Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases

Background: This phase III study compared the efficacy of the new potent bisphosphonate, ibandronate, with placebo as intravenous (i.v.) therapy in metastatic bone disease due to breast cancer. Patients and methods: A total of 466 patients were randomised to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) ibandronate every 3-4 weeks for up to 2 years. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use and safety were evaluated monthly. Results SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (P = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Treatment with ibandronate was well tolerated. Conclusions: These results indicate that 6 mg i.v. ibandronate is effective and safe in the treatment of bone metastases from breast cance

Phase II Study of Bevacizumab in Combination with Trastuzumab and Capecitabine as First-Line Treatment for HER-2-positive Locally Recurrent or Metastatic Breast Cancer

The first results from a phase II, open-label study designed to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab and capecitabine as first-line therapy for patients with human epidermal growth factor receptor-2–positive locally recurrent or metastatic breast cancer are reported

Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia.

Hypercalcaemia is an important cause of morbidity in malignant disease. We studied the efficacy and safety of intravenous ibandronate (a new, potent bisphosphonate) in a multicentre study of 147 patients with severe cancer-associated hypercalcaemia which had been resistant to treatment with rehydration alone. Of 131 randomized patients who were eligible for evaluation, 45 were allocated to receive 2 mg ibandronate, 44 patients to receive 4 mg and 42 patients to receive 6 mg. Serum calcium values fell progressively in each group from day 2, reaching a nadir at day 5, and in some patients normocalcaemia was maintained for up to 36 days after treatment. The 2-mg dose was significantly less effective than the 4-mg or 6-mg dose in correcting hypercalcaemia, as the number of patients who achieved serum calcium values below 2.7 mM after treatment was 50% in the 2-mg group compared with 75.6% in the 4-mg group and 77.4% in the 6-mg group (P < 0.05; 2 mg vs others). In a logistic regression analysis, three factors were found to predict response; ibandronate dose (higher doses were more effective), severity of presenting hypercalcaemia (severe hypercalcaemia was associated with less complete response) and tumour type (patients with breast carcinoma and haematological tumours responded better than those with other tumours). Ibandronate was generally well tolerated and no serious drug-related adverse events were observed. We conclude that ibandronate is a safe, well tolerated and effective treatment for cancer-associated hypercalcaemia, which should prove a useful addition to the current range of therapies available to treat this condition

PREOPERATIVE CHEMOTHERAPY FOR COLORECTAL CANCER LIVER METASTASES: SHORT-TERM RESULTS

Background. At present liver resection combined with chemotherapy is the only treatment for isolated resectable colorectal cancer liver metastases that potentially can achieve cure. Effective preoperative chemotherapy allows us to evaluate chemoresponsiveness of the tumor and increase metastases resectability.Materials and methods. Between 2006 and 2011, 60 patients with potentially resectable colorectal cancer liver metastases were included in the study. All patients received preoperative oxaliplatin- or irinotecan-based chemotherapy; average duration of treatment was 3.6 ± 0.11 months. Liver resection was performed after chemotherapy: 29 (48.3 %) pts underwent hemihepatectomy, 11 (18.3 %) pts – extended hemihepatectomy and 20 (33.4 %) pts – segmentectomy. Pathologic response in liver metastases was assessed to analyze efficacy of preoperative chemotherapy.Results. Objective response to preoperative chemotherapy was observed in 33 (55 %) pts. 23 (38.3 %) patients had stable disease. The maximum effect of preoperative chemotherapy was achieved in patients with bilobar liver metastases, receiving combination with oxaliplatin – in 23 (63.9 %) cases. Side effects of 334 cycles of preoperative chemotherapy were assessed. In most cases, adverse events were not clinically significant. Side effects of grade III/IV in 18 (5.4 %) cycles were observed in 12 (20 %) patients. 52 (86.7 %) patients underwent R0-resections; 8 pts had R1 (n = 5) и R2 (n = 3) resections of metastases. There were no postoperative deaths. Pathologic response was observed in 55/60 (91.7 %) cases: grade I was seen in 17 (28.3 %) cases; grade II – in 14 (23.3 %); grade III – in 20 (33.3 %) and grade IV – in 4 (6.8 %) cases. Pathologic response of grade III/IV occurred in 63.6 % patients with partial treatment response and 13 % pts – with stable disease (р = 0.01).Conclusions. Highest efficacy of preoperative chemotherapy in combined treatment of colorectal cancer was achieved in patients with bilobar liver metastases. Safety of two-component chemotherapy regimens was confirmed. This study presents significant correlation between preoperative chemotherapy efficacy and pathologic response in liver metastases

