Carmelo Pozzo

Benefit of adjuvant chemotherapy for resectable gastric cancer: A meta-analysis

CONTEXT Despite potentially curative resection of stomach cancer, 50% to 90% of patients die of disease relapse. Numerous randomized clinical trials (RCTs) have compared surgery alone with adjuvant chemotherapy, but definitive evidence is lacking. OBJECTIVES To perform an individual patient-level meta-analysis of all RCTs to quantify the potential benefit of chemotherapy after complete resection over surgery alone in terms of overall survival and disease-free survival, and to further study the role of regimens, including monochemotherapy; combined chemotherapy with fluorouracil derivatives, mitomycin C, and other therapies but no anthracyclines; combined chemotherapy with fluorouracil derivatives, mitomycin C, and anthracyclines; and other treatments. DATA SOURCES Data from all RCTs comparing adjuvant chemotherapy with surgery alone in patients with resectable gastric cancer. We searched MEDLINE (up to 2009), the Cochrane Central Register of Controlled Trials, the National Institutes of Health trial registry, and published proceedings from major oncologic and gastrointestinal cancer meetings. STUDY SELECTION All RCTs closed to patient recruitment before 2004 were eligible. Trials testing radiotherapy; neoadjuvant, perioperative, or intraperitoneal chemotherapy; or immunotherapy were excluded. Thirty-one eligible trials (6390 patients) were identified. DATA EXTRACTION As of 2010, individual patient data were available from 17 trials (3838 patients representing 60% of the targeted data) with a median follow-up exceeding 7 years. RESULTS There were 1000 deaths among 1924 patients assigned to chemotherapy groups and 1067 deaths among 1857 patients assigned to surgery-only groups. Adjuvant chemotherapy was associated with a statistically significant benefit in terms of overall survival (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.76-0.90; P < .001) and disease-free survival (HR, 0.82; 95% CI, 0.75-0.90; P < .001). There was no significant heterogeneity for overall survival across RCTs (P = .52) or the 4 regimen groups (P = .13). Five-year overall survival increased from 49.6% to 55.3% with chemotherapy. CONCLUSION Among the RCTs included, postoperative adjuvant chemotherapy based on fluorouracil regimens was associated with reduced risk of death in gastric cancer compared with surgery alone.

Final analysis of colorectal cancer patients treated with irinotecan and 5-fluorouracil plus folinic acid neoadjuvant chemotherapy for unresectable liver metastases

We have previously reported that neoadjuvant therapy with modified FOLFIRI enabled nearly a third of patients with metastatic colorectal cancer (mCRC) to undergo surgical resection of liver metastases. Here, we present data from the long-term follow-up of these patients. Forty patients received modified FOLFIRI: irinotecan 180 mg m−2, day 1; folinic acid, 200 mg m−2; and 5-fluorouracil: as a 400 mg m−2 bolus, days 1 and 2, and a 48-h continuous infusion 1200 mg m−2, from day 1. Treatment was repeated every 2 weeks, with response assessed every six cycles. Resected patients received six further cycles of chemotherapy postoperatively. Nineteen (47.5%) of 40 patients achieved an objective response; 13 (33%) underwent resection. After a median follow-up of 56 months, median survival for all patients was 31.5 months: for non-resected patients, median survival was 24 months and was not reached for resected patients. Median time to progression was 14.3 and 5.2 months for all and non-resected patients, respectively. Median disease-free (DF) survival in resected patients was 52.5 months. At 2 years, all patients were alive (8 DF), and at last follow-up, eight were alive (6 DF). Surgical resection of liver metastases after neoadjuvant treatment with modified FOLFIRI in CRC patients achieved favourable survival times.

A phase II study of irinotecan alternated with five days bolus of 5-fluorouracil and leucovorin in first-line chemotherapy of metastatic colorectal cancer

PURPOSE This multicenter phase II study was designed to assess the efficacy of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer (CRC). PATIENTS AND METHODS Patients with histologically proven metastatic colorectal cancer, and at least one bidimensionally measurable lesion, aged 18-70, with performance status < or = 2, normal baseline biological values and no prior chemotherapy (or only adjuvant chemotherapy completed > or = 6 months before study entry) were selected. Treatment was irinotecan 350 mg/m2, i.v., day 1, alternating with leucovorin 20 mg/m2 i.v. and 5-FU 425 mg/m2, i.v. daily for five consecutive days, day 22-26 (Mayo Clinic regimen). One alternating cycle was to be performed every six weeks. Patients were evaluated for efficacy every alternating cycle. Treatment was administered until five alternating cycles, disease progression, unacceptable toxicity or patient refusal. RESULTS Thirty-three patients (28 chemotherapy-naïve and five with prior adjuvant treatment completed > 1 year prior to accrual) were enrolled. The objective response rate (RR) was 30% (95% CI: 16-49; 10 patients/33; nine partial response and one complete response). All responses were reviewed by an independent external review committee. An additional 49% of patients had stable disease. The median survival was 16 months, the one year survival amounted to 58% and the median progression free survival was 7.2 months. Relative dose intensity was nearly 90% for both drugs. Grade 3-4 diarrhea and neutropenia were the most frequent severe toxic events, seen in 24% and 64% of patients, respectively. CONCLUSIONS The alternating schedule of CPT-11 350 mg/m2 with five days bolus of 5-FU and low dose LV is an active and feasible regimen as front-line therapy for metastatic CRC. It is well tolerated, without evidence of overlapping toxicity. The response rate appears promising with regard to that expected with either single agent. This regimen warrants further assessment in randomized trials.

Predictive value of thymidylate synthase expression in resected metastases of colorectal cancer.

Recent investigations have focused on the prognostic value of thymidylate synthase (TS) assessment in metastases of colorectal carcinoma (CRC). In order to evaluate the prognostic impact of TS expression after resection of metastases of colorectal cancer followed by systemic adjuvant chemotherapy, we performed an immunohistochemical characterisation of TS in the primary tumours and in the corresponding radically resected hepatic and pulmonary metastases. An additional objective was to compare the levels of TS in primary and metastatic disease. TS expression was assessed by immunohistochemistry using the monoclonal antibody TS 106. The study population consisted of 60 patients: 48 underwent liver and 12 lung resection. All of them received adjuvant chemotherapy after metastasectomy according to the Mayo Clinic schedule. In the 49 evaluable primary tumours, TS score was high in 53% and low in 47% of patients, while in the 60 metastatic samples TS immunostaining was high in 33% and low in 67%. There was a significantly smaller number of high TS expressors in metastatic than in primary tumours (P<0.04). No correlation was observed between TS expression and the site of the metastasis. TS status did not significantly correlate with the median disease-free interval (DFI) after metastasectomy, although this parameter was longer for patients with low TS immunoreactivity in the resected metastases than for those with high TS lesions (19.6 versus 13.8 months). Patients with high TS levels, however, had a significantly shorter median overall survival (OS) (27.6 months) than those with low TS expression (36.3 months) (P<0.008). TS status in the resected metastases confirmed its independent prognostic value in the multivariate analysis and was the only prognostic marker of OS in the subgroup of patients with resected liver metastases. These results suggest that high TS levels in resected metastases of colorectal cancer are associated with a poor outcome after surgery and 5-FU adjuvant therapy; therefore, a prospective assessment of TS levels in resected colorectal metastases could be useful to define which patients will most likely benefit from 5-FU adjuvant therapy after metastasectomy. Chemotherapeutic agents that target TS may not be the appropriate adjuvant treatment after metastasectomy for patients with a high TS expression in the resected metastases of colorectal cancer.

