ESMO Congress 2011

STOCKHOLM – Whether or not a woman had a hysterectomy made no impact on survival in a small phase III trial among patients with a complete response after chemoradiation, including brachytherapy, for early-stage ovarian cancer.

The primary end point of the event-free survival rate at 3 years was 72% in women who underwent extrafascial hysterectomy and 89% among those who did not (P = .17). Overall survival rates were also similar at 86% with hysterectomy and 97% without (P = .15), Dr. Philippe Morice reported at the European Multidisciplinary Cancer Congress.

"Even if our conclusion is diminished by the insufficient accrual of patients, in the analysis of 61 patients, we don’t observe any effect of completion hysterectomy on the overall and event-free survival of patients," said Dr. Morice, with the Institût de Cancérologie Gustave Roussy, Villejuif, France.

"With the development of new radiation and brachytherapy that increase the rate of local control, the place of the hysterectomy in this context is very probably disappearing during the next years," he added.

The National Federation of Cancer Campaign Centers GYNECO 02 trial was stopped in 2006 due to poor accrual after randomizing 31 women to hysterectomy after chemoradiotherapy (CRT) and 30 to CRT alone.

The two arms were well balanced, although 11 women in the hysterectomy arm had histologic residual disease in the cervix. Most of the cases were isolated cells, with three other cases having residual disease less than 1 cm and two having disease more than 1 cm, he said.

After a median follow-up of 3.8 years, 11 patients relapsed including 8 randomized to hysterectomy after CRT and 3 randomized to CRT alone.

In the CRT-alone arm, the site of first recurrence was centropelvic alone in two patients and distant without pelvic or nodal involvement in one, he said.

In the hysterectomy arm, the site of recurrence for one patient each was centropelvic alone, centropelvic plus nodal, pelvic node and distant, paraaortic nodes alone, and distant without pelvic or nodal, with three patients having paraaortic nodal involvement and distant recurrence.

"For the patient that undergoes complete treatment with chemoradiation and brachytherapy, we can see in this trial that the problem is not the local control of the disease, but the metastatic control," he said.

"More isn’t always better," observed discussant Dr. Nicholas Reed, a consultant clinical oncologist with Beatson Oncology Centre, Gartnavel General Hospital Glasgow, Scotland.

He suggested that positron emission tomography/computed tomography and other newer imaging modalities have a role in identifying select patients in whom hysterectomy could be avoided. If hysterectomy does not have a central role to play in early ovarian cancer, he suggested that modern imaging techniques and faster computer software systems can improve radiation quality by optimizing the tumor volume to be treated and the dose to organs at risk.

The GYNECO 02 trial asked whether surgery could reduce the risk of local or locoregional relapse in women with stage IB2/II cervical cancer and no extra-pelvic disease treated with pelvic external radiation therapy at 45-50 Gy and concomitant cisplatin 40 mg/m² per week, followed by utero-vaginal brachytherapy at 15 Gy.

A parametrial or nodal boost of 10-15 Gy was possible in cases of parametrial involvement with insufficient regression at the time of brachytherapy or in those with pelvic node involvement on initial imaging, said Dr. Morice. All women had a complete clinical and radiological response, based on magnetic resonance imaging, 6 to 8 weeks after brachytherapy.

The joint congress was sponsored by the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The study was funded by the Federation Nationale des Centres de Lutte Contre le Cancer.

STOCKHOLM – Whether or not a woman had a hysterectomy made no impact on survival in a small phase III trial among patients with a complete response after chemoradiation, including brachytherapy, for early-stage ovarian cancer.

The primary end point of the event-free survival rate at 3 years was 72% in women who underwent extrafascial hysterectomy and 89% among those who did not (P = .17). Overall survival rates were also similar at 86% with hysterectomy and 97% without (P = .15), Dr. Philippe Morice reported at the European Multidisciplinary Cancer Congress.

"Even if our conclusion is diminished by the insufficient accrual of patients, in the analysis of 61 patients, we don’t observe any effect of completion hysterectomy on the overall and event-free survival of patients," said Dr. Morice, with the Institût de Cancérologie Gustave Roussy, Villejuif, France.

"With the development of new radiation and brachytherapy that increase the rate of local control, the place of the hysterectomy in this context is very probably disappearing during the next years," he added.

The National Federation of Cancer Campaign Centers GYNECO 02 trial was stopped in 2006 due to poor accrual after randomizing 31 women to hysterectomy after chemoradiotherapy (CRT) and 30 to CRT alone.

The two arms were well balanced, although 11 women in the hysterectomy arm had histologic residual disease in the cervix. Most of the cases were isolated cells, with three other cases having residual disease less than 1 cm and two having disease more than 1 cm, he said.

After a median follow-up of 3.8 years, 11 patients relapsed including 8 randomized to hysterectomy after CRT and 3 randomized to CRT alone.

In the CRT-alone arm, the site of first recurrence was centropelvic alone in two patients and distant without pelvic or nodal involvement in one, he said.

In the hysterectomy arm, the site of recurrence for one patient each was centropelvic alone, centropelvic plus nodal, pelvic node and distant, paraaortic nodes alone, and distant without pelvic or nodal, with three patients having paraaortic nodal involvement and distant recurrence.

"For the patient that undergoes complete treatment with chemoradiation and brachytherapy, we can see in this trial that the problem is not the local control of the disease, but the metastatic control," he said.

"More isn’t always better," observed discussant Dr. Nicholas Reed, a consultant clinical oncologist with Beatson Oncology Centre, Gartnavel General Hospital Glasgow, Scotland.

He suggested that positron emission tomography/computed tomography and other newer imaging modalities have a role in identifying select patients in whom hysterectomy could be avoided. If hysterectomy does not have a central role to play in early ovarian cancer, he suggested that modern imaging techniques and faster computer software systems can improve radiation quality by optimizing the tumor volume to be treated and the dose to organs at risk.

The GYNECO 02 trial asked whether surgery could reduce the risk of local or locoregional relapse in women with stage IB2/II cervical cancer and no extra-pelvic disease treated with pelvic external radiation therapy at 45-50 Gy and concomitant cisplatin 40 mg/m² per week, followed by utero-vaginal brachytherapy at 15 Gy.

A parametrial or nodal boost of 10-15 Gy was possible in cases of parametrial involvement with insufficient regression at the time of brachytherapy or in those with pelvic node involvement on initial imaging, said Dr. Morice. All women had a complete clinical and radiological response, based on magnetic resonance imaging, 6 to 8 weeks after brachytherapy.

The joint congress was sponsored by the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The study was funded by the Federation Nationale des Centres de Lutte Contre le Cancer.

STOCKHOLM – Whether or not a woman had a hysterectomy made no impact on survival in a small phase III trial among patients with a complete response after chemoradiation, including brachytherapy, for early-stage ovarian cancer.

The primary end point of the event-free survival rate at 3 years was 72% in women who underwent extrafascial hysterectomy and 89% among those who did not (P = .17). Overall survival rates were also similar at 86% with hysterectomy and 97% without (P = .15), Dr. Philippe Morice reported at the European Multidisciplinary Cancer Congress.

"Even if our conclusion is diminished by the insufficient accrual of patients, in the analysis of 61 patients, we don’t observe any effect of completion hysterectomy on the overall and event-free survival of patients," said Dr. Morice, with the Institût de Cancérologie Gustave Roussy, Villejuif, France.

"With the development of new radiation and brachytherapy that increase the rate of local control, the place of the hysterectomy in this context is very probably disappearing during the next years," he added.

The National Federation of Cancer Campaign Centers GYNECO 02 trial was stopped in 2006 due to poor accrual after randomizing 31 women to hysterectomy after chemoradiotherapy (CRT) and 30 to CRT alone.

The two arms were well balanced, although 11 women in the hysterectomy arm had histologic residual disease in the cervix. Most of the cases were isolated cells, with three other cases having residual disease less than 1 cm and two having disease more than 1 cm, he said.

After a median follow-up of 3.8 years, 11 patients relapsed including 8 randomized to hysterectomy after CRT and 3 randomized to CRT alone.

In the CRT-alone arm, the site of first recurrence was centropelvic alone in two patients and distant without pelvic or nodal involvement in one, he said.

In the hysterectomy arm, the site of recurrence for one patient each was centropelvic alone, centropelvic plus nodal, pelvic node and distant, paraaortic nodes alone, and distant without pelvic or nodal, with three patients having paraaortic nodal involvement and distant recurrence.

"For the patient that undergoes complete treatment with chemoradiation and brachytherapy, we can see in this trial that the problem is not the local control of the disease, but the metastatic control," he said.

"More isn’t always better," observed discussant Dr. Nicholas Reed, a consultant clinical oncologist with Beatson Oncology Centre, Gartnavel General Hospital Glasgow, Scotland.

He suggested that positron emission tomography/computed tomography and other newer imaging modalities have a role in identifying select patients in whom hysterectomy could be avoided. If hysterectomy does not have a central role to play in early ovarian cancer, he suggested that modern imaging techniques and faster computer software systems can improve radiation quality by optimizing the tumor volume to be treated and the dose to organs at risk.

The GYNECO 02 trial asked whether surgery could reduce the risk of local or locoregional relapse in women with stage IB2/II cervical cancer and no extra-pelvic disease treated with pelvic external radiation therapy at 45-50 Gy and concomitant cisplatin 40 mg/m² per week, followed by utero-vaginal brachytherapy at 15 Gy.

A parametrial or nodal boost of 10-15 Gy was possible in cases of parametrial involvement with insufficient regression at the time of brachytherapy or in those with pelvic node involvement on initial imaging, said Dr. Morice. All women had a complete clinical and radiological response, based on magnetic resonance imaging, 6 to 8 weeks after brachytherapy.

The joint congress was sponsored by the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The study was funded by the Federation Nationale des Centres de Lutte Contre le Cancer.

STOCKHOLM – Patients aged 71 years and older with advanced non–small cell lung cancer showed significantly greater survival with carboplatin chemotherapy plus concurrent radiation than with radiotherapy alone in a Japan Clinical Oncology Group trial that included only elderly patients.

Median overall survival was significantly longer, at 22.4 months, for those who received chemoradiotherapy, compared with 16.9 months for those having radiation therapy alone (hazard ratio, 0.68; P = .0179). Median progression-free survival was also significantly longer (8.9 months) for those receiving chemoradiotherapy, compared with 6.8 months for those with radiation therapy alone (HR, 0.66; P = .0044).

"This is the first trial demonstrating the clinically significant benefits of concurrent chemoradiation therapy in elderly patients with stage III non–small-cell lung cancer," Dr. Shinji Atagi said at the European Multidisciplinary Cancer Congress.