Efficacy and safety of subcutaneous trastuzumab and intravenous trastuzumab as part of adjuvant therapy for HER2-positive early breast cancer: final analysis of the randomised, two-cohort PrefHer study

Aim To assess efficacy (event-free survival, EFS) and safety in patients followed up for 3 years in the PrefHer study (NCT01401166). Patients and methods Post surgery and post chemotherapy in the (neo)adjuvant setting, patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer were randomised to receive four cycles of the subcutaneous form of trastuzumab (Herceptin ® SC [H SC] via single-use injection device [Cohort 1] or delivery via a hand-held syringe from an SC Vial [Cohort 2]; 600 mg fixed dose) followed by four of the intravenous form of trastuzumab (Herceptin ® [H IV]; 8 mg/kg loading, 6 mg/kg maintenance doses) in the adjuvant setting or vice versa every 3 weeks. Patients could have received H before randomisation. H was then continued to complete a total of 18 cycles, including any cycles received before randomisation. Results A total of 488 patients were randomised across both cohorts. After median follow-up of 36.1 months, 3-year EFS across both groups in the evaluable intention-to-treat population (467 patients) was 90.6% overall, 89.9% in Cohort 1, and 91.1% in Cohort 2. No new safety signals were identified during long-term follow-up, with only one cardiac serious adverse event in the safety population (483 patients). Conclusions Three-year EFS data following H SC and H IV treatment are consistent with those reported by previous trials for H in the adjuvant setting. The overall safety profile during adjuvant treatment was as expected

Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer

BACKGROUND: Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. METHODS: This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. RESULTS: Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. CONCLUSIONS: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (ClinicalTrials.gov number, NCT00045032.)published_or_final_versio

