Axitinib and/or bevacizumab with modified FOLFOX-6 as first-line therapy for metastatic colorectal cancer: a randomized phase 2 study.

BACKGROUND: In this multicenter, open-label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first-line treatment of metastatic colorectal cancer (mCRC). METHODS: Patients with previously untreated mCRC were randomized 1:1:1 to receive continuous axitinib 5 mg twice daily, bevacizumab 5 mg/kg every 2 weeks, or axitinib 5 mg twice daily plus bevacizumab 2 mg/kg every 2 weeks, each in combination with modified 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX-6). The primary endpoint was the objective response rate (ORR). RESULTS: In all, 126 patients were enrolled from August 2007 to September 2008. The ORR was numerically inferior in the axitinib arm (n = 42) versus the bevacizumab arm (n = 43; 28.6% vs 48.8%; 1-sided P = .97). Progression-free survival (PFS) (11.0 months vs 15.9 months; 1-sided P = .57) and overall survival (OS) (18.1 months vs 21.6 months; 1-sided P = .69) also were numerically inferior in the axitinib arm. Similarly, efficacy endpoints for the axitinib/bevacizumab arm (n = 41) were numerically inferior (ORR, 39%; PFS, 12.5 months; OS, 19.7 months). The patients who received axitinib had fewer treatment cycles compared with other arms. Common all-grade adverse events across all 3 treatment arms were fatigue, diarrhea, and nausea (all ≥49%). Hypertension and headache were more frequent in the patients who received axitinib. Patients in the bevacizumab arm had the longest treatment exposures and the highest rates of peripheral neuropathy. CONCLUSIONS: Neither the addition of continuous axitinib nor the axitinib/bevacizumab combination to FOLFOX-6 improved ORR, PFS, or OS compared with bevacizumab as first-line treatment of mCRC.

Gallbladder cancer: current status.

Gallbladder cancer (GBC) is the most common biliary tract malignancy. There is a tremendous regional variability in its incidence. Risk factors include genetic susceptibility, gender, presence of gallstones, chronic biliary infections, diet and some anatomical anomalies. Several genetic abnormalities have been described which may be aetiologically important as well as carry prognostic significance. These include mutations in the proteins K-RAS and P53, and altered expression of P-glycoprotein, COX-2 and epidermal growth factor receptor. Most patients present at an advanced stage, overall prognosis is very poor. TNM stage and the extent of surgical resection are the most important prognostic factors. Surgery is the only curative therapy reserved for patients with early-stage disease. The role of adjuvant therapy is not fully defined. Patients with advanced disease are managed with systemic chemotherapy that is primarily palliative. Although 5-fluorouracil alone, or in combination, has been most commonly utilised, there is much greater enthusiasm for the combination of cisplatin and gemcitabine. The availability of better drugs and combinations may affect the use of chemotherapy in neoadjuvant and adjuvant settings. Novel targeted therapies require exploration alone or in combination with chemotherapy.

Prospective evaluation of efficacy and toxicity of 5-fu and folinic acid (Mayo Clinic regimen) in patients with advanced cancer of the gallbladder.

We evaluated the efficacy and toxicity of 5-fluorouracil (5-FU) and folinic acid (Mayo Clinic regimen) in previously untreated patients with advanced gallbladder cancer. Thirty patients with histologically confirmed adenocarcinoma of gallbladder were enrolled on this trial. All were symptomatic and had stage IV disease. Patients received 5-FU 425 mg/m2 daily for 5 consecutive days preceded by folinic acid 20 mg/m2/d. Treatment cycles were repeated every 28 days. Only two patients (7%) achieved an objective response to therapy. Another 10 (33%) had stable disease. Median time to progression was 4.7 months, and median overall survival was 14.8 months. Toxicity was moderate, and one treatment-related death occurred. In conclusion, 5-FU and folinic acid (Mayo Clinic regimen) is ineffective in the management of patients with advanced gallbladder cancer, and further trials with this regimen are not recommended.

Gemcitabine and Cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder.

We evaluated the efficacy and toxicity of gemcitabine with or without cisplatin in 11 chemonaive patients with histologically confirmed advanced gallbladder cancer. All were symptomatic and had stage IV disease. Eight patients received gemcitabine 1 g/m2 on days 1 and 8 along with cisplatin 70 mg/m2 on day 1. Three received gemcitabine alone. Treatment cycles were repeated every 21 days. One patient (9%) had complete remission of disease and 6 (55%) achieved a partial response to chemotherapy with an overall response rate of 64%. Median time to progression was 28 weeks and median overall survival was 42 weeks. Toxicity was easily manageable, and no treatment-related deaths occurred. We conclude that gemcitabine in combination with cisplatin may be one of the most effective therapies for patients with advanced gallbladder cancer. If confirmed by others, it may provide an important therapeutic option in managing these patients who otherwise have a dismal prognosis.

Darbepoetin alfa administered every three weeks is effective for the treatment of chemotherapy-induced anemia.

