Opinions concerning euthanasia, life-sustaining treatment and acceleration of death: results of an Italian Association of Medical Oncology (AIOM) survey.

BACKGROUND: Advance directives, acceleration of death, euthanasia and 'life-sustaining treatment' have sparked much heated debate among the media, the public, doctors and political leaders. We evaluate the personal opinions of Italian Association of Medical Oncology (AIOM) members. PATIENTS AND METHODS: A 30-item questionnaire was developed and delivered to all 1,832 AIOM members. RESULTS: Six-hundred and eighty-five (37%) oncologists completed and returned the questionnaires. Sixty-three per cent felt culturally and psychologically prepared to face these issues. Fifty-four per cent believed that what had been decided while the patient enjoyed good health is no longer applicable in an advanced state of terminal illness. Thirty-nine per cent believed that doctors should abide by these directives, while 49% believed that this should be discussed on a case-by-case basis. Fourteen per cent of oncologists were favourable towards euthanasia and 42% only in particular circumstances. Fifty-six per cent had received at least one request for accelerating death: 15% consented, 50% discussed it with the patient and 31% refused. CONCLUSION: Advance directives, euthanasia, accelerated death and life-sustaining treatment represent considerable challenges for Italian oncologists. Although prepared to face these issues, AIOM members ask for a debate within the medical world and for a shared judicial regulation.

Cardiac toxicity of high-dose chemotherapy.

Cardiac toxicity is an uncommon but potentially serious complication of high-dose (HD) chemotherapy and little is known about incidence, severity and underlying mechanisms. We have systematically reviewed the literature of the last 30 years to summarize and appraise the published evidence on cardiac toxicity associated with HD chemotherapy. HD cyclophosphamide-containing regimens have been most commonly associated with cardiac toxicity, with a progressively decreasing incidence over time. Dosage, application regimens and coadministration of other chemotherapeutic agents emerged as risk factors. While cardiac toxicity has been rarely associated with other cytotoxic drugs, an unexpected incidence of severe cardiotoxicity resulted from reduced-intensity conditioning regimens containing melphalan and fludarabine. Predictive value of cardiologic examination of patients is limited, and patients with a slight depression of cardiac performance could tolerate HD chemotherapy. Clinical examination, resting electrocardiography and dosage adjustment in overweight patients remain the mainstay of prevention, with bidimensional echocardiography (2D echo) for patients with a history of anthracycline exposure. Strategies to decrease the long-term negative impact of anthracycline administration on cardiac performance are being investigated. New 2D echo-based techniques and circulating markers of cardiac function hold promise for allowing identification of patients at high risk for and early diagnosis of cardiac toxicity.

Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study.

BACKGROUND: The conventional treatment of brain metastases not amenable to surgery is most often radiotherapy. Until now, pharmacologic issues related to the blood brain barrier (BBB) prevented a wide evaluation of chemotherapy. The authors previously reported that the combination of cisplatin (P) and etoposide (E) had strikingly high activity in patients with brain metastases from breast carcinoma. The purpose of this study was to assess, in a larger prospective study, the front-line activity of that combination against brain metastases from breast carcinoma (BC), nonsmall cell lung carcinoma (NSCLC), and malignant melanoma (MM) in patients previously untreated with radiotherapy. METHODS: From December 1986 to July 1993, 116 patients received P 100 mg/m2 on Day 1 and E 100 mg/m2 on Days 1, 3, and 5 or on Days 4, 6, and 8 every 3 weeks. An insignificant change in the E schedule using the same dose on a random basis assured the prospective enrollment and the registration of all cases. Six patients were not eligible and three patients were excluded from the analysis because they were lost to follow-up shortly after the date of registration. One-hundred seven patients were considered for analysis. The distribution according to the primary tumor site was BC in 56 patients (52%), NSCLC in 43 (40%), and MM in 8 (8%). The first evaluation of response was performed after two cycles. In cases of no disease progression, chemotherapy was continued to a maximum of six cycles. RESULTS: Among the 56 patients with BC, 7 achieved complete response (CR) (13%), 14 achieved partial response (PR), 12 had no change (NC), 15 had progressive disease (PD), and 8 had insufficient treatment or response was not assessed. The CR plus rate was 38%. Among the 43 patients with NSCLC, 3 achieved CR (7%), 10 achieved PR, 15 had SD, 7 had PD, and 8 had insufficient treatment or response was not assessed. The CR plus PR rate was 30%. None of the eight patients with MM achieved an objective response. The median survival was 31 weeks for patients with BC (range, 0-287), 32 for patients with NSCLC (0-392+), and 17 for patients with MM (2-48). CONCLUSIONS: The combination of P and E is effective for patients with brain metastases from BC and NSCLC. In this study, the response rate was of the same order as that reported for disseminated disease without central nervous system involvement. The survival figures compare favorably with some others reported in the literature for patients given radiotherapy. A randomized study is warranted to compare this chemotherapy followed by radiotherapy with radiotherapy alone for patients with brain metastases from BC or NSCLC not amenable to surgery or radiosurgery.

