Gastric cancer and adjuvant chemoradiotherapy: when and where, that's the question.

PURPOSE: Although the incidence of gastric cancer is decreasing, there were still 159,900 new cases and 118,200 deaths in Europe in 2006 representing the 5th highest incidence and 4th highest cause of cancer-related deaths. Postoperative adjuvant chemoradiotherapy has been demonstrated to result in a significant improvement in overall and disease-free survival. We studied the current role of adjuvant chemoradiotherapy in gastric cancer. METHODS: Randomized phase III studies and selected phase II studies for adjuvant chemoradiotherapy in gastric cancer were searched in PUBMED using key words. Also, international treatment guidelines as well as review papers were searched and analysed. RESULTS: Based on the published literature, treatment guidelines and reports from international meetings it is obvious that adjuvant chemoradiotherapy in gastric cancer contributes in improved treatment results. CONCLUSION: Surgical resection remains the cornerstone of curative treatment for gastric cancer. The combination of modern radiotherapy techniques with chemotherapy is feasible, safe and improves overall survival of patients with gastric cancer.

A preclinical survey on the efficacy of lactandrate in the treatment of colon carcinoma.

PURPOSE: There has been a recent and dramatic increase in the pace of drug development for colorectal cancer which holds promise to further improve curative therapy. We tested lactandrate, an alkylating ester of D-lactam androsterone, for antineoplastic activity against colon adenocarcinoma in vitro and in vivo. MATERIALS AND METHODS: The cytostatic and cytotoxic activity of lactandrate were evaluated in vitro against 9 human colon adenocarcinoma cell lines. The in vitro testing was performed with the sulforhodamine B (SRB) colorimetric assay and the mean concentrations of each drug that generated 50% (GI50) or total (100%) growth inhibition (TGI), as well as the drug concentrations that produced cytotoxicity against 50% of the cultured cells (IC50) were calculated. The in vivo antitumour effect was determined against two rodent colon carcinomas, the Colon 26 and the relatively chemoresistant Colon 38 carcinoma, as well as against the human xenograft CX-1 colon carcinoma. RESULTS: Lactandrate displayed a satisfactory activity against the 9 human colon cancer cell lines, inducing significant growth inhibition and cytotoxicity. Lactandrate induced antiproliferative activity against colon cancer cell lines linearly correlated with the carcinoembryonic antigen (CEA) production. There was a non-linear polynomial correlation between CEA production and the cytotoxic effect of lactandrate. The more differentiated cell lines DLD-1 and HCC2998 appeared more resistant to the cytostatic effect of lactandrate. In vivo, the compound produced a significant antitumour activity against Colon 26 and Colon 38, as well as a moderate antitumour effect against CX-1 colon carcinoma. CONCLUSION: Preclinical research supports the high in vitro and in vivo antitumour potential of lactandrate against colon carcinoma. Therefore, lactandrate represents an important candidate drug for further clinical development.

Weekly chemotherapy with carboplatin, docetaxel and irinotecan in advanced non-small-cell-lung cancer: a phase II study.

The aim of this study was to evaluate the efficacy and tolerability of carboplatin, docetaxel plus irinotecan given weekly to patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). 50 patients with previously untreated NSCLC (stage IIIB 10; stage IV 40; 44% squamous cell carcinoma; median Eastern Cooperative Oncology Group (ECOG) status 1) received intravenous (i.v.) carboplatin area under the curve (AUC) 2, docetaxel 20 mg/m(2) and irinotecan 60 mg/m(2) on days 1, 8 and 15, repeated every 5 weeks. Prophylactic granulocyte colony-stimulating factor (G-CSF) 150 ug/m(2) was given from days 3 to 6 and 10 to 13. Response was evaluated every two cycles. Four complete responses (8%) and 24 (48%) partial responses were observed, giving an overall intent-to-treat response rate of 56%. 8 patients (16%) achieved stable disease and 14 (28%) progressed. The median time to progression (TTP) was 9.6 months (range 2.5-21.8 months), median survival was 14.8 months (range 0.3-27+ months) and actuarial 1-year survival time was 55%. Grade 3/4 anaemia and thrombocytopenia occurred in 18 and 22% of patients, respectively; 13 patients (26%) developed grade 3/4 neutropenia and 7 (14%) had neutropenic fever that required hospitalisation, but was successfully treated with antibiotics and G-CSF support. One patient developed a severe allergy during docetaxel administration and was withdrawn. Other grade 3/4 adverse events included diarrhoea (n=14; 3 required hospitalisation), nausea/vomiting (n=9), neurotoxicity (n=5) and fatigue (n=5). 6 patients required a dose reduction. This combination of i.v. carboplatin AUC 2, docetaxel 20 mg/m(2) and irinotecan 60 mg/m(2) given weekly is highly effective in the treatment of chemotherapy-naïve advanced NSCLC. Toxicity was moderate, but manageable.

