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We report a case of a 27-year-old man with Ph1-positive chronic myelogenous leukaemia (CML). At the time of diagnosis 100% Ph1-positive cells were found with a trisomy 8 in 50% of them. In absence of therapy, his haematological status remained stable for 3 years. Subsequently a progressive regression of haematologic and cytogenetic data was observed. Eight years after diagnosis the karyotype showed only 37% Ph1-positive cells and the trisomy 8 had disappeared.

Resume Propos. – L’objectif de cette etude est d’evaluer la survie a long terme des patients ayant un cancer colorectal metastatique traites par chimiotherapie. Methodes. – Nous avons analyse retrospectivement la survie de 445 patients suivis pour un cancer colorectal metastatique qui sont entres dans des essais prospectifs de premiere ligne de chimiotherapie a base de 5-fluoro-uracile et d’acide folinique, entre 1985 et 1995. Resultats. – La mediane de survie a ete de 18 mois. La survie a 3 ans etait de 17,9 %, 4,5 % a 5 ans et 2,4 % a 10 ans. Soixante-quinze patients ont vecu plus de 3 ans parmi lesquels 10 ont presente une reponse complete et 34 une reponse partielle, 12 ont eu une chirurgie secondaire curatrice hepatique ou pulmonaire. Quinze patients ont vecu plus de 5 ans, dont 2 avaient une reponse complete, 7 une reponse partielle et 7 ont ete operes. Onze patients etaient encore en vie en 2002, parmi lesquels 7 en remission complete a 5 ans, dont 3 qui n’avaient pas eu de chirurgie de leurs metastases. Conclusion. – Cette etude montre que certains patients peuvent avoir une survie prolongee et que 1 % des patients ont pu etre gueris uniquement avec une chimiotherapie a base de 5-fluoro-uracile. Ces resultats seront probablement ameliores par l’utilisation de nouveaux medicaments, l’oxaliplatine et l’irinotecan.

Irinotecan has shown activity in advanced colorectal cancer resistant to leucovorin and fluorouracil. Preclinical experiments on cell cultures and human tumor xenografts indicated potential synergy when combining irinotecan and fluorouracil. We designed a new regimen combining leucovorin, fluorouracil, irinotecan, and hydroxyurea (FOLFIRI-2) and conducted a phase II study to establish its efficacy and tolerance in advanced colorectal cancer refractory to fluorouracil and oxaliplatin. Treatment was repeated every 2 weeks and consisted of leucovorin 400 mg/m2 on day 1, immediately followed by 46 hours of continuous infusion of fluorouracil 2,000 mg/m2, irinotecan 180 mg/m2 on day 3, and hydroxyurea 1,500 mg the day before leucovorin, and on days 1 and 2. Treatment was continued until progression or limiting toxicity. Twenty-nine heavily pretreated patients entered the study. Five patients achieved an objective response (17%), and 12 obtained stabilization of disease or minor response (52%). Five patients failed to continue treatment (17%) because of toxicity or worsening condition. From the start of FOLFIRI-2 treatment, median progression-free survival was 4.1 months and median survival was 9.7 months. Grade III/IV National Cancer Institute-Common Toxicity Criteria toxicities were nausea 17%, diarrhea 31%, mucositis 14%, neutropenia 52%, and febrile neutropenia 14%. FOLFIRI-2 achieved a good rate of response and stabilization in heavily pretreated patients despite significant toxicity.

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.

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].

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 ρ 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. Cancer 2001;91:2033–8. © 2001 American Cancer Society.

Summary Background: studies of bimonthly 48-hour regimens of highdose 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/m 2 ; FOLFOX3, 85 mg/m 2 ; and FOLFOX6, 100 mg/m 2 (added to a simplified LV-5-FU regimen), all as two-hour infusions. A total of 47 patients received low dose intensity oxaliplatin (LDI: J£ 85 mg/m 12 weeks) and 79 patients high dose intensity oxaliplatin (HDI: > 85 mg/m 2 /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.

