[Long term survival in metastatic colorectal cancer treated with leucovorin and 5-fluoro-uracil chemotherapy]. / Survie à long terme des cancers colorectaux métastatiques sous chimiothérapie par 5-fluoro-uracile.

PURPOSE: Median survival in advanced colorectal cancer patients treated with 5-fluoro-uracil (5FU) and leucovorin (LV) is between 12 and 18 months. The aim of this study was to evaluate long term survival in this disease. METHODS: We report here, retrospectively, the survival of 445 patients who entered in first-line prospective studies with LV-5FU-based regimen chemotherapy, between 1985 and 1995. RESULTS: Median survival was 18 months. The 3, 5 and 10 year survival were respectively 17.9%, 4.5% and 2.4%. Seventy-five patients survived more than 3 years, among them, 10 achieved a complete and 34 a partial response, 12 had curative liver or lung surgery. Fifteen patients lived more than 5 years, 2 achieved a complete and 7 a partial response. Seven had curative surgery. Eleven patients were still alive in 2002, among them 7 in complete remission at 5 years, including 3 who did not have surgery. CONCLUSION: This study shows that some patients with metastatic colorectal cancer can achieve long survival, especially when secondary curative surgery can be performed. However, 1% of the patients can be cured with LV-5FU chemotherapy alone. These results will be probably improve with the use of the new drugs: oxaliplatin and irinotecan.

Optimisation of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of hydroxyurea, leucovorin, 5-FU and cisplatin (HLFP regimen) for metastatic oesophageal cancer.

To improve the efficacy and tolerance of the 5-fluorouracil (5-FU)/cisplatin combination in metastatic esophageal cancer, we designed a new therapeutic schedule, the HLFP regimen. 42 patients with metastatic oesophageal adenocarcinoma (n=10) or squamous cell carcinoma (n=32) were prospectively enrolled in the study. All had bidimensionally measurable disease. The HLFP regimen consisted of twice-monthly oral administration of hydroxyurea 1 g/m(2) on days 0, 1 and 2; a 2-h infusion of leucovorin 200 mg/m(2) and a bolus of 5-FU 400 mg/m(2) followed by a 22-h infusion of 5-FU 600 mg/m(2) on days 1 and 2; and, every two cycles, 80 mg/m(2) cisplatin on day 3. Relief of dysphagia and other symptoms were monitored, together with body weight changes. Major objective responses were observed in 24 patients (57%, 95% Confidence Interval (CI): 42-72%), including four complete responses (10%). The median progression-free survival and overall survival times were 8 and 12.7 months, respectively. Weight gain was observed in 48% of patients, and dysphagia improved in 76%. Grade 3-4 toxicity occurred in 40% of patients, with grade 4 neutropenia in 12% and grade 3 thrombocytopenia, vomiting and diarrhoea in 7-9% of patients. There were no treatment-related deaths. These results suggest that the HLFP regimen is an active and well-tolerated chemotherapy for metastatic oesophageal carcinoma.

[Meningeal carcinomatosis in gastric cancer]. / Méningite carcinomateuse et cancer de l'estomac.

Meningeal carcinomatosis is an uncommon complication in patients with advanced gastric cancer. We report four cases of meningeal carcinomatosis occurring 18 months (mean) after the diagnosis. The presenting manifestations were headache, visual troubles and seizure. Cytological cerebrospinal fluid (CSF) examination was the most useful diagnostic tool for leptomeningeal carcinomatosis, considering the normality of brain CT scan and MRI in our patients. Intrathecal methotrexate administration achieved a rapid improvement in neurological symptoms in all cases, but for a short 2-3 months duration. We conclude that survival improvement in advanced gastric cancer, due to chemotherapy, may allow emergence of unusual complications such as carcinomatous meningitis. This diagnosis should be evoked in the presence of unexplained neurologic symptoms and confirmed by CSF examination in order to propose a treatment and to delay serious neurologic disability and prolong survival.

Correlation between progression free survival and response rate in patients with metastatic colorectal carcinoma.

BACKGROUND: All endpoint measures currently used to evaluate chemotherapeutic treatment benefit in clinical trials of patients with metastatic colorectal carcinoma (MCRC) have disadvantages. Overall survival (OS) is the most objective parameter but is flawed as an efficacy criterion, partly because potentially active second-line treatments are not controlled in many Phase III studies, and measured OS may be influenced (positively or negatively) to an unknown degree by second-line therapy. Measuring progression free survival (PFS) may be a means of isolating the real impact of first-line regimens. METHODS: To test this hypothesis, the authors analyzed pooled data from all Phase III studies on first-line treatment in patients with MCRC reported from 1990 through 2000 for correlations between PFS, response rate (RR), and OS in MCRC patients that may suggest PFS as an improved indicator of the efficacy of first-line treatment. Spearman rho correlation coefficients (r) and regression equations were used. RESULTS: The authors analyzed data from 29 studies involving nearly 13,500 patients. Significant correlations were found between PFS and RR (r = 0.655; P < 0.0001; a 10% RR increment corresponded to a 1-month increase in PFS), between RR and OS (r = 0.408; P = 0.0009; an 11.4% RR increment corresponded to a 1-month increase in OS), and between PFS and OS (r = 0.481; P < 0.0001; a 1-month increase in PFS corresponded to a 0.68-month increase in OS). CONCLUSIONS: PFS is the most appropriate primary endpoint for MCRC studies, because it can express the antitumor activity of a first-line chemotherapy regimen regardless of measures used after disease progression. PFS deserves further evaluation as an endpoint measure.

