Mary Ann Moon

The risk of recurrence (ROR) score provides clinically meaningful prognostic information after postmenopausal women with early-stage breast cancer complete 5 years of tamoxifen therapy, according to a report published online Oct. 27 in Journal of Clinical Oncology.

The ROR score is derived from a quantitative assessment of a tumor’s expression of 46 genes related to breast cancer plus a measure of the tumor’s size. In this study, it was added to the Clinical Treatment Score, a standard prognostic tool that takes into account nodal status, tumor size and grade, patient age, and treatment modalities, said Ivana Sestak, Ph.D., of the Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University, London, and her associates.

To examine the usefulness of the ROR score in assessing risk for late recurrence of breast cancer, researchers analyzed combined data from two large clinical trials involving 2,137 postmenopausal women with early-stage hormone receptor–positive breast cancer who received 5 years of endocrine therapy but no chemotherapy and were followed for a further 5 years. There were 148 distant recurrences during that time.

Women classified by ROR score as high risk were 6.9 times more likely to develop a late recurrence than were those classified as low risk, and women classified by ROR score as intermediate risk were 3.3 times more likely to develop a late recurrence. The addition of ROR score to the Clinical Treatment Score reclassified 32 women as high risk, and those women did go on to develop a late recurrence. Similarly, adding to ROR score to the Clinical Treatment Score reclassified three women as low risk, and those women did not go on to develop a late recurrence, the investigators said (J. Clin. Oncol. 2014 Oct. 27 [doi:10.1200/JCO.2014.55.6894]).

In particular, the ROR score was helpful in assigning a “low-risk” designation to women who had node-negative and node-negative/HER2-negative disease, even though some of them had large tumors. These women could safely be spared from further endocrine therapy. Likewise, the ROR score was helpful in identifying women at high risk of recurrence who may wish to extend endocrine therapy beyond 5 years, Dr. Sestak and her associates said.

The risk of recurrence (ROR) score provides clinically meaningful prognostic information after postmenopausal women with early-stage breast cancer complete 5 years of tamoxifen therapy, according to a report published online Oct. 27 in Journal of Clinical Oncology.

The ROR score is derived from a quantitative assessment of a tumor’s expression of 46 genes related to breast cancer plus a measure of the tumor’s size. In this study, it was added to the Clinical Treatment Score, a standard prognostic tool that takes into account nodal status, tumor size and grade, patient age, and treatment modalities, said Ivana Sestak, Ph.D., of the Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University, London, and her associates.

To examine the usefulness of the ROR score in assessing risk for late recurrence of breast cancer, researchers analyzed combined data from two large clinical trials involving 2,137 postmenopausal women with early-stage hormone receptor–positive breast cancer who received 5 years of endocrine therapy but no chemotherapy and were followed for a further 5 years. There were 148 distant recurrences during that time.

Women classified by ROR score as high risk were 6.9 times more likely to develop a late recurrence than were those classified as low risk, and women classified by ROR score as intermediate risk were 3.3 times more likely to develop a late recurrence. The addition of ROR score to the Clinical Treatment Score reclassified 32 women as high risk, and those women did go on to develop a late recurrence. Similarly, adding to ROR score to the Clinical Treatment Score reclassified three women as low risk, and those women did not go on to develop a late recurrence, the investigators said (J. Clin. Oncol. 2014 Oct. 27 [doi:10.1200/JCO.2014.55.6894]).

In particular, the ROR score was helpful in assigning a “low-risk” designation to women who had node-negative and node-negative/HER2-negative disease, even though some of them had large tumors. These women could safely be spared from further endocrine therapy. Likewise, the ROR score was helpful in identifying women at high risk of recurrence who may wish to extend endocrine therapy beyond 5 years, Dr. Sestak and her associates said.

The risk of recurrence (ROR) score provides clinically meaningful prognostic information after postmenopausal women with early-stage breast cancer complete 5 years of tamoxifen therapy, according to a report published online Oct. 27 in Journal of Clinical Oncology.

The ROR score is derived from a quantitative assessment of a tumor’s expression of 46 genes related to breast cancer plus a measure of the tumor’s size. In this study, it was added to the Clinical Treatment Score, a standard prognostic tool that takes into account nodal status, tumor size and grade, patient age, and treatment modalities, said Ivana Sestak, Ph.D., of the Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University, London, and her associates.

To examine the usefulness of the ROR score in assessing risk for late recurrence of breast cancer, researchers analyzed combined data from two large clinical trials involving 2,137 postmenopausal women with early-stage hormone receptor–positive breast cancer who received 5 years of endocrine therapy but no chemotherapy and were followed for a further 5 years. There were 148 distant recurrences during that time.

Women classified by ROR score as high risk were 6.9 times more likely to develop a late recurrence than were those classified as low risk, and women classified by ROR score as intermediate risk were 3.3 times more likely to develop a late recurrence. The addition of ROR score to the Clinical Treatment Score reclassified 32 women as high risk, and those women did go on to develop a late recurrence. Similarly, adding to ROR score to the Clinical Treatment Score reclassified three women as low risk, and those women did not go on to develop a late recurrence, the investigators said (J. Clin. Oncol. 2014 Oct. 27 [doi:10.1200/JCO.2014.55.6894]).

In particular, the ROR score was helpful in assigning a “low-risk” designation to women who had node-negative and node-negative/HER2-negative disease, even though some of them had large tumors. These women could safely be spared from further endocrine therapy. Likewise, the ROR score was helpful in identifying women at high risk of recurrence who may wish to extend endocrine therapy beyond 5 years, Dr. Sestak and her associates said.

None of the 19 potential biomarkers assessed in an exploratory study were found to help select which patients with HER2-positive metastatic breast cancer would benefit most from treatment with the monoclonal anti-HER2 antibody pertuzumab – other than the HER2 biomarker already in use for that purpose, according to a report published online Oct. 27 in Journal of Clinical Oncology.

Even though anti-HER2 therapies for metastatic breast cancer have been in use for more than 15 years, HER2 status itself remains the only marker of sensitivity to those agents, and it is an imperfect one. “We therefore aimed to explore within the HER2-positive patient population whether subgroups that derive differential progression-free survival or overall survival benefit from HER2-targeted treatment can be identified based on biomarker profiles,” said Dr. José Baselga, physician in chief and chief medical officer at Memorial Sloan Kettering Cancer Center, New York, and his associates.

They analyzed tumor, serum, and whole blood samples from 808 participants in a phase III randomized clinical trial assessing response to pertuzumab and trastuzumab therapy. These patients had locally recurrent nonresectable or metastatic breast cancer and had not received any chemotherapy. Each tissue sample was tested using a panel of 19 potentially useful biomarkers thought to be involved in either resistance to HER2-targeted agents or regulation of HER2-signaling pathways, the investigators said (J. Clin. Oncol. 2014 Oct. 27 [doi:10.1200/JCO.2013.54.5384]).

None of the biomarkers were found to correlate with treatment response, as measured by the patients’ progression-free and overall survival. One biomarker, a mutation in the PIK3CA gene, appeared to identify tumors that would not respond well to pertuzumab even though they expressed HER2, but further study of this possible association is needed, Dr. Baselga and his associates said.