Resume Propos Les progres realises dans les modalites d'administration du 5-fluorouracile ont permis d'ameliorer la qualite de vie et la survie des patients traites par chimiotherapie pour un cancer colorectal metastase. Afin de preciser la place de ces traitements chez les sujets âges, nous avons etudie la tolerance et l'efficacite de la chimiotherapie en traitement du cancer colorectal metastase chez les patients de plus de 75 ans. Methodes Il s'agit d'une etude retrospective des patients de 75 ans et plus traites pour un cancer colorectal metastase par une chimiotherapie ambulatoire de 48 heures, bimensuelle, comportant du 5-fluorouracile module par l'acide folinique. Les patients etaient evalues tous les six cycles (3 mois). Resultats Cinquante patients, (28 hommes et 22 femmes), âges de 75 a 87 ans, ont ete traites pour un adenocarcinome d'origine colique (37 patients) ou rectal (13 patients). Parmi les 45 patients evaluables, nous avons observe six reponses completes (13 %) et 14 reponses partielles (31 %), soit 44 % de reponses objectives, 18 stabilisations (40 %) et sept progressions (16 %). La duree mediane de survie sans progression etait de 8.8 mois, et celle de survie globale etait de 16,4 mois. L'incidence des toxicites severes etait faible (20 % de grade 3 ou 4). Nous avons observe une amelioration de l'etat general chez 56 % des patients pour lesquels il etait altere au depart (14/25). Conclusion Les patients âges de plus de 75 ans peuvent beneficier de chimiotherapies ambulatoires, bien tolerees, qui permettent de prolonger la survie dans une meme proportion que pour les patients plus jeunes.

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.

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.

Preliminary studies suggest synergy between oxaliplatin and fluorouracil (5-FU). To assess this issue, we performed a study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. Regimen consisted of oxaliplatin day 1, 130 mg/m2 every two cycles (folfox 1) or 100 mg/m2/cycle (folfox 2) or 85 mg/m2/cycle (folfox 3) and leucovorin 500 mg/m2 as a 2-hour infusion, followed by 5-FU 22 h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. One hundred and thirteen patients have been treated. One complete response (CR) and 32 partial responses (PRs) were observed for an overall response rate of 29.2%. Sixty-seven patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU than the one used in the folfox regimens, among them 18 had PRs (26.9%). The best response rate was observed in patients treated with the folfox 2 regimen: 41.7%. From start of folfox, median progression-free survival was 6 months and median survival 13 months. Limiting toxicities were peripheral neuropathy and neutropenia. Fifty-four percent of the patients experienced WHO toxicity > or = grade 3 with the folfox1 regimen, 45% with the folfox2 and 40% with the folfox3. The folfox regimens achieve a high response rate in pretreated patients with CRC. Further studies are needed to determine the best oxaliplatin dose-intensity.

BACKGROUND The rationale for the modulation of 5-fluorouracil (5-FU) with interferon-alpha (IFN) is inhibition of 5-FU catabolism and 5-FU resistance. Clinical trials have shown debatable results when IFN is given in high doses with 5-FU used as a bolus alone or in combination with leucovorin (LV). A first-line Phase II study was performed in 50 patients with metastatic colorectal carcinoma who were given a bimonthly combination of high dose LV, a high dose 48-hour infusion of 5-FU, and a low dose of IFN. METHODS The regimen was comprised of a 2-hour infusion of LV, 500 mg/m2, on each of 2 consecutive days, and a 48-hour infusion of 5-FU, 1.5 to 2 g/m2/24 hours, starting after Day 1 of LV treatment every 2 weeks until there was evidence of disease progression. IFN was administered subcutaneously three times weekly at a dose of 3 MU (body surface area [BSA] < 1.75 m2) or 4.5 MU (BSA ≥ 1.75 m2). RESULTS World Health Organization toxicity Grade 3-4 occurred in 21 patients (42%): diarrhea in 6%, mucositis in 12%, neutropenia in 30%, and alopecia in 8%. The overall response rate was 44%; 1 patient had a complete response (2%), 21 had partial responses (42%), 23 had stable disease (46%), and 5 had disease progression (10%). The median progression free survival was 9 months, and median survival was 25 months. CONCLUSIONS Bimonthly high dose LV, a high dose 48-hour infusion of 5-FU, and a low dose of IFN had good activity in patients with advanced colorectal carcinoma. However, as in other schedules of LV and 5-FU, IFN induces high grade toxicity. Cancer 1997; 79:1094-9. © 1997 American Cancer Society.

