Zeniplatin in advanced malignant melanoma and renal cancer: phase II studies with unexpected nephrotoxicity.

The antitumor activity of zeniplatin, a third-generation, water-soluble platinum compound that has shown broad preclinical antitumor activity and no significant nephrotoxicity in phase I trials, was tested in patients with advanced malignant melanoma and advanced renal cancer. Patients who had not previously been treated, except with local limb perfusion and immunotherapy, were given zeniplatin as bolus injections at 125 mg/m2 every 3 weeks. The main hematological toxicity was leukopenia (7/30 patients, WHO grade > or = 3) and the main nonhematological toxicity was nausea and vomiting (21/30 patients, WHO grade > or = 2). Serious nephrotoxicity was observed early in the renal cancer study and, later, also in the melanoma study. Hyperhydration did not prevent the nephrotoxicity, and the studies were stopped after 6 renal cancer patients and 24 malignant melanoma patients had been included. Zeniplatin gave objective responses in 3 of the 21 evaluable malignant melanoma patients [2 complete responses (CRs) in patients with lymph-node metastases lasted 5 and 14 months, respectively; 1 partial response (PR) in a patient with lymph-node and liver metastases lasted 6 months]. In the renal cancer study, only four patients were evaluable for response and none responded. The results show that zeniplatin has some activity (14%) in patients with advanced malignant melanoma, but no conclusion can be drawn regarding the activity of zeniplatin in renal cancer as the number of patients was too low. The main toxicities were leukopenia and nausea and vomiting. Unexpected and serious nephrotoxicity was observed, and for this reason the studies were terminated before the planned number of patients had been included. A possible explanation for the nephrotoxicity may be drug interactions, but no firm conclusion can yet be drawn.

Long-term morbidity after regional isolated perfusion with melphalan for melanoma of the limbs. The influence of acute regional toxic reactions.

OBJECTIVE: To determine the influence of acute regional toxic reactions on the incidence and characteristics of long-term morbidity after regional isolated perfusion with melphalan. DESIGN: Retrospective study. SETTING: The Amsterdam and Rotterdam perfusion centers, the Netherlands. PATIENTS: All patients with melanoma who were treated between 1978 and 1990 and had a minimum follow-up of 1 year after perfusion (n = 367). INTERVENTION: Fifty-four patients (15%) had perfusion of the upper limb, 313 (85%) had perfusion of the lower limb, and 164 patients (45%) underwent regional lymph node dissection at the time of perfusion. MAIN OUTCOME MEASURE: Incidence and characteristics of morbidity 1 year after perfusion and the influence of acute regional toxic reactions on long-term morbidity. RESULTS: One hundred sixty patients (44%) showed some degree of objective or subjective morbidity; most (104 [28%]) had lymphedema. Other long-term morbidity consisted of muscle atrophy or fibrosis (42 [11%]), limb malfunction (55 [15%]), neuropathy (13 [4%]), pain (28 [8%]), and recurrent infection (11 [3%]). Miscellaneous complications were seen in 14 patients (4%). Seventy-one patients (19%) had more than one complication. Acute regional toxic reactions had a statistically significant effect on the incidence of long-term morbidity (P < .01). Moderate to severe acute regional toxic reactions were strongly linked to the occurrence of muscle atrophy or fibrosis (P < .001) and limb malfunction (P < .001). Regional lymph node dissection was statistically significantly related to lymphedema (P = .05). CONCLUSION: Improvement of the perfusion technique should be pursued in an effort to reduce acute regional toxic reactions, and thereby long-term morbidity, without compromising the therapeutic effect.

A retrospective comparative study evaluating the results of mild hyperthermic versus controlled normothermic perfusion for recurrent melanoma of the extremities.

