Pierre Alberto

Docetaxel (Taxotere®)-cisplatin (TC): An effective drug combination in gastric carcinoma

PURPOSE A multi-centric trial was performed to explore the clinical activity, in terms of response and toxicity (primary objectives), duration of response and survival (secondary objectives), of docetaxel with cisplatin in advanced gastric cancer (AGC). PATIENTS AND METHODS Patients with measurable unresectable and/or metastatic gastric carcinoma, performance status < or = 1, normal hematological, hepatic and renal functions and not pretreated for advanced disease by chemotherapy received up to eight cycles of TC (docetaxel 85 mg/m2 dl, cisplatin 75 mg/m2 dl) q3w. Dose escalation to 100 mg/m2 was performed in five patients and was discontinued for excessive toxicity. RESULTS Forty-eight patients were accrued. A median of 5 cycles/patient was given. We observed 2 complete and 25 partial responses for an overall intent to treat response rate of 56% (95% CI: 41%-71%). Twelve patients had stable disease for > or = 9 weeks (3 cycles). The median time to progression and overall survival were 6.6 and 9 months, respectively. Grade > or = 3 toxicities were neutropenia 81%, anemia 32%, thrombocytopenia 4%, alopecia 36%, fatigue 9%, mucositis 9%, diarrhea 6%, nausea/vomiting 4%, neurologic 2%, and one anaphylaxis precluding treatment administration. We recorded nine episodes of non-fatal febrile neutropenia in eight patients, two of them with docetaxel at 100 mg/m2. There were no direct treatment-related deaths. CONCLUSIONS TC is active in AGC with a high response rate in a multicentric trial. Despite its hematotoxicity, this regimen is well tolerated and can be recycled as originally planned in 78% of the cases. These results may serve as basis for further developments of docetaxel containing regimens in this disease.

Randomized trial of low- versus high-dose medroxyprogesterone acetate in the induction treatment of postmenopausal patients with advanced breast cancer.

In a randomized trial, 210 postmenopausal women with advanced measurable breast cancer were allocated to two different schedules of medroxyprogesterone acetate (MPA). In the induction phase they received either 1,000 mg intramuscular (IM) MPA (high dose) daily or 500 mg IM MPA (low dose) twice weekly for four weeks. The maintenance treatment consisted of 500 mg MPA IM once weekly for all patients. In total, 184 patients were considered evaluable. The response rate was significantly higher (p = 0.004) for patients receiving high-dose MPA (30 [33%] of 91) as compared to the women receiving the low-dose regimen (14 [15%] of 93) and was consistent across all prognostic subgroups. These prognostic subgroups included soft-tissue and osseous metastases, two metastatic sites, patients greater than 60 years, disease-free interval greater than 60 months, no prior chemotherapy, patients with a response to the last hormonal treatment before MPA, unknown estrogen receptors, and positive progestin receptors. The two different schedules of MPA did not influence the time to progression and the survival. Toxicity was similar in both regimens. These results confirm that a higher response rate can be achieved with a more intensive MPA schedule. This treatment may represent an ideal second-line choice in the endocrine therapy of advanced breast cancer; however, its role as a first-line treatment remains to be defined.

Cladribine with cyclophosphamide and prednisone in the management of low-grade lymphoproliferative malignancies

SummaryThe feasibility of combining cladribine with cyclophosphamide and prednisone in the management of indolent lymphoid malignancies was determined. Nineteen patients [nine chronic lymphocytic leukaemia (CLL), seven non-Hodgkin’s lymphoma (NHL) and three macroglobulinaemia (M))] received cladribine 0.1 mg kg–1 per day as a subcutaneous bolus injection on days 1–3 (up to 5 injections) with intravenous cyclophosphamide 500 mg m–2 on day 1 and oral prednisone 40 mg m–2 on days 1–5 at 4-weekly intervals up to a maximum of six courses. A total of 80 courses were given. Overall response rate was 88%, with four patients achieving a complete clinical and haematological response and 12 achieving a partial response. Neutropenia WHO grade 4 in two patients and WHO grade 3 infection in one patient were the limiting toxicities on treatment. During the follow-up, WHO grade ≥3 haematological complications occurred in five patients and WHO grade ≥3 non-haematological complications in five patients. There were no treatment-related deaths. This study demonstrates the feasibility of the cladribine/cyclophosphamide/prednisone (CCP) combination that appears highly active and safe in the management of indolent lymphoid malignancies.