BACKGROUND It has been suggested that there is a relationship between 5-fluorouracil (5-FU) dose levels and response rates. A bimonthly 2-day regimen of leucovorin (LV) and 5-FU bolus plus infusion has been found to be superior to a monthly 5-FU bolus with low dose LV. Based on these reports, a first-line Phase II study was performed in 101 patients with advanced colorectal carcinoma who were given a bimonthly combination of high dose LV and a high dose 48-hour infusion of 5-FU. METHODS The selected regimen included a 2-hour infusion of LV, 500 mg/m2, on each of 2 consecutive days and a 48-hour infusion of 5-FU, 1.5 to 2 g/m2/24 hours starting after Day 1 of LV treatment every 2 weeks until there was evidence of disease progression. Evaluation was performed every six cycles. This study reports the treatment of 101 patients with measurable disease. RESULTS World Health Organization toxicity Grade 3-4 occurred in 15% of patients, nausea in 2%, diarrhea in 5.1%, mucositis in 4%, neutropenia in 4% (Grade 4: 2%), hand-foot syndrome in 2%, alopecia in 4%, and encephalopathy in 1%. The overall response rate was 33.7%. Five patients had a complete response (5%), and 29 had a partial response (28.7%). In 45 patients disease was stable (44.6%), and in 19 patients there was disease progression (18.8%). Three patients (3%) could not be evaluated. The median progression free survival was 8 months and median survival was 18 months. CONCLUSIONS In the current study, bimonthly high dose LV and a high dose 48-hour infusion of 5-FU had activity in patients with advanced colorectal carcinoma. Toxicity is notably low, and the regimen is suitable for use in combination with other drugs. Cancer 1997; 79:1100-5. © 1997 American Cancer Society.

Resume Le rationnel de la modulation du 5-fluorouracile (5-FU) et les resultats cliniques dans les cancers colorectaux sont presentes, en particulier les resultats du schema mensuel comportant acide folinique faible dose bolus et 5-FU bolus sur 5 jours (schema FUFOL faible) et ceux du schema bimensuel associant acide folinique forte dose, 5-FU bolus et 5-FU en perfusion continue deux jours de suite (LV5-FU2), considere comme un nouveau standard.

Resume L'etat des ganglions axillaires reste le facteur le plus important du pronostic du cancer du sein a un stade precoce. La survie des patientes sans atteinte ganglionnaire quoi que nettement meilleure que celle des patients avec atteinte glanglionnaire est relativement mediocre, avec seulement 70 % de survivants a 10 ans. Plusieurs essais controles recents montrent qu'un traitement systemique adjuvant (chimiotherapie ou hormonotherapie), augmente la survie sans rechute des patientes sans atteinte ganglionnaire. Une recente metaanalyse confirme et renforce ces constations en montrant une reduction du taux de rechutes et une amelioration de la survie globale a 10 ans non seulement chez les patientes avec atteinte ganglionnaire, mais aussi chez les patientes sans atteinte ganglionnaire, que ce soit par chimiotherapie, hormonotherapie ou l'association des deux. Ces resultats ont abouti a des recommandations lors d'une conference de consensus en 1992 en fonction de trois groupes de risque : faible, bon ou eleve. Les recommandations sont : pour le risque faible (essentiellement une petite taille tumorale inferieure a 1 cm) l'observation ; pour le bon risque (taille inferieure a 2 cm, recepteurs hormonaux positifs, grade histologique bien differencie) le tamoxifene ; et pour le haut risque (taille tumorale inferieure a 1 cm, mais sans recepteurs hormonaux, ou taille superieure a 2 cm mais avec recepteurs hormonaux, ou grade histologique III) la chimiotherapie en premenopause et l'hormonotherapie en postmenopause.