The aim of this study was to investigate the role of mild hyperthermia (39-40 degrees C) in isolated cytostatic perfusion for patients with recurrent melanoma of the extremities. A total of 218 patients treated with mild hyperthermic perfusion was compared to 166 patients perfused under controlled normothermic conditions (37-38 degrees C). Only patients whose lesions had been excised before or at the moment of perfusion were eligible for this study. A variety of prognostic factors was controlled for in a Cox proportional hazards analysis. The application of mild hyperthermia did not influence limb recurrence-free interval nor survival (corrected P values 0.46 and 0.18, respectively). In this retrospective comparative study, no benefit for mild hyperthermia in regional isolated perfusion could be identified.

Docetaxel (Taxotere) is active in non-small-cell lung cancer: a phase II trial of the EORTC Early Clinical Trials Group (ECTG)

In a multicentre trial of the EORTC ECTG we have treated 43 non-pretreated patients with advanced non-small-cell lung cancer (NSCLC) with the new semisynthetic taxoid docetaxel (Taxotere). Six patients were ineligible; of the 37 eligible patients, ten had prior radiotherapy and 18 prior surgery. They received 100 mg m-2 in 1 h i.v. every 3 weeks, usually in an outpatient setting. Prophylactic steroids, antihistaminics or antiemetics were not routinely given. Two patients were not evaluable because they withdrew from the study because of a hypersensitivity reaction after the second cycle. The main toxicity was neutropenia (80% of cycles), although infections were rare (4%). One patient died from sepsis during neutropenia. Hypersensitivity reactions necessitating interruption of docetaxel (Taxotere) infusions were found in only 10% of cycles. The overall response rate was 23% with one complete response, and seven partial responses. Stable disease was found in 16 patients. The median duration of response was 36 weeks, and the median survival of all patients was 11 months. Docetaxel (Taxotere) is among the most active drugs for treatment of NSCLC.

Limb recurrence-free interval and survival in patients with recurrent melanoma of the extremities treated with normothermic isolated perfusion.

To date, little is known about prognostic factors for limb recurrence-free interval and survival in patients with recurrent melanoma of the limbs treated with regional isolated perfusion. Therefore, 216 such patients treated with normothermic perfusion using melphalan during the period 1978 to 1990 were analyzed for patient and tumor related variables using a Cox proportional hazard model. The five year limb recurrence-free interval was 52 percent. For stage II (n = 67), IIIA (n = 71) and IIIAB and IIIB (n = 78) disease separately, these percentages were 53, 56 and 47 percent. In stage II disease, patients with a local recurrence adjacent to scar or skin graft had a significantly better five year limb recurrence-free interval than patients with satellites (75 versus 33 percent; p = 0.0009). Prognostic factors for limb recurrence-free interval were--in order of importance--tumor tissue left in situ, number of previous limb recurrences and total tumor surface area. The overall five year survival rate was 42 percent. For stages II, IIIA and IIIAB and IIIB disease, these percentages were 57, 45 and 25 percent, respectively. There was no survival benefit for patients with a local recurrence. Prognostic factors for survival were, in order of importance, stage of disease, gender, age, Breslow thickness, Clark level of infiltration of the primary melanoma and the number of lesions forming the indication for perfusion. The results of this study will eventually further delineate indications for perfusion.

Patient- and treatment-related factors associated with acute regional toxicity after isolated perfusion for melanoma of the extremities.

In order to gain some insight into the cause of acute regional toxicity after isolated perfusion using melphalan, 15 patient-related and perfusion-technique-related factors were tested in a logistic regression model. Acute toxicity was graded according to Wieberdink's grading system. In a group of 425 patients, 362 (85%) encountered no or slight toxicity with a grade I or II reaction, and 63 (15%) patients encountered more severe toxicity with a grade III, IV, or V reaction. Most patients were treated with a standard dose of 10 or 13 mg melphalan per liter of perfused tissue for leg and arm perfusions, respectively. Factors associated with a more severe toxicity reaction proved to be tissue temperatures of 40 degrees C or higher, female gender, a deterioration of the gas values of the venous perfusate during perfusion, and perfusion at a proximal level of isolation. Consideration of these prognostic factors may lead to a further decrease of acute regional toxicity in perfusion.

Is there an indication for a double perfusion schedule with melphalan for patients with recurrent melanoma of the limbs?

It has been reported that a double perfusion schedule shows a better complete remission rate than does the single procedure for recurrent melanoma of the limb. As more perfusion strategies approach the ideal of a 100% complete remission rate, the main issue now is to prolong the period of disease control in the limb, ie to reduce the limb recurrence rate. The follow up of 42 patients treated with a double perfusion schedule and of 45 patients treated with a single perfusion procedure was updated to compare the duration of limb disease control. Both treatment groups were well balanced with respect to patient and tumour characteristics. For patients treated with a double schedule, the dose of melphalan given in the first perfusion was low (6 mg/l limb volume; 1 h; normothermic) in order to make it possible to carry out a second perfusion (9 mg/l; 1 h; normothermic) with a planned short interval of 3-4 weeks. In the single perfusion group a normothermic perfusion with 10 mg melphalan/l was carried out. The acute tissue reactions and long-term side effects did not differ between the two treatment modalities. The response rate was significantly higher in the double perfusion group owing to a higher complete remission rate (76% vs 48%; P = 0.006). However, no significant difference was seen in limb disease control rates 3 years after perfusion (double schedule, 36%; single schedule, 30%), nor in overall 3-year survival (double schedule, 52%; single schedule, 45%). When evaluating perfusion regimens with equally high complete remission rates, attention should be focused on the duration of limb disease control.

Toxicity grading systems. A comparison between the WHO scoring system and the Common Toxicity Criteria when used for nausea and vomiting.

BACKGROUND: The Common Toxicity Criteria adopted by the NCI in the USA for grading toxicity in cancer clinical trials have been compared to the WHO scoring system which is still in use in Europe. PATIENTS & METHODS: Sixty-six patients undergoing emetic chemotherapy at the Netherlands Cancer Institute completed questionnaires, 32 according to the WHO criteria and 34 to the Common Toxicity Criteria, on the severity, frequency and duration of gastro-intestinal toxicity. Their answers were then compared to the scores coded by research nurses and physicians. The nurses coded acute toxicity when the patients were discharged, and the doctors coded overall toxicity when the patients returned for the subsequent course of chemotherapy. To evaluate the coding systems, an estimate was made of the percentage agreement between the patients' answers and the nurses' and doctors' ratings. RESULTS: The percentage agreement of the Common Toxicity Criteria with the patients' own experiences of nausea and vomiting was considerably better than that of the WHO score. The Gamma statistic confirmed this. The Common Toxicity Criteria have now been adopted for grading toxicity in studies of the Early Clinical Trials Group of the EORTC and are recommended for use in other clinical trials.

Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group.

The antitumour activity of docetaxel was investigated in patients with advanced malignant melanoma. Docetaxel, 100 mg/m2, intravenous, over 60 min, was administered every 3 weeks. Response evaluation was performed after two cycles. No prophylactic treatment with steroids or antihistamines was given. 38 patients were included, 36 were eligible and evaluable for toxicity and 30 patients were evaluable for response. The main haematological toxicity was neutropenia [17 patients with common toxicity criteria (CTC) grade 4 and 11 CTC grade 3] with nadir after 5-8 days and rapid recovery. The most frequent non-haematological toxicity was generalised alopecia (83% of the patients). Asthenia, malaise and fatigue were also seen in 58%. Skin toxicity was also frequent. Hypersensitivity reactions (erythematous rash, urticaria, blood pressure changes and tachycardia), seen in 42% of the patients, were mild to moderate. Oedema was registered in one fifth of the patients and developed after four or more treatment cycles. The overall response rate in the evaluable patients was 17% (five partial responders). We conclude that docetaxel has activity in advanced malignant melanoma.

Prognostic factors for tumor response and limb recurrence-free interval in patients with advanced melanoma of the limbs treated with regional isolated perfusion with melphalan.

BACKGROUND: At this time little is known about prognostic factors for tumor response and subsequent limb recurrence-free interval in patients suffering from advanced melanoma of the limbs who were treated with regional isolated perfusion. METHODS: A retrospective analysis was done, with a logistic regression model and a Cox proportional hazard analysis, looking at possible patient-, tumor-, and treatment-related prognostic factors in all 120 patients with advanced melanoma of the limbs who were treated with regional isolated perfusion with melphalan in the period 1978 to 1990 at our institutions. RESULTS: Complete remission was achieved in 65 patients (54%) with a median duration of 9+ months (range, 1 to 97+ months), and partial remission was seen in 30 patients (25%). Prognostic factors for complete remission were multiple versus single perfusion schedule, the absence of regional node involvement, and leg versus other tumor sites. The 3-year limb recurrence-free interval was 38%. Factors associated with this interval were one as opposed to more than one lesion, complete remission after perfusion, and female sex. Patients exhibiting complete remission after perfusion had a better overall 3-year survival rate than had patients without complete remission (60% vs 35%; p = 0.0012). CONCLUSIONS: In the present study prognostic factors for tumor response and limb recurrence-free interval could be determined. A multiple perfusion schedule may be more effective in providing complete remission in patients undergoing regional isolated perfusion than single perfusions are.

Systemic leakage during isolated limb perfusion for melanoma.

A hazard of regional perfusion for melanoma is incomplete isolation, resulting in leakage of the cytostatic drug into the systemic circulation. Data were analysed retrospectively on 438 melphalan perfusions performed for melanoma of the extremities during the period 1978-1990; continuous isotopic measurement of systemic leakage was carried out. The cumulative systemic leakage after 60 min perfusion was 0.9 per cent (95 per cent confidence interval 0.7-1.1 per cent). Systemic leakage of > or = 1 per cent was detected in 12.6 per cent of perfusions, > or = 5 per cent in 6.2 per cent and > or = 10 per cent in 1.4 per cent. In 2.3 per cent of patients, systemic side-effects in the form of mild transient bone marrow depression occurred. Six variables related to the perfusion technique were assessed by multivariate analysis for their influence on systemic leakage. The level of isolation and diameter of the venous cannula emerged as significant factors. In addition, ligation of the internal iliac vein provided optimal isolation during iliac perfusion.

A retrospective comparative study evaluating the results of a single-perfusion versus double-perfusion schedule with melphalan in patients with recurrent melanoma of the lower limb.

BACKGROUND: Forty-two patients with measurable recurrent melanoma of the lower limb were treated according to a double-perfusion schedule. METHODS: To assess the advantage of this schedule compared with that of a single-perfusion treatment, a retrospective study was done comparing the 42 patients with 45 patients who had undergone a single-perfusion procedure. Both groups were well balanced with respect to patient and tumor characteristics. For patients treated with a double schedule, the dose of melphalan given in the first perfusion was low (6 mg/l; 1 hour; normothermic conditions) to make it possible to perform a second perfusion (9 mg/l; 1 hour; normothermic conditions) with a planned short interval of 3-4 weeks. In the single-perfusion group, a normothermic perfusion with 10 mg melphalan/l was performed. RESULTS: The toxicity did not differ between the two treatment modalities. The response rate was significantly higher in the double-perfusion group (90% versus 68%; P = 0.007) because of a higher complete remission rate (76% versus 48%; P = 0.006). In both groups, approximately half of the patients with complete remission experienced disease recurrence in the perfused area (50% versus 52%). No significant differences were seen in the two groups in the regional node recurrence rate (33% in the double-perfusion group versus 20% in the single-perfusion group), distant recurrence rate (50% in the double-perfusion group versus 58% in the single-perfusion group), and their corresponding recurrence-free intervals. The overall 3-year survival rate was 46% in both groups. CONCLUSION: In the patient groups studied, the double-perfusion schedule shows a better complete remission benefit than does the single-perfusion procedure. No differences are seen in limb, regional node, and distant recurrence rates in the two groups. Thus, additional improvement of the perfusion methodology is warranted.