НЕПОСРЕДСТВЕННАЯ ЭФФЕКТИВНОСТЬ ПРЕДОПЕРАЦИОННОЙ ХИМИОТЕРАПИИ ПРИ МЕТАСТАЗАХ КОЛОРЕКТАЛЬНОГО РАКА В ПЕЧЕНИ

Background. At present liver resection combined with chemotherapy is the only treatment for isolated resectable colorectal cancer liver metastases that potentially can achieve cure. Effective preoperative chemotherapy allows us to evaluate chemoresponsiveness of the tumor and increase metastases resectability.Materials and methods. Between 2006 and 2011, 60 patients with potentially resectable colorectal cancer liver metastases were included in the study. All patients received preoperative oxaliplatin- or irinotecan-based chemotherapy; average duration of treatment was 3.6 ± 0.11 months. Liver resection was performed after chemotherapy: 29 (48.3 %) pts underwent hemihepatectomy, 11 (18.3 %) pts – extended hemihepatectomy and 20 (33.4 %) pts – segmentectomy. Pathologic response in liver metastases was assessed to analyze efficacy of preoperative chemotherapy.Results. Objective response to preoperative chemotherapy was observed in 33 (55 %) pts. 23 (38.3 %) patients had stable disease. The maximum effect of preoperative chemotherapy was achieved in patients with bilobar liver metastases, receiving combination with oxaliplatin – in 23 (63.9 %) cases. Side effects of 334 cycles of preoperative chemotherapy were assessed. In most cases, adverse events were not clinically significant. Side effects of grade III/IV in 18 (5.4 %) cycles were observed in 12 (20 %) patients. 52 (86.7 %) patients underwent R0-resections; 8 pts had R1 (n = 5) и R2 (n = 3) resections of metastases. There were no postoperative deaths. Pathologic response was observed in 55/60 (91.7 %) cases: grade I was seen in 17 (28.3 %) cases; grade II – in 14 (23.3 %); grade III – in 20 (33.3 %) and grade IV – in 4 (6.8 %) cases. Pathologic response of grade III/IV occurred in 63.6 % patients with partial treatment response and 13 % pts – with stable disease (р = 0.01).Conclusions. Highest efficacy of preoperative chemotherapy in combined treatment of colorectal cancer was achieved in patients with bilobar liver metastases. Safety of two-component chemotherapy regimens was confirmed. This study presents significant correlation between preoperative chemotherapy efficacy and pathologic response in liver metastases.Введение. В настоящее время резекция печени является единственным методом, позволяющим вместе с химиотерапией (ХТ) потенциально достичь излечения больных колоректальным раком (КРР) с изолированными резектабельными метастазами в печени. Предоперационная ХТ позволяет повысить резектабельность метастазов в печени и оценить химиочувствительность опухоли.Материалы и методы. С 2006 по 2011 г. в исследование включено 60 больных КРР с потенциально резектабельными метастазами в печени. Всем больным проведена предоперационная ХТ с включением фторпиримидинов и оксалиплатина или иринотекана; средняя продолжительность лечения составила 3,6 ± 0,11 мес. После завершения лекарственной терапии выполнена резекция печени: гемигепатэктомия – 29 (48,3 %) больным; расширенная гемигепатэктомия – 11 (18,3 %) и экономные резекции – 20 (33,4 %) больным. Для анализа эффективности предоперационной ХТ оценена выраженность лечебного патоморфоза в метастазах печени.Результаты. Объективный эффект предоперационной ХТ установлен у 33 (55 %) больных. Стабилизация заболевания отмечена в 23 (38,3 %) случаях. Максимальный эффект предоперационной ХТ достигнут у больных с билобарным поражением печени, получавших комбинации с оксалиплатином, – в 23 (63,9 %) случаях. Оценены побочные эффекты 334 курсов предоперационной ХТ. В большинстве случаев нежелательные явления были клинически незначимы. Побочные эффекты III–IV степени сопровождали 18 (5,4 %) курсов лечения у 12 (20 %) больных. У 52 (86,7 %) больных выполнены R0-резекции; у 8 больных – R1 (n = 5) и R2 (n = 3) резекции метастазов. В послеоперационном периоде летальных исходов не отмечено. При морфологическом исследовании у 55/60 (91,7 %) больных выявлены признаки лечебного патоморфоза. Патоморфоз I степени отмечен в 17 (28,3 %) случаях; II степени – в 14 (23,3 %) случаях; III степени – в 20 (33,3 %) и IV степени – в 4 (6,8 %). При частичном эффекте патоморфоз III–IV степени отмечен в 63,6 %; при стабилизации – в 13 % (р = 0,01).Выводы. Предоперационная ХТ как этап комбинированного лечения больных КРР продемонстрировала наибольшую эффективность при билобарных метастазах в печени. Подтверждена безопасность двухкомпонентных режимов ХТ. Степень лечебного патоморфоза достоверно коррелировала с эффективностью предоперационной ХТ

СОВРЕМЕННАЯ ЛЕЧЕБНАЯ ТАКТИКА ПРИ РАКЕ ПРЯМОЙ КИШКИ С СИНХРОННЫМИ ОТДАЛЕННЫМИ МЕТАСТАЗАМИ (КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ)

Treatment results of low rectal cancer patient with internal sphincter involvement and synchronous liver metastases is presented. After combined treatment including preoperative targeted therapy, chemotherapy, chemoradiotherapy a synchronous resection of primary tumour and liver metastases was carried out (R0). Synchronous right hepihepatectomy and proctectomy was performed with resection of the deep part of external sphincter, neorectum creation by transverse coloplasty, neoanal sphincter creation using colonic smooth muscle layer without preventive colostomy. A possibility of synchronous plastic sphincter-sparing surgery in metastatic rectal cancer patient with locally advanced tumour is demonstrated. Such treatment allows to remove the risk of primary tumour complications, facilitates further chemotherapy treatment and improves quality of life and long-term treatment outcome.В статье представлены результаты лечения больной, страдающей раком нижнеампулярного отдела прямой кишки с поражением внутреннего сфинктера и наличием синхронных отдаленных метастазов в печень. После проведения комплексного лечения с использованием в предоперационном периоде таргетной терапии и химиотерапии с последующим химиолучевым лечением пациентке произведено симультанное хирургическое вмешательство (R0). Выполнена правосторонняя гемигепатэктомия с одномоментной проктэктомией, удалением глубокой порции наружного сфинктера и выполнением реконструктивнопластического этапа в виде формирования неоректума путем поперечной колопластики и неосфинктера методом гладкомышечной манжетки без формирования превентивной кишечной стомы. В наблюдении показана целесообразность выполнения одномоментных реконструктивно-пластических операций у больных метастатическим раком прямой кишки даже с первично-распространенной опухолью. Это не только избавляет их от тяжелых осложнений опухоли и обеспечивает возможность дальнейшего проведения системной химиотерапии, но и улучшает качество жизни, продлевая жизнь данной тяжелой категории больных

Adjuvant pembrolizumab versus placebo in resected stage III melanoma

The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74;