Irinotecan and vinorelbine in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. A phase II study of the Hellenic Cooperative Oncology Group.

PURPOSE: To evaluate the efficacy and tolerability of irinotecan plus vinorelbine every 2 weeks in patients with advanced non-small cell lung cancer (NSCLC), previously treated with platinum-based chemotherapy. PATIENTS AND METHODS: Forty-one patients with advanced NSCLC, refractory or resistant to platinum derivatives, were treated on an out-patient basis with irinotecan 150 mg/m2 intravenous (i.v.) and vinorelbine 25 mg/m2 on days 1 and 15. Chemotherapy was repeated every 4 weeks. The response was evaluated every two cycles. RESULTS: On an intent-to-treat analysis, 6 patients (14.6%) [95% confidence interval (CI) 5.57% to 29.17%] achieved partial response (PR), 15 (36.6%) stable disease (SD) and 20 (48.8%) progressive disease (PD). The median time to tumor progression (TTP) was 4.9 months (range 0.17-15.5 months), the median survival time was 7.8 months (range 0.9 to 19.6 months) and the 1-year survival rate was 37%. Symptomatic benefit response including improvement of performance status (PS), dyspnea, anorexia and fatigue, cessation of hemoptysis, fever and reduction of cough and pain was seen in 10 to 42% of patients. No patient experienced grade 3/4 anemia. Grade 3/4 thrombocytopenia occurred in 2 (5%) patients. Five patients (12%) developed grade 3/4 neutropenia and 5 (12%) had neutropenic fever that required hospitalization, but was successfully treated with antibiotics and G-CSF support. One patient (2%) developed grade 4 fatigue and was withdrawn. Other grade 3/4 adverse events included diarrhea (n = 3; 2 required hospitalization), alopecia (n = 5) and neurotoxicity (n = 1). Six patients required a dose reduction. CONCLUSION: The combination of irinotecan plus vinorelbine administered every 2 weeks demonstrated rather low activity in advanced NSCLC patients who had previously failed platinum-based chemotherapy, but it was well-tolerated and was associated with increased 1-year survival rate and improvement in cancer related symptoms.

Primary carcinoid of the testis with metastases. Case report and review of the literature.

Primary carcinoid of the testis is an extremely rare neoplasm, making up 0.23% of all testicular neoplasms. The vast majority of the reported cases are primary carcinoids and 20-25% are associated with teratomas. Approximately 10% of these tumors will develop metastases. We present a case of a 50-year-old man with a primary testicular carcinoid who developed lymph node and lung metastases 4 months after left inguinal orchidectomy. Our case was not associated with testicular teratoma or carcinoid syndrome. Vigorous efforts were done postoperatively to exclude the possibility of carcinoid tumor metastatic to the testis. Our patient achieved a mixed response (lung metastases: complete response, lymph node metastases: partial response) with combined therapy that included chemotherapy (cisplatin, etoposide, ifosfamide, epirubicin), octreotide and radiotherapy to the metastatic lymph nodes. He remains well and asymptomatic. We herein review the literature and discuss all the possibilities to explain the origin of carcinoid tumors of the testis.