Adjuvant regional isolated perfusion with melphalan for patients with Clark V melanoma of the extremities.

From 1978 to 1990, 32 patients with Clark V melanoma were treated by wide excision of the primary and adjuvant regional isolated perfusion with melphalan. M.D. Anderson stage of disease was stage I in 22 and stage IIIb in 10 patients. Five-year survival rates were 58% and 27%, respectively. Seven patients developed a recurrence in the perfused limb [stage I, 2, stage IIIb, 5 patients (P = 0.03)], and 4 of 17 patients developed regional lymph node metastases. Of the well-known prognostic variables, only ulceration of the primary tumor significantly influenced survival (P = 0.03). We did not see any improvement in survival rates compared with literature data on nonperfused patients. In the absence of data on locoregional recurrence rates in nonperfused Clark V melanoma patients, we cannot say whether adjuvant perfusion diminished this risk. Therefore, the results of the prospective randomized EORTC/WHO trial in primary high-risk extremity melanoma have to be awaited.

Results of a double perfusion schedule with melphalan in patients with melanoma of the lower limb.

From 1985 to 1990 43 patients with measurable locally inoperable or recurrent melanoma of the lower limb were treated according to a double perfusion schedule. The dose of melphalan given in the first perfusion was low (6 mg/l; 1 h; normothermic) in order to make it possible to carry out a second perfusion (9 mg/l; 1 h; normothermic) with a planned short interval of 3-4 weeks. The toxicity after the first perfusion was slight; after the second it was higher with a Wieberdink grade III reaction in 15 patients. A clinical complete remission (CR) was seen in 33 patients (77%) and a partial one in 6 patients. 16 of the 33 patients with a CR recurred in the perfused area after 5 months (range 1-29); the others remained limb recurrence-free (7-44+ months). The overall 3-year survival rate is 50%, 19 patients are alive with no evidence of disease. The double perfusion schedule shows a high CR rate, an acceptable toxicity and is technically feasible.

The role of regional isolated perfusion in the eradication of melanoma micrometastases in the inguinal nodes: a comparison between an iliac and femoral perfusion procedure.

Regional perfusion therapy of melanoma is followed by an apparent decrease in lymph node metastases. When regional isolated perfusion is performed by cannulating the blood vessels at the iliac level, at least the middle and distal parts of the inguinal nodal zone are included. This is not the case with femoral perfusion. These two types of perfusion were therefore compared to determine whether iliac perfusion eradicates micrometastases present in the inguinal nodes. The regional node recurrence rate and time to regional node relapse of 97 patients treated with iliac perfusion were compared with those of 20 patients who received femoral perfusion. Prognostic factors such as sex, MD Anderson stage of disease, Breslow thickness and Clark level of the primary melanoma, and number of nodules of those with recurrent melanoma were equivalent in both groups. All patients were perfused with melphalan under normothermic conditions during the period 1978-1990. Five of 20 patients (25%) receiving femoral perfusion and 31 of 97 patients (32%) receiving iliac perfusion (P = 0.7, chi 2 test) developed inguinal node metastases after a median period of 25 (8-40) and 19 (2-71) months, respectively (Mann-Whitney U test, P = 0.9). There was no statistically significant difference in the 5-year survival rate (55% versus 62%, respectively; log rank test P = 0.5). Since no advantage could be seen in terms of reduction of inguinal node relapse for iliac perfusion, it is concluded that perfusion of the distal nodes is not the major cause of reduction of regional node metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I study of vintriptol, a tryptophan ester of vinblastine.

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.