“Fatigue and malaise” as a quality-of-life indicator in small-cell lung cancer patients

Abstract“Fatigue and malaise” (FM) is a frequent, non-specific symptom of cancer patients caused by the disease, its treatment and psychological distress. Since comprehensive quality of life assessment is often not feasible in multicentre clinical trials, short, but clinically relevant, quality of life indicators have to be defined. In a representative subsample of 127 patients in a phase-III randomized small-cell lung cancer trial comparing two different regimens of combination chemotherapy, quality of life was assessed at the beginning of each of the six treatment cycles with a self-rating questionnaire including an early version of the EORTC questionnaire, a mood adjective check list (Bf-S) and a single linear-analogue self-assessment scale (LASA) measuring general well-being. FM, measured with a five-item Likert subscale of the EORTC questionnaire, showed moderate to high intercorrelations with other EORTC subscales assessing disease symptoms, toxicity of treatment, role functioning, personal functioning, restriction of social activity, psychological distress, emotional (Bf-S) and general well-being (LASA). At baseline, FM was one of the most pronounced symptoms. Over the six cycles 43%–31% of the patients complained of moderate to severe fatigue. Over the first two cycles FM tended to decrease, slightly increasing during cycles 3 and 4 and decreasing again before cycle 6. In a multiple regression analysis over the six cycles, 53% of the variance of FM was explained by patient-rated symptoms of disease and toxicity (disease alone: 43%; toxicity alone: 35%). Initial performance status, previous weight loss, treatment arm, cycle number and age predicted the scores of FM over the six cycles. We conclude that, among other disease- and treatment-related scales, FM can be used as a global indicator of quality of life in small-cell lung cancer patients.

Intra-arterial chemotherapy in locally advanced or recurrent carcinomas of the penis and anal canal: an active treatment modality with curative potential

The prognosis of locally advanced or recurrent carcinomas of the penis (PE) and of the anal canal (AC) after conventional treatment is dismal. We report 16 patients (eight with AC carcinomas and eight with PE cancers) treated by intra-arterial (IA) chemotherapy. Fifteen of them were treated for locally advanced or recurrent disease and one in an adjuvant setting. The chemotherapy was administered via a femoral IA catheter with its tip located above the aortic bifurcation, under the inferior mesenteric artery. It consisted of eight push injections, given over a 48-h period, of the following drug combination: cisplatin 8.5 mg m–2, 5-FU 275 mg m–2, methotrexate 27.5 mg m–2, mitomycin C 1.2 mg m–2, and bleomycin 4 mg m–2. Leucovorin was given po, 4 × 15 mg day–1, during the chemotherapy and for 3 days thereafter. A total of 52 cycles of treatment were administered. Of the 15 patients evaluable for response, six obtained a CR (three PE, three AC) and eight a PR. Among the complete responders, four are alive and disease-free 2–15 years after treatment. The other patients enjoyed an objective response lasting 3–25 months (median 7 months). Four patients developed grade III/IV haematological toxicity with three episodes of febrile neutropenia, one of them with a fatal outcome due to patients failure to obtain medical attention at the onset of his fever, one a grade III mucositis of the glans, and four a grade III/IV cutaneous toxicity, the latter caused by the IA administration of bleomycin. In conclusion, IA chemotherapy is effective and potentially curative in locoregionally advanced or recurrent carcinomas of the penis and of the anus. Its contribution in the primary management of advanced penile or anal carcinoma should be prospectively investigated.

Phase II study of doxifluridine in advanced colorectal adenocarcinoma.

Doxifluridine, a new fluoropyrimidine derivative, was tested in a cooperative phase II trial by the Swiss Group for Clinical Cancer Research in advanced measurable colorectal cancer. The drug was given in a five consecutive day schedule by a bolus intravenous injection at a dose of 4 g/m2 per day and repeated every three to four weeks. Of 42 eligible patients, 40 had no previous chemotherapy. Response was defined in 27 patients having received two or more courses of doxifluridine. Seven responses (26%) were observed. Responses were seen only in sigmoid and rectum primary tumors. Toxicity consisted mainly of leukopenia (53% of the evaluable patients), nausea and vomiting (38%). Other toxicities such as dermatitis, myocardial injury, and hair loss were also observed. Doxifluridine has therapeutic activity, albeit limited, in advanced rectosigmoid adenocarcinoma.

A randomized comparison of doxifluridine and fluorouracil in colorectal carcinoma

In a randomized study 52 patients with advanced colorectal cancer and measurable lesions were treated with doxifluridine 4000 mg/m2 or fluorouracil 450 mg/m2 i.v. on 5 consecutive days over 3 weeks. None had prior fluoropyrimidines except two who received adjuvant fluorouracil. Partial responses with a duration ranging from 259 to 406 days were observed in five patients treated with doxifluridine and two patients treated with fluorouracil. Toxic reactions were evaluated in 88 doxifluridine courses and 105 fluorouracil courses. The most frequent adverse effects were neurotoxicity (48% of patients) and mucositis (43%) for doxifluridine, leukopenia (48%) and nausea/emesis (37%) for fluorouracil. Mucositis, diarrhea, nausea, emesis and skin reactions were observed in both treatment groups. Fluorouracil produced neurotoxic effects in 26% of patients. Reversible cardiac dysfunctions were observed in four patients treated with doxifluridine, expressed by ectopic ventricular beats (2) precordial pains (1) and ventricular fibrillation (1). This latter toxicity justified the premature interruption of the study. Doxifluridine is an active agent in colorectal cancer. Compared to fluorouracil it produces, when used i.v., a lower myelosuppression and a greater incidence of neurological and cardiac toxicity.

