Guido Ceci

Treatment of Metastatic Malignant Melanoma with Dacarbazine plus Tamoxifen

BACKGROUND Endocrine factors may affect the clinical course of malignant melanoma and the response to the treatment of this disease. The presence of estrogen receptors in melanomas has been suggested, and occasional responses to antiestrogen therapy have been reported. METHODS AND RESULTS We randomly assigned 117 patients with metastatic malignant melanoma to treatment with dacarbazine alone or dacarbazine in combination with tamoxifen. The overall rate of response, measured objectively, was higher (28 percent vs. 12 percent, P = 0.03) and survival was longer (median, 48 vs. 29 weeks, P = 0.02) among the patients who received dacarbazine plus tamoxifen than among those who received dacarbazine alone. Among women, both the response rate (38 percent vs. 10 percent, P = 0.04) and the median survival (69 vs. 30 weeks, P = 0.008) were better with dacarbazine plus tamoxifen than with dacarbazine alone, whereas among men the differences were smaller and not statistically significant. Among the patients given dacarbazine alone, there were no significant differences between women and men in response rate (10 percent vs. 13 percent) or survival (30 vs. 27 weeks), whereas among those given dacarbazine plus tamoxifen, women had better outcomes, as indicated by both response rate (38 percent vs. 19 percent, P = 0.15) and survival (69 vs. 31 weeks, P = 0.02). When we analyzed the Quetelet body-mass index (the weight in kilograms divided by the square of the height in meters) as an indirect indicator of the levels of endogenous estrogens in postmenopausal women and in men, survival was not affected by the body-mass index in the group given dacarbazine alone, whereas in the group given dacarbazine plus tamoxifen, survival was longer among patients whose Quetelet index was above the median value than among those with a Quetelet index lower than the median value (60 vs. 26 weeks, P less than 0.001). CONCLUSIONS In the treatment of metastatic malignant melanoma, dacarbazine plus tamoxifen is more effective than dacarbazine alone, as indicated by both the response rate and the median survival; the difference in efficacy is among women.

A phase II study of cisplatin in advanced gastric cancer

Twenty patients with recurrent or metastatic gastric adenocarcinoma and prior chemotherapy were treated with cisplatin, 60-120 mg/m2 as a 6-hr infusion repeated every 3 weeks. There were 4 partial responses in 18 evaluable patients. Seven patients had stable disease. Time to progression ranged from 6 to 28 weeks. Median WBC nadir was 3.2 X 10(3)/mm3 (range, 1.5-7.1) and platelet nadir 120 X 10(3)/mm3 (range, 13-220). A transient increase in serum creatinine was observed in 6 cases, and nausea and vomiting in all. We conclude that this drug is active in stomach cancer and that it warrants further trials in combination chemotherapy.

Cisplatin and etoposide as first-line chemotherapy for metastatic breast carcinoma: a prospective randomized trial of the Italian Oncology Group for Clinical Research.

In this prospective randomized study, first-line treatment with the combination of cisplatin (P) and etoposide (E) was compared with the standard cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in 140 patients. Complete remissions were obtained in 11% of 65 assessable patients on CMF and in 12% of 65 assessable patients on PE. Complete plus partial remission rates were 48% on CMF and 63% on PE (P = .08). Time to progression (median, 32 v 31 weeks), duration of response (48 v 39 weeks), and survival (75 v 76 weeks) were not different. Hematologic toxicity was significantly higher with PE, and gastrointestinal side effects were frequent with this treatment. This study demonstrated that the PE combination is effective as front-line chemotherapy. As far as response rate is concerned, a trend of superiority over CMF was observed, which was of borderline significance. Due to the lack of survival advantage and to toxicity, this combination is not recommended for routine clinical use. However, its high level of activity should be taken into account for further research.