Combination chemotherapy with cmf (cyclophosphamide, methotrexate, 5-Fluorouracil) versus cnf (mitoxantrone, 5-Fluorouracil, cyclophosphamide) in advanced breast-cancer - a multicenter randomized study.

A multicentric randomized study was conducted to compare the CNF regimen (cyclophosphamide at 600 mg/m2/iv, mitoxantrone at 10 mg/m2/iv, 5-fluorouracil at 600 mg/m2/iv) with the CMF regimen (methotrexate at 40 mg/m2/iv instead of mitoxantrone) administered every 3 weeks to previously untreated locally advanced or metastatic breast cancer patients. In 119 patients evaluable for therapeutic response, complete plus partial response rate was 44% for CNF and 29% for CMF (p>0.05; 95% C.I.: CNF=32%-56%, CMF=18%-40%). No statistically significant difference regarding time to progression, over survival or response to second-line chemotherapy with Epidoxorubicin was observed between the two regimens. Both regimens were well tolerated, but the percent of alopecia and leucopenia was significantly higher in the CNF patient group (31% versus 5% and 18% versus 0%, respectively; p<0.01). In conclusion, CNF was demonstrated to be slightly more toxic but more effective as compared to CMF (global response: 44% versus 29%, respectively). These findings should be taken into consideration when planning future studies of adjuvant chemotherapy.

Pharmacokinetics and tumor concentration of intraarterial and intravenous cisplatin in patients with head and neck squamous cancer.

Tumor-tissue platinum levels and major pharmacokinetic parameters were determined in 11 patients with head and neck squamous cancer (HNSC) who were given cisplatin (50 mg/m2 daily x 2 days) and 5-fluorouracil (5-FU; 1000 mg/m2, continuous infusion x 5 days) either i.a. or i.v. The plasma peak platinum concentrations (cmax) and the areas under the curve for total platinum concentration versus time (AUC) during i.a. infusions were lower than the i.v. cmax (mean, 1.92 +/- 0.28 and 4.08 +/- 2.80 mg/l, for i.a. and i.v. infusions, respectively) and AUC values (mean, 22.55 +/- 4.96 and 40.66 +/- 10.71 mg h-1 l-1 for i.a. and i.v. treatment, respectively), suggesting a first-passage extraction of the drug by the tumor mass during i.a. infusion. However, no statistically significant difference was found in platinum tumor concentrations after i.a. administration versus i.v. infusion. The lack of a difference in tumor platinum concentrations between the i.a. and the i.v. administration routes might be explained either by a relatively high blood supply to the tumor area, enabling efflux of the surplus free platinum from the tissue, or by the delay between drug infusion and biopsy. After three cycles of i.a. treatment good tumor remission was obtained with minimal local toxicity. Larger clinical studies testing the advantages of the i.a. administration route over i.v. infusion appear to be necessary.

Oral ondansetron (GR 38032F) for the control of CMF-induced emesis in the outpatient.