Docetaxel and oxaliplatin combination in second-line treatment of patients with advanced gastric cancer

BackgroundIn advanced gastric cancer few data are available on the efficacy or safety of new drug combination regimens after progression following first-line chemotherapy.MethodsPatients with histologically confirmed advanced gastric cancer and Eastern Cooperative Oncology Group (ECOG) performance status (PS) less than 2, progressing after first-line chemotherapy, were eligible. Patients were treated with docetaxel 75 mg/m2 on day 1 and oxaliplatin 80 mg/m2 on day 2, every 3 weeks, until progression or unacceptable toxicity.ResultsBetween May 2002 and April 2005, 38 patients were enrolled. Men accounted for 73.7% of the patients and the median age was 59 years. The primary tumor was not resected in 47.4% of the patients; the peritoneum was the most frequent metastatic site (60.5%). The first-line treatment was cisplatin, epirubicin, and infusional 5-fluorouracil (ECF) in 81.5% of the patients and cisplatin and infusional 5-fluorouracil (CF) in 15.7%. The median number of cycles was 4.3. The treatment was well tolerated, with no toxic deaths. National Cancer Institute (NCI) grade III-IV neutropenia was frequent (26.3%), but no febrile neutropenia was reported. Severe asthenia (15.7%) and severe nausea (15.7%) required dose reductions in 2 patients and treatment discontinuation in another. The overall response rate was 10.5%, and 18 patients (47.3%) experienced disease stabilization (7 of them with significant clinical benefit). Median time to progression was 4.0 months (range, 2–8 months) and median overall survival was 8.1 months (range, 3–26 months). Thirteen patients (34.2%) also received third-line chemotherapy, with an irinotecan-containing regimen, and their median overall survival was higher than that of the other patients (16.3 vs 6.0 months)ConclusionThe combination of oxaliplatin and docetaxel shows only marginal activity as second-line treatment, but it has a good tolerability profile. This suggests that there is room for optimizing the schedule as well as for planning sequential treatments in gastric cancer.

Coronary artery spasm induced by capecitabine.

Capecitabine is a new chemotherapeutic agent considered highly specific for sensitive tumour cells, which convert the drug to 5-fluorouracil. Capecitabine is administered on an ambulatory basis for the treatment of metastatic breast and colorectal cancer, and both general practitioners and specialists are likely to deal with patients treated with this drug. We describe the case of a 44-year-old woman, with no cardiovascular risk factors, who started therapy with capecitabine for relapsing of breast carcinoma. She subsequently developed effort angina. Standard electrocardiogram and echocardiography were normal, whereas ST-segment elevation and angina were induced during exercise stress test. Capecitabine was withdrawn and therapy with diltiazem and transdermal nitroglycerine was started. The patient became asymptomatic and repeated symptom-limited exercise stress test did not induce any ST-segment changes or angina, even after withdrawal of anti-ischaemic therapy, thus confirming the hypothesis of capecitabine-induced coronary artery spasm as the cause of patients symptoms.

Treatment of patients with advanced gastric carcinoma with a 5-fluorouracil-based or a cisplatin-based regimen: two parallel randomized phase II studies.

Although many drug combination therapies have been proposed, there is no standard therapy for patients with advanced gastric carcinoma. The superiority of combination therapy over monochemotherapy has not been demonstrated convincingly. To explore the role of monochemotherapy, the authors evaluated 5‐fluorouracil (5‐FU), modulated by 6S‐leucovorin (6S‐LV) and a cisplatin‐containing regimen, which was comprised of epirubicin, etoposide, and cisplatin with the addition of the reversal agent lonidamine (EEP‐L).

Long-Term Follow-Up of a Pilot Phase II Study with Neoadjuvant Epidoxorubicin, Etoposide and Cisplatin in Gastric Cancer