"This combined modality is considered as the standard treatment for this population [in Japan]," added Dr. Atagi of the National Hospital Organization Kinki-Chuo Chest Medical Center in Osaka, Japan.

Invited discussant Dr. Johanna Kazmierska shared the enthusiasm about the trial and its results. "The study suggests that age is not the only determinant of management of the [older] patient. The overall patient status [usually] is not taken into consideration," said Dr. Kazmierska of the radiotherapy department at the Greater Poland Cancer Centre in Poznan, Poland.

"Assessment of potential differences in treatment results – for example, overall survival – [provides] a strong argument for us in the discussion of the treatment of elderly patients," she added.

Patients were included in the trial if they had cytologically and/or histologically confirmed stage IIA (except T3N1M0) or IIIB non–small cell lung cancer (NSCLC). They had to be at least 71 years of age and have had no previous chemotherapy or radiotherapy. They also could not be candidates for cisplatin-based combination chemotherapy.

Patients were randomly assigned to the radiotherapy (RT) arm or the chemoradiotherapy (CRT) arm. In all, 98 patients were randomized to receive RT alone and 99 patients received CRT. The median age for both groups was 77 years.

The RT consisted of 60 Gy in 30 fractions over 6 weeks. In the CRT arm, patients received the same radiotherapy dose as in the RT arm as well as concurrent intravenous administration of carboplatin (30 mg/m² in a 30-minute infusion) 1 hour before every radiation treatment up to the first 20 fractions.

In March 2011 – after the second interim analysis was performed – the Data and SafetyMonitoring Board recommended early publication of this trial in accordance with a prespecified rule.

The overall objective response rate (complete plus partial response) was 52% in the CRT arm vs. 45% in the RT arm. The difference between the two groups was not significant, however.

Safety results showed 64% and 59% of patients in the CRT arm had grade 3/4 leukocytopenia and neutropenia, but there were no grade 3/4 cases of either side effect in the RT arm. The CRT group also had a greater incidence of grade 3/4 infection (15% vs. 4%). Four treatment-related deaths occurred in the RT arm, and three occurred in the CRT arm.

The joint congress was sponsored by the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiation and Oncology (ESTRO).

The study was sponsored by the Japan Clinical Oncology Group, with support from Japanese Ministry of Health, Labour, and Welfare. No personal disclosures were presented.

STOCKHOLM – Patients aged 71 years and older with advanced non–small cell lung cancer showed significantly greater survival with carboplatin chemotherapy plus concurrent radiation than with radiotherapy alone in a Japan Clinical Oncology Group trial that included only elderly patients.

Median overall survival was significantly longer, at 22.4 months, for those who received chemoradiotherapy, compared with 16.9 months for those having radiation therapy alone (hazard ratio, 0.68; P = .0179). Median progression-free survival was also significantly longer (8.9 months) for those receiving chemoradiotherapy, compared with 6.8 months for those with radiation therapy alone (HR, 0.66; P = .0044).

"This is the first trial demonstrating the clinically significant benefits of concurrent chemoradiation therapy in elderly patients with stage III non–small-cell lung cancer," Dr. Shinji Atagi said at the European Multidisciplinary Cancer Congress.

"This combined modality is considered as the standard treatment for this population [in Japan]," added Dr. Atagi of the National Hospital Organization Kinki-Chuo Chest Medical Center in Osaka, Japan.

Invited discussant Dr. Johanna Kazmierska shared the enthusiasm about the trial and its results. "The study suggests that age is not the only determinant of management of the [older] patient. The overall patient status [usually] is not taken into consideration," said Dr. Kazmierska of the radiotherapy department at the Greater Poland Cancer Centre in Poznan, Poland.

"Assessment of potential differences in treatment results – for example, overall survival – [provides] a strong argument for us in the discussion of the treatment of elderly patients," she added.

Patients were included in the trial if they had cytologically and/or histologically confirmed stage IIA (except T3N1M0) or IIIB non–small cell lung cancer (NSCLC). They had to be at least 71 years of age and have had no previous chemotherapy or radiotherapy. They also could not be candidates for cisplatin-based combination chemotherapy.

Patients were randomly assigned to the radiotherapy (RT) arm or the chemoradiotherapy (CRT) arm. In all, 98 patients were randomized to receive RT alone and 99 patients received CRT. The median age for both groups was 77 years.

The RT consisted of 60 Gy in 30 fractions over 6 weeks. In the CRT arm, patients received the same radiotherapy dose as in the RT arm as well as concurrent intravenous administration of carboplatin (30 mg/m² in a 30-minute infusion) 1 hour before every radiation treatment up to the first 20 fractions.

In March 2011 – after the second interim analysis was performed – the Data and SafetyMonitoring Board recommended early publication of this trial in accordance with a prespecified rule.

The overall objective response rate (complete plus partial response) was 52% in the CRT arm vs. 45% in the RT arm. The difference between the two groups was not significant, however.

Safety results showed 64% and 59% of patients in the CRT arm had grade 3/4 leukocytopenia and neutropenia, but there were no grade 3/4 cases of either side effect in the RT arm. The CRT group also had a greater incidence of grade 3/4 infection (15% vs. 4%). Four treatment-related deaths occurred in the RT arm, and three occurred in the CRT arm.

The joint congress was sponsored by the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiation and Oncology (ESTRO).

The study was sponsored by the Japan Clinical Oncology Group, with support from Japanese Ministry of Health, Labour, and Welfare. No personal disclosures were presented.

STOCKHOLM – Patients aged 71 years and older with advanced non–small cell lung cancer showed significantly greater survival with carboplatin chemotherapy plus concurrent radiation than with radiotherapy alone in a Japan Clinical Oncology Group trial that included only elderly patients.

Median overall survival was significantly longer, at 22.4 months, for those who received chemoradiotherapy, compared with 16.9 months for those having radiation therapy alone (hazard ratio, 0.68; P = .0179). Median progression-free survival was also significantly longer (8.9 months) for those receiving chemoradiotherapy, compared with 6.8 months for those with radiation therapy alone (HR, 0.66; P = .0044).

"This is the first trial demonstrating the clinically significant benefits of concurrent chemoradiation therapy in elderly patients with stage III non–small-cell lung cancer," Dr. Shinji Atagi said at the European Multidisciplinary Cancer Congress.

"This combined modality is considered as the standard treatment for this population [in Japan]," added Dr. Atagi of the National Hospital Organization Kinki-Chuo Chest Medical Center in Osaka, Japan.

Invited discussant Dr. Johanna Kazmierska shared the enthusiasm about the trial and its results. "The study suggests that age is not the only determinant of management of the [older] patient. The overall patient status [usually] is not taken into consideration," said Dr. Kazmierska of the radiotherapy department at the Greater Poland Cancer Centre in Poznan, Poland.

"Assessment of potential differences in treatment results – for example, overall survival – [provides] a strong argument for us in the discussion of the treatment of elderly patients," she added.

Patients were included in the trial if they had cytologically and/or histologically confirmed stage IIA (except T3N1M0) or IIIB non–small cell lung cancer (NSCLC). They had to be at least 71 years of age and have had no previous chemotherapy or radiotherapy. They also could not be candidates for cisplatin-based combination chemotherapy.

Patients were randomly assigned to the radiotherapy (RT) arm or the chemoradiotherapy (CRT) arm. In all, 98 patients were randomized to receive RT alone and 99 patients received CRT. The median age for both groups was 77 years.

The RT consisted of 60 Gy in 30 fractions over 6 weeks. In the CRT arm, patients received the same radiotherapy dose as in the RT arm as well as concurrent intravenous administration of carboplatin (30 mg/m² in a 30-minute infusion) 1 hour before every radiation treatment up to the first 20 fractions.

In March 2011 – after the second interim analysis was performed – the Data and SafetyMonitoring Board recommended early publication of this trial in accordance with a prespecified rule.

The overall objective response rate (complete plus partial response) was 52% in the CRT arm vs. 45% in the RT arm. The difference between the two groups was not significant, however.

Safety results showed 64% and 59% of patients in the CRT arm had grade 3/4 leukocytopenia and neutropenia, but there were no grade 3/4 cases of either side effect in the RT arm. The CRT group also had a greater incidence of grade 3/4 infection (15% vs. 4%). Four treatment-related deaths occurred in the RT arm, and three occurred in the CRT arm.

The joint congress was sponsored by the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiation and Oncology (ESTRO).

The study was sponsored by the Japan Clinical Oncology Group, with support from Japanese Ministry of Health, Labour, and Welfare. No personal disclosures were presented.

STOCKHOLM – Denosumab prolongs bone metastasis-free survival across a variety of nonmetastatic, castrate-resistant prostate cancer subgroups, according to subanalyses of a phase III study.

Denosumab (Xgeva) improved bone metastasis-free survival compared with placebo in men with dual prostate-specific antigen risk factors (hazard ratio, 0.83; P = .07), a single PSA risk factor (HR, 0.87; P = .20), a Gleason score of 2-7 (HR, 0.85, P = .12), and Gleason score of 8-10 (HR, 0.81; P = .10).

The advantage with denosumab was observed regardless of patient age, geographic region, or race, Dr. Stephane Oudard said at the European Multidisciplinary Cancer Congress.

Overall, the primary end point of bone metastasis-free survival was increased from 25.2 months with placebo to 29.5 months with denosumab. This corresponds to a relative risk reduction of 15% (hazard ratio, 0.85; P = .028).

Dr. Oudard pointed out that nearly all men with prostate cancer develop bone metastases, and that this is "the first randomized study to demonstrate that targeting bone microenvironment prevents bone metastasis in men with prostate cancer."

Denosumab is a monoclonal antibody that inhibits RANK ligand, a key mediator of bone osteoclast activity. The drug was approved in 2010 for the treatment of postmenopausal osteoporosis under the trade name Prolia, and later that year for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

In September 2011, two new indications were added for denosumab: to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer.

The phase III denosumab 147 study evenly randomized 1,432 men with nonmetastatic, castrate-resistant prostate cancer to monthly subcutaneous denosumab 120 mg or placebo. Bone metastases were detected by bone scan and confirmed by scintigraphy.

"[This is] the first randomized study to demonstrate that targeting bone micro-environment prevents bone metastasis in men with prostate cancer."

The men were at high risk of developing bone metastasis as defined by a PSA of 8.0 ng/mL for 3 months prior to randomization or a PSA doubling time of 10 months or less. These dual PSA risk factors were present in 48% of the men. At least one-third of the men had a Gleason score of 8 or more at diagnosis.