The efficacy of the serotonin antagonist ondansetron (GR 38032F) was evaluated in the prevention of nausea and vomiting induced by CMF chemotherapy in 29 breast cancer patients. At their first treatment course of CMF, all given IV on day 1 q 21 days, patients were given oral antiemetic treatment as follows: ondansetron 8 mg, 2 h prior to CMF, repeated after 5 and 10 h the day of chemotherapy and then 8 mg tds for a minimum of 3 days to a maximum of 5 days following chemotherapy. At first course of CMF, complete protection from emesis and nausea was observed in 86.2% and 62% of patients, respectively. At subsequent CMF courses with ondansetron, complete control of emesis was observed in 80% of patients. Side effects were mild and no dystonic reactions were observed. Ondansetron represents an effective, safe, and easily administered outpatient regimen. The addition of a corticosteroid to ondansetron could further improve control of CMF-induced emesis.

Oral ondansetron (GR38032F) for the control of acute and delayed cyclophosphamide-induced emesis.

The efficacy of the serotonin antagonist ondansetron (GR38032F, Glaxo) was evaluated in the prevention of nausea and vomiting induced by combinations containing cyclophosphamide (CTX) greater than or equal to 600 mg/m2 IV day. At their first treatment course, 55 patients (10 males, 45 females) median age 55 years (range 31-76) were given ondansetron 8 mg orally tds for a minimum of 3 to a maximum of 5 days. 54 patients were evaluable. Complete and major control of acute (day 1) emesis was observed in 94.5% of patients and acute nausea was graded as absent or mild in 83.3% of cases. Complete and major control of emesis improved on subsequent study days from 96.1% on study day 2 to 100% on study day 5. Side effects were mild. Ondansetron is a safe and effective antiemetic drug.

LH-RH analogue Zoladex in the treatment of pre- and perimenopausal women with metastatic breast cancer (results of the Italian Cooperative Study).

From May 1987 to May 1989 sixty one pre- and perimenopausal women with advanced or recurrent breast cancer entered in an open non comparative study. They were treated, as a first-line therapy, with goserelin (Zoladex ICI-118630) a long acting gonadotropin-releasing hormone (LH-RH)-analogue in a depot formulation. Fifty three patients were evaluable for response; median age at entry was 41 years (range 28-56). Serum concentrations of 17 beta estradiol, LH and FSH were significantly suppressed within the first four weeks of therapy and remained suppressed for the whole duration of treatment. Subjective responses were observed, such as pain reduction and/or performance status improvement in 58% of patients. Overall objective response (CR + PR) occurred in 16 (30.2%) patients in all major sites of disease with a median time to response of 12 weeks (range 8 to 48 weeks) and a lifetable median duration of response of 36 weeks (range 16 to 76 weeks). The lifetable median time to progression was 17 weeks (range 5 to 76 weeks). Goserelin depot was well tolerated with no withdrawal due to possible adverse reactions. The observed subjective and objective response rates are comparable to those induced by surgical oophorectomy. Goserelin provides a well tolerated medical alternative to ovarian ablation, without the morbidity associated to surgery. In conclusion the present paper suggests that this innovative chemical estrogen deprivation, in premenopausal breast cancer patients, might be favorably investigated as an adjuvant therapy in future clinical trials.

Response and toxicity of cisplatin and 120-h 5-fluorouracil infusion in pretreated and untreated patients with advanced epidermoid cancer of the head and neck.

Eighty-two patients with advanced or recurrent squamous cell carcinoma of the head and neck were treated with bolus cisplatin and 120-h infusion of 5-fluorouracil. Among 49 pretreated patients, there were 9 complete and 12 partial responses, for an overall response rate of 43% and a median estimated survival of 8 months. Hematologic toxicity in this group was relevant, with 4 early deaths and 30% of cases with moderate to severe leukopenia; mucosal and renal toxicities were also important. Among 33 patients with no prior therapy, there were 8 complete and 17 partial responses, for an overall response rate of 76%. Fifteen of the 25 responding patients received subsequent locoregional treatment. The median estimated survival in this group was 29 months. Hematologic, mucosal, and renal toxicities were only mild to moderate. Episodes of possible 5-fluorouracil-related cardiotoxicity were recorded in both pretreated and untreated patients. Twelve of 41 partial responses observed after the second cycle of therapy were converted to complete responses with a third (8 cases) and also a fourth (4 cases) course. This study confirmed that cisplatin plus 5-fluorouracil is a first-choice combination in previously untreated patients. Definitive evidence that chemotherapy can favorable influence survival awaits confirmation by randomized trials, using a control arm with conventional locoregional treatment. In previously treated patients with recurrent disease, less intensive regimens not requiring hospitalization seem more useful for the quality of life.

Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial.

From February 1983 to January 1985, 497 patients with advanced breast cancer were randomly allocated to receive either epirubicin or doxorubicin in the following combination chemotherapy regimen: fluorouracil (5-FU) 500 mg/m2 intravenous (IV) on days 1 and 8; epirubicin or doxorubicin 50 mg/m2 IV on day 1; cyclophosphamide 500 mg/m2 IV on day 1 (FEC or FAC). Cycles were repeated every 21 days until progression or to cumulative doses of 700 mg/m2 for epirubicin and 550 mg/m2 for doxorubicin. Dose reductions were applied according to the standard criteria. Activity was evaluated in 443 patients (222 in the FEC arm and 221 in the FAC arm). The two experimental groups were comparable in age, performance status, menopausal status, histology, previous treatments, and site of the disease. The overall response rate (complete response and partial response [CR + PR]) was not significantly different: 53.6% for FEC and 56.5% for FAC. The median time to progression was 273 days for FEC and 314 days for FAC; the median survival time was 591 and 613 days, respectively. Leukopenia, anemia, nausea, and vomiting were significantly lower in patients treated with FEC. As for cardiotoxicity, four cases of congestive heart failure (CHF) were recorded among patients treated with FAC while only one was observed in the FEC group. These results indicate that epirubicin in a combination chemotherapy regimen is as active as doxorubicin and is significantly less toxic.

High-dose medroxyprogesterone in disseminated breast cancer. Correlation between bioavailability and clinical response.

Clinical response to high-dose medroxyprogesterone (MPA), administered following three different routes of administration (i.m., p.o. + i.m., p.o.) and monitoring drug plasma levels, was evaluated in pretreated advanced breast cancer patients. Fifty-eight of 68 eligible patients were considered evaluable for response. Age ranged between 36 years and 82 years. Fifty-six of 58 evaluable patients were postmenopausal. An overall remission rate of 48% was achieved with i.m. MPA, 50% with combined (i.m. + p.o.) modalities; only a 19% remission rate was recorded in the p.o. group. Response rate and MPA plasma concentrations were correlated, and a drug level of 80 ng/ml, by means of a GLC method, seems to identify a subset of patients with high probability of response. Only mild toxic effects were recorded.

Peptichemio in pretreated patients with plasmacell neoplasms.

Twenty-one patients with alkylator-resistant plasmacell neoplasms were treated with Peptichemio (PTC) at a dose of 40 mg/m2 for 3 days every 3 weeks or, in the case of persistent leukopenia and/or thrombocytopenia, at the single dose of 70 mg/m2 every 2-3 weeks according to haematological recovery. Seventeen patients, 10 with multiple myeloma and seven with extramedullary plasmacytoma (EMP), were fully evaluable. Six of 17 patients (35%) responded: three of seven EMP patients had a complete remission and 3 of 10 multiple myeloma patients had an objective response greater than 50%. The median duration of response was 8.5 months. An EMP patient obtained a complete response lasting for 16 months. The most frequent toxic effect were phlebosclerosis, occurring in all the patients, and myelosuppression, which was severe in only one case. PTC appears to be an active drug in patients with plasmacell neoplasms even if resistant to alkylating agents.

Cisplatin plus vindesine versus cisplatin plus VP16 versus doxorubicin plus cytoxan in non-small-cell carcinoma of the lung. A randomized study.