Patients with cancer receiving chemotherapy often have chemotherapy-induced anemia (CIA) and reduced quality of life. Darbepoetin alfa can effectively treat CIA when administered at an extended dosing interval of once every 3 weeks (Q3W). Darbepoetin alfa administered Q3W may allow synchronization of darbepoetin alfa therapy with chemotherapy administered Q3W. This multicenter, open-label, 16-week study evaluated the effectiveness and safety of darbepoetin alfa administered as a fixed dose (300 mug) Q3W in patients with CIA. Eligible patients (> or =18 years) were anemic (hemoglobin <11g/dl), had a nonmyeloid malignancy, and were receiving multicycle chemotherapy. This analysis includes 1,493 patients who received at least one dose of darbepoetin alfa. The effect of baseline hemoglobin (<10 or > or =10 g/dl) on clinical outcomes was evaluated. Patients in the > or =10-g/dl stratum achieved the hemoglobin target range (11-13 g/dl)in less time than patients in the <10-g/dlstratum (3 weeks vs. 9 weeks). More patients in the > or =10-g/dl stratum achieved the hemoglobin target range (87% vs. 66%); however, similar proportions of patients in both strata maintained hemoglobin within the target range (73% vs. 71%). Fewer patients in the > or =10-g/dl stratum received RBC transfusions from week 5 to the end of the study (12% vs. 28%). Over 50% of patients in both strata reported clinically significant improvements (> or =3-point increase) in Functional Assessment of Cancer Therapy-Fatigue score. Twenty-eight percent of patients reported serious adverse events; 3% of all patients had a venous or arterial thrombotic event. This study demonstrates that darbepoetin alfa Q3W is well tolerated and effective for treating CIA.

Clinicopathological features and management of gallbladder cancer in Pakistan: a prospective study of 233 cases.

BACKGROUND AND AIMS: Gallbladder cancer is common in Pakistan and has an extremely poor prognosis. Treatment is primarily surgical. Chemotherapy is frequently used in patients with advanced disease. This study was performed to evaluate and compare the clinicopathological features and management of gallbladder cancer in Pakistani patients, with particular emphasis on factors that influence survival. METHODS: Two hundred and thirty-three patients with histologically proven gallbladder cancer were studied. Information was prospectively collected on demographic features, clinical and laboratory findings at the time of presentation, influence of therapy, and survival. Data were analyzed to evaluate variables that influenced survival. Kaplan-Meier analysis was used to calculate survival. RESULTS: Most patients were women (77%). Mean age was 55 years (+/-11 years). Fourteen per cent of females were nulliparous. Twenty-six per cent had five or more children. Only 4% of patients had a documented history of typhoid fever. The majority (69%) had a history of symptomatic gallbladder disease. The commonest presenting symptom was pain (89%), followed by nausea and vomiting (52%), weight loss (42%), and jaundice (33%). One-quarter of patients had a palpable abdominal mass. Most had abnormal hepatic function tests and 58% had elevated carcinoma embryonic antigen levels. Stage (P < 0.001), jaundice (P = 0.01) and palpable mass (P = 0.02) were statistically significant variables. However, on multivariate analysis, tumor node metastases (TNM) stage was the only factor influencing survival. Median survival of the patients was 44 months for patients with stage I disease, 23 months for stage II, 17 months for stage III and 6 months for stage IV. CONCLUSION: These data are comparable with those reported from other developing countries. Most patients presented at an advanced stage of disease and had an extremely poor prognosis. Systemic therapy did not provide any survival benefit. The TNM stage remains the most important factor influencing survival.

Use of CAM results in delay in seeking medical advice for breast cancer.

Cancer patients in developing countries often delay seeking medical advice. It can adversely influence the clinicopathological behavior and out-come of the disease process. This study was undertaken to obtain information about initial perceptions of patients presenting with breast lump, subsequent efforts to seek medical advice, frequency and reasons for delay in seeking medical advice and its possible impact on clinicopathological characteristics. We prospectively gathered data from 138 recently diagnosed (< or = 3 months) breast cancer patients who had initially presented with a breast lump and were referred to the medical oncology service for further treatment. Delay in seeking medical advice was defined as time period of > or = 1 month between initial perception of lump and first physician visit. The study was conducted at the National Cancer Institute, Karachi, Pakistan. Most (85%) patients discovered the lump accidentally. In other cases, lump was discovered by the family physician or by the patient as part of regular self-examination. Etiologic perceptions included malignancy (17%), benign growth (26%), milk clot (19%), trauma (23%) and infection (10%). On average, patients took 8.7 weeks to inform the family and 17.2 weeks to first physician visit. Fifty three percent delayed seeking medical advice. Common reasons were; antecedent use of complimentary/alternative therapies (34%), lack of significance attached to the lump (23%), fear of surgery (22%), conflicting personal commitments (7%), fear of cancer (5%), and others (8%). Twenty nine percent practiced CAM before visiting any physician. Common methods used were homeopathy (70%), spiritual therapy (15%) and Ayurvedic medicine (13%). CAM use was associated with delay in seeking medical advice (OR: 5.6; 95% CI: 2.3, 13.3) and presentation at an advanced stage of disease (OR: 2.2; 95% CI: 1.01, 4.6). Patients who delayed seeking medical advice more often had positive axillary nodes and stage III/IV disease. Breast cancer patients in Pakistan frequently (53%) delay seeking medical advice. Antecedent practice of CAM is widespread and a common underlying reason. The delay results in significant worsening of the disease process.

Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan.

The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution that genetic factors make to these high rates, we have conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from two major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7% (95% confidence interval [CI] 4.1%-9.4%), and that among case subjects with ovarian cancer was 15.8% (95% CI 9.2%-22.4%). Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. The majority of detected mutations are unique to Pakistan. Five BRCA1 mutations (2080insA, 3889delAG, 4184del4, 4284delAG, and IVS14-1A-->G) and one BRCA2 mutation (3337C-->T) were found in multiple case subjects and represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 is comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1-mutation-positive case subjects was 48% and was 37% for first-degree relatives of the BRCA2-mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio [OR] 2.1; 95% CI 1.4-3.3; P=.001). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age <40 years) (OR=2.7; 95% CI 1.5-4.9; P=.0008) and case subjects with ovarian cancer (OR=2.4; 95% CI 1.4-4.2; P=.002). These results suggest that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan.