Jean-Pierre M. Ayoub

Superior Survival With Capecitabine Plus Docetaxel Combination Therapy in Anthracycline-Pretreated Patients With Advanced Breast Cancer: Phase III Trial Results

PURPOSE Docetaxel and capecitabine, a tumor-activated oral fluoropyrimidine, show high single-agent efficacy in metastatic breast cancer (MBC) and synergy in preclinical studies. This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC. PATIENTS AND METHODS Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or to docetaxel 100 mg/m(2) on day 1 (n = 256). RESULTS Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780; P =.0001; median, 6.1 v 4.2 months), overall survival (hazard ratio, 0.775; 95% CI, 0.634 to 0.947; P =.0126; median, 14.5 v 11.5 months), and objective tumor response rate (42% v 30%, P =.006) compared with docetaxel. Gastrointestinal side effects and hand-foot syndrome were more common with combination therapy, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel. More grade 3 adverse events occurred with combination therapy (71% v 49%, respectively), whereas grade 4 events were slightly more common with docetaxel (31% v 25% with combination). CONCLUSION The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m(2), with the manageable toxicity profile, indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m(2). Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC.

Pharmacokinetics, Safety, and Efficacy of Trastuzumab Administered Every Three Weeks in Combination With Paclitaxel

PURPOSE This phase II study evaluated the pharmacokinetics and safety of trastuzumab and paclitaxel given every 3 weeks to women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. PATIENTS AND METHODS Thirty-two patients received a loading dose of trastuzumab 8 mg/kg intravenously (day 1) and paclitaxel 175 mg/m2 (day 0). Thereafter, trastuzumab 6 mg/kg was administered on the same day as paclitaxel 175 mg/m2 every 3 weeks for seven cycles. In responding patients, trastuzumab monotherapy every 3 weeks was then continued until disease progression or patient withdrawal. RESULTS Trastuzumab trough levels were more than 20 mug/mL by the end of cycle 1. The half-life of trastuzumab was estimated to be 18 to 27 days, although this may be an underestimate. The combination of paclitaxel and trastuzumab was generally well tolerated, with no unexpected toxicities and no pharmacokinetic interaction. The most common adverse events were myalgia, paresthesias, alopecia, arthralgia, and fatigue. Events associated with trastuzumab included infusion-related reactions and cardiac dysfunction. Ten patients had a > or = 15% decrease in ejection fraction, but only one had symptomatic heart failure. The investigator-assessed objective response rate was 59% (four complete and 15 partial responses) and seven patients (22%) had stable disease. The median duration of response was 10.5 months and median time to progression was 12.2 months. CONCLUSION Additional investigation of trastuzumab administered every 3 weeks is warranted. In combination with paclitaxel, it is generally well tolerated. Plasma trastuzumab trough levels and clinical response rates compare favorably with those achieved with the standard weekly trastuzumab regimen plus chemotherapy. The presence of trastuzumab does not alter exposure to paclitaxel.

An Open-Label Phase II Study Evaluating the Safety and Efficacy of Ramucirumab Combined With mFOLFOX-6 as First-Line Therapy for Metastatic Colorectal Cancer

BACKGROUND Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) are believed to mediate angiogenesis in colorectal cancer (CRC). Ramucirumab (RAM; IMC-1121B) is a human IgG1 monoclonal antibody that inhibits VEGF ligand binding to VEGFR-2, inhibiting VEGFR-2 activation and signaling. METHODS Patients with metastatic CRC, Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function who had not received chemotherapy for metastatic disease received RAM and the modified FOLFOX-6 regimen every 2 weeks. Endpoints included progression-free survival (PFS), objective response rate, overall survival, and safety. The sample size was based on a potentially improved median PFS from 8 months to 11 months. RESULTS Forty-eight patients received therapy. Median PFS was 11.5 months (95% confidence interval [CI]: 8.6-13.1 months). The objective response rate was 58.3% (95% CI: 43.21-72.39). The disease control rate (complete or partial response plus stable disease) was 93.8% (95% CI: 82.8-98.7). Median overall survival was 20.4 months (95% CI: 18.5-25.1 months). The most frequent grade 3-4 adverse events included neutropenia (grade 3: 33.3%; grade 4: 8.3%), hypertension (grade 3: 16.7%), and neuropathy (grade 3: 12.5%). Two patients died during the study due to myocardial infarction and cardiopulmonary arrest. CONCLUSION RAM may enhance the efficacy of modified FOLFOX-6 chemotherapy with an acceptable safety profile in metastatic CRC.

Clinical features and course of brain metastases in colorectal cancer: an experience from a single institution

OBJECTIVES Brain metastases from colorectal cancer (crc) are quite rare. Here, we review the characteristics, presentation, and clinical course of such patients at our institution. METHODS We reviewed the medical records of patients with brain metastases from crc treated during 2000-2009. Associations between patient, tumour characteristics, treatment modality, and survival were assessed using the Kaplan-Meier method. RESULTS We identified 48 patients (25 men, 23 women) who developed brain metastases from crc. The median age at diagnosis of the brain metastases was 63 years (range: 37-84 years). In 23 of the patients (48%), the primary tumour occurred in the rectum. At diagnosis of brain metastases, 43 patients (90%) also had other systemic metastases (mainly pulmonary and hepatic). The median interval between diagnosis of the primary tumour and of the brain metastases was 24 months. Median survival after a diagnosis of brain metastasis from crc was 4 months (range: 1-13 months). We observed substantially better survival (13 months, p < 0.001) in patients treated with surgery followed by whole-brain radiotherapy (wbrt) than in those treated with radiotherapy or surgery alone. Sex, age, location and number of brain metastases, and timing of diagnosis did not affect survival. CONCLUSIONS Brain metastases from crc develop late in the course of the disease, given that most patients already have other secondary lesions. Prognosis in these patients is poor, with those receiving treatment with surgery and wbrt having the best overall survival. Early detection and treatment of brain metastases with new systemic therapies may improve outcomes.

Phase III randomized, placebo-controlled trial of carboplatin (C) and paclitaxel (P) with/without veliparib (ABT-888) in HER2- BRCA-associated locally advanced or metastatic breast cancer (BC).

155 Background: BRCA-mutated tumors are more susceptible to platinum therapy and PARP inhibitors due to underlying defects in homologous recombination repair of DNA damage. In preclinical models the potent oral PARP1/2 inhibitor veliparib was shown to enhance sensitivity to C and to have single-agent activity in BRCA+ cell lines. Phase 1 trials suggest promising antitumor activity and acceptable toxicity of veliparib plus C/P in triple-negative BC (Puhalla et al. Cancer Res 2012;72:PD09-06) and single-agent activity of veliparib in BRCA+ BC (Somlo et al. J Clin Oncol 2014;32:abstr. 1021). This phase III trial assesses efficacy and toxicity of veliparib plus C/P vs C/P alone in patients with HER2- BRCA-associated locally advanced or metastatic BC (NCT02163694). METHODS Phase III randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients (female or male; ≥ 18 years) have HER2-metastatic/locally advanced unresectable BC with (suspected) deleterious BRCA1/2 germline mutations and received 2 or fewer prior lines of DNA-damaging chemotherapy for metastatic BC. In addition, patients must have received ≤ 1 prior line of platinum therapy (any setting) without progression within 12 months of completing treatment. Patients are randomized 2:1 to C/P with veliparib or C/P with placebo, stratified by estrogen and/or progesterone receptor expression, prior platinum therapy, and central nervous system metastases. Veliparib (120 mg p.o. BID) or placebo will be given on Days -2 to 5, C (AUC 6 mg/mL/min i.v.) on Day 1, and P (80 mg/m2i.v.) on Days 1, 8, and 15 (21-day cycles). Treatment continues until unacceptable toxicity or progressive disease (PD). Patients in the placebo arm who discontinue due to PD are eligible for crossover to veliparib monotherapy. The primary objective is to assess if the addition of veliparib to C/P increases progression-free survival; additional objectives include evaluation of overall survival, clinical benefit rate, objective response rate, quality of life, and safety. Enrollment began in July 2014 with a planned sample size of 270 patients. CLINICAL TRIAL INFORMATION NCT02163694.

Systemic Treatment in Recurrent and Metastatic Unresectable Rectal Cancer

Most patients with recurrent and metastatic rectal cancer cannot be cured. Selected patients with local recurrence or liver and/or lung-limited metastatic disease are sometimes curable with radiation therapy (RT) or surgery. However, for the majority of patients, treatment is palliative and systemic therapy remains the mainstay treatment. Over the last ten years, survival of patients with unresectable metastatic or recurrent rectal cancer has considerably improved. The median survival is about two years due to availability of new chemotherapy regimens and targeted therapies. For decades, 5-fluorouracil (5-FU) was the only active and available agent. Since the year 2000, irinotecan and oxaliplatin were approved. Access to all these three active agents strongly correlates with improved survival. More progress was achieved recently with the development of targeted therapies. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF). Cetuximab and panitumumab are two monoclonal antibodies targeting the epidermal growth factor receptor (EGFR). Combinations of these different drugs are now commonly used. In non-curable patients, goals are improvement of survival and quality of life. The purpose of this chapter is to review data from clinical trials evaluating systemic therapy in unresectable recurrent or metastatic rectal cancer. Commonly used chemotherapy regimens and biologic agents will be described as well as their side effects. General principles of treatment and specific treatment recommendations will also be discussed.

Characteristics and treatment effect of senior patients with metastatic colorectal cancer (mCRC): A retrospective analysis.

e14085 Background: Colorectal cancer affects many elderly patients as approximately 50% of cases are diagnosed in patients older than 70 years of age. We retrospectively studied characteristics, presentation, treatment and clinical course of our senior patients with mCRC. METHODS Medical records of all patients ≥70 years with mCRC treated in our institution from 2006-2009 were reviewed. A multivariate Coxs proportional hazards model was applied to estimate the effect of chemotherapy (CT) on survival, while adjusting for other factors measured at time of diagnosis (age, sex, comorbidities, and number of metastases). RESULTS Ninety-four patients (48 men and 46 women) ≥70 year-old with mCRC were identified. Anemia, systemic symptoms, abdominal pain and lower GI bleed were the most common presenting symptoms. Fifty-seven patients did not receive CT mainly because of patient/family refusal, alteration of general status and presence of comorbidities. CT (N=37) was associated with an improved median survival (20.1 months) compared to non-treated group (3.6 months), with hazard ratio (0.20; 95% CI, 0.094 to 0.43; p<0.0001). In the multivariate analysis, age (70-74 vs 75-79 vs ≥80 years), sex, comorbidities (0 vs 1 vs 2 vs ≥3), and number of metastatic sites (1 vs ≥2) were not independently associated with survival. ECOG-PS was not mentioned in the medical record of most patients. Sixty-three percent of the 70-74 year-old patients, 34.6% of the 75-79 year-old group, and only 23.7% of the ≥80 year-old patients received CT. Treatment benefit was seen with either 5-FU monotherapy (HR: 0.30; 95% CI, 0.12 to 0.75), irinotecan-based (HR: 0.26; 95% CI, 0.083 to 0.79), or oxaliplatin-based CT (HR; 0.079; 95% CI, 0.02 to 0.31). CONCLUSIONS Most elderly patients with mCRC do not receive CT, yet in this retrospective study, treatment was associated with a clear survival benefit. The presence of multiple comorbidities did not affect treatment benefit. Although performance status could not be ascertained in this study, it likely influenced survival and the decision to treat with CT or not. Oncogeriatric assessment may be useful in better selecting elderly patients for systemic treatment.