60 patients with metastatic breast cancer were entered in a phase II study using folinic acid, 5-fluorouracil bolus and infusion and mitoxantrone with or without cyclophosphamide. 47 had measurable visceral metastases and 13 had exclusively bone metastases. 36 had received previous adjuvant or metastatic treatment ( 33 36 with anthracycline-based regimens). Overall response rate in visceral metastatic patients was 57.1% [95% confidence interval (CI) 35.4–78.8%]; 45.5% and 70% in previously and non-previously treated patients, respectively; duration of response was 9 and 13 months, respectively. 10 out 13 patients with exclusive bone metastases improved for a median time of 18 months. Median survival was 22 months for the 60 patients; 18 and 31 months for previously and non-previously treated patients, respectively. Cyclophosphamide was scheduled only in the absence of nadir grade 4 neutropenia. However, this toxicity occurred in the first 7 patients. For this reason, we chose to avoid cyclophosphamide in patients over 60 years, or with a performance status of 1–2, or who had received previous chemotherapy. Overall, cyclophosphamide was stopped due to nadir grade 4 neutropenia in 17 24 patients for whom this drug was planned. When mitoxantrone, 5-fluorouracil and folinic acid were used at the doses scheduled, the addition of cyclophosphamide appeared feasible in only about 25% of the patients. Furthermore, survival was identical for patients receiving or not receiving cyclophosphamide. Therefore, cyclophosphamide does not contribute substantially to this regimen. This study confirms the value of folinic acid, 5-fluorouracil and mitoxantrone in metastatic breast cancer.

We studied the levamisole toxic effects in adjuvant therapy for colorectal cancer. The therapy toxic effects on 127 patients were statistically more important in the levamisole-treated group compared to patients treated with folinic acid and 5-fluorouracil alone. Randomized studies in progress will demonstrate the real therapeutic value of levamisole.

40 patients with advanced ovarian cancer were treated with immediate debulking followed by sequential cisplatin and doxorubicin every 4 weeks, followed by second-look laparotomy (SLL). Six courses were given when residual disease (RD) was under 2 cm. When RD was over 2 cm, three courses were followed by early debulking and six more courses before SLL. Immediate debulking was optimal in 15 patients (38%) and early debulking in an additional 15 (38%). Pathological complete responses (34 evaluable cases) were observed in 14 cases (41%), partial response in 13 (38%), stable disease in 3 (9%) and progression in 5 (15%). Toxicity was mainly haematological. 11 patients with negative SLL and 15 with RD under 2 cm received intraperitoneal cisplatin 200 mg/m2 alone or with cytarabine. Median survival was 45 months: 58 months for RD under 2 cm at initial laparotomy and 31 months for RD over 2 cm. Median survival was 46 months when early debulking was successful. 5 year disease-free survival was only 16%. However, this multimodal treatment offers prolonged survival, especially in patients optimally debulked either at initial laparotomy or at early debulking surgery.

Plasma cell leukemia (PCL) is a very rare disease. We report two cases of PCL with complex chromosomal abnormalities: long arm trisomy and short arm partial monosomy of chromosome 1, a marker derived from chromosome 8, and monosomy 13 were found in both cases: other additional chromosome abnormalities were also present in each case. Bastard et al. [15] reports two similar cases in this issue. Cytogenetic studies in PCL have seldom been reported in the literature: chromosomal abnormalities are most often complex: chromosomes 1, 8, 11, 13, and 14 are those most frequently involved. Such cytogenetic findings are observed in advanced multiple myeloma. Cytogenetic, clinical, and immunological findings observed in PCL and the advanced stage of multiple myeloma are arguments for the single origin of pathogenesis.

Resume L'atteinte osseuse de la sarcoidose s'observe dans 10 a 15 p 100 des cas, le plus souvent au niveau des extremites. Ces formes volontiers cortico-dependantes aggravent le pronostic de la maladie. Nous rapportons chez une femme âgee de 58 ans, l'observation d'une sarcoidose evoluant depuis 14 ans et qui presente une atteinte specifique osseuse unique du calcaneeum. Une telle localisation n'avait a notre connaissance jamais ete decrite.