Successful treatment of subacute cerebellar degeneration in ovarian carcinoma with plasmapheresis a case report

Subacute cerebellar degeneration is a rare complication of some neoplasms, and is generally resistant to therapy. A case of subacute cerebellar degeneration in a 50‐year‐old woman with a Stage II grade 3 serous ovarian adenocarcinoma is reported. The onset of the neurologic symptoms preceded the diagnosis of cancer and progressively worsened during and after four cycles of chemotherapy. A quick, partial improvement of the neurologic syndrome was documented after three weekly treatments with plasmapheresis. The contribution of circulating factors in inducing subacute cerebellar degeneration can be postulated. A trial using this new type of treatment should be performed in patients who have this therapeutically refractory clinical condition.

Cisplatin and etoposide (VP-16) as a single regimen for small cell lung cancer. A phase II trial.

Forty‐seven consecutive patients with small cell lung cancer (SCLC) were treated with a combination chemotherapy program including 60 mg/m2 of cisplatin (P) on day 1 and 120 mg/m2 of etoposide (E) on day 4, 6, 8, every 21 days. Limited disease (LD) patients, achieving complete response (CR) or partial response (PR) after the three initial courses, received radiotherapy (RT) to the pretreatment primary tumor volume and, those achieving CR, additional RT to the brain. During RT, chemotherapy was administered with 50% dose reduction. Forty‐three patients were evaluable for therapeutic response. In the 19 patients with LD, CR was achieved in 63% of patients and the PR rate was 32%. In 24 patients with extensive disease (ED), CR was 34% and PR rate was 54%. Median duration of survival was 66 weeks for LD and 48 weeks for ED. Six patients were disease‐free after 2 years. Leucocyte count <2000/mm3 was seen in 26% of patients; platelet count <50000/mm3 was observed in 9%. Nonhematologic toxicity included universal nausea or vomiting and severe neurotoxicity in 7%. These data indicate that PE combination is a very active front‐line regimen in SCLC and could be suggested as one of the reference treatments.

Platinum and etoposide in chemotherapy refractory metastatic breast cancer. A phase II trial of the Italian oncology group for clinical research (G.O.I.R.C.)

Twenty-four evaluable extensively pretreated advanced breast cancer patients received a combination of platinum and etoposide. Platinum was given i.v. at the dose of 80 mg/mq at day 1. Etoposide was given at the dose of 120 mg/mq i.v. at day 1, and p.o. at the dose of 200 mg/mq at day 3 and 5. Treatment was repeated every 3 weeks. CR was never obtained. PR was observed in four patients (17%), MR in two, NC in seven and PD in 11 patients. PR plus MR occurred in six patients (25%). Considering the extensive pretreatment of patients, the results seem to indicate that this combination is active and can be included among the possible options in treating chemotherapy refractory advanced breast cancer. Moreover, it deserves further evaluation in an earlier phase of the disease.

Fatal hepatic vascular toxicity of DTIC. Is it really a rare event

A fatal massive hepatic necrosis with widespread thrombotic occlusion of the small hepatic veins developed in two of 68 patients treated with DTIC for advanced melanoma in a randomized study. Thirteen similar reactions, in patients treated with single‐agent DTIC, are reported in the literature. Several clinical and pathologic features distinguish this DTIC toxicity from Budd‐Chiari syndrome and veno‐occlusive disease (both well‐known types of possibly drug‐related hepatic vascular disease) and make it a distinctive syndrome. We were impressed by the repeated occurrence of this complication in a relatively small set of patients, in contrast with the rarity of the literature reports. We suggest that this dramatic complication could occur more frequently than commonly thought. Therefore, caution should be used with DTIC, particularly in curable patients.

Low-dose aminoglutethimide with and without hydrocortisone replacement as a first-line endocrine treatment in advanced breast cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research.

