatment-related adverse events included febrile neutropenia (two events grade 3 and two grade 4), anemia (five events, all grade 3), neutropenia (five grade 3 and 10 grade 4), thrombocytopenia (four grade 3 events), and elevated alanine aminotransferase levels (two grade 3 events).

Myelosuppression was transient and manageable with granulocyte colony-stimulating factor, the investigators said.

The study was supported by PharmaMar. Dr. Subbiah disclosed travel, accommodations, and/or expenses from the company and from Bayer; a consulting or advisory role with MedImmune; and institutional research funding from PharmaMar and multiple other companies.

SOURCE: Subbiah V et al. ASCO 2018, Abstract 11519.

CHICAGO – Single-agent lurbinectedin (PM1183, Zepsyre) showed “encouraging” activity against advanced Ewing’s Sarcoma in previously treated adults, results of a phase 2 study indicated.

Among 28 adults with Ewing’s sarcoma (ES) that had relapsed after up to two prior lines of therapy, treatment with lurbinectedin was associated with five partial responses and six cases of stable disease, reported Vivek Subbiah, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“Treatment in combination with other agents is warranted in this patient population,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

Lurbinectedin’s mechanism of action is through blocking DNA transcription and inducing DNA double-strand breaks, which leads to programmed cell death.

“Moreover, in sarcomas associated with translocations, such as ES, in which the translocation produces a fusion protein that acts as a deregulated transcription factor, lurbinectedin might interfere with the binding of this protein to specific DNA promoters and thus with the synthesis of downstream proteins,” the investigators wrote.

This agent is being investigated against ES as part of a phase 2 basket trial, which is testing the drug against a variety of malignancies. The ES cohort in this study included 15 adults who had received up to two prior chemotherapy regimens. The trial rules called for recruitment of a minimum of 10 more patients if at least one of the first 15 had a confirmed response. There were two responses among the 15 patients, leading to an expansion cohort with 13 patients, for a total of 28 in the current analysis.

The median patient age was 33 years (range, 18-74 years). The majority of patients had good performance status, with Eastern Cooperative Oncology Group scores of 0 (11 patients) or 1 (15 patients); one patient had an ECOG PS score of 2, and one had unknown status.

All but one patient had received a minimum of two prior lines of therapy.

The patients were treated with lurbinectedin 3.2 mg/m² in a 1-hour infusion on day 1 of every 21-day cycle, with the longest duration of therapy out to 14 cycles.

Among 25 evaluable patients, eight had tumor shrinkage, ranging from less than 5% (two patients) to more than 45% (four patients).

Median progression-free survival (PFS) was 2.7 months. The 4-month PFS rate was 42.9%, and the 6-month rates was 21.4%.

A total of 11 patients had some clinical benefit, including five partial responses and six cases of stable disease.

Grade 3 or 4 treatment-related adverse events included febrile neutropenia (two events grade 3 and two grade 4), anemia (five events, all grade 3), neutropenia (five grade 3 and 10 grade 4), thrombocytopenia (four grade 3 events), and elevated alanine aminotransferase levels (two grade 3 events).

Myelosuppression was transient and manageable with granulocyte colony-stimulating factor, the investigators said.

The study was supported by PharmaMar. Dr. Subbiah disclosed travel, accommodations, and/or expenses from the company and from Bayer; a consulting or advisory role with MedImmune; and institutional research funding from PharmaMar and multiple other companies.

SOURCE: Subbiah V et al. ASCO 2018, Abstract 11519.