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-naive patients.

We report an additional cytogenetic study of a metastatic Merkel cell carcinoma. Even though the cells analyzed were from a metastatic lesion, chromosomal abnormalities were not complex. Similarities between cytogenetic findings described in small-cell lung carcinoma and the present case are observed. However, further studies are needed to define the relationship between these two neuroendocrine small-cell malignancies.

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.

Oxaliplatin has shown in vivo cytotoxic activity against colorectal cell lines. Preliminary studies suggest potentiation of fluorouracil (5-FU). To assess this issue, we performed a phase II study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. The regimen (FOLFOX2) consisted of oxaliplatin 100 mg/m2 as a 2-h infusion on day 1; leucovorin 500 mg/m2 as a 2-h infusion, followed by 5-FU 24-h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. The initial 5-FU dose was 1.5 g/m2 for two cycles and increased to 2 g/m2 in case of no toxicity > grade 2. 46 patients were treated, all with disease progression on leucovorin and 5-FU therapy for metastatic disease, or relapse less than 6 months after the end of adjuvant therapy. One complete response (CR) and 20 partial responses (PRs) were observed for an overall response rate of 46%. 22 patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU as the one used in the FOLFOX2 regimen, and among them, 10 had PRs (45%). From the start of FOLFOX2, median progression-free survival was 7 months and median survival 17 months. WHO toxicity > or = grade 3 per patient was: peripheral neuropathy 9%, nausea 4%, diarrhoea 9%, mucositis 13%, neutropenia 39%, thrombocytopenia 11%, alopecia 9%, and allergy 2%. Overall, 21 patients (46%) experienced grade 3-4 toxicity. This combination of leucovorin, 5-FU and oxaliplatin achieves a high response rate in pretreated patients with CRC resistant to leucovorin and 5-FU. Limiting toxicities are neutropenia and peripheral neuropathy.

MOST PATIENTS with pancreatic adenocarcinoma present with unresectable advanced disease. 5-Fluorouracil (5FU), streptozotocin and mitomycin-C have demonstrated limited antitumoral activity [1] and combined regimens did not improve results [2]. Folinic acid has been reported to enhance the activity of 5FU [3]. 5FU was given as a continuous infusion with an added bolus in a 2-day/2-week schedule to maximise 5FU doses and to avoid the cumulative toxicity of 5-day consecutive regimens.This combination has been used with low toxicity in advanced colorectal [4] and gastric cancers [5]. 20 previously untreated patients (13 males/7 females, mean age: 53 years, range 30-76) with advanced non-resectable measurable histologically confirmed pancreatic adenocarcinoma entered the study. They received a 2-h infusion of folinic acid 200 mg/m 2, followed by 5FU 400 mg/m 2 bolus and a further 600 mg/m 2 in a 22-h infusion on days 1 and 2, every 2 weeks (LV5FU2). Performance status was 0 in 4 patients, 1 in 9, 2 in 5 and 3 in 2. 16 patients had liver metastases, 6 had peritoneal carcinomatosis, 5 had lymph node involvement and 3 had pleural or lung metastases. Extension and tumour size were evaluated by computed tomography scan prior to therapy. The first evaluation was made after 3 months and subsequently at 3month intervals. Responders and stable patients continued on the same treatment until progression. Response was evaluated according to W H O criteria. Duration of response and survival were calculated from the beginning of treatment until progressive disease or death, respectively. Radiotherapy was given in patients with pain, as evaluated on distant metastases. The median follow-up time in October 1992 was 25 months. Two partial responses (10.5%; 95% confidence interval: 0.1-24.6%) and six stabilisations (one minor response) (31.6%) were observed in 19 evaluable patients. Partial responses lasted 10+ and 12 months and the minor response lasted 17+ months. Median survival was 6 months, 4 patients were alive at 1 year. Treatment was well tolerated, grade 2 and 3 W H O toxicity