None of the 19 potential biomarkers assessed in an exploratory study were found to help select which patients with HER2-positive metastatic breast cancer would benefit most from treatment with the monoclonal anti-HER2 antibody pertuzumab – other than the HER2 biomarker already in use for that purpose, according to a report published online Oct. 27 in Journal of Clinical Oncology.

Even though anti-HER2 therapies for metastatic breast cancer have been in use for more than 15 years, HER2 status itself remains the only marker of sensitivity to those agents, and it is an imperfect one. “We therefore aimed to explore within the HER2-positive patient population whether subgroups that derive differential progression-free survival or overall survival benefit from HER2-targeted treatment can be identified based on biomarker profiles,” said Dr. José Baselga, physician in chief and chief medical officer at Memorial Sloan Kettering Cancer Center, New York, and his associates.

They analyzed tumor, serum, and whole blood samples from 808 participants in a phase III randomized clinical trial assessing response to pertuzumab and trastuzumab therapy. These patients had locally recurrent nonresectable or metastatic breast cancer and had not received any chemotherapy. Each tissue sample was tested using a panel of 19 potentially useful biomarkers thought to be involved in either resistance to HER2-targeted agents or regulation of HER2-signaling pathways, the investigators said (J. Clin. Oncol. 2014 Oct. 27 [doi:10.1200/JCO.2013.54.5384]).

None of the biomarkers were found to correlate with treatment response, as measured by the patients’ progression-free and overall survival. One biomarker, a mutation in the PIK3CA gene, appeared to identify tumors that would not respond well to pertuzumab even though they expressed HER2, but further study of this possible association is needed, Dr. Baselga and his associates said.

None of the 19 potential biomarkers assessed in an exploratory study were found to help select which patients with HER2-positive metastatic breast cancer would benefit most from treatment with the monoclonal anti-HER2 antibody pertuzumab – other than the HER2 biomarker already in use for that purpose, according to a report published online Oct. 27 in Journal of Clinical Oncology.

Even though anti-HER2 therapies for metastatic breast cancer have been in use for more than 15 years, HER2 status itself remains the only marker of sensitivity to those agents, and it is an imperfect one. “We therefore aimed to explore within the HER2-positive patient population whether subgroups that derive differential progression-free survival or overall survival benefit from HER2-targeted treatment can be identified based on biomarker profiles,” said Dr. José Baselga, physician in chief and chief medical officer at Memorial Sloan Kettering Cancer Center, New York, and his associates.

They analyzed tumor, serum, and whole blood samples from 808 participants in a phase III randomized clinical trial assessing response to pertuzumab and trastuzumab therapy. These patients had locally recurrent nonresectable or metastatic breast cancer and had not received any chemotherapy. Each tissue sample was tested using a panel of 19 potentially useful biomarkers thought to be involved in either resistance to HER2-targeted agents or regulation of HER2-signaling pathways, the investigators said (J. Clin. Oncol. 2014 Oct. 27 [doi:10.1200/JCO.2013.54.5384]).

None of the biomarkers were found to correlate with treatment response, as measured by the patients’ progression-free and overall survival. One biomarker, a mutation in the PIK3CA gene, appeared to identify tumors that would not respond well to pertuzumab even though they expressed HER2, but further study of this possible association is needed, Dr. Baselga and his associates said.

A 9-week course of multiagent biochemotherapy markedly improved relapse-free survival in patients with high-risk melanoma, compared with the 1-year course of high-dose interferon that has been the unchallenged standard of care for this disease for decades, according to a report published online Oct. 27 in the Journal of Clinical Oncology.

“This [phase III] randomized trial is the first to compare a multiagent regimen against high-dose interferon … and the first to demonstrate a statistically significant relapse-free survival benefit for any treatment regimen over high-dose interferon,” said Dr. Lawrence E. Flaherty of Wayne State University and the Karmanos Cancer Institute, Detroit, and his associates.

Moreover, the median relapse-free survival of 4 years achieved with biochemotherapy “represents a value not previously observed in any adjuvant therapy trial for patients with high-risk melanoma,” the investigators said. Unfortunately, this benefit did not translate into increased overall survival in this study, which was 56% at 5 years for both treatment groups.

The investigators enrolled patients aged 10-74 years (median age, 47 years) who had undergone wide excision of a cutaneous primary melanoma (stage IIIA-N2a and above) with pathologically negative margins and a complete regional lymphadenectomy. These study participants had no clinical, radiologic, or pathologic evidence of residual or metastatic melanoma, and had never undergone radiotherapy, chemotherapy, or immunotherapy for any type of cancer. They were randomly assigned to receive either high-dose intravenous interferon for 52 weeks (203 patients), or cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon every 21 days for a total of three cycles (199 patients).

After a median of 7.2 years of follow-up, the median relapse-free survival was 4.0 years for biochemotherapy, compared with only 1.9 years for high-dose interferon alone. The 5-year relapse-free survival rate was 48% for biochemotherapy, compared with only 39% for high-dose interferon alone. However, there was no corresponding improvement in overall survival: The median overall survival was 9.9 years for biochemotherapy, compared with 6.7 years for high-dose interferon alone, and 5-year overall survival was 56% for both study groups, Dr. Flaherty and his associates reported (J. Clin. Oncol. October 2014 [doi:10.1200/JCO.2013.53.1590]).

“Toxicities for biochemotherapy and high-dose interferon are different but comparable in magnitude, particularly when discontinuation for toxicity is considered,” they wrote. Biochemotherapy was associated with a higher rate of grade 4 toxicity (40% vs 7%), but rates of grade 3 and 4 toxicity were similar (76% vs 64%), and most toxicity related to biochemotherapy was hematologic and of short duration. The rate of discontinuation of treatment was 15% for biochemotherapy and 19% for high-dose interferon alone, a nonsignificant difference.

These findings indicate that biochemotherapy can be considered an alternative adjuvant treatment for high-risk melanoma “in appropriately selected patients by physicians at centers experienced in the use of this regimen,” Dr. Flaherty and his associates said.

A 9-week course of multiagent biochemotherapy markedly improved relapse-free survival in patients with high-risk melanoma, compared with the 1-year course of high-dose interferon that has been the unchallenged standard of care for this disease for decades, according to a report published online Oct. 27 in the Journal of Clinical Oncology.

“This [phase III] randomized trial is the first to compare a multiagent regimen against high-dose interferon … and the first to demonstrate a statistically significant relapse-free survival benefit for any treatment regimen over high-dose interferon,” said Dr. Lawrence E. Flaherty of Wayne State University and the Karmanos Cancer Institute, Detroit, and his associates.

Moreover, the median relapse-free survival of 4 years achieved with biochemotherapy “represents a value not previously observed in any adjuvant therapy trial for patients with high-risk melanoma,” the investigators said. Unfortunately, this benefit did not translate into increased overall survival in this study, which was 56% at 5 years for both treatment groups.

The investigators enrolled patients aged 10-74 years (median age, 47 years) who had undergone wide excision of a cutaneous primary melanoma (stage IIIA-N2a and above) with pathologically negative margins and a complete regional lymphadenectomy. These study participants had no clinical, radiologic, or pathologic evidence of residual or metastatic melanoma, and had never undergone radiotherapy, chemotherapy, or immunotherapy for any type of cancer. They were randomly assigned to receive either high-dose intravenous interferon for 52 weeks (203 patients), or cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon every 21 days for a total of three cycles (199 patients).

