Search

Carcinosarcomas of the female genital tract are highly malignant tumours composed of carcinomatous and sarcomatous elements. In the past, these tumours were frequently treated as sarcomas. However, a number of arguments, including the sensitivity of these tumours to platinum-based chemotherapy, suggest that these tumours behave more like poorly differentiated carcinomas. The European Organization for Research and Treatment of Cancer (EORTC) Gynaecological Cancer Group therefore decided to perform a prospective phase II study in patients with advanced or metastatic carcinosarcoma with an approach such as that used in gynaecological carcinomas. Eligible patients could have primary or recurrent disease, but prior radiotherapy or chemotherapy was not allowed. The treatment plan recommended upfront debulking, followed by chemotherapy with cisplatin, ifosfamide and doxorubicin. Patients who could be debulked to non-measurable disease remained eligible for the study, but the response assessment was restricted to patients who had measurable disease before the start of chemotherapy. A total of 48 patients (39 primary disease, 9 recurrent disease) were registered, 41 of them being eligible. In 9 patients, all macroscopic lesions could be removed, 32 patients were left with residual disease and were assessable for response. The overall response rate was 56%: a complete response (CR) was observed in 11 (34%) patients and partial response (PR) in 7 (22%) patients. No change occurred in 5 patients and progression in 2 patients. In 7 patients, response could not be assessed. Median survival for all of the 41 eligible patients was 26 months. Severe leucopenia and thrombocytopenia were common and necessitated dose reductions or delays in 60% of patients. From a clinical point of view, the most severe non-haematological toxicity was renal dysfunction, and one patient died of this complication in the absence of disease progression. The results of this study are in-line with the hypothesis that carcinosarcomas are chemosensitive, in particular for the currently investigated regimen. The treatment also included upfront cytoreduction when feasible. Considering the observed toxicities, alternative platinum-based regimens with more favourable toxicity profiles should be explored.

Alkylphosphocholines are a novel class of antitumour agents structurally related to ether lipids that interact with the cell membrane and influence intracellular growth signal transduction pathways. We performed a phase I trial with an analogue of miltefosine, perifosine (D-21266), which was expected to induce less gastrointestinal toxicity. Objectives of the trial were: to determine the maximum-tolerated dose (MTD) for daily administration, to identify the dose-limiting toxicity (DLT) of this schedule, to assess drug accumulation and to determine the relevant pharmacokinetic parameters. 22 patients with advanced solid tumours were treated at doses ranging from 50 to 350 mg/day for 3 weeks, followed by 1 week of rest. Toxicity consisted mainly of gastrointestinal side-effects: nausea was reported by 11 patients (52%, 10 patients Common Toxicity Criteria (CTC) grades 1-2 and 1 patient CTC grade 3), vomiting by 8 (38%, all CTC grades 1-2), and diarrhoea by 9 (43%, 8 patients CTC grades 1-2 and 1 patient CTC grade 3). The severity of these side effects appeared to increase with increasing doses. Another common side-effect was fatigue, occurring in 9 patients (43%). No haematology toxicity was observed. Dose-limiting toxicity (DLT) was not reached, but gastrointestinal complaints led to an early treatment discontinuation in an increasing number of patients at the higher dose levels. Therefore, MTD was established at 200 mg/day. The pharmacokinetic studies suggested dose proportionality.

The aim of this prospective study was to assess the efficacy, clinical benefit and safety of CPT-11 (irinotecan) in patients with stringently-defined 5-fluorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18-53+). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from first administration of CPT-11 was 10.4 months or 45 weeks (range: 3-66+ weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade > or = 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical benefit. The toxicity profile of CPT-11 is becoming better understood and has been considerably improved.

