Giorgio Cocconi

Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial

BACKGROUND Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. METHODS 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. RESULTS After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded. CONCLUSIONS Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.

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.

Fluorouracil, doxorubicin, and mitomycin combination versus PELF chemotherapy in advanced gastric cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research.

PURPOSE The combination of cisplatin, epirubicin, and leucovorin preceding fluorouracil (PELF) includes three novel agents compared with the standard combination of fluorouracil, doxorubicin, and mitomycin (FAM) in the treatment of advanced gastric carcinoma. We report the results of a prospective randomized comparison of the two combinations in previously untreated patients. PATIENTS AND METHODS One hundred thirty assessable patients were entered onto the trial; 52 received FAM and 85 PELF. A 1:2 unbalanced randomization in favor of the experimental treatment was chosen. Approximately 90% of patients had measurable tumor masses. RESULTS The overall response rates (complete responses [CRs] and partial responses [PRs]) were 15% and 43% for the FAM and the PELF regimens, respectively, with a statistically significant advantage for the experimental treatment (P = .001). Time to progression (median, 2.6 and 4.7 months), duration of response (median, 10.7 and 10.2 months), and survival durations (median, 5.6 and 8.1 months) were not significantly different between the FAM and PELF regimens, respectively. The PELF combination was more toxic compared with FAM, but generally tolerable. CONCLUSION This study showed that the PELF combination is about three times more effective than the FAM combination in inducing objective responses. Due to tolerability, it is not recommended for routine clinical use. However, it should be considered, among other second-generation chemotherapy combinations, in future randomized studies aimed to improve the therapeutic outcome in gastric carcinoma.

Combination Therapy with Platinum and Etoposide of Brain Metastases from Breast Carcinoma

Twenty-two consecutive patients with brain metastases from breast carcinoma were treated with a combination of platinum (100 mg/m2 day 1) and etoposide (100 mg/m2 days 4, 6, 8) every three weeks. Five (23%) achieved a complete response (CR) while 7 (32%) obtained a partial response (PR) for an overall response rate of 55%. The 95% confidence interval for combined CR and PR was 34-76%. Five patients received brain irradiation after reaching the maximum degree of objective remission by chemotherapy. Median duration of combined CR plus PR was 40 weeks (12+; 152). Median duration of survival was 58 weeks (2; 208+). Fifty-five percent of the patients were alive at one year. Our study demonstrates that this combination treatment is highly effective in the management of brain metastases from breast carcinoma.

Problems in evaluating response of primary breast cancer to systemic therapy

SummaryThe evaluation of the response of primary breast cancer to systemic therapy is difficult. Evaluable primary lesions may be assessed both by physical and by mammographic examination. In this study, response to therapy was evaluated after 4 cycles of CMF or CMF plus tamoxifen in 49 patients with locally advanced breast cancer entering a prospective randomized trial. In 35 patients response was evaluated by both physical examination and mammography. In some cases there was disagreement between physical examination and mammograhy in quantifying the magnitude of response. In 8 of 35 (22.9%), the overall response was overestimated by physical examination versus mammography, while in 3 of 35 (8.6%) the reverse was true. Taking into consideration different criteria in attributing the overall response, i.e. selecting physical examination only, mammography only, or the most favorable or the least favorable response between the two methods of assessment, the objective remission rates were 65.7%, 54.3%, 71.4% and 45.7%, respectively. The data suggest that both physical examination and mammography should be used in evaluating the response of primary breast cancer to a systemic treatment. Should these two methods yield contrasting results, the data obtained with each method should be reported. The best observed response may be employed in determining the overall response.

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.

First generation aromatase inhibitors : aminoglutethimide and testololactone

SummaryAminoglutethimide and testololactone may be considered the first generation aromatase inhibitors for the endocrine treatment of breast carcinoma. Initially, both of these agents were designed and used clinically based on different concepts of their mechanisms of action. Only later were they both demonstrated to inhibit aromatase.Curiously, testololactone was earlier and more widely used than aminoglutethimide in treating advanced breast carcinoma. The discovery of the peripheral aromatase inhibition as the proper mechanism of action was delayed for both the agents but was relatively more timely for aminoglutethimide. Paradoxically, the clinical use of testololactone has become already obsolete since its true mechanism of action was discovered.Aminoglutethimide is still the most widely used aromatase inhibitor in treating advanced breast carcinoma. Due to the initial misinterpretation of its mechanism of action, aminoglutethimide was used for a long time at a relative high daily dose, always combined with hydrocortisone. Subsequent phase II and then randomized phase III studies demonstrated an equivalent efficacy using half (500 mg) of the previous conventional daily dose (1000 mg), with hydrocortisone. Very recently, a randomized clinical trial demonstrated that administering this lower dose without hydrocortisone did not significantly decrease the clinical efficacy.By decreasing the dose of aminoglutethimide, the incidence of side effects has been reduced. So, the last paradoxical aspect of the aminoglutethimide story is that this agent seemed initially very toxic but finally, with the new schedules, shows a very low toxicity profile, especially after the first few weeks of treatment.

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.