Successful management of extracranial metastases from cerebral high-grade oligodendroglioma: report of a case with literature review.

The prognosis of high-grade oligodendroglioma has been reported poor with an average survival of approximately 17 months. Local recurrence after surgery is seen in about 50% of the patients, but distant extracranial metastases have been described rarely. Frequent extracranial metastases have been reported in the lungs, pleura, lymph nodes, bones, liver, adrenal glands, kidneys and other sites. We present a case of 16-year-old girl with high-grade oligodendroglioma who developed bilateral pulmonary metastases 19 months following complete resection of the primary brain tumor. She did not respond to first-line chemotherapy; however, the patient achieved an almost complete response with cisplatin (CDDP) and etoposide (VP-16) salvage chemotherapy. She remains well and asymptomatic 18 months after the end of chemotherapy. We herein review the literature and discuss all the possible mechanisms for extracranial dissemination of primary brain tumours.

Methotrexate, etoposide, ifosfamide and cisplatin (MVIP): An effective salvage therapy for patients with refractory or relapsed germ-cell tumors.

PURPOSE: To study the efficacy and toxicity of a combination of methotrexate, etoposide, ifosfamide and cisplatin (MVIP) in patients with germ-cell tumors (GCTs) refractory to or relapsed after first-line platinum-based chemotherapy. PATIENTS AND METHODS: Between 1989 and 2001 22 male patients with GCTs refractory (n=7) or relapsed (n=15) after first-line platinum-based chemotherapy entered prospectively the study. Their median age was 29 years. Methotrexate 250 mg/m(2) as 4-hour infusion plus folinic acid were administered on day 1. On day 3 cisplatin 100 mg/m(2) with pre and posthydration was given as 30-min infusion; and ifosfamide 5 g/m(2) with mesna as 24-hour infusion. Etoposide 100 mg/m(2)/day as 1-hour infusion was administered on days 3-5. Cycles were repeated every 3 weeks. Granulocyte colony stimulating factor (GCSF) was administered either therapeutically (grade 3-4 neutropenia-/+antibiotics) or prophylactically (nadir grade 3-4 neutropenia in the previous chemotherapy cycle). RESULTS: All patients were evaluable for response, toxicity and survival. A total of 95 cycles (median 4 cycles per patient) of MVIP were administered. Fourteen (63.6%) patient achieved complete response (CR), and 8 (36.4%) were treatment failures. Long-term disease-free survival (DFS) with MVIP was achieved in 11 out of 14 (78.6%) CR patients or 50% of all patients. After a median follow-up period of 55.04(+) months (range 4-147(+) months) overall survival is 59.09%. Good performance status (PS) was the only significant predictor for survival. Toxicity was easily manageable with no deaths or therapy delays. CONCLUSION: MVIP conventional chemotherapy proved particularly effective in terms of CR rate, overall survival and long-term DFS in this very poor prognosis patient population. Toxicity was tolerable. The results obtained are equal or even superior compared with those taken by more intensive regimens, including high-dose chemotherapy. MVIP justifies further studies in patients with refractory/ relapsed GCTs.

Methotrexate, etoposide, ifosfamide and cisplatin (MVIP): an effective first-line therapy for IGCCC intermediate / poor prognosis patients with germ-cell tumors. Single institution experience.

PURPOSE: To evaluate the antitumor activity and toxicity of methotrexate (M), etoposide (V), ifosfamide (I) and cisplatin (P) combination chemotherapy (MVIP) administered to chemotherapy-naive patients with intermediate / poor prognosis germ-cell tumors (GCT) according to the International Germ Cell Cancer Collaborative Group (IGCCCG) consensus classification system (IGCCC). PATIENTS AND METHODS: From 1992 to 2001 24 consecutive intermediate (n=14)/poor prognosis (n=10) GCT male patients entered prospectively this phase II trial. Patients received methotrexate 250 mg/m(2), day 1, with folinic acid rescue; cisplatin 100 mg/m(2) with appropriate hydration, day 3; ifosfamide 5 g/m(2) with mesna uroprotection, day 3; and etoposide 100 mg/m(2)/day, days 3-5. MVIP was repeated every 3 weeks. RESULTS: After 120 cycles of MVIP (median 5, range 2- 7) 18 (75%) patients achieved complete remission (CR). CR was attained by 12 out of 14 (86%) intermediate prognosis and 6 out of 10 (60%) poor prognosis patients. Three CR patients (2 intermediate, 1 poor prognosis) of out 18 (16.7%) relapsed after a median of 6 months and 1 of them (poor prognosis) achieved a durable CR with second-line chemotherapy. After a median follow-up of 37 months (range 5-115 months) 16 patients (10, 71% intermediate and 6, 60% poor prognosis) are long-term survivors with no evidence of disease (NED), and 2 (one of each group) are alive with disease. Actuarial overall survival at 3 and more years is 75% and NED survival is 67%. Hematologic toxicity was most common and easily manageable (grade 3-4 neutropenia 46% of the cycles and thrombocytopenia 25% of the cycles). There were no deaths, withdrawals or delays in chemotherapy administration because of toxicity. CONCLUSION: MVIP conventional chemotherapy proved very effective in terms of CR rate, overall survival and longterm NED survival in these unfavorable groups of GCT patients. The results obtained are encouraging and compare favorably with those taken by more intensive regimens including high-dose chemotherapy. We believe that MVIP justifies further studies.

The RACOX phase I study: radiation (RA), capecitabine (C) and oxaliplatin (OX) as adjuvant treatment of stage II and III rectal cancer.

PURPOSE: The aim of this phase I trial was to deter- mine the maximum tolerated dose (MTD) of adjuvant che- motherapy (CT) with oxaliplatin in combination with capecitabine during concomitant pelvic radiotherapy (RT) in patients with rectal cancer. PATIENTS AND METHODS: Eligible patients had pathological stage II (T3-4N0M0) or III (any T N1-2M0) rectal adenocarcinoma, and no prior treatment other than curative resection. Fixed capecitabine dose (825 mg/m(2) bid on days 1-14 and 22-35) was given and external beam RT was delivered to the pelvis (50.4 Gy in 27 fractions in 5.5 weeks, with field reduction after 45 Gy in linear accelerator, 18Mev). Oxaliplatin was tested at 4 dose levels: 100, 110, 120 and 130 mg/m(2). The dose of oxaliplatin was escalated when all 3 entered patients at each level had been monitored for at least 8 weeks after the CT/RT course without dose limiting toxicities (DLTs). In the presence of a DLT at any dose level, a further 3 patients were enrolled. If only 1 of the 6 patients experienced a DLT, escalation could proceed. The MTD was defined as the level at which >/= 2 of 3 to 6 patients experienced DLTs. Fifteen patients (10 males and 5 females, median age 62 years) were enrolled at oxaliplatin dose levels of 100 (n=3), 110 (n=3), 120 (n=3) and 130 mg/m(2) (n=6). RESULTS: All patients completed the planned CT/RT course. Dose reduction or delay of the 2nd CT cycle was not required. No DLTs were observed at all dose levels. Overall, gastrointestinal and neurological toxicities were mild and transient. Toxicities included non-dose-limiting nausea / vomiting, diarrhea, dysesthesias in 2 level III and in 1 level IV patients. Grade II myelotoxicity, mainly neutropenia, was seen in 6 patients. With a median follow-up of 4 months (range 2-12) after the completion of CT/RT, late toxicities were restricted to grade II radiation colitis and dermatitis in 2 and 2 patients, respectively. CONCLUSION: The combination of pelvic RT, capecitabine and 3-weekly oxaliplatin is feasible and well tolerated. The MTD was not reached up to the dose of 130 mg/m(2) of oxaliplatin, which is the recommended dose.