After a median of 7.2 years of follow-up, the median relapse-free survival was 4.0 years for biochemotherapy, compared with only 1.9 years for high-dose interferon alone. The 5-year relapse-free survival rate was 48% for biochemotherapy, compared with only 39% for high-dose interferon alone. However, there was no corresponding improvement in overall survival: The median overall survival was 9.9 years for biochemotherapy, compared with 6.7 years for high-dose interferon alone, and 5-year overall survival was 56% for both study groups, Dr. Flaherty and his associates reported (J. Clin. Oncol. October 2014 [doi:10.1200/JCO.2013.53.1590]).

“Toxicities for biochemotherapy and high-dose interferon are different but comparable in magnitude, particularly when discontinuation for toxicity is considered,” they wrote. Biochemotherapy was associated with a higher rate of grade 4 toxicity (40% vs 7%), but rates of grade 3 and 4 toxicity were similar (76% vs 64%), and most toxicity related to biochemotherapy was hematologic and of short duration. The rate of discontinuation of treatment was 15% for biochemotherapy and 19% for high-dose interferon alone, a nonsignificant difference.

These findings indicate that biochemotherapy can be considered an alternative adjuvant treatment for high-risk melanoma “in appropriately selected patients by physicians at centers experienced in the use of this regimen,” Dr. Flaherty and his associates said.

A 9-week course of multiagent biochemotherapy markedly improved relapse-free survival in patients with high-risk melanoma, compared with the 1-year course of high-dose interferon that has been the unchallenged standard of care for this disease for decades, according to a report published online Oct. 27 in the Journal of Clinical Oncology.

“This [phase III] randomized trial is the first to compare a multiagent regimen against high-dose interferon … and the first to demonstrate a statistically significant relapse-free survival benefit for any treatment regimen over high-dose interferon,” said Dr. Lawrence E. Flaherty of Wayne State University and the Karmanos Cancer Institute, Detroit, and his associates.

Moreover, the median relapse-free survival of 4 years achieved with biochemotherapy “represents a value not previously observed in any adjuvant therapy trial for patients with high-risk melanoma,” the investigators said. Unfortunately, this benefit did not translate into increased overall survival in this study, which was 56% at 5 years for both treatment groups.

The investigators enrolled patients aged 10-74 years (median age, 47 years) who had undergone wide excision of a cutaneous primary melanoma (stage IIIA-N2a and above) with pathologically negative margins and a complete regional lymphadenectomy. These study participants had no clinical, radiologic, or pathologic evidence of residual or metastatic melanoma, and had never undergone radiotherapy, chemotherapy, or immunotherapy for any type of cancer. They were randomly assigned to receive either high-dose intravenous interferon for 52 weeks (203 patients), or cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon every 21 days for a total of three cycles (199 patients).

After a median of 7.2 years of follow-up, the median relapse-free survival was 4.0 years for biochemotherapy, compared with only 1.9 years for high-dose interferon alone. The 5-year relapse-free survival rate was 48% for biochemotherapy, compared with only 39% for high-dose interferon alone. However, there was no corresponding improvement in overall survival: The median overall survival was 9.9 years for biochemotherapy, compared with 6.7 years for high-dose interferon alone, and 5-year overall survival was 56% for both study groups, Dr. Flaherty and his associates reported (J. Clin. Oncol. October 2014 [doi:10.1200/JCO.2013.53.1590]).

“Toxicities for biochemotherapy and high-dose interferon are different but comparable in magnitude, particularly when discontinuation for toxicity is considered,” they wrote. Biochemotherapy was associated with a higher rate of grade 4 toxicity (40% vs 7%), but rates of grade 3 and 4 toxicity were similar (76% vs 64%), and most toxicity related to biochemotherapy was hematologic and of short duration. The rate of discontinuation of treatment was 15% for biochemotherapy and 19% for high-dose interferon alone, a nonsignificant difference.

These findings indicate that biochemotherapy can be considered an alternative adjuvant treatment for high-risk melanoma “in appropriately selected patients by physicians at centers experienced in the use of this regimen,” Dr. Flaherty and his associates said.

Imaging to assess brain microstructure identified increased fractional anisotropy in the anterior right arcuate fasciculus of patients with chronic fatigue syndrome, which was not present in age- and sex-matched control subjects.

The right-sided abnormality was particularly marked in right-handed chronic fatigue syndrome (CFS) patients, and the degree of increase correlated with the severity of their disorder. A finding of increased fractional anisotropy in this area of the brain may eventually serve as a biomarker for CFS, said Dr. Michael M. Zeineh of the department of radiology at Stanford (Calif.) University, and his associates (Radiology 2014 Oct. 29 [doi:10.1148/radiol.14141079]).

Courtesy Radiological Society of North America

In what they described as the first study to examine brain microstructure in CFS, the investigators used volumetric MRI with diffusion-tensor imaging (DTI) to detect microstructural abnormalities in the patients – who had been evaluated at the university’s CFS Clinic during the preceding 5 years – and in healthy volunteers. The researchers also performed gray- and white-matter volumetric studies to identify differences between the two study groups in gross brain structure, as well as pseudocontinuous arterial spin labeling to assess global alterations in brain perfusion.

The mean age of the study participants was 46 years, and the mean duration of CFS symptoms was 12 years.

In the DTI analysis, the only significant difference between the two study groups was that the anterior right arcuate fasciculus – identified in 13 of 15 CFS patients and in all 14 control subjects in the study – showed significantly higher fractional anisotropy in CFS patients than in control subjects. This was confirmed in a second dataset from the same study subjects. The difference between CFS patients and control subjects was most pronounced in the subgroup of right-handed participants, “suggesting that hemispheric differences with handedness and language are an additional source of variance,” Dr. Zeineh and his associates said.

In addition, “two cortical regions connected via the arcuate fasciculus exhibited increased thickness: the right middle temporal and precentral gyri,” they noted.

The volumetric studies showed significantly lower total supratentorial white-matter volume in CFS, even after the data were adjusted to account for subject age, total intracranial volume, and handedness. However, total cortical gray-matter volume was equivalent between the two study groups, as were prefrontal cortex volume and global cortical thickness.

There were no differences between patients and controls in any perfusion measure, including perfusion to the cortex, supratentorial white matter, basal ganglia, thalami, or hippocampi. This finding is consistent with the results of a previous perfusion study involving monozygotic twins. Taken together, the findings suggest that brain perfusion is not affected in CFS.

Given the small number of subjects in this study, the findings must be verified in larger studies. It also would be valuable to assess possible changes in brain microstructure over time in a longitudinal study, and to determine whether treatment interventions exert any beneficial effects, the investigators added.

Imaging to assess brain microstructure identified increased fractional anisotropy in the anterior right arcuate fasciculus of patients with chronic fatigue syndrome, which was not present in age- and sex-matched control subjects.

