Further evidence for preoperative chemoradiotherapy and transanal endoscopic surgery (TEM) in T2-3s,N0,M0 rectal cancer.

PURPOSE: Preoperative chemoradiotherapy and local excision via transanal endoscopic surgery (TEM) in T2-3s,N0,M0 rectal cancer achieve promising results in selected patients. We describe our long-term follow-up experience with this combination, and evaluate complete clinical and pathological responses, local recurrence and overall survival. METHODS: The prospective observational follow-up study carried out since 2007. Out of 476 consecutive patients treated with TEM, we selected those with adenocarcinoma of low or moderate grade of differentiation, clinical stages T2-superficial T3,N0,M0, who refused radical surgery. Preoperative chemoradiotherapy comprised 5-fluorouracil or capecitabine combined with radiotherapy at a dose of 50.4 Gy. TEM was performed after 8 weeks. Complications were recorded and long-term follow-up was conducted. RESULTS: Fifteen patients undergoing preoperative chemoradiotherapy and TEM (median age 76 years, 95 % CI 70.3-80.4, and median follow-up 38 months, 95 % CI 20-44) were studied. No local recurrence was observed, and only one patient (6.7 %) presented systemic relapse. The overall survival was 76 %. Complete clinical response was achieved in seven patients (46.7 %) and complete pathological response in four (26.7 %). With regard to toxicity associated with neoadjuvant treatment, four patients (26.7 %) developed grade 3 adverse effects; no grade 4 or 5 adverse effects were observed. There was no postoperative mortality. CONCLUSIONS: The results of our study, with a response rate of 26.7 % and without local relapse, support the treatment of T2-3s,N0,M0 of rectal cancer with preoperative chemoradiotherapy and local excision (TEM).

Multicenter phase II study of oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of cisplatin and fluoropyrimidine treatment. A GEMCAD study.

BACKGROUND: Cisplatin and fluoropyrimidine (CF) are standard first- line treatment in advanced gastric cancer, but no second-line treatment has yet been established. We present a phase II study in which we evaluated the efficacy and toxicity of the combination of Sorafenib (S), and Oxaliplatin as second-line therapy. METHODS: Patients with progressive gastric adenocarcinoma after CF- first-line, ECOG 0-2, and measurable disease were included. The primary objective was PFS. Treatment doses were Oxaliplatin 130 mg/m²/3 weeks and Sorafenib 800 mg/bid/d. RESULTS: We included 40 patients. CR was 2.5% and SD was 47.2%. Grade 3-4 toxic effects were neutropenia (9.8%), thrombocytopenia (7.3%), neurotoxicity (4.9%) and diarrhea (4.9%). Median PFS was 3 months (95%CI: 2.3-4.1) and median OS was 6.5 months (95% CI: 5.2-9.6). Time to progression (TTP) to first line therapy was a prognosis factor. Median OS was 9.7 months when time-to-progression during first-line chemotherapy was >6 months and 5.6 m when it was <6 months (p = 0.04). CONCLUSIONS: Time-to-progression under a CF-based first-line therapy determines subgroups of GC patients with different prognosis. The combination of Oxaliplatin-Sorafenib in advanced GC patients previously treated with CF appears safe, but our results do not support the implementation of a phase III trial.

Extravasation of oxaliplatin: an infrequent and irritant toxicity.

Oxaliplatin has been classified as an irritant drug. Less than 10 cases of oxaliplatin extravasation through a central venous access have been described to date. We present a case of extravasation through a central venous access, of the highest dose (165 mg) of oxaliplatin reported to date. We confirmed the irritant effect, and full recovery from toxicity was achieved. We describe the treatment administered and offer a review of literature.

A prospective observational study of the effectiveness, safety, and effect on fatigue of darbepoetin alfa for the treatment of chemotherapy-induced anaemia.

OBJECTIVE: Anaemia is common in cancer patients treated with chemotherapy. Darbepoetin alfa (DA) is the only erythropoiesis-stimulating protein approved for administration at weekly and every-three-week intervals in cancer patients receiving chemotherapy. This article investigates the effectiveness, tolerability and effect on fatigue of DA. METHODS: Prospective, observational study performed in 30 Spanish centres. Eligible patients were > or = 18 years of age, anaemic (haemoglobin [Hb] < or = 11 g/dL), with non-myeloid malignancies, receiving chemotherapy. DA (150 mug) was administered weekly for a maximum of 16 weeks (dosage doubled if Hb increased < 1 g/dL after 4 weeks). MAIN OUTCOME MEASURES: Haematopoietic response (Hb increase > or = 2 g/dL or Hb > or = 12 g/dL in the absence of transfusions in the previous 28 days), transfusion required between Weeks 5 and 16 and fatigue measured by the Fatigue subscale of the Functional Assessment of Cancer Therapy. RESULTS: 293 adults were recruited (56.4% women), with lymphoproliferative malignancies (44.3%) or solid tumours (55.7%). Baseline Hb was 9-11 g/dL in 83.7% of patients. Sixty-four per cent (95% CI: 58.1-69.4%) had a haematopoietic response and 12% required transfusions. After adjusting for performance status, concomitant diseases and chemotherapy type, an increase in Hb level was significantly associated with an improvement in Fatigue subscale (+1.9 points per 1 g/dL). Only 2% of patients had treatment-related adverse events: thromboembolic pulmonary disease (0.3%); hypersensitivity reaction (0.3%); local pain following DA administration (0.3%); insomnia (0.3%); thrombocytosis (0.3%) and deep vein thrombosis (0.3%). CONCLUSIONS: Fixed-dose DA administered once weekly seems to be an effective, well-tolerated treatment for chemotherapy-induced anaemia in patients with non-myeloid malignancies, and there is an indication of a possible benefit on fatigue in the clinical practice.

Gastrointestinal stromal tumors.

BACKGROUND: We reviewed radiologic features of gastrointestinal stromal tumors (GISTs) and correlated them with clinical and pathologic findings. METHODS: We investigated a series of 39 c-Kit-positive GISTs. Clinical and radiologic findings and management of these patients were recorded. RESULTS: Twenty women and 19 men (mean age 64 years) had histologically proved GIST. Tumor locations were the small bowel (n = 20), stomach (n = 14), rectum (n = 4), and omentum (n = l). Symptoms at presentation were most frequently gastrointestinal bleeding (n = 14) and abdominal pain (n = l1). Tumors were classified as very low risk (n = 2), low risk (n = 10), intermediate risk (n = 12), and high risk (n = 11). Ultrasonography, computed tomography, magnetic resonance, digital subtraction angiography, and barium series were used in the evaluation of these tumors. Most tumors were seen as well-delineated soft tissue masses with heterogeneous contrast enhancement. Necrosis, calcification, and ulceration were most commonly seen in large tumors that presented a more aggressive behavior. CONCLUSION: GISTs can arise anywhere in the gastrointestinal tract and present a great variety of clinical and radiologic features, depending mostly on size and location.

[Prospective assessment of clinical outcomes in patients with lung cancer]. / Evaluación prospectiva de resultados clínicos en los pacientes con cáncer de pulmón.

BACKGROUND: The aim of this study was to assess the outcome in patients with lung cancer. PATIENTS AND METHODS: Prospective study in 93 patients with lung cancer in 3 community hospitals. In each evaluation (4-6 weeks) the following results were obtained: a) questionnaire on the quality of life or performance status (QoL/PS), based on different instruments (Karnofsky Performance Scale [KPS], ECOG, QLQ-C30, and the Nottingham Health Profile [NHP], and b) a clinical questionnaire. Active follow-up was for 18 months and survival tracking was to five years. A descriptive analysis of the outcome variables and a survival analysis (Kaplan-Meier) were done. The prognostic value of each instrument (Cox) and the correlation between the instruments (Spearman) were also evaluated. RESULTS: The mean values recorded at the time of diagnosis between 60% and 70% of the maximum value possible. Mean survival was 12.4 months; accumulated survival was 30% to one year and 4% to 55 months. Only 17% of patients presented any disease-free period. Toxicity of treatment was almost always irrelevant. The correlation between the KPS, the QLQ-30 and the NHP was acceptable and their initial values were important prognostic factors. The QoL/PS scores for the survivors were similar to their initial values, but the global values were 11%. CONCLUSIONS: The outcomes measures used in this study provide very useful information, although registration and analysis of the necessary data should be systematic. The KPS was comparable to the other QoL/PS indicators used, but it is shorter, more acceptable and easier to use. Better QoL/PS measurement instruments are needed to evaluate outcomes in the practice of clinical oncology.

Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function.

INTRODUCTION: Bladder cancer is a frequently occurring tumour in Spain and usually affects elderly patients with renal impairment. The development of new combination therapies for such patients is thus of vital importance. PATIENTS AND METHODS: Between 1997 and 1998, 17 patients with locally advanced non-surgical or metastatic bladder tumours were treated at our centres. Treatment consisted of 1,000 mg/m(2) of gemcitabine administered on days 1 and 8, and carboplatin (area under the concentration curve = 5) on day 1, every 21 days. RESULTS: The mean age of the patients [4 females (26%) and 13 males] was 69 years (range: 54-78 years). The average Karnofsky performance status was 80% (range: 50-100%). Mean creatinine clearance was 45.4 ml/min (range: 21-55 ml/min). There were 2 complete responses, 7 partial responses (RO: 56%; range 31-81%), 6 patients had stable disease and 1 disease progression. Haematological toxicities were as follows: grade I anaemia in 2 patients, grade III in 3; grade I granulocytopenia in 2 patients, grade III-IV in 4 patients; grade III thrombocytopenia in 3 patients. Toxic death occurred in the course of one grade IV neutropenic event. Non-haematological toxicities were as follows: grade I-II vomiting in 3 patients and grade III in 1. One patient had grade III hepatic toxicity. One patient had grade III renal toxicity, and 3 patients grade II alopecia. CONCLUSIONS: The above-mentioned treatment has low toxicity, is easy to administer and offers promising results in this group of patients.

A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC).

This was an open-label randomized Phase III study of 207 patients with either unresectable or metastatic non-small cell lung cancer (NSCLC) who were treated with docetaxel plus best supportive care (BSC) or best supportive care alone. Patients in the chemotherapy arm of the study received docetaxel 100 mg/m(2) as a 1 h intravenous infusion every 21 days until they showed evidence of progressive disease, or estimated maximum benefit obtained or unacceptable side effects. Patients who received docetaxel were pretreated with oral dexamethasone. Patients in the BSC arm should not receive chemotherapy or anticancer therapy except for palliative radiotherapy. Overall survival obtained in the docetaxel arm was significantly longer than in the BSC arm (P=0.026). Two-year survival in the docetaxel arm was 12%, whereas none of the BSC patients survived after 20 months. The response rate was 13.1% (95% CI, 7.5-18.8%). There was a significantly longer time to progression in the docetaxel versus the BSC arm (P<0.001), and statistically significant improvement of clinical symptoms with docetaxel compared to BSC. The quality-of-life descriptors were in favor of docetaxel, and the difference was significant for pain, dyspnea and emotional functioning. The safety profile of docetaxel for this study was similar to that already reported in this patient population.

Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer.

PURPOSE: The efficacy of adjuvant chemotherapy in gastric cancer is controversial. We conducted a phase III, randomized, multicentric clinical trial with the goal of assessing the efficacy of the combination of mitomycin plus tegafur in prolonging the disease-free survival and overall survival of patients with resected stage III gastric cancer. PATIENTS AND METHODS: Patients with resected stage III gastric adenocarcinoma were randomly assigned, using sealed envelopes, to receive either chemotherapy or no further treatment. Chemotherapy was started within 28 days after surgery according to the following schedule: mitomycin 20 mg/m(2) intravenously (bolus) at day 1 of chemotherapy; 30 days later, oral tegafur at 400 mg bid daily for 3 months. Disease-free survival and overall survival were estimated using the Kaplan-Meier analysis and the Cox proportional hazards model. RESULTS: Between January 1988 and September 1994, 148 patients from 10 hospitals in Catalonia, Spain, were included in the study. The median follow-up period was 37 months. The tolerability of the treatment was excellent. The overall survival and disease-free survival were higher in the group of patients treated with chemotherapy (P =.04 for survival and P =.01 for disease-free survival in the log-rank test). The overall 5-year survival rate and the 5-year disease-free survival rate were, respectively, 56% and 51% in the treatment group and 36% and 31% in the control group. CONCLUSION: Our positive results are consistent with the results of recent studies; which conclude that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer.

Protracted treatment with tegafur and low dose oral leucovorin in patients with advanced colorectal carcinoma.

BACKGROUND: Protracted oral administration of tegafur (TG) and leucovorin (LV) attempts to simulate the continuous infusion of 5-fluorouracil, with a higher intracellular folate pool. In a prior dose-finding study with a fixed TG dose of 0.75 g/m2/day for a period of 21 days and continuous oral LV, the recommended dose of LV was 45 mg/day in 28-day cycles. METHODS: Thirty-nine patients with histologic confirmation of adenocarcinoma of the colon or rectum, either advanced or metastatic disease, and who were not candidates for radical treatment were included in a Phase II study using this schedule. RESULTS: One hundred sixty-three cycles of chemotherapy were delivered (median, 4 cycles per patient). Toxicity was observed in the form of diarrhea, which was severe in 12 patients (30.7%). Grade 3 (according to the World Health Organization criteria) oral mucositis was recorded in 7 patients (18%). Asthenia was severe in 10% of the patients. Recuperation from toxicity was rapid and managed primarily on an outpatient basis. Two complete (5.1%) and 13 partial (33.3%) responses were observed, with a global response index of 38.5% (95% confidence interval, 23.2-53.6%). The median overall survival was 11.3 months. CONCLUSIONS: The results of this study show that an all-oral regimen of tegafur and leucovorin can obtain biochemical modulation, with a significant response rate, in patients with advanced colorectal carcinoma. Randomized trials are needed to assess the possible advantage of this regimen over intravenous schedules.

Clinical experience with tegafur and low dose oral leucovorin: a dose-finding study.

Tegafur is an effective oral fluoropyrimidine that shows the same activity as 5-fluorouracil for a similar spectrum of cancers. Their biochemical modulation with oral Leucovorin (LV) attempts to simulate treatment with a continuous infusion of 5-fluorouracil and LV with the added advantage of outpatient administration. Thirty-three patients with advanced adenocarcinoma were included in the study. The treatment consisted of tegafur, 0.75 g/m2/day, for 21 days, with oral LV at different dose levels, 15, 30, 45, 60 and 90 mg/day, in a 28-day cycle. A correlation between the LV dose and an increase in grade III/IV toxicity (especially diarrhea, oral mucositis and fatigue) was established in the nonlinear regression model, reaching a plateau at 60 mg of LV. For the tegafur dose used, the recommended dose of LV is in the range of 45-60 mg/day. This schedule could be considered to evaluate the possible therapeutic effect in phase II trials.

Consumption of alcohol, coffee, and tobacco, and gastric cancer in Spain.

A case-control study on gastric cancer was carried out between 1987 and 1989 in four regions of Spain. Three hundred and fifty-four cases of histologically confirmed adenocarcinoma were included (235 men and 119 women). For each case, a control was selected, matched by sex, age, and area of residence, from the same hospital as the case. No association was observed with smoking, nor with the consumption of coffee or tea. The usual consumption of alcohol was associated with gastric cancer in men (odds ratio = 1.54, 95 percent confidence interval = 1.03-2.31), but there was no dose-response relationship. No association was observed in women. All estimations were carried out taking into account the effect of the dietary factors associated with gastric cancer. In accordance with previous evidence, the association observed between gastric cancer and alcohol appears not to be causal.

Dietary factors and stomach cancer in Spain: a multi-centre case-control study.

A multi-centre case-control study of diet and gastric cancer was carried out in 4 regions of Spain (Aragon, Castile, Catalonia and Galicia). We selected 354 cases of pathologically confirmed gastric adenocarcinoma from 15 hospitals, representative of nearly all those in the study areas. A control for each case, matched by age, sex and area of residence, was selected from the same hospital as the case. Habitual diet was investigated by the dietary history method, and past diet by means of a frequency questionnaire. The results regarding consumption of food items are presented here. With respect to habitual diet, an increase in risk was associated with consumption of preserved fish, cold cuts and oleaginous fruits. A high intake of cooked green vegetables, fresh noncitrus fruit and dried fruit showed an inverse association with the risk of gastric cancer. Simultaneous intake of 2 groups of food which increase or decrease the risk of cancer strengthens the respective individual effect. The intake of protective food items seems to neutralize the effects of food items which increase risk. With reference to past diet, a possible protective effect was observed for daily consumption of fresh fruit and green vegetables.

Five-year results of combined chemotherapy and mediastinal radiation therapy in small cell lung cancer.

Eighty-five patients with small cell lung cancer (limited disease = LD in 39, extensive disease = ED in 46) received the combination of cyclophosphamide, methotrexate, vincristine and CCNU, and mediastinal radiotherapy given simultaneously after the third course of chemotherapy. The duration of treatment was approximately 12 months. A complete response was obtained in 41% of LD and in 15% of ED patients, and a partial response in 38 and 22%, respectively. Median survival was 55 weeks for LD and 37 weeks for ED patients. Two patients (5%) with LD have survived free of disease more than 3 years since their diagnosis.