Oxaliplatin plus high-dose leucovorin and 5-fluorouracil in pretreated advanced breast cancer: a phase II study.

BACKGROUND: The purpose of this study was to evaluate the efficacy and toxicity of oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. PATIENTS AND METHODS: Fifty anthracycline- and taxane-pretreated MBC patients were treated with oxaliplatin 85 mg/m(2) as a 2-h infusion on day 1, LV 200 mg/m(2)/day as a 2-h infusion followed by bolus 5-FU 400 mg/m(2)/day and a 22-h infusion of 5-FU 600 mg/m(2)/day for 2 consecutive days. Treatment was repeated every 3 weeks. Patients were evaluated for response every two cycles. RESULTS: The median age was 51 years (range 34-75). Twenty patients (40%) had received three or more chemotherapeutic regimens, 64% had three or four metastatic sites and 78% had visceral metastases. All patients had prior exposure to anthracyclines and taxanes. Based on an intention-to-treat analysis, one patient (2%) achieved a complete response and 16 (32%) a partial response, for a 34% overall response rate. Twenty-one patients (42%) had stable disease and 12 (24%) progressive disease. The median time to tumor progression was 5.3 months (range 0.5-12.8) and the median overall survival was 12.3 months (range 0.5-19.2). Toxicity was mild to moderate. Grade 3/4 neutropenia and thrombocytopenia occurred in 32% and 18%, respectively. Febrile neutropenia was experienced by three patients (6%), who were successfully treated. Grade 3/4 neurotoxicity was reported in 14% of the patients and gradually declined after treatment discontinuation. Cycle delays were reported in 28% of patients and dose reductions in 26%. Alopecia, nausea-vomiting, diarrhea and mucositis were not significant. There were no treatment-related deaths. CONCLUSION: The combination of oxaliplatin plus 5-FU/LV seems to be an active regimen in patients with MBC and prior exposure to anthracyclines and taxanes with a good safety profile. The incidence of severe toxicity was quite low and the compliance of patients to the treatment was satisfactory. The results obtained with this regimen could be considered encouraging in this heavily pretreated group of breast cancer patients with a high incidence of visceral metastases.

Weekly chemotherapy with docetaxel, gemcitabine and cisplatin in advanced transitional cell urothelial cancer: a phase II trial.

PURPOSE: To evaluate the efficacy and toxicity of a combination of weekly docetaxel, gemcitabine and cisplatin in advanced transitional cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Thirty-five chemotherapy-naïve (adjuvant and neoadjuvant chemotherapy was allowed) patients with advanced TCC received intravenous docetaxel 35 mg/m2, gemcitabine 800 mg/m2 and cisplatin 35 mg/m2, on days 1 and 8 every 3 weeks. Prophylactic granulocyte-colony stimulating factor was given from days 3 to 6 and days 10 to 15, anti-emetics were used routinely. RESULTS: Most (27) patients (77.1%) had a performance status of 0 to 1 and eight (22.9%) had received prior adjuvant or neoadjuvant cisplatin-based chemotherapy. In the intention-to-treat analysis, the objective response rate was 65.6% [23/35 patients, 95% confidence interval (CI) 47.8% to 80.9%]. Ten patients (28.5%) achieved a complete response (95% CI 14.6% to 46.3%) and 13 (37.1%) a partial response (95% CI 21.5% to 55.0%). Median survival time was 15.5 months, median duration of response was 10.2 months and median time to progression was 8.9 months. Ten patients (28.5%) developed grade 3/4 neutropenia, including five (14.3%) who experienced febrile neutropenia, which was successfully treated. Grade 3/4 anaemia and thrombocytopenia occurred in 20% and 25.7% of patients, respectively; four patients required platelet transfusions. There were no treatment-related deaths. CONCLUSIONS: Weekly docetaxel, gemcitabine plus cisplatin is a highly effective treatment for chemotherapy-naïve advanced TCC, and causes only moderate toxicity. This regimen should be considered as a suitable option that deserves further prospective evaluation through randomised phase III trials.