The right-sided abnormality was particularly marked in right-handed chronic fatigue syndrome (CFS) patients, and the degree of increase correlated with the severity of their disorder. A finding of increased fractional anisotropy in this area of the brain may eventually serve as a biomarker for CFS, said Dr. Michael M. Zeineh of the department of radiology at Stanford (Calif.) University, and his associates (Radiology 2014 Oct. 29 [doi:10.1148/radiol.14141079]).

Courtesy Radiological Society of North America

In what they described as the first study to examine brain microstructure in CFS, the investigators used volumetric MRI with diffusion-tensor imaging (DTI) to detect microstructural abnormalities in the patients – who had been evaluated at the university’s CFS Clinic during the preceding 5 years – and in healthy volunteers. The researchers also performed gray- and white-matter volumetric studies to identify differences between the two study groups in gross brain structure, as well as pseudocontinuous arterial spin labeling to assess global alterations in brain perfusion.

The mean age of the study participants was 46 years, and the mean duration of CFS symptoms was 12 years.

In the DTI analysis, the only significant difference between the two study groups was that the anterior right arcuate fasciculus – identified in 13 of 15 CFS patients and in all 14 control subjects in the study – showed significantly higher fractional anisotropy in CFS patients than in control subjects. This was confirmed in a second dataset from the same study subjects. The difference between CFS patients and control subjects was most pronounced in the subgroup of right-handed participants, “suggesting that hemispheric differences with handedness and language are an additional source of variance,” Dr. Zeineh and his associates said.

In addition, “two cortical regions connected via the arcuate fasciculus exhibited increased thickness: the right middle temporal and precentral gyri,” they noted.

The volumetric studies showed significantly lower total supratentorial white-matter volume in CFS, even after the data were adjusted to account for subject age, total intracranial volume, and handedness. However, total cortical gray-matter volume was equivalent between the two study groups, as were prefrontal cortex volume and global cortical thickness.

There were no differences between patients and controls in any perfusion measure, including perfusion to the cortex, supratentorial white matter, basal ganglia, thalami, or hippocampi. This finding is consistent with the results of a previous perfusion study involving monozygotic twins. Taken together, the findings suggest that brain perfusion is not affected in CFS.

Given the small number of subjects in this study, the findings must be verified in larger studies. It also would be valuable to assess possible changes in brain microstructure over time in a longitudinal study, and to determine whether treatment interventions exert any beneficial effects, the investigators added.

Imaging to assess brain microstructure identified increased fractional anisotropy in the anterior right arcuate fasciculus of patients with chronic fatigue syndrome, which was not present in age- and sex-matched control subjects.

The right-sided abnormality was particularly marked in right-handed chronic fatigue syndrome (CFS) patients, and the degree of increase correlated with the severity of their disorder. A finding of increased fractional anisotropy in this area of the brain may eventually serve as a biomarker for CFS, said Dr. Michael M. Zeineh of the department of radiology at Stanford (Calif.) University, and his associates (Radiology 2014 Oct. 29 [doi:10.1148/radiol.14141079]).

Courtesy Radiological Society of North America

In what they described as the first study to examine brain microstructure in CFS, the investigators used volumetric MRI with diffusion-tensor imaging (DTI) to detect microstructural abnormalities in the patients – who had been evaluated at the university’s CFS Clinic during the preceding 5 years – and in healthy volunteers. The researchers also performed gray- and white-matter volumetric studies to identify differences between the two study groups in gross brain structure, as well as pseudocontinuous arterial spin labeling to assess global alterations in brain perfusion.

The mean age of the study participants was 46 years, and the mean duration of CFS symptoms was 12 years.

In the DTI analysis, the only significant difference between the two study groups was that the anterior right arcuate fasciculus – identified in 13 of 15 CFS patients and in all 14 control subjects in the study – showed significantly higher fractional anisotropy in CFS patients than in control subjects. This was confirmed in a second dataset from the same study subjects. The difference between CFS patients and control subjects was most pronounced in the subgroup of right-handed participants, “suggesting that hemispheric differences with handedness and language are an additional source of variance,” Dr. Zeineh and his associates said.

In addition, “two cortical regions connected via the arcuate fasciculus exhibited increased thickness: the right middle temporal and precentral gyri,” they noted.

The volumetric studies showed significantly lower total supratentorial white-matter volume in CFS, even after the data were adjusted to account for subject age, total intracranial volume, and handedness. However, total cortical gray-matter volume was equivalent between the two study groups, as were prefrontal cortex volume and global cortical thickness.

There were no differences between patients and controls in any perfusion measure, including perfusion to the cortex, supratentorial white matter, basal ganglia, thalami, or hippocampi. This finding is consistent with the results of a previous perfusion study involving monozygotic twins. Taken together, the findings suggest that brain perfusion is not affected in CFS.

Given the small number of subjects in this study, the findings must be verified in larger studies. It also would be valuable to assess possible changes in brain microstructure over time in a longitudinal study, and to determine whether treatment interventions exert any beneficial effects, the investigators added.

For premenopausal women who have undergone definitive surgery for node-negative invasive breast cancer, adjuvant therapy with tamoxifen plus ovarian function suppression significantly impairs quality of life, compared with tamoxifen alone, according to a report published online October 27 in Journal of Clinical Oncology.

The role of ovarian function suppression in this setting remains uncertain because most studies examining the issue have been relatively short (2 years or less) and have included patients undergoing cytotoxic chemotherapy, which makes it difficult to tease out which drugs produce which outcomes of interest. In contrast, this open-label, phase III, randomized trial by the Eastern Cooperative Oncology Group had a mean follow-up of 10 years, and it included only women with hormone receptor–positive tumors measuring 3 cm or less who received no adjuvant chemotherapy, said Dr. Amye J. Tevaawerk of the University of Wisconsin, Madison, and her associates.

The 345 study participants were randomly assigned to receive either tamoxifen plus ovarian function suppression via goserelin, leuprolide, surgical ablation, or radiation ablation (174 women) or tamoxifen alone (171 women). The median age at baseline was 45 years (range, 26-55 years). The trial was designed to compare multiple outcomes, including disease-free survival, overall survival, and quality of life, but it was terminated early because of slow accrual and ultimately was only powered to detect differences in quality of life (QOL).

Throughout follow-up, women who received tamoxifen plus ovarian suppression reported inferior health-related QOL as measured by the Functional Assessment of Cancer Therapy – General (FACT-G) and the Functional Assessment of Cancer Therapy – Breast (FACT-B). They had more menopausal symptoms and lower levels of sexual function than women who received tamoxifen alone, regardless of patient age or race, tumor hormone-receptor status, tumor size, or type of surgical procedure. The differences between the two study groups were both statistically significant and clinically meaningful, Dr. Tevaawerk and her associates said (J. Clin. Oncol. 2014 October 27 [doi:10.1200/JCO.2014.55.6993]).

The negative impact of ovarian suppression gradually diminished after 3 years, most likely because increasing numbers of women receiving tamoxifen alone reached menopause. “Our results suggest that [studies with] durations of less than 3 years fail to capture the adverse effect peak and the health-related QOL nadir from ovarian function suppression,” the investigators said. “Given these data and in the absence of definitive data for improvement in disease-free survival or overall survival with ovarian function suppression, the American Society of Clinical Oncology guidelines are appropriately cautious about adding ovarian function suppression to tamoxifen,” they noted.