The purpose of this study was to investigate the influence of hyperthermia on cisplatin pharmacokinetics and DNA adduct formation. The latter was investigated both in tumour cell lines in vitro and in tumour cells and buccal cells from cancer patients. The patients had advanced ovarian carcinoma and were entered into a phase I study for cytoreductive surgery followed by hyperthermia in combination with intraperitoneal cisplatin administration. The cisplatin-DNA modifications in vivo and in vitro were studied by an immunocytochemical method with the polyclonal antiserum NKI-A59. The patient samples for pharmacokinetic determinations were analysed by flameless atomic absorption spectrometry. In vitro, the combination of hyperthermia and cisplatin enhanced cell killing compared with either treatment alone, such that the cisplatin-resistant ovarian cell line A2780/DDP became almost as sensitive as the parent A2780 cell line (resistance factor reduced from 30 to 2 at the IC50). In addition, increased cisplatin-DNA adducts were observed in the resistant cell line after the combined treatment compared with cisplatin alone. A good correlation was found between nuclear staining density and surviving fraction for all groups, indicating that the DNA adducts generated are an important determinant of toxicity and that the mechanism by which hyperthermia enhances kill is by increasing adduct levels. In the patients, the ratio of drug concentration in the peritoneal perfusate compared with that in plasma was found to be approximately 15, indicating a favourable pharmacokinetic ratio. Cisplatin-DNA adduct formation in tumour cells from patients was higher than in buccal cells, reflecting this higher drug exposure, i.e. local plus systemic versus systemic only. In addition, the tumour cells but not buccal cells were exposed to hyperthermia. The higher number of tumour adducts also suggests that a favourable therapeutic ratio could be achieved. Platinum-DNA adduct formation was found to decrease with distance from the surface of the tumour nodules. However, at a distance of 3-5 mm, the nuclear staining density levels were still measurable and higher than in buccal cells. In conclusion, the combined pharmacokinetic and adduct data in patients support the advantages of the intraperitoneal route for drug administration, and the addition of heat.

Docetaxel is one of the most active drugs used in the treatment of breast cancer. However, its major side-effect, myelosuppression, hampers full-dose combination chemotherapy. We have, therefore, developed an alternating schedule of docetaxel with epirubicin and cyclophosphamide, together with granulocyte colony-stimulating factor, to ameliorate neutropenia. We studied the feasibility of such a strategy, decreasing the treatment interval from 21 days to 14 days, thus further increasing the dose intensity. As expected, myelosuppression was common, complicated by neutropenic fever, which did not exceed preset criteria. Other side-effects were also as expected: alopecia, malaise, nausea and vomiting. After two alternating courses of chemotherapy, a partial response was documented in 15 of 17 patients. We conclude that this alternating schedule is very active against breast cancer and warrants further phase II studies.

In a phase II trial, the activity of EO9, a new bioreductive alkylating agent, was assessed. EO9 was used as second-line chemotherapy in breast cancer patients and as first-line chemotherapy for patients with gastric, pancreatic and colorectal cancer. EO9 was given as a 5 min i.v. infusion at a weekly dose of 12 mg/m2. 92 patients were entered; 22 with breast cancer, 26 with colon cancer, 24 with pancreatic cancer and 20 with gastric cancer. In general, the drug was well tolerated with nausea and vomiting occurring in 26.42 and 13.3% of courses, respectively. Reversible proteinuria was the main toxicity occurring in 45% of courses. Antitumour activity was not observed. At this dose and schedule, EO9 is not an active drug in the type of tumour studied.

Myocardial adrenergic neuron integrity and function were evaluated in 21 patients who had received doxorubicin or epirubicin for various malignancies. Myocardial uptake of iodine-123 metaiodobenzylguanidine ([123I]MIBG), a marker suitable for the study of myocardial neuron injury, was calculated from planar scintigraphic images after 4 h and the washout between 15 min and 4 h. In 13 patients with normal left ventricle ejection fraction (LVEF) analysed at three cumulative dose levels (no, low and middle dose), [123I]MIBG uptake tended to be significantly impaired (z = -2.772, P = 0.0056), at higher cumulative dose levels, before significant LVEF changes were observed. [123I]MIBG values were considerably decreased in 2/7 patients investigated at low cumulative dose and in 3/8 cases at the middle dose level. On follow-up, 1 of these patients, who had normal LVEF after completion of chemotherapy but whose [123I]MIBG values had progressively deteriorated during anthracycline therapy, subsequently developed congestive heart failure; another patient, whose [123I]MIBG values were impaired at the middle dose level, developed persistent reduced LVEF 5 months after completing therapy. In 8 patients, who had developed persistently, reduced LVEF at high doxorubicin cumulative dose levels, [123I]MIBG, performed in the period after chemotherapy discontinuation, was invariably abnormal. These data suggest that myocardial adrenergic derangement plays a role in anthracycline-associated cardiotoxicity: its appearance, even at low cumulative anthracycline dose levels, may reflect impairment of the intravesicular norepinephrine storage by incipient anthracycline-associated cardiac neuron injury. [123I]MIBG scintigraphy may be useful to assess myocardial adrenergic derangement during and in the follow-up of anthracycline therapy and potentially detect patients who are at risk.

