Multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial.

Evaluation of new drug combinations is needed to improve patients' prognosis in advanced hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the safety and efficacy of the capecitabine-oxaliplatine combination (XELOX) in HCC patients. First-line chemotherapy with XELOX regimen consisting of a 3-week cycle of intravenous oxaliplatin (130 mg m(-2)) on Day 1, and oral capecitabine twice daily from Days 1-14 (1000 mg m(-2)) was administered in patients with measurable, unresectable HCC. Fifty patients (male, 88%; median age, 68 years) received a total of 295 cycles (median, 6) of treatment. Disease control (three partial responses, 29 stable diseases) rate was 72% (95% CI 57-83%). Median overall and median progression-free (PFS) survival was 9.3 months and 4.1 months, respectively. Progression-free survival rates at 6 and 12 months were 38% (95% CI 26-52%) and 14% (95% CI 7-26%), respectively. Main grade 3-4 drug-related toxicities included diarrhoea (16%), elevation of aminotransferases and/or bilirubin (16%), thrombocytopenia (12%), and neurotoxicity (6%). Capecitabine plus oxaliplatin regimen showed modest anti-tumour activity with tolerable toxicities in patients with advanced HCC. However, the manageable toxicity profile and the encouraging disease control rate deserve further attention for this convenient, outpatient-based chemotherapy regimen.

Phase II trial of thalidomide in renal-cell carcinoma.

BACKGROUND: Thalidomide has been reported to yield anti-tumor activity in cancer. We performed a phase II trial of this drug in patients with metastatic renal cell carcinoma to determine its efficacy. PATIENTS AND METHODS: Patients with proven metastatic renal cell cancer, measurable progressive disease and a performance status of 0-2 were enrolled in this study. Thalidomide was given daily at a starting dose of 400 mg, followed by a 400 mg increment to 800 mg and then to 1200 mg with 6-12 weeks at each dose level. The response rate at 6 months was the primary end point. Toxicity, overall survival, tumor vascularization depicted on color Doppler ultrasonography and serum vascular endothelial growth factor, basic fibroblast growth factor, interleukin-12 and tumor necrosis factor-alpha levels were secondary end points. RESULTS: Forty patients were enrolled. Two partial responses were observed (5%) and disease remained stable in nine patients after 6 months. Median survival was 10 months. Toxicity was high, with frequent manifestations of fatigue, constipation and lethargy. The incidence of neuropathy detected on electromyography (EMG) attained 70% at 6 months, and 100% in patients on thalidomide for 12 months. Nine patients developed venous thromboembolism during the first 12 weeks of treatment, and three of them experienced pulmonary embolism. One unexpected (and unexplained) death occurred. CONCLUSIONS: Despite undisputed, albeit marginal, activity in renal cell cancer, high-dose thalidomide cannot be recommended using this schedule since the level of toxicity is high.

[Radiotherapy using a combination of photons and protons for locally aggressive intracranial tumors. Preliminary results of protocol CPO 94-C1]. / Radiothérapie des tumeurs intracrâniennes localement agressives par une combinaison de photons et de protons. Résultats préliminaires du protocole CPO 94-C1.

PURPOSE: From October 1993 through July 1998, 48 assessable adult patients with non-resectable aggressive intracranial tumors were treated by a combination of high dose photon + proton therapy at the Centre de Protonthérapie d'Orsay. PATIENTS AND METHODS: Grade 1 and 4 gliomas were excluded. Patients benefited from a 3D dose calculation based on high-definition CT and MRI, a stereotactic positioning using implanted fiducial markers and a thermoplastic mask. Mean tumor dose ranged between 63 and 67 Gy delivered in five weekly sessions of 1.8 Gy in most patients, according to the histological types (doses in Co Gy Equivalent, with a mean proton-RBE of 1.1). RESULTS: With a median 18-month follow-up (range: four-58 months), local control in tumors located in the envelopes and in the skull base was 97% (33/34), and in parenchymal tumors, 43% (6/14) only. Two patients (5%) presented with a clinically severe radiation-induced necrosis (temporal lobe and chiasm). CONCLUSION: In our experience, high-dose radiation combining photons and protons is a safe and highly efficient procedure in selected malignancies of the skull base and envelopes.