From March 1981 to January 1984, 116 patients with advanced non-small-cell carcinoma of the lung (NSCCL) were randomly assigned to 3 combinations as follows: CDDP + DVA, CDDP + VP16 and DXR + CTX. 94 patients were evaluable for response, 106 for toxicity and survival. Of 31 patients, 15 (48%; 3 CRs and 12 PRs) responded to CDDP + DVA; of 33 patients, 12 (36%, 2 CRs and 10 PRs) responded to CDDP + VP16; of 30 patients, 3 (10%) obtained a PR with DXR + CTX (CDDP + DVA vs DXR + CTX, P less than 0.005; CDDP + VP16 vs DXR + CTX, P less than 0.05; CDDP + DVA vs CDDP + VP16, P = NS). The median duration of response was 22 weeks in the CDDP-DVA group, 17 weeks in the CDDP-VP16 group, and 16 weeks in the DXR + CTX group. No significant difference in survival was observed among the 3 groups (median: 43, 47, 41 weeks, respectively). Hematologic and neurologic toxicities were significantly higher in the DVA-containing regimen. Despite the lack of improvement of overall survival with the CDDP-containing combinations over the DXR + CTX control group, the good response rate makes them suitable to be used in combined therapeutic strategies.

Phase II study of cisplatin, 5-FU, and allopurinol in advanced esophageal cancer.

Forty patients with advanced squamous cell carcinoma of the esophagus were treated with a combination of cisplatin, 5-FU (by continuous 5-day infusion), and allopurinol; 37 are evaluable for response. Thirteen remissions (35%) were obtained, including three complete and ten partial, with a median duration of 9 months. After chemotherapy, seven responding patients underwent a surgical procedure, which was radical in four. The most frequent side effects were nausea and vomiting. This regimen is effective and can be included in a multimodality approach.

Peptichemio in advanced breast cancer: a clinical evaluation in 32 patients.

A clinical evaluation of peptichemio (40-45 mg/m2/day for 3 days every 3-4 weeks) was conducted in 32 patients with advanced breast cancer, 28 of whom were evaluable for both toxicity and response. The overall response rate was 18% (one complete remission and four partial remissions), with a median duration of 4 months (range, 2-6). The major side effects were cumulative myelotoxicity, phlebitis, mild nausea, and vomiting. A posttreatment heparin infusion was used to prevent phlebitis.

MPA plasma levels after oral administration in gastrectomized cancer patients during chemotherapy.

Five patients (3 females; 2 males) who underwent gastrectomy for carcinoma were administered adjuvant chemotherapy and high dose medroxyprogesterone acetate (HD-MPA) as supportive therapy. MPA administered p.o. was regularly absorbed; the drug was well tolerated and was almost lacking in toxicity. MPA, thanks to its myeloprotective activity and its anabolic effects, can be used as supportive therapy in the treatment of a wide range of malignancies.

Peptichemio in pretreated patients with ovarian cancer.

From January 1978 to October 1982, 47 patients with histological diagnosis of epithelial cancer of the ovary received peptichemio (PTC) at a dose of 70 mg/m2 (maximum, 120 mg total) every 15 days. Forty-two patients are now evaluable: 27 with stage III and 15 with stage IV disease. All patients but four with stage IV disease had been pretreated and had received at least one drug combination (median, three drugs per patient, including alkylating agents). Before the administration of PTC, the tumor extension in the abdomen was carefully assessed in all patients: ten patients had residual tumor less than 2 cm in diameter, while 32 patients had tumor greater than 2 cm in diameter. Objective responses were obtained in ten patients (23.8%): six complete remissions and one partial remission were observed in stage III patients and one complete remission and two partial remissions were observed in stage IV patients. Of the ten responding patients, eight had tumors less than 2 cm in diameter before receiving PTC. The median duration of response was 16 months. The most frequent side effects were myelosuppression and phlebosclerosis. Bone marrow depression was a common finding after the third course in heavily pretreated patients. Accordingly, in these patients a schedule interval of 3 weeks should be more appropriate. Since most of the responders were in the "small tumor" category, PTC appears to be an active drug in patients with ovarian cancer having small tumors (less than 2 cm). On the other hand, the response rate in a nonselected population of patients remains to be clearly defined with further studies.