The median time from diagnosis was 6 years and duration of androgen-deprivation therapy 4 years, said Dr. Oudard, chief of oncology at Georges Pompidou Hospital in Paris.

Denosumab significantly delayed the time to symptomatic bone metastases (HR, 0.67; P = .01), which translates into a 33% relative risk reduction. Similar benefits were observed for this end point across all disease and patient demographic characteristics, he said.

The overall results of the trial were reported earlier this year at the American Urological Association meeting. Despite delaying bone metastases, patients taking denosumab did not live longer than did those given placebo. Median overall survival was approximately 44 months in both groups (HR, 1.01; P = .91).

Serious adverse event rates were nearly identical at 46% in each arm; hypocalcemia was higher in the denosumab group at 1.7% vs. 0.3% with placebo. Another side effect, osteonecrosis of the jaw, was also slightly increased with denosumab at a cumulative incidence of 1.1% in year 1, 2.9% in year 2, and 4.2% in year 3 vs. 0% for all three years in the placebo group, Dr. Oudard said at the meeting, a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Invited discussant Dr. Joaquim Bellmunt, with Hospital Valle de Hebron in Barcelona, said delaying the development of bone metastasis in men with castrate-resistant prostate cancer represents an important unmet medical need, and that screening for bone metastasis is often inadequate in clinical practice.

He went on to say that long-term quality of life data are needed, since the study showed only that denosumab prolongs the period before metastasis, where the patients’ quality of life has not yet suffered to a great extent.

Finally, Dr. Bellmunt took issue with the lack of survival benefit with denosumab, observing that patients with bone metastases have an almost five-time higher risk of death compared with those patients without.

Prevention of skeletal-related events and pain control are important in multimodality treatment of bone metastasis, he said, but "I want to stress that survival and quality of life is critical in these patients."

The study was funded by Amgen Inc. Disclosures were not presented at the meeting.

Christine Kilgore contributed to this report.

STOCKHOLM – Denosumab prolongs bone metastasis-free survival across a variety of nonmetastatic, castrate-resistant prostate cancer subgroups, according to subanalyses of a phase III study.

Denosumab (Xgeva) improved bone metastasis-free survival compared with placebo in men with dual prostate-specific antigen risk factors (hazard ratio, 0.83; P = .07), a single PSA risk factor (HR, 0.87; P = .20), a Gleason score of 2-7 (HR, 0.85, P = .12), and Gleason score of 8-10 (HR, 0.81; P = .10).

The advantage with denosumab was observed regardless of patient age, geographic region, or race, Dr. Stephane Oudard said at the European Multidisciplinary Cancer Congress.

Overall, the primary end point of bone metastasis-free survival was increased from 25.2 months with placebo to 29.5 months with denosumab. This corresponds to a relative risk reduction of 15% (hazard ratio, 0.85; P = .028).

Dr. Oudard pointed out that nearly all men with prostate cancer develop bone metastases, and that this is "the first randomized study to demonstrate that targeting bone microenvironment prevents bone metastasis in men with prostate cancer."

Denosumab is a monoclonal antibody that inhibits RANK ligand, a key mediator of bone osteoclast activity. The drug was approved in 2010 for the treatment of postmenopausal osteoporosis under the trade name Prolia, and later that year for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

In September 2011, two new indications were added for denosumab: to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer.

The phase III denosumab 147 study evenly randomized 1,432 men with nonmetastatic, castrate-resistant prostate cancer to monthly subcutaneous denosumab 120 mg or placebo. Bone metastases were detected by bone scan and confirmed by scintigraphy.

"[This is] the first randomized study to demonstrate that targeting bone micro-environment prevents bone metastasis in men with prostate cancer."

The men were at high risk of developing bone metastasis as defined by a PSA of 8.0 ng/mL for 3 months prior to randomization or a PSA doubling time of 10 months or less. These dual PSA risk factors were present in 48% of the men. At least one-third of the men had a Gleason score of 8 or more at diagnosis.

The median time from diagnosis was 6 years and duration of androgen-deprivation therapy 4 years, said Dr. Oudard, chief of oncology at Georges Pompidou Hospital in Paris.

Denosumab significantly delayed the time to symptomatic bone metastases (HR, 0.67; P = .01), which translates into a 33% relative risk reduction. Similar benefits were observed for this end point across all disease and patient demographic characteristics, he said.

The overall results of the trial were reported earlier this year at the American Urological Association meeting. Despite delaying bone metastases, patients taking denosumab did not live longer than did those given placebo. Median overall survival was approximately 44 months in both groups (HR, 1.01; P = .91).

Serious adverse event rates were nearly identical at 46% in each arm; hypocalcemia was higher in the denosumab group at 1.7% vs. 0.3% with placebo. Another side effect, osteonecrosis of the jaw, was also slightly increased with denosumab at a cumulative incidence of 1.1% in year 1, 2.9% in year 2, and 4.2% in year 3 vs. 0% for all three years in the placebo group, Dr. Oudard said at the meeting, a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Invited discussant Dr. Joaquim Bellmunt, with Hospital Valle de Hebron in Barcelona, said delaying the development of bone metastasis in men with castrate-resistant prostate cancer represents an important unmet medical need, and that screening for bone metastasis is often inadequate in clinical practice.

He went on to say that long-term quality of life data are needed, since the study showed only that denosumab prolongs the period before metastasis, where the patients’ quality of life has not yet suffered to a great extent.

Finally, Dr. Bellmunt took issue with the lack of survival benefit with denosumab, observing that patients with bone metastases have an almost five-time higher risk of death compared with those patients without.

Prevention of skeletal-related events and pain control are important in multimodality treatment of bone metastasis, he said, but "I want to stress that survival and quality of life is critical in these patients."

The study was funded by Amgen Inc. Disclosures were not presented at the meeting.

Christine Kilgore contributed to this report.

STOCKHOLM – Denosumab prolongs bone metastasis-free survival across a variety of nonmetastatic, castrate-resistant prostate cancer subgroups, according to subanalyses of a phase III study.

Denosumab (Xgeva) improved bone metastasis-free survival compared with placebo in men with dual prostate-specific antigen risk factors (hazard ratio, 0.83; P = .07), a single PSA risk factor (HR, 0.87; P = .20), a Gleason score of 2-7 (HR, 0.85, P = .12), and Gleason score of 8-10 (HR, 0.81; P = .10).

The advantage with denosumab was observed regardless of patient age, geographic region, or race, Dr. Stephane Oudard said at the European Multidisciplinary Cancer Congress.

Overall, the primary end point of bone metastasis-free survival was increased from 25.2 months with placebo to 29.5 months with denosumab. This corresponds to a relative risk reduction of 15% (hazard ratio, 0.85; P = .028).

Dr. Oudard pointed out that nearly all men with prostate cancer develop bone metastases, and that this is "the first randomized study to demonstrate that targeting bone microenvironment prevents bone metastasis in men with prostate cancer."

Denosumab is a monoclonal antibody that inhibits RANK ligand, a key mediator of bone osteoclast activity. The drug was approved in 2010 for the treatment of postmenopausal osteoporosis under the trade name Prolia, and later that year for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

In September 2011, two new indications were added for denosumab: to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer.

The phase III denosumab 147 study evenly randomized 1,432 men with nonmetastatic, castrate-resistant prostate cancer to monthly subcutaneous denosumab 120 mg or placebo. Bone metastases were detected by bone scan and confirmed by scintigraphy.

"[This is] the first randomized study to demonstrate that targeting bone micro-environment prevents bone metastasis in men with prostate cancer."

The men were at high risk of developing bone metastasis as defined by a PSA of 8.0 ng/mL for 3 months prior to randomization or a PSA doubling time of 10 months or less. These dual PSA risk factors were present in 48% of the men. At least one-third of the men had a Gleason score of 8 or more at diagnosis.

The median time from diagnosis was 6 years and duration of androgen-deprivation therapy 4 years, said Dr. Oudard, chief of oncology at Georges Pompidou Hospital in Paris.

Denosumab significantly delayed the time to symptomatic bone metastases (HR, 0.67; P = .01), which translates into a 33% relative risk reduction. Similar benefits were observed for this end point across all disease and patient demographic characteristics, he said.

The overall results of the trial were reported earlier this year at the American Urological Association meeting. Despite delaying bone metastases, patients taking denosumab did not live longer than did those given placebo. Median overall survival was approximately 44 months in both groups (HR, 1.01; P = .91).

Serious adverse event rates were nearly identical at 46% in each arm; hypocalcemia was higher in the denosumab group at 1.7% vs. 0.3% with placebo. Another side effect, osteonecrosis of the jaw, was also slightly increased with denosumab at a cumulative incidence of 1.1% in year 1, 2.9% in year 2, and 4.2% in year 3 vs. 0% for all three years in the placebo group, Dr. Oudard said at the meeting, a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Invited discussant Dr. Joaquim Bellmunt, with Hospital Valle de Hebron in Barcelona, said delaying the development of bone metastasis in men with castrate-resistant prostate cancer represents an important unmet medical need, and that screening for bone metastasis is often inadequate in clinical practice.

He went on to say that long-term quality of life data are needed, since the study showed only that denosumab prolongs the period before metastasis, where the patients’ quality of life has not yet suffered to a great extent.

Finally, Dr. Bellmunt took issue with the lack of survival benefit with denosumab, observing that patients with bone metastases have an almost five-time higher risk of death compared with those patients without.

Prevention of skeletal-related events and pain control are important in multimodality treatment of bone metastasis, he said, but "I want to stress that survival and quality of life is critical in these patients."

The study was funded by Amgen Inc. Disclosures were not presented at the meeting.

Christine Kilgore contributed to this report.

STOCKHOLM – Celecoxib shows no evidence of activity when it’s added to hormone therapy in men with metastatic or high-risk nonmetastatic prostate cancer, according to first results from the six-arm STAMPEDE trial.

The use of celecoxib (Celebrex) plus hormone therapy did not extend failure-free survival, compared with hormone therapy alone (adjusted hazard ratio, 0.98). The 305 failure-free survival events were largely prostate-specific antigen (PSA) failures in 78% of both groups and new metastases in 16% of both groups, Dr. Noel W. Clarke reported on behalf of the STAMPEDE investigators at the European Multidisciplinary Cancer Congress.

Other failure-free survival events were local progression in 2% of both groups, lymph node invasion in 2% of the hormone-only group and in 0% of the hormone-plus-celecoxib group, and prostate cancer-related death in 1% and 4%, respectively.

Toxicity among the 874 patients was not significantly different, with 23% of the hormone-only group and 25% of the celecoxib group experiencing any grade 3-5 toxicity, he said.