Preliminary results of the EORTC-GPMC controlled clinical trial H7 in early-stage Hodgkin's disease. EORTC Lymphoma Cooperative Group. Groupe Pierre-et-Marie-Curie.

In this phase III trial, 770 patients with clinical stage I-II Hodgkin's disease (HD) have been enrolled since November 1988. Preliminary results are given for the 605 (79%) patients who have completed their initial therapy. Patients were grouped according to 6 pretreatment prognostic characteristics. In the very favourable (VF) group, treatment consisted of mantle field alone. In the favourable (F) group, patients were randomized to either subtotal nodal irradiation (STNI), or 6 cycles of EBVP (epirubicin, bleomycin, vinblastine, prednisone) followed by involved-field irradiation (IF-RT). Unfavourable (U) patients were randomized to either 6 cycles of EBVP plus IF-RT, or to 6 cycles of MOPP/ABV hybrid plus IF-RT. Of the 35 VF patients, none have progressed during radiotherapy. Four patients relapsed and were salvaged. Three-year failure-free survival (FFS) was 82%; overall survival (OS) was 100%. Of the 254 F patients, 130 were treated with STNI and 124 with EBVP plus IF-RT. At 3 years, FFS rates were 81% (1 progression, 14 relapses) and 79% (5 progressions, 8 relapses), respectively. Corresponding OS rates were 99% and 100%. Of the 316 U patients, 160 received EBVP and 156 MOPP/ABV. At 3 years, FFS rates were 72% (18 progressions, 20 relapses) and 88% (7 progressions, 6 relapses), respectively (p < 0.001). Although OS rates were identical (92%), the entry in the U-EBVP arm was stopped in November 1992. We conclude that a treatment strategy based on prognostic factors allows the use of less aggressive treatment in favourable patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Late relapse in early-stage Hodgkin's disease patients enrolled on European Organization for Research and Treatment of Cancer protocols.

PURPOSE: The great majority of relapses after the treatment for early-stage Hodgkin's disease are observed within 4 to 5 years after treatment completion. This study describes the characteristics and outcome of patients who had late relapses, which was defined as relapses that occurred 5 or more years after initial treatment start. PATIENTS AND METHODS: A total of 1,082 adult patients with early clinical stage Hodgkin's disease were enrolled on three consecutive European Organization for Research and Treatment of Cancer (EORTC) protocols (H1, H2, and H5 trials) from 1964 to 1981. Of these, 1,044 patients satisfied the eligibility criteria with a supradiaphragmatic localization, age greater than 15 years, and initial complete remission. Overall, 341 patients (32.6%) relapsed, 304 (29.1%) early and 37 (3.5%) late. For each of these 37 late relapsers, questionnaires were sent to the participating centers and detailed information for 34 relapses was obtained. Cumulative probabilities for developing a late relapse were estimated using the Kaplan and Meier method. Quantification of the relationship between late relapse and several confounding variables was performed using the Cox's proportional hazards model. RESULTS: The 10- and 15-year cumulative probabilities of late relapse in patients who were disease-free at 5 years were 4.8% and 8.3%, respectively. Patients treated on more recent protocols had a higher incidence of late relapse, possibly due to an attempt to tailor therapy to the specific prognostic factors (10-year cumulative probabilities, 4.6%, 2.6%, and 7.5% in trials H1, H2, and H5, respectively). Incidence of late relapses significantly correlated with male sex, B symptoms, mediastinal involvement, and treatment modality. Salvage treatment induced a complete response in 27 patients (79%) and a prolonged complete remission in 24 patients (71%). Twenty years after initial treatment start, similar overall survival rates were observed for late relapsing (72%) and nonrelapsing patients (75%). CONCLUSION: Late relapses of Hodgkin's disease are uncommon, but may be more frequent with recent protocols tailored to specific prognostic factors. If treated, their outcome is favorable. Late relapse is therefore another factor indicating that careful, long-term follow-up is needed for patients with Hodgkin's disease.

Therapeutic implications and sites of relapse predicted by elevated posttherapy erythrocyte sedimentation rate in early stage Hodgkin disease.