We studied survival in 36 patients with Stage III/IV ovarian cancer who received intraperitoneal high-dose cisplatin (200 mg/m2) alone or in combination with cytarabine (2 g), after intravenous (i.v.) cisplatin-based chemotherapy followed by second-look laparotomy. Complete responders were scheduled for three courses of IP chemotherapy, and others for six. Eight patients (22%) did not complete treatment (6 catheter failures and 2 renal failures). Peritoneal cytology remained positive in 6 patients (17%). Median overall and progression-free survival after second-look laparotomy were 44 and 37 months, respectively, for 13 complete responders to i.v. chemotherapy; 24 months and 11 months for patients with residual tumors less than 2 cm (17 cases); 15 and 12 months with tumors greater than 2 cm (6 cases). There was a significant difference in overall (p = 0.05) and progression-free (p = 0.001) survival between complete responders to i.v. chemotherapy and patients whose tumor was less than 2 cm. We find no evidence that high-dose cisplatin-based intraperitoneal chemotherapy given after second-look laparotomy will enhance survival in advanced ovarian cancer with zero or minimal residual disease.

We report a phase II study in pretreated CRC. Regimen (FOLFOX2) was administered every two weeks. It consisted of oxaliplatin 100 mg/m2 iv day 1; FA 500 mg/m2 over 2 h, followed by 5FU 1.5–2 g/m2 24 h CI days 1&2. Initial 5FU dose was 1.5 g/m2 for two cycles and increased to 2 g/m2 in case of no toxicity > grade 2. 40 pts have been evaluated: 25 M/15 F, mean age 60 yrs, liver metastasis 33 pts, lung 11, peritoneal 4, other 11, multiple 13, performance status (WHO) 0: 20, 1–2: 20. Previous chemotherapy consisted in different optimal FA-5FU modulations ± hydroxyurea. 16 previously received the same high-dose FA and 5FU CI regimen alone or with interferon-α. All pts had disease progression on first-line therapy for metastatic disease or

Paclitaxel is a new antimitotic derived from yew-tree, used for the treatment of ovarian and breast cancers. The local toxicity of paclitaxel is still poorly known. We report one of the first observations of accidental subcutaneous extravastion of paclitaxel. Local epidermic necrosis was observed and evolution was good with local treatment only. Treatments of such extravasation are discussed.

Summary Twenty patients with documented progression after two or three cisplatin-based regimens for advanced epithelial ovarian carcinoma were treated with high-dose folinic acid (200 mg/m2), 5-fluorouracil bolus (400 mg/m2) and continuous infusion (600 mg/m2) for two consecutive days every two weeks. One clinically complete and two partial responses were observed in 16 evaluable patients, with 5 remaining stable. Median survival was 9 months. Toxicity was mild. This combination achieved a 19%(95% confidence interval 4%-46%) response rate in heavily pretreated cisplatin-resistant patients.

Des progres considerables ont ete accomplis dans le traitement des cancers du testicule depuis une quinzaine d’annees. Pour les tumeurs non seminomateuses de stade precoce (I et II) les taux de guerison avoisinent les 100% du fait de l’efficacite de la chimiotherapie de rattrapage des rechutes. Pour les stades cliniques I, la tendance est a la surveillance apres castration sans curage. Pour les stades avances metastases, l’apparition du platinum a revolutionne les performances de la chimiotherapie qui permet de guerir 75 a 80% de ces patients. Il reste a ameliorer les resultats d’un groupe de mauvais pronostic a forte masse tumorale. Les seminomes a un stade localise (cas le plus frequent) sont gueris par la radiotherapie; a un stade avance, ils se montrent aussi sensibles a la chimiotherapie que les tumeurs non seminomateuses.