Based on the lack of benefit, accrual to the celecoxib arm was halted. Celecoxib treatment was also discontinued in a second arm of the trial that coupled the cyclooxygenase-2 (COX-2) inhibitor with hormone therapy and zoledronic acid (Zometa), said Dr. Clarke, honorary professor of urological cancer at the University of Manchester (England).

STAMPEDE uses a novel and ambitious multiarm, multistage design to simultaneously assess whether the addition of one or two of three agents – docetaxel (Taxotere), zoledronic acid, or celecoxib – improves overall survival in men who have metastatic or high-risk nonmetastatic prostate cancer and are starting long-term hormone therapy. Accrual continues in the remaining arms, and assessment of a new agent, abiraterone (Zytiga), is now underway, he said.

The rationale for using celecoxib is threefold: COX-2 is associated with carcinogenesis in prostate and other cancers, case-control studies show a reduction in the risk of prostate cancer associated with nonsteroidal drugs, and pathological studies show that COX-2 is up-regulated in prostate cancer, Dr. Clarke explained.

Invited discussant Dr. Karim Fizazi of Institut de Cancérologie Gustave Roussy in Villejuif, France, said that the rationale for using celecoxib is much weaker than that for the other agents. Docetaxel has demonstrated an overall survival benefit in castrate-resistant prostate cancer, whereas zoledronic acid is known to delay skeletal-related events in this setting.

He also faulted the study’s heterogeneous population and the inclusion of PSA failure in the definition of failure-free survival, because active agents – such as zoledronic acid, denosumab (Xgeva), and sipuleucel-T (Provenge) – do not typically induce a PSA decrease.

Strengths of STAMPEDE include its ability to accrue almost 70 patients per month, its flexibility in dropping an arm if a drug is inactive rather than starting a separate new trial, and its homogeneous endocrine therapy that included 98% of patients taking LHRH (luteinizing hormone-releasing hormone) agonists, Dr. Fizazi said.

STAMPEDE has randomized 2,043 patients overall, including 583 to standard hormone therapy and 291 to hormone therapy plus celecoxib 400 mg twice daily for up to 1 year, or until a failure-free survival event. The median age in the current analysis was 65 years, and 77% had a performance status of 0. The median PSA was 67 ng/mL in the hormone group and 58 ng/mL in the celecoxib group.

Surprisingly, just 42% of patients who were randomized to celecoxib completed treatment, with a significant number dropping off within the first year because of either disease progression (28%) or excessive toxicity (11%), Dr. Clarke said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

STAMPEDE is led by Dr. Nicholas James of Queen Elizabeth Hospital in Birmingham, England, and is sponsored by the U.K. Medical Research Council, Cancer Research U.K., Novartis, Sanofi-Aventis, and Pfizer. Dr. Clarke reported no conflicts of interest, although several coauthors are employed by the Medical Research Council. Dr. Fizazi reports serving on advisory boards or as a speaker for Amgen, Dendreon, Exelixis, Janssen, Novartis, and Sanofi-Aventis.

STOCKHOLM – Celecoxib shows no evidence of activity when it’s added to hormone therapy in men with metastatic or high-risk nonmetastatic prostate cancer, according to first results from the six-arm STAMPEDE trial.

The use of celecoxib (Celebrex) plus hormone therapy did not extend failure-free survival, compared with hormone therapy alone (adjusted hazard ratio, 0.98). The 305 failure-free survival events were largely prostate-specific antigen (PSA) failures in 78% of both groups and new metastases in 16% of both groups, Dr. Noel W. Clarke reported on behalf of the STAMPEDE investigators at the European Multidisciplinary Cancer Congress.

Other failure-free survival events were local progression in 2% of both groups, lymph node invasion in 2% of the hormone-only group and in 0% of the hormone-plus-celecoxib group, and prostate cancer-related death in 1% and 4%, respectively.

Toxicity among the 874 patients was not significantly different, with 23% of the hormone-only group and 25% of the celecoxib group experiencing any grade 3-5 toxicity, he said.

Based on the lack of benefit, accrual to the celecoxib arm was halted. Celecoxib treatment was also discontinued in a second arm of the trial that coupled the cyclooxygenase-2 (COX-2) inhibitor with hormone therapy and zoledronic acid (Zometa), said Dr. Clarke, honorary professor of urological cancer at the University of Manchester (England).

STAMPEDE uses a novel and ambitious multiarm, multistage design to simultaneously assess whether the addition of one or two of three agents – docetaxel (Taxotere), zoledronic acid, or celecoxib – improves overall survival in men who have metastatic or high-risk nonmetastatic prostate cancer and are starting long-term hormone therapy. Accrual continues in the remaining arms, and assessment of a new agent, abiraterone (Zytiga), is now underway, he said.

The rationale for using celecoxib is threefold: COX-2 is associated with carcinogenesis in prostate and other cancers, case-control studies show a reduction in the risk of prostate cancer associated with nonsteroidal drugs, and pathological studies show that COX-2 is up-regulated in prostate cancer, Dr. Clarke explained.

Invited discussant Dr. Karim Fizazi of Institut de Cancérologie Gustave Roussy in Villejuif, France, said that the rationale for using celecoxib is much weaker than that for the other agents. Docetaxel has demonstrated an overall survival benefit in castrate-resistant prostate cancer, whereas zoledronic acid is known to delay skeletal-related events in this setting.

He also faulted the study’s heterogeneous population and the inclusion of PSA failure in the definition of failure-free survival, because active agents – such as zoledronic acid, denosumab (Xgeva), and sipuleucel-T (Provenge) – do not typically induce a PSA decrease.

Strengths of STAMPEDE include its ability to accrue almost 70 patients per month, its flexibility in dropping an arm if a drug is inactive rather than starting a separate new trial, and its homogeneous endocrine therapy that included 98% of patients taking LHRH (luteinizing hormone-releasing hormone) agonists, Dr. Fizazi said.

STAMPEDE has randomized 2,043 patients overall, including 583 to standard hormone therapy and 291 to hormone therapy plus celecoxib 400 mg twice daily for up to 1 year, or until a failure-free survival event. The median age in the current analysis was 65 years, and 77% had a performance status of 0. The median PSA was 67 ng/mL in the hormone group and 58 ng/mL in the celecoxib group.

Surprisingly, just 42% of patients who were randomized to celecoxib completed treatment, with a significant number dropping off within the first year because of either disease progression (28%) or excessive toxicity (11%), Dr. Clarke said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

STAMPEDE is led by Dr. Nicholas James of Queen Elizabeth Hospital in Birmingham, England, and is sponsored by the U.K. Medical Research Council, Cancer Research U.K., Novartis, Sanofi-Aventis, and Pfizer. Dr. Clarke reported no conflicts of interest, although several coauthors are employed by the Medical Research Council. Dr. Fizazi reports serving on advisory boards or as a speaker for Amgen, Dendreon, Exelixis, Janssen, Novartis, and Sanofi-Aventis.

STOCKHOLM – Celecoxib shows no evidence of activity when it’s added to hormone therapy in men with metastatic or high-risk nonmetastatic prostate cancer, according to first results from the six-arm STAMPEDE trial.

The use of celecoxib (Celebrex) plus hormone therapy did not extend failure-free survival, compared with hormone therapy alone (adjusted hazard ratio, 0.98). The 305 failure-free survival events were largely prostate-specific antigen (PSA) failures in 78% of both groups and new metastases in 16% of both groups, Dr. Noel W. Clarke reported on behalf of the STAMPEDE investigators at the European Multidisciplinary Cancer Congress.

Other failure-free survival events were local progression in 2% of both groups, lymph node invasion in 2% of the hormone-only group and in 0% of the hormone-plus-celecoxib group, and prostate cancer-related death in 1% and 4%, respectively.

Toxicity among the 874 patients was not significantly different, with 23% of the hormone-only group and 25% of the celecoxib group experiencing any grade 3-5 toxicity, he said.

Based on the lack of benefit, accrual to the celecoxib arm was halted. Celecoxib treatment was also discontinued in a second arm of the trial that coupled the cyclooxygenase-2 (COX-2) inhibitor with hormone therapy and zoledronic acid (Zometa), said Dr. Clarke, honorary professor of urological cancer at the University of Manchester (England).

STAMPEDE uses a novel and ambitious multiarm, multistage design to simultaneously assess whether the addition of one or two of three agents – docetaxel (Taxotere), zoledronic acid, or celecoxib – improves overall survival in men who have metastatic or high-risk nonmetastatic prostate cancer and are starting long-term hormone therapy. Accrual continues in the remaining arms, and assessment of a new agent, abiraterone (Zytiga), is now underway, he said.

The rationale for using celecoxib is threefold: COX-2 is associated with carcinogenesis in prostate and other cancers, case-control studies show a reduction in the risk of prostate cancer associated with nonsteroidal drugs, and pathological studies show that COX-2 is up-regulated in prostate cancer, Dr. Clarke explained.

Invited discussant Dr. Karim Fizazi of Institut de Cancérologie Gustave Roussy in Villejuif, France, said that the rationale for using celecoxib is much weaker than that for the other agents. Docetaxel has demonstrated an overall survival benefit in castrate-resistant prostate cancer, whereas zoledronic acid is known to delay skeletal-related events in this setting.

He also faulted the study’s heterogeneous population and the inclusion of PSA failure in the definition of failure-free survival, because active agents – such as zoledronic acid, denosumab (Xgeva), and sipuleucel-T (Provenge) – do not typically induce a PSA decrease.

Strengths of STAMPEDE include its ability to accrue almost 70 patients per month, its flexibility in dropping an arm if a drug is inactive rather than starting a separate new trial, and its homogeneous endocrine therapy that included 98% of patients taking LHRH (luteinizing hormone-releasing hormone) agonists, Dr. Fizazi said.

STAMPEDE has randomized 2,043 patients overall, including 583 to standard hormone therapy and 291 to hormone therapy plus celecoxib 400 mg twice daily for up to 1 year, or until a failure-free survival event. The median age in the current analysis was 65 years, and 77% had a performance status of 0. The median PSA was 67 ng/mL in the hormone group and 58 ng/mL in the celecoxib group.

Surprisingly, just 42% of patients who were randomized to celecoxib completed treatment, with a significant number dropping off within the first year because of either disease progression (28%) or excessive toxicity (11%), Dr. Clarke said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

STAMPEDE is led by Dr. Nicholas James of Queen Elizabeth Hospital in Birmingham, England, and is sponsored by the U.K. Medical Research Council, Cancer Research U.K., Novartis, Sanofi-Aventis, and Pfizer. Dr. Clarke reported no conflicts of interest, although several coauthors are employed by the Medical Research Council. Dr. Fizazi reports serving on advisory boards or as a speaker for Amgen, Dendreon, Exelixis, Janssen, Novartis, and Sanofi-Aventis.