For premenopausal women who have undergone definitive surgery for node-negative invasive breast cancer, adjuvant therapy with tamoxifen plus ovarian function suppression significantly impairs quality of life, compared with tamoxifen alone, according to a report published online October 27 in Journal of Clinical Oncology.

The role of ovarian function suppression in this setting remains uncertain because most studies examining the issue have been relatively short (2 years or less) and have included patients undergoing cytotoxic chemotherapy, which makes it difficult to tease out which drugs produce which outcomes of interest. In contrast, this open-label, phase III, randomized trial by the Eastern Cooperative Oncology Group had a mean follow-up of 10 years, and it included only women with hormone receptor–positive tumors measuring 3 cm or less who received no adjuvant chemotherapy, said Dr. Amye J. Tevaawerk of the University of Wisconsin, Madison, and her associates.

The 345 study participants were randomly assigned to receive either tamoxifen plus ovarian function suppression via goserelin, leuprolide, surgical ablation, or radiation ablation (174 women) or tamoxifen alone (171 women). The median age at baseline was 45 years (range, 26-55 years). The trial was designed to compare multiple outcomes, including disease-free survival, overall survival, and quality of life, but it was terminated early because of slow accrual and ultimately was only powered to detect differences in quality of life (QOL).

Throughout follow-up, women who received tamoxifen plus ovarian suppression reported inferior health-related QOL as measured by the Functional Assessment of Cancer Therapy – General (FACT-G) and the Functional Assessment of Cancer Therapy – Breast (FACT-B). They had more menopausal symptoms and lower levels of sexual function than women who received tamoxifen alone, regardless of patient age or race, tumor hormone-receptor status, tumor size, or type of surgical procedure. The differences between the two study groups were both statistically significant and clinically meaningful, Dr. Tevaawerk and her associates said (J. Clin. Oncol. 2014 October 27 [doi:10.1200/JCO.2014.55.6993]).

The negative impact of ovarian suppression gradually diminished after 3 years, most likely because increasing numbers of women receiving tamoxifen alone reached menopause. “Our results suggest that [studies with] durations of less than 3 years fail to capture the adverse effect peak and the health-related QOL nadir from ovarian function suppression,” the investigators said. “Given these data and in the absence of definitive data for improvement in disease-free survival or overall survival with ovarian function suppression, the American Society of Clinical Oncology guidelines are appropriately cautious about adding ovarian function suppression to tamoxifen,” they noted.

For premenopausal women who have undergone definitive surgery for node-negative invasive breast cancer, adjuvant therapy with tamoxifen plus ovarian function suppression significantly impairs quality of life, compared with tamoxifen alone, according to a report published online October 27 in Journal of Clinical Oncology.

The role of ovarian function suppression in this setting remains uncertain because most studies examining the issue have been relatively short (2 years or less) and have included patients undergoing cytotoxic chemotherapy, which makes it difficult to tease out which drugs produce which outcomes of interest. In contrast, this open-label, phase III, randomized trial by the Eastern Cooperative Oncology Group had a mean follow-up of 10 years, and it included only women with hormone receptor–positive tumors measuring 3 cm or less who received no adjuvant chemotherapy, said Dr. Amye J. Tevaawerk of the University of Wisconsin, Madison, and her associates.

The 345 study participants were randomly assigned to receive either tamoxifen plus ovarian function suppression via goserelin, leuprolide, surgical ablation, or radiation ablation (174 women) or tamoxifen alone (171 women). The median age at baseline was 45 years (range, 26-55 years). The trial was designed to compare multiple outcomes, including disease-free survival, overall survival, and quality of life, but it was terminated early because of slow accrual and ultimately was only powered to detect differences in quality of life (QOL).

Throughout follow-up, women who received tamoxifen plus ovarian suppression reported inferior health-related QOL as measured by the Functional Assessment of Cancer Therapy – General (FACT-G) and the Functional Assessment of Cancer Therapy – Breast (FACT-B). They had more menopausal symptoms and lower levels of sexual function than women who received tamoxifen alone, regardless of patient age or race, tumor hormone-receptor status, tumor size, or type of surgical procedure. The differences between the two study groups were both statistically significant and clinically meaningful, Dr. Tevaawerk and her associates said (J. Clin. Oncol. 2014 October 27 [doi:10.1200/JCO.2014.55.6993]).

The negative impact of ovarian suppression gradually diminished after 3 years, most likely because increasing numbers of women receiving tamoxifen alone reached menopause. “Our results suggest that [studies with] durations of less than 3 years fail to capture the adverse effect peak and the health-related QOL nadir from ovarian function suppression,” the investigators said. “Given these data and in the absence of definitive data for improvement in disease-free survival or overall survival with ovarian function suppression, the American Society of Clinical Oncology guidelines are appropriately cautious about adding ovarian function suppression to tamoxifen,” they noted.

Stereotactic body radiation therapy dramatically prolonged progression-free survival and overall survival in a phase II study of 24 patients who had limited but progressive metastatic non–small-cell lung cancer.

The findings were published online Oct. 27 in Journal of Clinical Oncology.

When added to erlotinib, the aggressive local radiation technique, which delivers high doses in a few treatment sessions to extracranial malignant deposits, more than doubled progression-free and overall survival, compared with that in historical control subjects. These findings “encourage consideration of a new treatment paradigm with the inclusion of aggressive noninvasive local therapy in the form of stereotactic body radiation therapy,” said Dr. Puneeth Iyengar, a radiation oncologist at the University of Texas Southwestern Medical Center, Dallas, and his associates.

The study participants were adults with stage IV NSCLC who had undergone at least one systemic chemotherapy regimen and still had up to six metastases, most often in the lung parenchyma, mediastinal or hilar nodes, adrenal glands, liver, and spine. The contours of 52 metastatic deposits were mapped and treated with stereotactic body radiation therapy (SBRT). All the patients also received erlotinib, beginning 1 week before radiotherapy began and continuing until disease progressed or patients opted to stop the drug.

The primary efficacy outcome, median 6-month progression-free survival, was 69%. After a mean follow-up of 17 months (range, 3-60 months), median progression-free survival was 14.7 months and median overall survival was 20.4 months. In comparison, progression-free survival was only 2-4 months and overall survival only 6-9 months in historical cohorts of patients with stage IV NSCLC who progressed through multiple rounds of cytotoxic chemotherapy but did not receive SBRT.

At 3-month follow-up, 10 of 47 evaluable lesions were no longer visible and 24 others showed a reduction in volume of at least 30%. None of the metastases treated with SBRT showed any progression for at least 9 months.

“Our approach dramatically changed the pattern of relapse, with a shift in failure from existing sites (i.e., local) to new sites (i.e., distant). One-third of patients were able to receive additional cytotoxic chemotherapy after progression on our trial, with SBRT potentially allowing this subset to tolerate subsequent agents by delaying continued use,” Dr. Iyengar and his associates wrote (J. Clin. Oncol. 2014 Oct. 27 [doi:10.1200/JCO.2014.56.7412]).

Stereotactic body radiation therapy dramatically prolonged progression-free survival and overall survival in a phase II study of 24 patients who had limited but progressive metastatic non–small-cell lung cancer.

The findings were published online Oct. 27 in Journal of Clinical Oncology.

When added to erlotinib, the aggressive local radiation technique, which delivers high doses in a few treatment sessions to extracranial malignant deposits, more than doubled progression-free and overall survival, compared with that in historical control subjects. These findings “encourage consideration of a new treatment paradigm with the inclusion of aggressive noninvasive local therapy in the form of stereotactic body radiation therapy,” said Dr. Puneeth Iyengar, a radiation oncologist at the University of Texas Southwestern Medical Center, Dallas, and his associates.

The study participants were adults with stage IV NSCLC who had undergone at least one systemic chemotherapy regimen and still had up to six metastases, most often in the lung parenchyma, mediastinal or hilar nodes, adrenal glands, liver, and spine. The contours of 52 metastatic deposits were mapped and treated with stereotactic body radiation therapy (SBRT). All the patients also received erlotinib, beginning 1 week before radiotherapy began and continuing until disease progressed or patients opted to stop the drug.

The primary efficacy outcome, median 6-month progression-free survival, was 69%. After a mean follow-up of 17 months (range, 3-60 months), median progression-free survival was 14.7 months and median overall survival was 20.4 months. In comparison, progression-free survival was only 2-4 months and overall survival only 6-9 months in historical cohorts of patients with stage IV NSCLC who progressed through multiple rounds of cytotoxic chemotherapy but did not receive SBRT.

At 3-month follow-up, 10 of 47 evaluable lesions were no longer visible and 24 others showed a reduction in volume of at least 30%. None of the metastases treated with SBRT showed any progression for at least 9 months.

“Our approach dramatically changed the pattern of relapse, with a shift in failure from existing sites (i.e., local) to new sites (i.e., distant). One-third of patients were able to receive additional cytotoxic chemotherapy after progression on our trial, with SBRT potentially allowing this subset to tolerate subsequent agents by delaying continued use,” Dr. Iyengar and his associates wrote (J. Clin. Oncol. 2014 Oct. 27 [doi:10.1200/JCO.2014.56.7412]).

Stereotactic body radiation therapy dramatically prolonged progression-free survival and overall survival in a phase II study of 24 patients who had limited but progressive metastatic non–small-cell lung cancer.

The findings were published online Oct. 27 in Journal of Clinical Oncology.

When added to erlotinib, the aggressive local radiation technique, which delivers high doses in a few treatment sessions to extracranial malignant deposits, more than doubled progression-free and overall survival, compared with that in historical control subjects. These findings “encourage consideration of a new treatment paradigm with the inclusion of aggressive noninvasive local therapy in the form of stereotactic body radiation therapy,” said Dr. Puneeth Iyengar, a radiation oncologist at the University of Texas Southwestern Medical Center, Dallas, and his associates.

The study participants were adults with stage IV NSCLC who had undergone at least one systemic chemotherapy regimen and still had up to six metastases, most often in the lung parenchyma, mediastinal or hilar nodes, adrenal glands, liver, and spine. The contours of 52 metastatic deposits were mapped and treated with stereotactic body radiation therapy (SBRT). All the patients also received erlotinib, beginning 1 week before radiotherapy began and continuing until disease progressed or patients opted to stop the drug.

The primary efficacy outcome, median 6-month progression-free survival, was 69%. After a mean follow-up of 17 months (range, 3-60 months), median progression-free survival was 14.7 months and median overall survival was 20.4 months. In comparison, progression-free survival was only 2-4 months and overall survival only 6-9 months in historical cohorts of patients with stage IV NSCLC who progressed through multiple rounds of cytotoxic chemotherapy but did not receive SBRT.

At 3-month follow-up, 10 of 47 evaluable lesions were no longer visible and 24 others showed a reduction in volume of at least 30%. None of the metastases treated with SBRT showed any progression for at least 9 months.

“Our approach dramatically changed the pattern of relapse, with a shift in failure from existing sites (i.e., local) to new sites (i.e., distant). One-third of patients were able to receive additional cytotoxic chemotherapy after progression on our trial, with SBRT potentially allowing this subset to tolerate subsequent agents by delaying continued use,” Dr. Iyengar and his associates wrote (J. Clin. Oncol. 2014 Oct. 27 [doi:10.1200/JCO.2014.56.7412]).

Three different short-course treatment regimens for tuberculosis failed to show noninferiority to the standard 6-month course in separate phase III randomized clinical trials, even though the experimental regimens produced a more rapid decline in bacterial load, as expected, according to reports published online Oct. 23 in the New England Journal of Medicine.

The main reason that the short-course (4-month) approaches failed to measure up to standard treatment was that, despite their greater bactericidal activity, the rate of relapse was excessive after treatment was completed.

Photo Credit: Janice Carr, Centers for Disease Control and Prevention

Researchers undertook these large international trials because the data from several phase II and murine studies had been so promising: replacing either the isoniazid or the ethambutol in the standard anti-TB regimen with a fluoroquinolone appeared to permit shortening of the treatment period without sacrificing efficacy. But the consistently negative results from these phase III studies clearly demonstrate that this approach is not effective.

The first trial involved 1,931 adults with newly diagnosed and untreated Mycobacterium tuberculosis infection who were treated in South Africa, India, Tanzania, Kenya, Thailand, Malaysia, Zambia, China, and Mexico. These patients were randomly assigned to receive the standard regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid plus rifampin (control group, 640 participants); or an experimental regimen in which ethambutol was replaced by moxifloxacin for 17 weeks, followed by 9 weeks of placebo (655 participants); or an experimental regimen in which isoniazid was replaced by moxifloxacin in the same way (636 participants), said Dr. Stephen H. Gillespie of the University of St. Andrews (England) and University College London and his associates.

Patients in the two experimental groups converted to culture-negative status more rapidly than did those in the control group. However, in a per-protocol analysis, 92% of the control group achieved a favorable final outcome, compared with only 85% and 80% of the experimental groups, respectively. Results of a modified intention-to-treat analysis and of more than 20 sensitivity analyses showed the same pattern. At the end of active treatment, only 12 patients in the control group had a relapse of TB infection, compared with 64 patients and 46 patients, respectively, in the experimental groups, Dr. Gillespie and his colleagues said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1407426]).

The second trial was an open-label noninferiority study involving 1,836 patients in Benin, Guinea, Kenya, Senegal, and South Africa. They were randomly assigned to standard 6-month treatment (919 control subjects) or an experimental treatment in which gatifloxacin was substituted for ethambutol and the course of therapy was shortened to 4 months (917 patients), said Dr. Corinne S. Merle of the London School of Hygiene and Tropical Medicine and her associates.

The primary efficacy endpoint, the percentage of patients with an unfavorable outcome after 24 months, was 17.2% in the control group and 21.0% in the experimental group, a significant difference. In particular, more than twice as many patients in the experimental group (14.6%) had a relapse than in the control group (7.1%). As with Dr. Gillespie’s study, Dr. Merle’s study failed to show that the short-course regimen was noninferior to the standard regimen. Again, “the expectations raised by [phase I and II trials] were not borne out in this phase III trial,” they said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1315817]).

The third trial, involving 827 patients in South Africa, Zimbabwe, Botswana, and Zambia, compared the standard control regimen against a 4-month regimen in which isoniazid was replaced by moxifloxacin and a 6-month regimen in which isoniazid was replaced by moxifloxacin, said Dr. Amina Jindani of St. George’s University of London and University College London and her associates.

In the per-protocol analysis, unfavorable outcomes occurred in 4.9% of the control group and 3.2% of the 6-month experimental group, compared with 18.2% of the short-course experimental group. The corresponding figures for the intention-to-treat analysis were 14.4%, 13.7%, and 26.9%, respectively.

Again, this discrepancy was attributed primarily to the significantly higher relapse rate in the short-course, compared with the control treatments – 26 cases with 4 months of treatment vs. 5 cases each with 6 months, Dr. Jindani and her associates said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1314210]).

Three different short-course treatment regimens for tuberculosis failed to show noninferiority to the standard 6-month course in separate phase III randomized clinical trials, even though the experimental regimens produced a more rapid decline in bacterial load, as expected, according to reports published online Oct. 23 in the New England Journal of Medicine.

The main reason that the short-course (4-month) approaches failed to measure up to standard treatment was that, despite their greater bactericidal activity, the rate of relapse was excessive after treatment was completed.

Photo Credit: Janice Carr, Centers for Disease Control and Prevention

Researchers undertook these large international trials because the data from several phase II and murine studies had been so promising: replacing either the isoniazid or the ethambutol in the standard anti-TB regimen with a fluoroquinolone appeared to permit shortening of the treatment period without sacrificing efficacy. But the consistently negative results from these phase III studies clearly demonstrate that this approach is not effective.

The first trial involved 1,931 adults with newly diagnosed and untreated Mycobacterium tuberculosis infection who were treated in South Africa, India, Tanzania, Kenya, Thailand, Malaysia, Zambia, China, and Mexico. These patients were randomly assigned to receive the standard regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid plus rifampin (control group, 640 participants); or an experimental regimen in which ethambutol was replaced by moxifloxacin for 17 weeks, followed by 9 weeks of placebo (655 participants); or an experimental regimen in which isoniazid was replaced by moxifloxacin in the same way (636 participants), said Dr. Stephen H. Gillespie of the University of St. Andrews (England) and University College London and his associates.

Patients in the two experimental groups converted to culture-negative status more rapidly than did those in the control group. However, in a per-protocol analysis, 92% of the control group achieved a favorable final outcome, compared with only 85% and 80% of the experimental groups, respectively. Results of a modified intention-to-treat analysis and of more than 20 sensitivity analyses showed the same pattern. At the end of active treatment, only 12 patients in the control group had a relapse of TB infection, compared with 64 patients and 46 patients, respectively, in the experimental groups, Dr. Gillespie and his colleagues said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1407426]).

The second trial was an open-label noninferiority study involving 1,836 patients in Benin, Guinea, Kenya, Senegal, and South Africa. They were randomly assigned to standard 6-month treatment (919 control subjects) or an experimental treatment in which gatifloxacin was substituted for ethambutol and the course of therapy was shortened to 4 months (917 patients), said Dr. Corinne S. Merle of the London School of Hygiene and Tropical Medicine and her associates.

The primary efficacy endpoint, the percentage of patients with an unfavorable outcome after 24 months, was 17.2% in the control group and 21.0% in the experimental group, a significant difference. In particular, more than twice as many patients in the experimental group (14.6%) had a relapse than in the control group (7.1%). As with Dr. Gillespie’s study, Dr. Merle’s study failed to show that the short-course regimen was noninferior to the standard regimen. Again, “the expectations raised by [phase I and II trials] were not borne out in this phase III trial,” they said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1315817]).

The third trial, involving 827 patients in South Africa, Zimbabwe, Botswana, and Zambia, compared the standard control regimen against a 4-month regimen in which isoniazid was replaced by moxifloxacin and a 6-month regimen in which isoniazid was replaced by moxifloxacin, said Dr. Amina Jindani of St. George’s University of London and University College London and her associates.

In the per-protocol analysis, unfavorable outcomes occurred in 4.9% of the control group and 3.2% of the 6-month experimental group, compared with 18.2% of the short-course experimental group. The corresponding figures for the intention-to-treat analysis were 14.4%, 13.7%, and 26.9%, respectively.

Again, this discrepancy was attributed primarily to the significantly higher relapse rate in the short-course, compared with the control treatments – 26 cases with 4 months of treatment vs. 5 cases each with 6 months, Dr. Jindani and her associates said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1314210]).

Three different short-course treatment regimens for tuberculosis failed to show noninferiority to the standard 6-month course in separate phase III randomized clinical trials, even though the experimental regimens produced a more rapid decline in bacterial load, as expected, according to reports published online Oct. 23 in the New England Journal of Medicine.

The main reason that the short-course (4-month) approaches failed to measure up to standard treatment was that, despite their greater bactericidal activity, the rate of relapse was excessive after treatment was completed.

Photo Credit: Janice Carr, Centers for Disease Control and Prevention

Researchers undertook these large international trials because the data from several phase II and murine studies had been so promising: replacing either the isoniazid or the ethambutol in the standard anti-TB regimen with a fluoroquinolone appeared to permit shortening of the treatment period without sacrificing efficacy. But the consistently negative results from these phase III studies clearly demonstrate that this approach is not effective.

The first trial involved 1,931 adults with newly diagnosed and untreated Mycobacterium tuberculosis infection who were treated in South Africa, India, Tanzania, Kenya, Thailand, Malaysia, Zambia, China, and Mexico. These patients were randomly assigned to receive the standard regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid plus rifampin (control group, 640 participants); or an experimental regimen in which ethambutol was replaced by moxifloxacin for 17 weeks, followed by 9 weeks of placebo (655 participants); or an experimental regimen in which isoniazid was replaced by moxifloxacin in the same way (636 participants), said Dr. Stephen H. Gillespie of the University of St. Andrews (England) and University College London and his associates.

Patients in the two experimental groups converted to culture-negative status more rapidly than did those in the control group. However, in a per-protocol analysis, 92% of the control group achieved a favorable final outcome, compared with only 85% and 80% of the experimental groups, respectively. Results of a modified intention-to-treat analysis and of more than 20 sensitivity analyses showed the same pattern. At the end of active treatment, only 12 patients in the control group had a relapse of TB infection, compared with 64 patients and 46 patients, respectively, in the experimental groups, Dr. Gillespie and his colleagues said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1407426]).

The second trial was an open-label noninferiority study involving 1,836 patients in Benin, Guinea, Kenya, Senegal, and South Africa. They were randomly assigned to standard 6-month treatment (919 control subjects) or an experimental treatment in which gatifloxacin was substituted for ethambutol and the course of therapy was shortened to 4 months (917 patients), said Dr. Corinne S. Merle of the London School of Hygiene and Tropical Medicine and her associates.