High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7).

This phase II study examined a regimen (FOLFOX7) of leucovorin (LV), high-dose intensity oxaliplatin, and 5-fluorouracil (5-FU), as second-line therapy for metastatic colorectal cancer. 48 patients were enrolled - 36 refractory and 12 resistant to prior therapy with LV-5-FU. Oxaliplatin (130 mg/m2) was infused with LV (400 mg/m2) over 2 h on day 1, followed by bolus 400 mg/m2 and a 46-h infusion (2400 g/m2) of 5-FU, every 2 weeks. Patients who responded or were stable received eight cycles. Patients were evaluated every 2 months. 20 patients (42%) had partial responses (95% confidence interval (CI): 28-56%), 19 (40%) had stable disease and 9 (19%) progressed. Median progression-free survival (PFS) was 6 months and median survival 16.1 months. Toxic effects of National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grade 3/4 were: peripheral neuropathy 15%, nausea 8%, diarrhoea 11%, neutropenia 9%, thrombocytopenia 11%. Overall, 38% of patients experienced grade 3/4 toxicities, and 64% received 90% or more of the scheduled oxaliplatin dose intensity during the first four cycles. FOLFOX7 was highly active, with good tolerability, in pretreated patients resistant to LV-5-FU [corrected].

Elementos para la evaluación del dolor en el paciente con cáncer / Elements for reevaluation of pain in cancer patients

El dolor asociado a cáncer requiere una evaluación integral del paciente y de su enfermedad, para establecer una adecuada terapéutica, así como tambíen, una reevaluación periódica en el caso en que se presenten diferentes tipos de dolor o cambios en la evolución del mismo. La evaluación clínica del paciente con dolor por cáncer comprende la identificación de las causas del dolor, el análisis del mecanismo implicado y la evaluación de la intensidad del dolor; ésta última se realiza mediante diversas técnicas disponibles, como escalas unidimensionales globales o métodos comportamentales, que permiten indicar la dimensión de la queja dolorosa, aunque no pueden presumir la causa o definir el componente orgánico y psicológico presente. Debido a que el paciente con dolor por cáncer presenta síntomas psicológicos como sentimientos de inutilidad, stress, incomprensión o pérdida de autoestima, el papel del medio familiar se constituye en un soporte para una mejor calidad de vida del paciente

Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Oncology Multidisciplinary Research Group (GERCOR).

BACKGROUND: Studies of bimonthly 48-hour regimens of high-dose leucovorin (LV) (FOLinic acid), 5-fluorouracil (5-FU) by continuous infusion combined with OXaliplatin (FOLFOX) in pretreated patients with metastatic colorectal cancer suggest that oxaliplatin dose intensity is an important prognostic factor for response rate and progression-free survival (PFS). To help define the optimal dose schedule for oxaliplatin in pretreated metastatic colorectal cancer, we retrospectively analyzed data from three phase II studies using different FOLFOX regimens (FOLFOX2, 3 and 6). PATIENTS AND METHODS: Data on 126/161 patients were analyzed. FOLFOX2 included oxaliplatin 100 mg/m2; FOLFOX3, 85 mg/m2; and FOLFOX6, 100 mg/m2 (added to a simplified LV-5-FU regimen), all as two-hour infusions. A total of 47 patients received low dose intensity oxaliplatin (LDI: < or = 85 mg/m2/2 weeks) and 79 patients high dose intensity oxaliplatin (HDI: > 85 mg/m2/2 weeks). RESULTS: Objective responses occurred in 31 (39%) HDI patients and 9 (19%) LDI patients (P = 0.03). Median PFS was 28 weeks, with 52% of HDI patients progression free at 6 months, and 26 weeks with 36% of LDI patients progression free at six months (P = 0.02). Increased oxaliplatin dose intensity was not associated with increased neurotoxicity or other toxicities. FOLFOX are among the most effective regimens for treating LV-5-FU-resistant metastatic colorectal cancer. CONCLUSIONS: This study shows that oxaliplatin dose intensification significantly improves response rate and PFS in pretreated metastatic disease without increasing severe toxicity.

[Bimonthly 5-fluorouracil in elderly patients with metastatic colorectal cancer. Study of 50 patients]. / 5-fluorouracile bimensuel en traitement du cancer colorectal métastasé chez le sujet âgé. Etude de 50 patients.

PURPOSE: Recent advances in the management of colorectal cancer have improved the quality of life and the survival of patients treated with chemotherapy. In order to define the contribution of chemotherapy in elderly patients, we studied the tolerance and the efficacy of first-line chemotherapy in patients with metastatic colorectal cancer. METHODS: Patients aged over 75 years received, as outpatient therapy, a bimonthly 48 h leucovorin and fluorouracil regimen. Evaluation was assessed every six cycles (i.e., three months). RESULTS: Fifty patients were studied: 28 males and 22 females, aged between 75 to 87 years, 37 with colon cancer and 13 with rectal cancer. Among 45 patients capable of being evaluated, the response rate was 44%, with six complete responses (13%) and 14 partial responses (31%). Eighteen patients had stable disease (40%) and seven patients progressive disease (16%). Median progression-free survival was 8.8 months and median survival 16.4 months. Grade 3 to 4 toxicity occurred in 20% of the patients. Performance status improved in 56% of the patients. CONCLUSION: The bimonthly regimen is well tolerated in elderly patients and appears to prolong survival as well in younger patients.

Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR.

For patients resistant to leucovorin (LV) and 5-fluorouracil (5-FU), the addition of oxaliplatin (85 or 100 mg/m2) to bimonthly LV-5-FU has given a response rate of 20-46%. The highest response rate has been observed with oxaliplatin 100 mg/m2 (FOLFOX2). The present phase II study (FOLFOX6) infused oxaliplatin (100 mg/m2) with LV (400 mg/m2) as a 2-h infusion on day 1, followed by bolus 400 mg/m2 and a 46-h infusion (2.4-3 g/m2) of 5-FU, every 2 weeks. Among the 60 patients treated, 16 (27%) had partial responses (95% confidence interval: 15-38), 27 (45%) had stable disease, 15 (25%) experienced disease progression and 2 (3%) had non-measurable disease. From the start of FOLFOX6, median progression-free survival was 5.3 months and median survival 10.8 months. From the 448 cycles analysed, NCI-CTC grade 3-4 toxicities per patient were: peripheral neuropathy 16%, nausea 7%, diarrhoea 7%, mucositis 5%, neutropenia 24%, thrombocytopenia 2%. Overall 26 (46%) patients experienced grade 3-4 toxicities. Because of toxicity, only 36% of the patients received > or = 90% of the scheduled oxaliplatin dose intensity. FOLFOX6 was active in pretreated patients resistant to LV-5-FU and is being investigated as first-line therapy. We are now investigating FOLFOX7, a regimen with a higher oxaliplatin dose intensity and a lower 5-FU dose.

CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR.

CPT-11 (irinotecan) has shown activity in patients with advanced colorectal cancer resistant to leucovorin (LV) and 5-fluorouracil (5-FU). In this study, the simplified bimonthly LV-5-FU regimen was combined with CPT-11 (FOLFIRI) as third-line therapy for patients with advanced colorectal cancer. Continuous infusion of 5-FU was administered with disposable pumps as outpatient therapy. FOLFIRI consisted of CPT-11 180 mg/m2 as a 90-min infusion day 1; LV 400 mg/m2 as a 2-h infusion during CPT-11, immediately followed by 5-FU bolus 400 mg/m2 and 46-h continuous infusion of 2.4-3 g/m2 every 2 weeks. Among the 33 patients treated, 2 had partial responses for an overall response rate of 6%; 20 patients were stabilised (61%) and 11 had disease progression (33%). From the start of FOLFIRI, median progression-free survival was 18 weeks and median survival was 43 weeks. For the 242 cycles analysed, NCI-CTC toxicities grade 3-4 per patient were nausea 15%, diarrhoea 12% and neutropenia 15%. Overall, 10 patients (30%) experienced grade 3-4 toxicity. 7 patients (21%) had grade 2 alopecia. FOLFIRI generated activity and acceptable toxicity, in heavily pretreated patients, with limited diarrhoea, mostly asymptomatic neutropenia and manageable nausea and relatively uncommon alopecia. This regimen is suitable for studies in chemotherapy-naïve patients.

A review of GERCOD trials of bimonthly leucovorin plus 5-fluorouracil 48-h continuous infusion in advanced colorectal cancer: evolution of a regimen. Groupe d'Etude et de Recherche sur les Cancers de l'Ovaire et Digestifs (GERCOD).