STOCKHOLM – Laparoscopic surgery offers the same radical resection for noninvasive rectal cancer as does open surgery, according to short-term outcomes of the randomized, noninferiority phase III COLOR II trial.

The circumferential resection margin, described as the most important parameter for rectal cancer surgery, was 1.3 cm after laparoscopic and open surgery (P = .16). The distal margin was similar at 3.6 cm (P = .68).

The proximal margin was 17.0 cm in the laparoscopic group and 19.0 cm in the open group. The difference was statistically significant (P less than .001), but "clinically, totally irrelevant since a 17-cm margin is wide enough for a safe tumor resection," lead author Dr. H. Jaap Bonjer said at the European Multidisciplinary Cancer Congress.

COLOR II (Colorectal Cancer Laparoscopic or Open Resection) sought to answer whether laparoscopic total mesorectal excision is as oncologically safe as open surgery is. Removing the entire mesorectum, or fatty tissue around the rectum, is important because the radial spread of rectal cancer is more prominent than is longitudinal spread, explained Dr. Bonjer of the surgery department at Vrije University Medical Centre, Amsterdam.

Researchers at 30 centers in eight countries, including Canada, randomized 1,103 patients with a single rectal carcinoma within 15 cm of the anal verge, staged T1, T2, or T3 with a margin to the endopelvic fascia greater than 2 mm, to laparoscopic or open surgery. The analysis included 699 patients in the laparoscopic arm and 345 in the open surgery arm.

The technically demanding nature of laparoscopic surgery resulted in a longer operating time than with open surgery (median 240 minutes vs. 188 minutes, P less than .001), but blood loss was cut in half (median 200 mL vs. 400 mL, P less than .001), Dr. Bonjer said.

The number of lymph nodes harvested was similar at 13 in the laparoscopic group and 14 in the open group.

The overall positive resection margin rate, defined as less than 2 mm, was 9% in the laparoscopic group and 10% in the open group (P = .078), Dr. Bonjer said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Subgroup analyses showed similar positive resection margin rates in the upper rectum (10% vs. 9%, P = .92) and middle rectum (9% vs. 3%, P = .073), but a significantly better rate in the lower rectum after laparoscopic surgery at 9% vs. 21% after open surgery (P = .013).

The laparoscopic group also had improved postoperative recovery compared with the open group including a shorter time to first bowel movement (2.9 days vs. 3.7 days, P = .001), time to intake of 1 liter of fluid (2.6 days vs. 2.8 days P = .006) and hospital stay (11.9 days vs. 12.1 days, P = .037), he said.

Anastomotic leakage occurred in 7% of patients after laparoscopic surgery and 6% after open surgery (P = .63). One-third of patients had a diverting ileostomy.

Mortality rates within 28 days after surgery did not differ between the laparoscopic and open groups (1.1% vs. 1.7%, P = .41), nor did morbidity (39.5% vs. 36.5%, P = .28), Dr. Bonjer said.

Dr. Peter Naredi, invited discussant and president of the European Society of Surgical Oncology, said COLOR II was very well performed, and that the large number of laparoscopic patients "will make a huge impact on the results of how good laparoscopic surgery is versus open surgery" when added to the current database.

He highlighted a meta-analysis published this spring of six randomized trials enrolling 1,033 patients that showed no difference between the two techniques with regard to number of lymph nodes harvested, involvement of the circumferential resection margin, 3-year-overall survival, and disease-free survival (Int. J. Colorectal. Dis. 2011;26:415-21).

Dr. Naredi, chair of surgery at Umeå (Sweden) University, expressed concern, however, about the 21% positive resection margin rates in the lower rectum for the open group, and said this would likely convert into differences in local recurrence between the two groups. He also stressed the importance of standardization when evaluating multimodal treatments, and pointed out that preoperative radiotherapy was used in 72% of the lower rectal cancer patients treated with laparoscopy and only 63% treated with open surgery.

Ethicon EndoSurgery supported the trial. No individual disclosures were presented.

STOCKHOLM – Laparoscopic surgery offers the same radical resection for noninvasive rectal cancer as does open surgery, according to short-term outcomes of the randomized, noninferiority phase III COLOR II trial.

The circumferential resection margin, described as the most important parameter for rectal cancer surgery, was 1.3 cm after laparoscopic and open surgery (P = .16). The distal margin was similar at 3.6 cm (P = .68).

The proximal margin was 17.0 cm in the laparoscopic group and 19.0 cm in the open group. The difference was statistically significant (P less than .001), but "clinically, totally irrelevant since a 17-cm margin is wide enough for a safe tumor resection," lead author Dr. H. Jaap Bonjer said at the European Multidisciplinary Cancer Congress.

COLOR II (Colorectal Cancer Laparoscopic or Open Resection) sought to answer whether laparoscopic total mesorectal excision is as oncologically safe as open surgery is. Removing the entire mesorectum, or fatty tissue around the rectum, is important because the radial spread of rectal cancer is more prominent than is longitudinal spread, explained Dr. Bonjer of the surgery department at Vrije University Medical Centre, Amsterdam.

Researchers at 30 centers in eight countries, including Canada, randomized 1,103 patients with a single rectal carcinoma within 15 cm of the anal verge, staged T1, T2, or T3 with a margin to the endopelvic fascia greater than 2 mm, to laparoscopic or open surgery. The analysis included 699 patients in the laparoscopic arm and 345 in the open surgery arm.

The technically demanding nature of laparoscopic surgery resulted in a longer operating time than with open surgery (median 240 minutes vs. 188 minutes, P less than .001), but blood loss was cut in half (median 200 mL vs. 400 mL, P less than .001), Dr. Bonjer said.

The number of lymph nodes harvested was similar at 13 in the laparoscopic group and 14 in the open group.

The overall positive resection margin rate, defined as less than 2 mm, was 9% in the laparoscopic group and 10% in the open group (P = .078), Dr. Bonjer said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Subgroup analyses showed similar positive resection margin rates in the upper rectum (10% vs. 9%, P = .92) and middle rectum (9% vs. 3%, P = .073), but a significantly better rate in the lower rectum after laparoscopic surgery at 9% vs. 21% after open surgery (P = .013).

The laparoscopic group also had improved postoperative recovery compared with the open group including a shorter time to first bowel movement (2.9 days vs. 3.7 days, P = .001), time to intake of 1 liter of fluid (2.6 days vs. 2.8 days P = .006) and hospital stay (11.9 days vs. 12.1 days, P = .037), he said.

Anastomotic leakage occurred in 7% of patients after laparoscopic surgery and 6% after open surgery (P = .63). One-third of patients had a diverting ileostomy.

Mortality rates within 28 days after surgery did not differ between the laparoscopic and open groups (1.1% vs. 1.7%, P = .41), nor did morbidity (39.5% vs. 36.5%, P = .28), Dr. Bonjer said.

Dr. Peter Naredi, invited discussant and president of the European Society of Surgical Oncology, said COLOR II was very well performed, and that the large number of laparoscopic patients "will make a huge impact on the results of how good laparoscopic surgery is versus open surgery" when added to the current database.

He highlighted a meta-analysis published this spring of six randomized trials enrolling 1,033 patients that showed no difference between the two techniques with regard to number of lymph nodes harvested, involvement of the circumferential resection margin, 3-year-overall survival, and disease-free survival (Int. J. Colorectal. Dis. 2011;26:415-21).

Dr. Naredi, chair of surgery at Umeå (Sweden) University, expressed concern, however, about the 21% positive resection margin rates in the lower rectum for the open group, and said this would likely convert into differences in local recurrence between the two groups. He also stressed the importance of standardization when evaluating multimodal treatments, and pointed out that preoperative radiotherapy was used in 72% of the lower rectal cancer patients treated with laparoscopy and only 63% treated with open surgery.

Ethicon EndoSurgery supported the trial. No individual disclosures were presented.

STOCKHOLM – Laparoscopic surgery offers the same radical resection for noninvasive rectal cancer as does open surgery, according to short-term outcomes of the randomized, noninferiority phase III COLOR II trial.

The circumferential resection margin, described as the most important parameter for rectal cancer surgery, was 1.3 cm after laparoscopic and open surgery (P = .16). The distal margin was similar at 3.6 cm (P = .68).

The proximal margin was 17.0 cm in the laparoscopic group and 19.0 cm in the open group. The difference was statistically significant (P less than .001), but "clinically, totally irrelevant since a 17-cm margin is wide enough for a safe tumor resection," lead author Dr. H. Jaap Bonjer said at the European Multidisciplinary Cancer Congress.

COLOR II (Colorectal Cancer Laparoscopic or Open Resection) sought to answer whether laparoscopic total mesorectal excision is as oncologically safe as open surgery is. Removing the entire mesorectum, or fatty tissue around the rectum, is important because the radial spread of rectal cancer is more prominent than is longitudinal spread, explained Dr. Bonjer of the surgery department at Vrije University Medical Centre, Amsterdam.

Researchers at 30 centers in eight countries, including Canada, randomized 1,103 patients with a single rectal carcinoma within 15 cm of the anal verge, staged T1, T2, or T3 with a margin to the endopelvic fascia greater than 2 mm, to laparoscopic or open surgery. The analysis included 699 patients in the laparoscopic arm and 345 in the open surgery arm.

The technically demanding nature of laparoscopic surgery resulted in a longer operating time than with open surgery (median 240 minutes vs. 188 minutes, P less than .001), but blood loss was cut in half (median 200 mL vs. 400 mL, P less than .001), Dr. Bonjer said.

The number of lymph nodes harvested was similar at 13 in the laparoscopic group and 14 in the open group.

The overall positive resection margin rate, defined as less than 2 mm, was 9% in the laparoscopic group and 10% in the open group (P = .078), Dr. Bonjer said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Subgroup analyses showed similar positive resection margin rates in the upper rectum (10% vs. 9%, P = .92) and middle rectum (9% vs. 3%, P = .073), but a significantly better rate in the lower rectum after laparoscopic surgery at 9% vs. 21% after open surgery (P = .013).

The laparoscopic group also had improved postoperative recovery compared with the open group including a shorter time to first bowel movement (2.9 days vs. 3.7 days, P = .001), time to intake of 1 liter of fluid (2.6 days vs. 2.8 days P = .006) and hospital stay (11.9 days vs. 12.1 days, P = .037), he said.

Anastomotic leakage occurred in 7% of patients after laparoscopic surgery and 6% after open surgery (P = .63). One-third of patients had a diverting ileostomy.