Spiroplatin was investigated in a multicentre phase I study. 67 patients with advanced solid tumours received 151 cycles either by short-term or prolonged infusion, repeated every 3 weeks, at 2.5-40 mg/m2. Myelosuppression and renal toxicity were dose-limiting. Proteinuria, which was dose- and schedule-dependent, indicated glomerular and tubular damage. The maximum tolerated doses (MTD) for poor-risk and good-risk patients were 35 and 40 mg/m2, respectively. The area under the curve (AUC) at the MTD did not correspond with the AUC at the LD10 in mice with ratios of 0.3 for free platinum and 2.6 for total platinum; these were not suitable for predicting the MTD. 1 complete response was observed in a patient with breast cancer and lung metastases and 1 partial response in a patient with adenocarcinoma of the lung. The recommended dose for phase II studies was 30 mg/m2 by 4 h infusion every 3 weeks.

In two studies initiated in 1979 and 1981, 377 patients were treated for advanced epithelial ovarian cancer. In the first study patients were randomly assigned to receive Hexa-CAF (hexamethylmelamine, cyclophosphamide, methotrexate, 5-fluorouracil) or CHAP-5 (cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin for 5 days) and in the second study to receive CHAP-5 or CP (cyclophosphamide, cisplatin on 1 day). Patients who did not respond to Hexa-CAF were offered subsequent treatment that included cisplatin. Median follow-up of patients in the first study was 9.5 years and in the second study 7.7 years. At 10 years 9% of the patients initially treated with Hexa-CAF and 21% of patients assigned to CHAP-5 were alive. Among the 10-year survivors treated with Hexa-CAF, 50% had experienced progressive disease but were alive as a result of retreatment with a cisplatin regimen. The survival curves of both studies revealed that approximately 60% of the patients who reached a complete remission were alive at 5 years and 40% at 10 years. Patients with microscopic disease at second-look had a less favourable outlook: 35% survived 5 years. Not recognised at first publication of both studies was the influence of tumour grade on survival. Before 5 years of follow-up, the good prognosis of grade 1 tumours (well differentiated) could not be detected. About 50% of patients with grade 1 tumours were alive at 5 and 30% at 10 years while these survival rates were halved for the other grades. Combination chemotherapy with cisplatin can enhance survival by more than 10% at 5 and 10 years compared with the best treatment of the precisplatin era: Hexa-CAF.

From 1979 to 1983 the EORTC GU Group treated 239 patients with disseminated non-seminomatous testicular cancer with combination chemotherapy comprising cisplatin, vinblastine and bleomycin in a prospectively controlled trial. The protocol required complete resection of residual masses after induction chemotherapy, provided that serum tumour markers were normal. 102 patients were operated on. 27 patients had mature teratoma (teratoma differentiated) in the resected specimens and 23 had viable cancer. Follow-up data were available for 26 and 22 of these patients, respectively. 23 of 26 patients (88%) with mature teratoma are alive and disease free after a follow-up of 53-110 months (median 92 months). 3 patients developed progressive disease; 1 died. A peculiar case of growing mature teratoma on the forearm is described. 13 of 22 patients (59%) with residual carcinoma are alive and disease free after a follow-up of 74-112 months (median 95 months). The prognosis of patients with carcinoma is shown to be correlated with the completeness of surgery, which in turn is correlated with the initial tumour mass before chemotherapy.

Vintriptol, a tryptophan ester of vinblastine, is a new vinca alkaloid derivative. Preclinical studies have demonstrated its antitumour activity in a large variety of animal models. In this phase I study, 47 patients with advanced cancer were exposed to escalating doses of vintriptol, starting at 6 mg/m2 and following a modified Fibonacci schedule. The drug was administered as an intravenous push on a weekly schedule. Myelosuppression was the dose-limiting toxicity and the maximum tolerated dose was 45 mg/m2. Other toxicities consisted of mild nausea and vomiting and the occurrence of fever and dryness of the mouth immediately after drug administration. Neurotoxicity, a major side-effect of other vinca alkaloids, was insignificant. 1 partial remission in a patient suffering from colorectal cancer and 1 minor response in a patient with a metastatic tumour of the cutaneous appendagous glands were documented. Pharmacokinetics of vintriptol were evaluated at the highest dose levels. A dose schedule of 40 mg/m2 vintriptol per week is recommended for phase II studies.

35 evaluable patients were treated with 5'-deoxy-5-fluorouridine (doxifluridine), a fluoropyrimidine derivative. All patients had been heavily pretreated and had refractory disease. Treatment with doxifluridine at a dosage of 3000 mg/m2 given intravenously for 5 successive days at 3-week intervals led to 6 partial remissions (17%). The main side-effects were central neurotoxicity, stomatitis and myelotoxicity, resulting in 2 toxic deaths. In patients with renal function disturbances, toxicity proved to be more severe. We concluded that the drug should not be used in patients with renal impairment. Because responses have been encountered, further evaluation of the drug may be warranted in the less toxic oral form.