An analysis was performed of all 57 early relapses (ER) (within 18 months of therapy initiation) seen in a group of 301 patients treated on three successive European Organization for Research and Treatment of Cancer (EORTC) protocols from 1964 to 1981; to determine whether a posttherapy elevated erythrocyte sedimentation rate (ESR) (greater than or equal to 30 mm) could predict the type of relapse and the effect upon the relapse of different therapies received. Overall most ER occurred in extranodal (EN) (42%) or irradiated transdiaphragmatic nodal (TDN) (40%) sites. Compared to patients with normal posttherapy ESR (n = 12), patients with elevated posttherapy ESR (n = 45) had the same proportions of outfield and late relapses; more frequent multiple sites of ER (38% vs. 25%), increased proportions of early EN relapses (16% vs. 3%), TDN relapses (17% vs. 2%), and other ER (6% vs. 1%). ER were most frequently observed between 1964 and 1971, and "modern" radiotherapy (Rt) decreased ER overall from 27% to 13% and for elevated posttherapy ESR patients from 54% to 25%. When chemotherapy (Ct) was used as either adjuvant or initial therapy, ER were greatly reduced vs. Rt alone [overall (6% vs. 28%) and for patients with elevated posttherapy ESR (10% vs. 39%)]. Stepwise logistic regression showed Ct to be the most important factor "protecting" from EN relapse, but elevated posttherapy ESR was still significant. For early TDN relapse, elevated posttherapy ESR had the highest predictive value for relapse, greater than the types of radiation fields used and chemotherapy. An unexplained elevated posttherapy ESR, regardless of previous therapy, predicts for ER from aggressive HD, frequently in EN and irradiated areas, and warrants further early therapy.

Evolution of erythrocyte sedimentation rate as predictor of early relapse in posttherapy early-stage Hodgkin's disease.

A retrospective study was undertaken at the Institut Gustave Roussy (IGR) to determine the predictive ability of changes in the erythrocyte sedimentation rate (ESR) during posttherapy periods for early relapse (within 18 months from start of therapy) and long-term survival in Hodgkin's disease (HD). Three hundred one patients with clinical stages (CS) I or II HD entered in the European Organization for Research and Treatment of Cancer (EORTC) clinical trials were included in this study. All relevant data and long-term follow-up were available for these patients. A stepwise logistic regression was performed to assess the prognostic value of ESR changes independent of other prognostic parameters and treatment. The incidence of early relapse was found to be significantly increased in patients in whom ESR remained elevated (greater than 30 mm at one hour) after completion of therapy, regardless of the value before therapy. This was true whether the ESR was elevated in plateau fashion, oscillating between normal and abnormal, or was lower than at onset, but still abnormal. Moreover, early relapse predicted by elevated ESR posttherapy was associated with poor survival despite subsequent initiation of combination chemotherapy. Thus, the persistence of an abnormal ESR appears to be a reliable indicator for high probability of early relapse and subsequent poor prognosis. This might be introduced as a prognostic variable in the design of future therapy programs for HD.

Late toxicity of radiotherapy in Hodgkin's disease. The role of fraction size.

From 1972 to 1976 patients at the Gustave Roussy Institute were irradiated for Hodgkin's disease using a modified fractionation schedule (3 fractions of 3.3 Gy per week) for operational reasons. From 1964 to 1971 and from 1977 to 1981, a more conventional regimen (4 fractions of 2.5 Gy per week) was used. The rates of the late complications in these two subsets of patients treated with different fractionation schedules at the same total dose of 40 Gy during the same overall time were compared. Mediastinitis was observed in 19% of the '4 X 2.5 Gy/week' group versus 56% in the '3 X 3.3 Gy/week' group. Pericarditis in 0% versus 9%, gastroduodenal ulceration and severe gastritis in 10 versus 21% and small bowel obstruction in 5 versus 8%. When using the linear quadratic model with an alpha/beta of 2.5 Gy to evaluate the equivalent dose of 40 Gy given in 12 fractions of 3.3 Gy when delivered by fractions of 2.5 Gy, a value of 46.6 Gy is found. This difference of 6.6 Gy in the equivalent doses (for late toxicity) is likely to account for the significant increase of late radiation injuries, such as mediastinitis and pericarditis, in the present study. The local relapse rate was found to be slightly lower in the 3 X 3.3 Gy group. However, this possible benefit cannot offset the considerable increase of late complications.