Mortality rates within 28 days after surgery did not differ between the laparoscopic and open groups (1.1% vs. 1.7%, P = .41), nor did morbidity (39.5% vs. 36.5%, P = .28), Dr. Bonjer said.

Dr. Peter Naredi, invited discussant and president of the European Society of Surgical Oncology, said COLOR II was very well performed, and that the large number of laparoscopic patients "will make a huge impact on the results of how good laparoscopic surgery is versus open surgery" when added to the current database.

He highlighted a meta-analysis published this spring of six randomized trials enrolling 1,033 patients that showed no difference between the two techniques with regard to number of lymph nodes harvested, involvement of the circumferential resection margin, 3-year-overall survival, and disease-free survival (Int. J. Colorectal. Dis. 2011;26:415-21).

Dr. Naredi, chair of surgery at Umeå (Sweden) University, expressed concern, however, about the 21% positive resection margin rates in the lower rectum for the open group, and said this would likely convert into differences in local recurrence between the two groups. He also stressed the importance of standardization when evaluating multimodal treatments, and pointed out that preoperative radiotherapy was used in 72% of the lower rectal cancer patients treated with laparoscopy and only 63% treated with open surgery.

Ethicon EndoSurgery supported the trial. No individual disclosures were presented.

STOCKHOLM – Adding the investigational drug iniparib to a gemcitabine and cisplatin doublet failed to improve outcomes significantly in a phase II study of 119 patients with advanced non–small-cell lung cancer.

The disappointing result follows a phase III trial in which iniparib failed to confirm survival gains when added to gemcitabine (Gemzar) and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer.

Iniparib (BSI-201) had been the leading agent in a new class of therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, but the phase III flop in breast cancer left researchers questioning whether it has a different mechanism of action.

In the current lung cancer trial, median progression-free survival was slightly longer at 5.7 months in those who received iniparib in addition to gemcitabine/cisplatinchemotherapy, compared with 4.3 months for those on gemcitabine/cisplatin alone. The difference was not statistically significant, however (hazard ratio, 0.89; P = .48).

Based on preliminary data at a median follow-up of 8.4 months, median overall survival was 8.5 months for the doublet-only arm and 11.2 months for the iniparib arm, Dr. Silvia Novello reported at the European Multidisciplinary Cancer Congress. Both survival measures were secondary end points.

"Be cautious when interpreting the 1.4-month increase in median progression-free survival and when interpreting the preliminary 2.7 months in median OS [overall survival] seen in the investigational arm vs. the chemotherapy arm because this could be due to differences in baseline patient characteristics," Dr. Novello told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

In particular, ECOG (Eastern Cooperative Oncology Group) performance status and sex were not balanced, with more patients having a performance status of 0 (61% vs. 49%) and more men (80% vs. 67%) in the investigational arm than in the control group, explained Dr. Novello, a thoracic oncologist at the University of Torino (Italy).

The study’s primary end point was overall response rate as determined by investigators using RECIST 1.1. The investigators previously reported this measure of complete and partial responses was higher in the control group – 26% for those on gemcitabine/cisplatin alone and 20% for those in the doublet plus iniparib group. The only complete response was in a patient given iniparib.

The study included patients who had measurable, untreated stage IV non–small-cell lung cancer (NSCLC) and an ECOG performance status of 0-1. They were randomized 2:1 to receive gemcitabine/cisplatin plus iniparib (80 patients) or gemcitabine/cisplatin alone (39 patients).

Roughly half of patients in each group completed five to six cycles – 44% vs. 50% for the chemotherapy and investigational arms.

Gemcitabine 1,250 mg/m² was given intravenously on days 1 and 8, and cisplatin was given 75 mg/m² intravenously on day 1 in 21-day cycles. Iniparib 5.6 mg/kg also was given intravenously on days 1, 4, 8, and 11 in the experimental arm. Patients underwent a maximum of six cycles, with no maintenance phase.

Safety data showed 82% of the chemotherapy arm and 85% of the iniparib arm had any grade 3/4 treatment-emergent adverse events.

Anemia and nausea were more common in the iniparib arm, but other common adverse events were essentially the same.

Biomarker studies are ongoing potentially to define a subgroup of patients who may benefit from iniparib treatment, according to Dr. Novello.

Invited discussant Dr. Luis Paz-Ares, medial oncology chief of service at Hospital Universitario Virgen del Rocio in Seville, Spain, emphasized the importance of this substudy. "I think it would be very relevant to know if there are some subsets of patients that may benefit," he said. "I think the main part of this trial is the markers, and I will be very interested to see the results of this."

The study is sponsored by Sanofi-Aventis in collaboration with BiPar Sciences. Dr. Novello has previously reported that she has no relevant financial disclosures.

STOCKHOLM – Adding the investigational drug iniparib to a gemcitabine and cisplatin doublet failed to improve outcomes significantly in a phase II study of 119 patients with advanced non–small-cell lung cancer.

The disappointing result follows a phase III trial in which iniparib failed to confirm survival gains when added to gemcitabine (Gemzar) and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer.

Iniparib (BSI-201) had been the leading agent in a new class of therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, but the phase III flop in breast cancer left researchers questioning whether it has a different mechanism of action.

In the current lung cancer trial, median progression-free survival was slightly longer at 5.7 months in those who received iniparib in addition to gemcitabine/cisplatinchemotherapy, compared with 4.3 months for those on gemcitabine/cisplatin alone. The difference was not statistically significant, however (hazard ratio, 0.89; P = .48).

Based on preliminary data at a median follow-up of 8.4 months, median overall survival was 8.5 months for the doublet-only arm and 11.2 months for the iniparib arm, Dr. Silvia Novello reported at the European Multidisciplinary Cancer Congress. Both survival measures were secondary end points.

"Be cautious when interpreting the 1.4-month increase in median progression-free survival and when interpreting the preliminary 2.7 months in median OS [overall survival] seen in the investigational arm vs. the chemotherapy arm because this could be due to differences in baseline patient characteristics," Dr. Novello told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

In particular, ECOG (Eastern Cooperative Oncology Group) performance status and sex were not balanced, with more patients having a performance status of 0 (61% vs. 49%) and more men (80% vs. 67%) in the investigational arm than in the control group, explained Dr. Novello, a thoracic oncologist at the University of Torino (Italy).

The study’s primary end point was overall response rate as determined by investigators using RECIST 1.1. The investigators previously reported this measure of complete and partial responses was higher in the control group – 26% for those on gemcitabine/cisplatin alone and 20% for those in the doublet plus iniparib group. The only complete response was in a patient given iniparib.

The study included patients who had measurable, untreated stage IV non–small-cell lung cancer (NSCLC) and an ECOG performance status of 0-1. They were randomized 2:1 to receive gemcitabine/cisplatin plus iniparib (80 patients) or gemcitabine/cisplatin alone (39 patients).

Roughly half of patients in each group completed five to six cycles – 44% vs. 50% for the chemotherapy and investigational arms.

Gemcitabine 1,250 mg/m² was given intravenously on days 1 and 8, and cisplatin was given 75 mg/m² intravenously on day 1 in 21-day cycles. Iniparib 5.6 mg/kg also was given intravenously on days 1, 4, 8, and 11 in the experimental arm. Patients underwent a maximum of six cycles, with no maintenance phase.

Safety data showed 82% of the chemotherapy arm and 85% of the iniparib arm had any grade 3/4 treatment-emergent adverse events.

Anemia and nausea were more common in the iniparib arm, but other common adverse events were essentially the same.

Biomarker studies are ongoing potentially to define a subgroup of patients who may benefit from iniparib treatment, according to Dr. Novello.

Invited discussant Dr. Luis Paz-Ares, medial oncology chief of service at Hospital Universitario Virgen del Rocio in Seville, Spain, emphasized the importance of this substudy. "I think it would be very relevant to know if there are some subsets of patients that may benefit," he said. "I think the main part of this trial is the markers, and I will be very interested to see the results of this."

The study is sponsored by Sanofi-Aventis in collaboration with BiPar Sciences. Dr. Novello has previously reported that she has no relevant financial disclosures.

STOCKHOLM – Adding the investigational drug iniparib to a gemcitabine and cisplatin doublet failed to improve outcomes significantly in a phase II study of 119 patients with advanced non–small-cell lung cancer.

The disappointing result follows a phase III trial in which iniparib failed to confirm survival gains when added to gemcitabine (Gemzar) and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer.

Iniparib (BSI-201) had been the leading agent in a new class of therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, but the phase III flop in breast cancer left researchers questioning whether it has a different mechanism of action.

In the current lung cancer trial, median progression-free survival was slightly longer at 5.7 months in those who received iniparib in addition to gemcitabine/cisplatinchemotherapy, compared with 4.3 months for those on gemcitabine/cisplatin alone. The difference was not statistically significant, however (hazard ratio, 0.89; P = .48).

Based on preliminary data at a median follow-up of 8.4 months, median overall survival was 8.5 months for the doublet-only arm and 11.2 months for the iniparib arm, Dr. Silvia Novello reported at the European Multidisciplinary Cancer Congress. Both survival measures were secondary end points.

"Be cautious when interpreting the 1.4-month increase in median progression-free survival and when interpreting the preliminary 2.7 months in median OS [overall survival] seen in the investigational arm vs. the chemotherapy arm because this could be due to differences in baseline patient characteristics," Dr. Novello told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

In particular, ECOG (Eastern Cooperative Oncology Group) performance status and sex were not balanced, with more patients having a performance status of 0 (61% vs. 49%) and more men (80% vs. 67%) in the investigational arm than in the control group, explained Dr. Novello, a thoracic oncologist at the University of Torino (Italy).

The study’s primary end point was overall response rate as determined by investigators using RECIST 1.1. The investigators previously reported this measure of complete and partial responses was higher in the control group – 26% for those on gemcitabine/cisplatin alone and 20% for those in the doublet plus iniparib group. The only complete response was in a patient given iniparib.

The study included patients who had measurable, untreated stage IV non–small-cell lung cancer (NSCLC) and an ECOG performance status of 0-1. They were randomized 2:1 to receive gemcitabine/cisplatin plus iniparib (80 patients) or gemcitabine/cisplatin alone (39 patients).

Roughly half of patients in each group completed five to six cycles – 44% vs. 50% for the chemotherapy and investigational arms.

Gemcitabine 1,250 mg/m² was given intravenously on days 1 and 8, and cisplatin was given 75 mg/m² intravenously on day 1 in 21-day cycles. Iniparib 5.6 mg/kg also was given intravenously on days 1, 4, 8, and 11 in the experimental arm. Patients underwent a maximum of six cycles, with no maintenance phase.