Objective: The prognosis in T3–T4 or N+ gastric cancer is dismal, and the role of adjuvant therapy remains uncertain. Neoadjuvant chemotherapy could improve both resectability and survival. Here, we report the results of the long-term follow-up of a pilot study aimed at evaluating a neoadjuvant treatment in a group of patients carefully staged by computed tomography (CT), endoscopic ultrasound and laparoscopy. Methods: Twenty-five stage II–III patients with histologically proven gastric adenocarcinoma were enrolled in the study. All patients gave informed consent and were thoroughly staged. Patients were treated with epidoxorubicin (40 mg/m2 i.v.) on days 1 and 4, etoposide (VP-16; 100 mg/m2) on days 1, 3 and 4 and cisplatinum (80 mg/m2) on day 2, every 21–28 days for 3 pre-operative cycles before CT clinical restaging followed by laparotomy and D2 gastrectomy. Three further cycles of chemotherapy were planned after radical surgery. Results: Twenty-four patients received the planned pre-operative chemotherapy and underwent surgical resection; total (13 patients) or subtotal (7 patients) R0 D2 gastrectomy was possible in 20 patients. One patient died as a result of gastric bleeding. Perioperative complications occurred in 5 patients (failure of anastomosis in 1 patient and wound infection in the other 4). The pathologic response rate included 7 partial responses (29.1%) and 10 patients with stable disease (41.7%). The main toxicity was grade 3/4 neutropenia (68%), which occurred more frequently during the postoperative chemotherapy, and fatigue (68%). Fever or infection, however, were never observed. The median disease-free survival was 37 months, and median survival has not been reached after 40 months of median follow-up. One-, 2- and 3-year survival rates were 80, 64 and 60%, respectively. Conclusion: The notable long-term survival in the present study suggests a comparison between the neoadjuvant approach, including new drug combinations, and adjuvant chemo- or chemoradio-therapy in locally advanced gastric cancer.

Advances in neoadjuvant therapy for colorectal cancer with liver metastases

Metastatic colorectal cancer (CRC) is most frequently seen in the liver. Resection of metastases remains the treatment of choice; however, the majority of patients are ineligible for surgery due to unfavorable location, size, or number of metastases; insufficient liver reserve; or extrahepatic disease. The activity of irinotecan- and oxaliplatin-based regimens as first-line therapy has prompted the investigation of these agents as neoadjuvant therapy in patients with resectable and unresectable disease. Although studies suggest considerable promise for a neoadjuvant strategy in patients with unresectable liver metastases, the heterogeneity, small size, and retrospective nature of many of these studies precludes drawing firm clinical conclusions at this time, especially in patients with resectable disease. Therefore large, prospective trials that examine the impact of preoperative chemotherapy in patients with initially unresectable or resectable liver metastases are needed. These trials must include well-defined criteria for resectability and clear reporting of the extent of resection.

Weekly Gemcitabine and 24-Hour Infusional 5-Fluorouracil in Advanced Pancreatic Cancer: A Phase I–II Study

Objective: In this phase I–II study we explored the potential of the combination of weekly gemcitabine (GEM) and 24-hour continuous infusion of 5-fluorouracil (5-FU) in order to determine the toxicity profile in pancreatic cancer. The efficacy of this drug combination was studied as a secondary endpoint. Methods: Twenty-one patients with histologically or cytologically proven unresectable or metastatic previously untreated pancreatic adenocarcinoma were included in this study. Two dose levels of GEM and two dose levels of 5-FU were evaluated in three cohorts of patients who received GEM 1,000 mg/m2 and 5-FU 2,000 mg/m2, GEM 1,200 mg/m2 and 5-FU 2,000 mg/m2, or GEM 1,200 mg/m2 and 5-FU 2,250 mg/m2, on days 1, 8, and 15, every 4 weeks, respectively. Results: Grade 3–4 neutropenia was observed in 10% of the cycles. Non-myelosuppressive toxicities included fatigue (22%), grade 1–2 diarrhea (12%) and grade 1 liver toxicity. There was no limiting toxicity and the maximum tolerated dose has not been reached. Two patients experienced a partial response (9.5 ± 12.6%) and 12 patients had stable disease (57.1 ± 21.2%). Seven of the 14 symptomatic patients improved their disease-related symptoms and 4 of the 8 patients evaluable for clinical benefit had a clinically beneficial response (50 ± 34.6%). The median progression-free survival was 6 months (range 2–28), median survival was 11 months (range 3–32+), and the actuarial 1-year survival rate 33%. Conclusion: The weekly administration of GEM combined with 24-hour continuous infusion of 5-FU shows a good safety profile at the dose levels evaluated. Some partial responses had also been achieved, disregarding the dose level of the two drugs. Survival confirms the activity of this drug combination.