The primary efficacy endpoint, the percentage of patients with an unfavorable outcome after 24 months, was 17.2% in the control group and 21.0% in the experimental group, a significant difference. In particular, more than twice as many patients in the experimental group (14.6%) had a relapse than in the control group (7.1%). As with Dr. Gillespie’s study, Dr. Merle’s study failed to show that the short-course regimen was noninferior to the standard regimen. Again, “the expectations raised by [phase I and II trials] were not borne out in this phase III trial,” they said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1315817]).

The third trial, involving 827 patients in South Africa, Zimbabwe, Botswana, and Zambia, compared the standard control regimen against a 4-month regimen in which isoniazid was replaced by moxifloxacin and a 6-month regimen in which isoniazid was replaced by moxifloxacin, said Dr. Amina Jindani of St. George’s University of London and University College London and her associates.

In the per-protocol analysis, unfavorable outcomes occurred in 4.9% of the control group and 3.2% of the 6-month experimental group, compared with 18.2% of the short-course experimental group. The corresponding figures for the intention-to-treat analysis were 14.4%, 13.7%, and 26.9%, respectively.

Again, this discrepancy was attributed primarily to the significantly higher relapse rate in the short-course, compared with the control treatments – 26 cases with 4 months of treatment vs. 5 cases each with 6 months, Dr. Jindani and her associates said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1314210]).

Initial treatment with FOLFOXIRI plus bevacizumab, rather than FOLFIRI plus bevacizumab, improved progression-free survival in adults with inoperable metastatic colorectal cancer participating in a phase III randomized clinical trial, according to a report published online Oct. 23 in the New England Journal of Medicine.

However, patients who received FOLFOXIRI developed more grade 3 or 4 adverse events such as neutropenia, diarrhea, stomatitis, and peripheral neuropathy. The trial assessed treatment efficacy but not quality of life, so the impact of these toxicities was not addressed, said Dr. Fotios Loupakis of the University of Pisa and his associates in the Triplet plus Bevacizumab (TRIBE) trial.

In the open-label study, patients with unresectable metastatic colorectal cancer who had not received chemotherapy or biologic therapy for their metastatic disease were treated at 34 medical centers across Italy. They were randomly assigned to receive up to 12 cycles of either the experimental treatment FOLFOXIRI (fluorouracil plus leucovorin and irinotecan and oxaliplatin) plus bevacizumab (252 patients) or the control treatment FOLFIRI (fluorouracil plus leucovorin and irinotecan) plus bevacizumab (256 patients). Both study groups then received maintenance therapy with fluorouracil plus bevacizumab until the cancer progressed or they withdrew from the study.

After a median follow-up of 32 months (range, 24.7-40.6 months), the primary outcome measure, progression-free survival, was 12.1 months with the experimental therapy, which was significantly longer than the 9.7 months in the control group (hazard ratio, 0.75) was. In addition, the treatment response rate was 12% higher and median overall survival was 5 months longer in the experimental group, the investigators said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1403108]).

The percentage of bevacizumab-related adverse events was not significantly different between the two study groups, which indicates that intensifying the chemotherapy doesn’t affect the safety profile of the antiangiogenic agent. The rate of adverse events was significantly higher in the experimental-therapy group, but the rate of serious adverse events was similar (20.4% with FOLFOXIRI and 19.7% with FOLFIRI), as was the number of patients who died from adverse events (6 and 4, respectively).

Initial treatment with FOLFOXIRI plus bevacizumab, rather than FOLFIRI plus bevacizumab, improved progression-free survival in adults with inoperable metastatic colorectal cancer participating in a phase III randomized clinical trial, according to a report published online Oct. 23 in the New England Journal of Medicine.

However, patients who received FOLFOXIRI developed more grade 3 or 4 adverse events such as neutropenia, diarrhea, stomatitis, and peripheral neuropathy. The trial assessed treatment efficacy but not quality of life, so the impact of these toxicities was not addressed, said Dr. Fotios Loupakis of the University of Pisa and his associates in the Triplet plus Bevacizumab (TRIBE) trial.

In the open-label study, patients with unresectable metastatic colorectal cancer who had not received chemotherapy or biologic therapy for their metastatic disease were treated at 34 medical centers across Italy. They were randomly assigned to receive up to 12 cycles of either the experimental treatment FOLFOXIRI (fluorouracil plus leucovorin and irinotecan and oxaliplatin) plus bevacizumab (252 patients) or the control treatment FOLFIRI (fluorouracil plus leucovorin and irinotecan) plus bevacizumab (256 patients). Both study groups then received maintenance therapy with fluorouracil plus bevacizumab until the cancer progressed or they withdrew from the study.

After a median follow-up of 32 months (range, 24.7-40.6 months), the primary outcome measure, progression-free survival, was 12.1 months with the experimental therapy, which was significantly longer than the 9.7 months in the control group (hazard ratio, 0.75) was. In addition, the treatment response rate was 12% higher and median overall survival was 5 months longer in the experimental group, the investigators said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1403108]).

The percentage of bevacizumab-related adverse events was not significantly different between the two study groups, which indicates that intensifying the chemotherapy doesn’t affect the safety profile of the antiangiogenic agent. The rate of adverse events was significantly higher in the experimental-therapy group, but the rate of serious adverse events was similar (20.4% with FOLFOXIRI and 19.7% with FOLFIRI), as was the number of patients who died from adverse events (6 and 4, respectively).

Initial treatment with FOLFOXIRI plus bevacizumab, rather than FOLFIRI plus bevacizumab, improved progression-free survival in adults with inoperable metastatic colorectal cancer participating in a phase III randomized clinical trial, according to a report published online Oct. 23 in the New England Journal of Medicine.

However, patients who received FOLFOXIRI developed more grade 3 or 4 adverse events such as neutropenia, diarrhea, stomatitis, and peripheral neuropathy. The trial assessed treatment efficacy but not quality of life, so the impact of these toxicities was not addressed, said Dr. Fotios Loupakis of the University of Pisa and his associates in the Triplet plus Bevacizumab (TRIBE) trial.

In the open-label study, patients with unresectable metastatic colorectal cancer who had not received chemotherapy or biologic therapy for their metastatic disease were treated at 34 medical centers across Italy. They were randomly assigned to receive up to 12 cycles of either the experimental treatment FOLFOXIRI (fluorouracil plus leucovorin and irinotecan and oxaliplatin) plus bevacizumab (252 patients) or the control treatment FOLFIRI (fluorouracil plus leucovorin and irinotecan) plus bevacizumab (256 patients). Both study groups then received maintenance therapy with fluorouracil plus bevacizumab until the cancer progressed or they withdrew from the study.

After a median follow-up of 32 months (range, 24.7-40.6 months), the primary outcome measure, progression-free survival, was 12.1 months with the experimental therapy, which was significantly longer than the 9.7 months in the control group (hazard ratio, 0.75) was. In addition, the treatment response rate was 12% higher and median overall survival was 5 months longer in the experimental group, the investigators said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1403108]).

The percentage of bevacizumab-related adverse events was not significantly different between the two study groups, which indicates that intensifying the chemotherapy doesn’t affect the safety profile of the antiangiogenic agent. The rate of adverse events was significantly higher in the experimental-therapy group, but the rate of serious adverse events was similar (20.4% with FOLFOXIRI and 19.7% with FOLFIRI), as was the number of patients who died from adverse events (6 and 4, respectively).