Safety data showed 82% of the chemotherapy arm and 85% of the iniparib arm had any grade 3/4 treatment-emergent adverse events.

Anemia and nausea were more common in the iniparib arm, but other common adverse events were essentially the same.

Biomarker studies are ongoing potentially to define a subgroup of patients who may benefit from iniparib treatment, according to Dr. Novello.

Invited discussant Dr. Luis Paz-Ares, medial oncology chief of service at Hospital Universitario Virgen del Rocio in Seville, Spain, emphasized the importance of this substudy. "I think it would be very relevant to know if there are some subsets of patients that may benefit," he said. "I think the main part of this trial is the markers, and I will be very interested to see the results of this."

The study is sponsored by Sanofi-Aventis in collaboration with BiPar Sciences. Dr. Novello has previously reported that she has no relevant financial disclosures.

STOCKHOLM – The experimental oral drug vismodegib provided a "substantial clinical benefit" for patients with locally advanced and metastatic basal cell carcinoma in a phase II trial involving 104 patients.

"Nearly all patients did have some tumor shrinkage," Dr. Luc Dirix said at the European Multidisciplinary Cancer Congress. The overall majority of those with locally advanced disease "had huge responses, with major decreases in tumor size."

The primary end point of overall response rate by independent review was reached in 43% of patients with locally advanced basal cell carcinoma (P less than .0001) and in 30% of those with metastatic disease (P = .0011). Response rates per investigator reached 60% and 45.5%, respectively.

Only a small minority of basal cell carcinomas (BCCs) become locally advanced or metastatic, but the consequences can be disfiguring and ultimately life threatening. For these patients, there is no clear standard of care, and thus this is an unmet medical need, explained Dr. Dirix of the Iridium Kankernetwerk at Sint-Augustinus Hospital in Wilrijk, Belgium.

Vismodegib is a first-in-class small-molecule inhibitor of the hedgehog signaling pathway, which is activated in more than 90% of BCC. Genentech, a member of the Roche group, is studying the drug in a variety of cancers. Based on the current phase II data, it filed a New Drug Application, announced on Sept. 12, 2011, with the Food and Drug Administration for vismodegib in the treatment of advanced, inoperable BCC.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma, but I think that long-term tolerance is really an issue," the invited discussant, Dr. Caroline Robert, said at the meeting, which was a joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

"It’s not a very serious adverse event, but [rather] the chronic effect [of] fatigue, loss of appetite, muscular pain that will impact the patients," said Dr. Robert, chief of dermatology at the Institut Cancérologie Gustave Roussy in Villejuif, France.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma."

Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, taste loss, weight loss, and fatigue, but they were mainly grade 1 and 2, Dr. Dirix said.

Serious adverse events were reported in 26 patients (25%), of which four were possibly related to vismodegib. They included cholestasis; dehydration with syncope; pneumonia and cardiac failure; and pulmonary embolism. No fatal events were linked to the drug, he said.

The efficacy analysis was based on 63 patients who had locally advanced BCC that was inoperable or for whom surgery would be significantly disfiguring, and 33 patients with histologically confirmed, RECIST (Response Evaluation Criteria in Solid Tumors)–measurable metastatic BCC.

Patients received 150-mg oral vismodegib daily until disease progression or intolerable toxicity. Their mean age was 61 years.

Three-fourths of patients in both cohorts had a clinical benefit (defined as a response at any time plus stable disease), Dr. Dirix said. The response often occurred before week 8, and lasted a median of 7.6 months in both cohorts, based on independent review.

Median progression-free survival by independent review was 9.5 months in both cohorts.

The current phase II trial, called ERIVANCE BCC, was prompted by a phase I trial reporting a 55% response rate in 33 patients with advanced BCC, including 2 complete responses and 16 partial responses (N. Engl. J. Med. 2009;361:1164-72). Only one patient withdrew because of adverse events.

In a recent unpublished phase II study, however, 28% of 41 patients taking vismodegib for Gorlin's syndrome dropped out because of an adverse event, Dr. Robert said during the presidential session. She called for other treatment modalities for advanced BCC, and suggested that vismodegib may be optimal at lower doses, when used sequentially, or as a 3-month course prior to surgery.

"This is very important, I think, because it may lead us to the use of this drug in the neoadjuvant setting, where we can do surgery after the tumor has already shrunk," she added.

Genentech supported the trial. Dr. Dirix reported that a coauthor is a Genentech employee.

STOCKHOLM – The experimental oral drug vismodegib provided a "substantial clinical benefit" for patients with locally advanced and metastatic basal cell carcinoma in a phase II trial involving 104 patients.

"Nearly all patients did have some tumor shrinkage," Dr. Luc Dirix said at the European Multidisciplinary Cancer Congress. The overall majority of those with locally advanced disease "had huge responses, with major decreases in tumor size."

The primary end point of overall response rate by independent review was reached in 43% of patients with locally advanced basal cell carcinoma (P less than .0001) and in 30% of those with metastatic disease (P = .0011). Response rates per investigator reached 60% and 45.5%, respectively.

Only a small minority of basal cell carcinomas (BCCs) become locally advanced or metastatic, but the consequences can be disfiguring and ultimately life threatening. For these patients, there is no clear standard of care, and thus this is an unmet medical need, explained Dr. Dirix of the Iridium Kankernetwerk at Sint-Augustinus Hospital in Wilrijk, Belgium.

Vismodegib is a first-in-class small-molecule inhibitor of the hedgehog signaling pathway, which is activated in more than 90% of BCC. Genentech, a member of the Roche group, is studying the drug in a variety of cancers. Based on the current phase II data, it filed a New Drug Application, announced on Sept. 12, 2011, with the Food and Drug Administration for vismodegib in the treatment of advanced, inoperable BCC.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma, but I think that long-term tolerance is really an issue," the invited discussant, Dr. Caroline Robert, said at the meeting, which was a joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

"It’s not a very serious adverse event, but [rather] the chronic effect [of] fatigue, loss of appetite, muscular pain that will impact the patients," said Dr. Robert, chief of dermatology at the Institut Cancérologie Gustave Roussy in Villejuif, France.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma."

Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, taste loss, weight loss, and fatigue, but they were mainly grade 1 and 2, Dr. Dirix said.

Serious adverse events were reported in 26 patients (25%), of which four were possibly related to vismodegib. They included cholestasis; dehydration with syncope; pneumonia and cardiac failure; and pulmonary embolism. No fatal events were linked to the drug, he said.

The efficacy analysis was based on 63 patients who had locally advanced BCC that was inoperable or for whom surgery would be significantly disfiguring, and 33 patients with histologically confirmed, RECIST (Response Evaluation Criteria in Solid Tumors)–measurable metastatic BCC.

Patients received 150-mg oral vismodegib daily until disease progression or intolerable toxicity. Their mean age was 61 years.

Three-fourths of patients in both cohorts had a clinical benefit (defined as a response at any time plus stable disease), Dr. Dirix said. The response often occurred before week 8, and lasted a median of 7.6 months in both cohorts, based on independent review.

Median progression-free survival by independent review was 9.5 months in both cohorts.

The current phase II trial, called ERIVANCE BCC, was prompted by a phase I trial reporting a 55% response rate in 33 patients with advanced BCC, including 2 complete responses and 16 partial responses (N. Engl. J. Med. 2009;361:1164-72). Only one patient withdrew because of adverse events.

In a recent unpublished phase II study, however, 28% of 41 patients taking vismodegib for Gorlin's syndrome dropped out because of an adverse event, Dr. Robert said during the presidential session. She called for other treatment modalities for advanced BCC, and suggested that vismodegib may be optimal at lower doses, when used sequentially, or as a 3-month course prior to surgery.

"This is very important, I think, because it may lead us to the use of this drug in the neoadjuvant setting, where we can do surgery after the tumor has already shrunk," she added.

Genentech supported the trial. Dr. Dirix reported that a coauthor is a Genentech employee.

STOCKHOLM – The experimental oral drug vismodegib provided a "substantial clinical benefit" for patients with locally advanced and metastatic basal cell carcinoma in a phase II trial involving 104 patients.

"Nearly all patients did have some tumor shrinkage," Dr. Luc Dirix said at the European Multidisciplinary Cancer Congress. The overall majority of those with locally advanced disease "had huge responses, with major decreases in tumor size."

The primary end point of overall response rate by independent review was reached in 43% of patients with locally advanced basal cell carcinoma (P less than .0001) and in 30% of those with metastatic disease (P = .0011). Response rates per investigator reached 60% and 45.5%, respectively.

Only a small minority of basal cell carcinomas (BCCs) become locally advanced or metastatic, but the consequences can be disfiguring and ultimately life threatening. For these patients, there is no clear standard of care, and thus this is an unmet medical need, explained Dr. Dirix of the Iridium Kankernetwerk at Sint-Augustinus Hospital in Wilrijk, Belgium.

Vismodegib is a first-in-class small-molecule inhibitor of the hedgehog signaling pathway, which is activated in more than 90% of BCC. Genentech, a member of the Roche group, is studying the drug in a variety of cancers. Based on the current phase II data, it filed a New Drug Application, announced on Sept. 12, 2011, with the Food and Drug Administration for vismodegib in the treatment of advanced, inoperable BCC.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma, but I think that long-term tolerance is really an issue," the invited discussant, Dr. Caroline Robert, said at the meeting, which was a joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

"It’s not a very serious adverse event, but [rather] the chronic effect [of] fatigue, loss of appetite, muscular pain that will impact the patients," said Dr. Robert, chief of dermatology at the Institut Cancérologie Gustave Roussy in Villejuif, France.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma."

Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, taste loss, weight loss, and fatigue, but they were mainly grade 1 and 2, Dr. Dirix said.

Serious adverse events were reported in 26 patients (25%), of which four were possibly related to vismodegib. They included cholestasis; dehydration with syncope; pneumonia and cardiac failure; and pulmonary embolism. No fatal events were linked to the drug, he said.

The efficacy analysis was based on 63 patients who had locally advanced BCC that was inoperable or for whom surgery would be significantly disfiguring, and 33 patients with histologically confirmed, RECIST (Response Evaluation Criteria in Solid Tumors)–measurable metastatic BCC.

Patients received 150-mg oral vismodegib daily until disease progression or intolerable toxicity. Their mean age was 61 years.

Three-fourths of patients in both cohorts had a clinical benefit (defined as a response at any time plus stable disease), Dr. Dirix said. The response often occurred before week 8, and lasted a median of 7.6 months in both cohorts, based on independent review.

Median progression-free survival by independent review was 9.5 months in both cohorts.