The addition of leucovorin (LV) to 5-fluorouracil (5-FU) in advanced colorectal cancer has shown improved tumour response rates in many trials, but the optimal LV/5-FU regimen has yet to be determined. Seven studies carried out over the last 12 years to evaluate the safety and efficacy of various LV/5-FU regimens are reviewed. The initial bimonthly high-dose LV/5-FU regimen consisted of high-dose LV as a 2-h infusion followed by 5-FU as an intravenous (i.v.) bolus plus a 22-h continuous infusion (CI), repeated for two consecutive days every 2 weeks. A randomised comparison of this bimonthly high-dose LV/5-FU regimen and the NCCTG-Mayo Clinic regimen (LV [20 mg/m2/day] followed by 5-FU bolus [425 mg/m2/day] daily x 5, every 4 weeks) showed that the bimonthly high-dose LV/5-FU regimen was superior to the NCCTG-Mayo Clinic regimen in response rate and progression-free survival, but showed no difference in overall survival. In addition, toxicity was less with the bimonthly high-dose LV/5-FU regimen. These promising results led to a phase II trial of a simplified bimonthly high-dose LV/5-FU regimen consisting of LV (500 mg/m2/day) and a 48-h CI of 5-FU (1.5-2 g/m2/day) which has been administered alone or in combination. In summary, GERCOD-sponsored studies have further demonstrated that high doses of both LV and 5-FU given as a CI can improve response rates still more with acceptable toxicity. Further studies are focused on the effectiveness of combination with oxaliplatin or CPT-11 in metastatic disease and the use of high-dose LV/5-FU regimens for colorectal cancer in the adjuvant setting.

Long-term follow-up after adjuvant chemotherapy in completely resected early stage ovarian carcinoma.

OBJECTIVE: To evaluate the impact of standardized staging, surgery and adjuvant chemotherapy on survival of patients with completely resected early ovarian carcinoma. STUDY DESIGN: We performed a multicentric retrospective analysis of 283 patients with early stage ovarian carcinoma consecutively treated between 1977 and 1993. Borderline tumours were excluded. A comprehensive staging was performed during initial laparotomy. Patients were treated by standardized surgical resection and all excepted stage IA received a 6-course adjuvant chemotherapy. RESULTS: Eighty patients were excluded because of incorrect substaging, inadequate surgery and adjuvant therapy. The analysis was performed on 203 patients with completely resected early stage ovarian cancer (139, stage I; 64, stage II). Relapse-free survival and overall survival rates for stage I were 66 and 69%, respectively. Relapse-free survival and overall survival rates for stage II were 57 and 61% respectively. Median time of relapse was 18 months (range, 1-107 months). Sites of relapse were peritoneum (45%), retroperitoneal lymph nodes (37%) and distant metastases (18%). Relapses occurring within 18 months had a median survival after relapse of 9 months while later relapses had a median survival of 22 months (P = 0.005). There was no significant difference in relapse-free and overall survival according to the age, performance status and pathology. Cisplatin-based chemotherapy improved the 10-year overall survival of patients with stage IIB and IIC as compared to chemotherapy without cisplatin (oral melphalan. CMF regimen); 91 vs. 33% (P = 0.012) and 75 vs. 42% (P = 0.05), respectively. Cisplatin-based regimens did not improve survival in stage IA, IB and IIA. CONCLUSIONS: Early ovarian cancers have a good prognosis after comprehensive staging, complete surgery and adjuvant chemotherapy. Cisplatin-based regimens compared to melphalan and CMF showed a significant increase of survival in stage IIB and IIC. Prognosis of relapse depends on the relapse-free interval duration.

[Krükenberg tumors and ovarian metastases of breast cancer]. / Tumeurs de Krükenberg et métastases ovariennes du cancer du sein.

Metastasis to the ovary has been estimated occur in 6 to 27.8% of all cancers. The wide variation resulting both from methodology and the small, often microscopic size of these secondary tumors. Many are mucocellular tumors or Krükenberg's tumors (ovarian carcinoma mucocellular) considered by some to include all ovarian metastases and by others to be limited to metastasis of gastrointestinal or gastric cancer. The work presented in this issue by Le bouëdec et al. concentrates on a homogeneous series of clinically diagnosed ovarian carcinoma mucocellular secondary to breast cancer. Manifestations of ovarian metastasis, pelvic weight or ascitis, usually develop approximately 5 years after diagnosis of localized breast cancer and occur with other metastatic localizations in half the cases. Ovarian metastasis is particularly frequent from invasive lobular breast cancer; the primary tumoral type was invasive lobular carcinoma in 8 out to the 10 patients in the series reported here by Le Bouëdec et al., while this type is found in only 8% of breast cancers. This observation is further supported by data in the literature demonstrating the unusual propagation routes of these infiltrating lobular cancers. The authors draw the reader's attention to the short median survival after diagnosis, 18 months, emphasizing the importance of careful follow-up after diagnosis and treatment of breast cancer.