Twenty-five patients with advanced measurable gastric cancer were treated with high-dose folinic acid (200 mg/m2), 5-fluorouracil bolus (400 mg/m2) and continuous infusion (600 mg/m2) for two consecutive days every two weeks. Fourteen patients over 65 yr old and/or with a poor general status received first-line treatment, and eleven younger patients second-line. The response rate was 43.5% in 23 evaluable patients. There were 2 complete responses (8.7%) and 8 partial responses (34.8%). Median survival was 6 months in first-line and 8 months, calculated from start of folinic acid-5FU, in second-line. Toxicity was mild without WHO Grade greater than 2 events. This combination is effective for advanced gastric cancer in poor-prognosis patients and requires further studies.

Hydroxyurea (HU) enhances both 5FU and cisplatin. We designed a phase II study in advanced gastric cancer with the HLFP regimen, based on this dual modulation by HU. Regimen consisted in HU 1.5 to 2 g orally days 0, 1 and 2, folinic acid 200 mg/m 2 in 2-h infusion, followed by 5FU 400 mg/m 2 bolus and 600 mg/m 2 22-h infusion days I & 2 every 14 days. Cisplatin was administered at 80 mg/m 2 day 3 every 2 courses. 74 consecutive eligible pts were included (12 too early), this report concerns the first 62 pts (53 M/9 F, mean age 59.8 yrs, range 31–78). Initial PS (WHO) was 0 (17 pts), 1 (31) and 2 (14). 7 pts presented a locally advanced disease without melastases. The 55 remaining pts presented peritoneal carcinomatosis (24), liver (21), lymph nodes (32) or lung (8 pts) metastases, associated with local disease in 41. 800 courses were delivered. Toxicity (> WHO gr 2) was: vomiting (7 pts), neutropenia (8), with only 2 febrile neutropenia episodes, anemia (3), diarrhea (2), thrombocytopenia (1), alopecia (1) and mucositis (1). Maximal toxicity was gr 3–4 in 29% of pts. 10/62 pts with non mesurable peritoneal carcinomatosis or local disease were not evaluable for response. 5 CR and 32 PR were observed in 52 mesurable pts (RR: 71.1%, 95% Cl: $5.6–83.6%). $6% of pts had a gain of weight, 77% a rapid disappearance of symptoms. Median follow-up time is 18 months. Median progression-free and overall survival were 9 and 11 months respectively. This combination should be tested in phase III trials.

HLFP regimen is active in advanced gastric cancer. We tested this combination in a phase II study for patients with advanced squamous cell carcinoma of the esophagus. Regimen consisted in hydroxyurea 1.5 to 2 g orally days 0, 1 and 2, folinic acid 200 mg/m2 in 2-h infusion, followed by 5FU 400 mg/m2 bolus and 600 mg/m2 22-h infusion days 1 & 2 every 14 days. Cisplatin was administered at 80 mg/m2 day 3 every 2 courses. HLFP regimen was given until progression. 32 patients were included, this preliminary report concerns the first 26 (22 males, 4 females) analysed pts (6 too early). Mean age was 62.7 yrs ± 8.8 (44−74). 9 presented an advanced locoregional disease, and 17 a metastatic disease (distant lymph nodes: 17; liver: 6; lung: 3). Initial performance status (WHO) was 0 (11 pts), 1 (11) or 2 (4). 118 courses were administered. Toxicity (> WHO grade 2) was leucopenia (3 pts), thrombopenia (2 pts), vomiting (1 pt), diarrhea (2 pts). Overall, maximal toxicity per pt was gr 0 (1 pt), gr 1 (10), 2 (9), 3 (4) and 4 (2), giving a gr 3−4 rate of toxicity of 23%. Response rate was 69.2%, with 4 CR and 14 PR. 4 pts underwent surgery after chemotherapy, and 8 radiotherapy. 53.8% of pts had a weight gain during treatment, dysphagia disappeared in 67% of pts. Median follow-up is 11 months. At 11 months, 79% of pts are alive, 56% without evidence of progression. This combination is active in advanced esophageal cancer. The study is ongoing.

Hydroxyurea inhibits lowers the dUMP pool while increase of dUMP is a mechanism of resistance to 5FU. 71 metastatic colorectal cancer patients were treated with hydroxyure a, folinic neid and 5FU. Hydroxyurea can sometimes restore 5FU antitumoral activity without significant toxicity.