The current phase II trial, called ERIVANCE BCC, was prompted by a phase I trial reporting a 55% response rate in 33 patients with advanced BCC, including 2 complete responses and 16 partial responses (N. Engl. J. Med. 2009;361:1164-72). Only one patient withdrew because of adverse events.

In a recent unpublished phase II study, however, 28% of 41 patients taking vismodegib for Gorlin's syndrome dropped out because of an adverse event, Dr. Robert said during the presidential session. She called for other treatment modalities for advanced BCC, and suggested that vismodegib may be optimal at lower doses, when used sequentially, or as a 3-month course prior to surgery.

"This is very important, I think, because it may lead us to the use of this drug in the neoadjuvant setting, where we can do surgery after the tumor has already shrunk," she added.

Genentech supported the trial. Dr. Dirix reported that a coauthor is a Genentech employee.

STOCKHOLM – The experimental cytotoxic agent TAS-102 significantly reduced the risk of death in a placebo-controlled phase II trial of patients with metastatic colorectal cancer refractory to current treatments.

Patients receiving oral TAS-102 plus best supportive care had a median overall survival of 9 months, compared with 6.6 months for placebo and best supportive care (hazard ratio, 0.56; P = .001).

TAS-102 also doubled median progression-free survival from 1 month to 2 months (HR, 0.41; P less than .0001), Dr. Yasutoshi Kuboki reported at the European Multidisciplinary Cancer Congress.

KRAS mutation testing revealed that TAS-102 offers a significant survival advantage for patients harboring a KRAS mutation, a biomarker of nonresponsiveness to the approved targeted agents cetuximab (Erbitux) and panitumumab (Vectibix).

KRAS mutation-positive patients treated with TAS-102 had a median overall survival of 13.0 months, compared with 6.9 months for placebo (HR, 0.44; P = .006,), and a progression-free survival of 2.8 months vs. 1.0 month (HR, 0.34; P less than .0001).

In the KRAS wild-type subset, median overall survival was similar at 7.2 months with TAS-102 and 7.0 months with placebo (HR, 0.70; P = .19), although time to disease progression increased from 1.0 to 1.9 months with TAS-102 (HR, 0.47; P = .0004).

Dr. Kuboki said a phase III trial is needed to confirm the promising results, but that "TAS-102 is the first cytotoxic agent to prolong survival in patients with metastatic colorectal cancer refractory to conventional cytotoxic agents."

Invited discussant Dr. Eric van Cutsem, of the University of Leuven, Belgium, said, "It’s less sexy, less fashionable to talk about cytotoxics in colorectal cancer because we have the impression we’ve seen it all," but the study is important nonetheless and the outcome "very impressive."

"It’s a phase II study, but if we could see similar numbers in a phase III study with hazard rates of 0.56, then we could say we have a new drug," he said.

Dr. van Cutsem pointed out that the hazard ratios observed with TAS-102 in the phase II study are similar to those reported in submission approvals for cetuximab and panitumumab in advanced, chemotherapy-refractory colorectal cancer.

TAS-102 is a novel agent that combines trifluorothymidine and thymidine phosphorylase inhibitor at a molar ratio of 1 to 0.5, explained Dr. Kuboki, with the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo.

Researchers at 10 Japanese centers recruited 172 patients with refractory metastatic colorectal cancer after at least two lines of chemotherapy containing fluoropyrimidine, irinotecan, and oxaliplatin. Prior treatment also included cetuximab in two-thirds and bevacizumab (Avastin) in at least three-fourths of the population.

Patients were randomized double-blind 2:1 to best supportive care plus placebo or TAS-102 70 mg/m² twice daily on days 1-5 and days 8-12 every 4 weeks.

Among 169 evaluable patients, the disease control rate was 43.8% with TAS-102 vs. 10.5% with placebo, Dr. Kuboki said at the meeting, which was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

Treatment with TAS-102 was well tolerated in the heavily pretreated cohort, and there were no treatment-related deaths. Neutropenia was the main side effect (17.6%), but there was no neutropenic sepsis, he said.

Taiho Pharmaceutical Co. sponsored the study. Dr. Kuboki and his coauthors reported no conflicts of interest.

STOCKHOLM – The experimental cytotoxic agent TAS-102 significantly reduced the risk of death in a placebo-controlled phase II trial of patients with metastatic colorectal cancer refractory to current treatments.

Patients receiving oral TAS-102 plus best supportive care had a median overall survival of 9 months, compared with 6.6 months for placebo and best supportive care (hazard ratio, 0.56; P = .001).

TAS-102 also doubled median progression-free survival from 1 month to 2 months (HR, 0.41; P less than .0001), Dr. Yasutoshi Kuboki reported at the European Multidisciplinary Cancer Congress.

KRAS mutation testing revealed that TAS-102 offers a significant survival advantage for patients harboring a KRAS mutation, a biomarker of nonresponsiveness to the approved targeted agents cetuximab (Erbitux) and panitumumab (Vectibix).

KRAS mutation-positive patients treated with TAS-102 had a median overall survival of 13.0 months, compared with 6.9 months for placebo (HR, 0.44; P = .006,), and a progression-free survival of 2.8 months vs. 1.0 month (HR, 0.34; P less than .0001).

In the KRAS wild-type subset, median overall survival was similar at 7.2 months with TAS-102 and 7.0 months with placebo (HR, 0.70; P = .19), although time to disease progression increased from 1.0 to 1.9 months with TAS-102 (HR, 0.47; P = .0004).

Dr. Kuboki said a phase III trial is needed to confirm the promising results, but that "TAS-102 is the first cytotoxic agent to prolong survival in patients with metastatic colorectal cancer refractory to conventional cytotoxic agents."

Invited discussant Dr. Eric van Cutsem, of the University of Leuven, Belgium, said, "It’s less sexy, less fashionable to talk about cytotoxics in colorectal cancer because we have the impression we’ve seen it all," but the study is important nonetheless and the outcome "very impressive."

"It’s a phase II study, but if we could see similar numbers in a phase III study with hazard rates of 0.56, then we could say we have a new drug," he said.

Dr. van Cutsem pointed out that the hazard ratios observed with TAS-102 in the phase II study are similar to those reported in submission approvals for cetuximab and panitumumab in advanced, chemotherapy-refractory colorectal cancer.

TAS-102 is a novel agent that combines trifluorothymidine and thymidine phosphorylase inhibitor at a molar ratio of 1 to 0.5, explained Dr. Kuboki, with the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo.

Researchers at 10 Japanese centers recruited 172 patients with refractory metastatic colorectal cancer after at least two lines of chemotherapy containing fluoropyrimidine, irinotecan, and oxaliplatin. Prior treatment also included cetuximab in two-thirds and bevacizumab (Avastin) in at least three-fourths of the population.

Patients were randomized double-blind 2:1 to best supportive care plus placebo or TAS-102 70 mg/m² twice daily on days 1-5 and days 8-12 every 4 weeks.

Among 169 evaluable patients, the disease control rate was 43.8% with TAS-102 vs. 10.5% with placebo, Dr. Kuboki said at the meeting, which was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

Treatment with TAS-102 was well tolerated in the heavily pretreated cohort, and there were no treatment-related deaths. Neutropenia was the main side effect (17.6%), but there was no neutropenic sepsis, he said.

Taiho Pharmaceutical Co. sponsored the study. Dr. Kuboki and his coauthors reported no conflicts of interest.

STOCKHOLM – The experimental cytotoxic agent TAS-102 significantly reduced the risk of death in a placebo-controlled phase II trial of patients with metastatic colorectal cancer refractory to current treatments.

Patients receiving oral TAS-102 plus best supportive care had a median overall survival of 9 months, compared with 6.6 months for placebo and best supportive care (hazard ratio, 0.56; P = .001).

TAS-102 also doubled median progression-free survival from 1 month to 2 months (HR, 0.41; P less than .0001), Dr. Yasutoshi Kuboki reported at the European Multidisciplinary Cancer Congress.

KRAS mutation testing revealed that TAS-102 offers a significant survival advantage for patients harboring a KRAS mutation, a biomarker of nonresponsiveness to the approved targeted agents cetuximab (Erbitux) and panitumumab (Vectibix).

KRAS mutation-positive patients treated with TAS-102 had a median overall survival of 13.0 months, compared with 6.9 months for placebo (HR, 0.44; P = .006,), and a progression-free survival of 2.8 months vs. 1.0 month (HR, 0.34; P less than .0001).

In the KRAS wild-type subset, median overall survival was similar at 7.2 months with TAS-102 and 7.0 months with placebo (HR, 0.70; P = .19), although time to disease progression increased from 1.0 to 1.9 months with TAS-102 (HR, 0.47; P = .0004).

Dr. Kuboki said a phase III trial is needed to confirm the promising results, but that "TAS-102 is the first cytotoxic agent to prolong survival in patients with metastatic colorectal cancer refractory to conventional cytotoxic agents."

Invited discussant Dr. Eric van Cutsem, of the University of Leuven, Belgium, said, "It’s less sexy, less fashionable to talk about cytotoxics in colorectal cancer because we have the impression we’ve seen it all," but the study is important nonetheless and the outcome "very impressive."

"It’s a phase II study, but if we could see similar numbers in a phase III study with hazard rates of 0.56, then we could say we have a new drug," he said.

Dr. van Cutsem pointed out that the hazard ratios observed with TAS-102 in the phase II study are similar to those reported in submission approvals for cetuximab and panitumumab in advanced, chemotherapy-refractory colorectal cancer.

TAS-102 is a novel agent that combines trifluorothymidine and thymidine phosphorylase inhibitor at a molar ratio of 1 to 0.5, explained Dr. Kuboki, with the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo.

Researchers at 10 Japanese centers recruited 172 patients with refractory metastatic colorectal cancer after at least two lines of chemotherapy containing fluoropyrimidine, irinotecan, and oxaliplatin. Prior treatment also included cetuximab in two-thirds and bevacizumab (Avastin) in at least three-fourths of the population.

Patients were randomized double-blind 2:1 to best supportive care plus placebo or TAS-102 70 mg/m² twice daily on days 1-5 and days 8-12 every 4 weeks.

Among 169 evaluable patients, the disease control rate was 43.8% with TAS-102 vs. 10.5% with placebo, Dr. Kuboki said at the meeting, which was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

Treatment with TAS-102 was well tolerated in the heavily pretreated cohort, and there were no treatment-related deaths. Neutropenia was the main side effect (17.6%), but there was no neutropenic sepsis, he said.

Taiho Pharmaceutical Co. sponsored the study. Dr. Kuboki and his coauthors reported no conflicts of interest.