Randomized trial of 3 different regimens of combination chemotherapy in patients receiving simultaneously a hormonal treatment for advanced breast cancer

We report the results of a randomized trial carried out by the Swiss Group for Clinical Cancer Research (SAKK) and in which 230 patients with advanced breast cancer receiving concurrently a hormonal treatment (oophorectomy for pre- and tamoxifen for postmenopausal women) were randomly allocated to three different regimens of combination chemotherapy. The therapeutic results registered with the two more intensive combinations (LMP/FVP and LMFP/ADM) were similar with regard to response rates, time to progression and survival. The patients receiving the low-dose chemotherapy lmfp showed a statistically significant lower response rate (32%, P less than 0.001) and a shorter survival (P = 0.03) than the results observed in patients treated with the two other regimens. This difference was particularly pronounced, at least regarding survival, in the following subgroups: postmenopausal women, patients with a poor performance status, dominant visceral lesions, two sites of disease and a disease-free interval longer than 12 months. Patients with bony metastases as dominant lesion fared similarly with all three regimens of chemotherapy. This latter subset of advanced breast cancer patients should probably be spared too intensive cytotoxic treatment. This is, to our knowledge, the first report of a randomized trial showing an evident correlation between response rate and survival in various subgroups of patients with advanced breast cancer treated with different chemotherapeutic regimens.

Combination chemotherapy with mitomycin, vindesine, and cisplatin for non-small cell lung cancer. Association of antitumor activity with initial tumor burden and treatment center.

From 1984 through 1986, 205 patients with non‐small cell lung cancer were entered into a group‐wide trial of the Swiss Group for Clinical Cancer Research (SAKK). This trial evaluated the combination of mitomycin (8 mg/m2 intravenously [IV] on day 1), vindesine (3 mg/m2 IV on days 1 and 8), and cisplatin (60 mg/m2 IV on day 1) with forced diuresis, repeated every 4 weeks (MiViP regimen). One hundred eighty‐three patients were evaluable. Six complete and 69 partial responses were documented for an overall response rate of 41% (95% confidence interval, 34% to 50%). In the multivariate analysis the strongest predictors for response were the participating institution and the number of initially involved organ sites. The estimated median time to progression for patients with a complete response, partial response, or stable disease was 155 days (estimated inter‐quartile range, 99 to 258 days). In the multivariate analysis the time to progression was significantly associated with the number of involved organ sites (P = 0.041). The estimated median survival time for the 183 evaluable patients was 239 days (estimated interquartile range, 137 to 436 days). In univariate and multivariate analyses performance status, number of involved organ sites, pretreatment status with radiation therapy, and participating institution were all significantly associated with survival. The principal toxicities were myelosuppression and nausea and vomiting with 16% of the patients refusing further treatment after a median of four cycles of chemotherapy. In conclusion, the MiViP regimen was an active combination chemotherapy in patients with non‐small cell lung cancer in a large trial performed by the SAKK. The prognostic value of the participating institution and the number of organ sites involved by metastatic deposits in non‐small cell lung cancer needs further investigation.

Transfusion-associated graft-versus-host disease in a patient treated with Cladribine (2-chlorodeoxyadenosine): demonstration of exogenous DNA in various tissue extracts by PCR analysis.

Transfusion-associated graft-versus-host disease can occur in both immunocompetent and immunocompromised hosts. Cladribine is a synthetic analogue of adenine used in the treatment of lymphoid malignancies, commonly associated with a decrease in T lymphocytes. Cladribine was given for a low-grade non-Hodgkins lymphoma with thrombocytopenia as the main side-effect. Six units of pooled non-irradiated platelets were transfused from six unrelated donors; 10 d later a clinical picture typical of graft-versus-host disease resulted. Polymerase chain reaction of the highly polymorphic DNA minisatellites and HLA-DR oligotyping were used to demonstrate the exogenous DNA. In the patients blood and tissues, only the pattern of donor 5 was found. The patient (DRB1*0301/1101; DRB3*0101/02) and this donor (DRB1*0301/1104; DRB3*02) by chance shared a partial common haplotype. This complication highlights the sensitivity of DNA minisatellite analysis. It further raises the question of transfusion and of prophylactic irradiation of all blood products in immunosuppressed patients and those treated with cladribine. This case represents a previously unreported situation where an immunosuppressed patient was able to eliminate cells from five totally HLA-DR dissimilar donors but not from one heterozygous donor with strong HLA-DR similarity.