PURPOSE A randomized study comparing low-dose aminoglutethimide (AG) with and without hydrocortisone (HC) was performed to investigate whether corticosteroid replacement contributes to the therapeutic effects of the drug administered as a front-line endocrine therapy in postmenopausal advanced breast cancer. PATIENTS AND METHODS Postmenopausal patients who had not had prior endocrine therapy for advanced disease and with estrogen receptor (ER) or progesterone receptor (PgR) status positive or unknown were eligible. AG was administered at a dose of 250 mg twice a day orally (125 mg twice a day during the first month) with or without HC (20 mg twice a day orally). Seventy-nine and 74 patients were assessable for response on the AG plus HC arm and on the AG arm, respectively. The two treatment groups were well balanced and patients were largely untreated. Approximately 60% had not received any adjuvant treatment, and approximately 75% had not received any medical treatment after relapse. RESULTS The overall responses (complete response [CR] plus partial response [PR]) were 44% and 41% for the AG plus HC and the AG arm, respectively, showing no significant difference. Time to progression (median, 8.1 and 6.3 months), duration of response (median, 15.8 and 13.7 months), and duration of survival (median, 34.2 and 36.3 months) were not significantly different between the two treatment arms. Side effects were infrequent and mild in both arms, with no significant differences. CONCLUSION We conclude that half of the conventional daily dose of AG has optimal therapeutic activity as a front-line endocrine treatment of postmenopausal advanced breast cancer and that HC does not significantly contribute to the therapeutic effects.

Cisplatin and VP16 in metastatic breast carcinoma as a third-line chemotherapy: A randomized study comparing low versus high doses of cisplatin

Aims and background The study was designed to define the activity of the combination of cisplatin and etoposide as third-line chemotherapy for advanced breast cancer and to investigate the role of the dosage of cisplatin on the effectiveness of the combination. Methods Ninety-five eligible patients with advanced breast cancer who had failed or relapsed on two previous lines of chemotherapy were randomized to receive cisplatin at a high dose (100 mg/m2 i.v. day 1, arm A) or a low dose (60 mg/m2 day 1, arm B), combined with etoposide (100 mg/m2 i.v. days 4, 6 and 8). Cycles were repeated every 3 weeks. Results Of the 78 patients evaluable for response (39 in arm A and 39 in arm B), 9 (12%) showed complete or partial response, 5 (13%) in the high-dose arm and 4 (10%) in the low-dose arm. One complete response was seen in the high-dose arm and none in the low-dose arm. The only 2 patients with brain involvement showed an objective response (one CR in arm A and one PR in arm B). Median time to progression was 14 weeks in arm A and 10 weeks in arm B, median duration of remission 28 and 34 weeks, and survival 36 and 35 weeks, respectively. The differences were not significant. As expected, the patients in the high-dose arm experienced more severe toxicity. One toxic death was observed in each arm due to sepsis in agranulocytosis. The difference was statistically significant regarding nausea and vomiting. Neurotoxicity and ototoxicity were not relevant problems in this patient setting. Conclusions Considering the very poor prognostic factors presented by these patients, the combination showed a certain activity, and further evaluation in earlier stages of disease is warranted. A particular responsiveness on brain metastases is suggested. The dose of cisplatin was not proven to be of significant importance.

The value of bone marrow biopsy in breast cancer at time of diagnosis: A prospective study

Bone marrow biopsies (BMB) were performed in 173 consecutive unselected breast cancer patients at the time of diagnosis to define the value of this diagnostic tool in the initial staging of mammary carcinoma. In a group of 160 patients with a negative standard staging work‐up, BMB was positive in two (1%). Both of them had negative x‐ray but bone scan was positive in one and doubtful in the other. Bone marrow biopsy was positive in 31% of 13 additional patients with metastatic disease and in 44% of the nine among them with radiologically involved skeleton. These results exclude that BMB is able to discover micrometastatic foci of neoplastic disease. Its positivity appears strictly correlated with that of bone x‐ray and scan. Based on the results of this prospective study, BMB is not required when both bone survey and scan are negative, but could be useful in clarifying diagnostic doubts of skeletal involvement.