Response of sensitive and resistant IgM immunocytomas to cis-diamminedichloroplatinum (II) does not correlate with the platination level or with the formation or removal of DNA adducts.

An IgM immunocytoma cell line sensitive to cis-diamminedichloroplatinum(II) (CDDP) and a subline with acquired resistance were grown in LOU/M rats. In a previous study with such rats that had been treated with a high dose of CDDP (10 mg/kg) the tumors did not show differences in cellular platinum content or DNA-adduct levels, either immediately after treatment or 24 h later. Recently, this high dose was found to overcome resistance. Therefore, the study was repeated with a 10-fold lower dose (1 mg/kg, i.v.). At 1 and 24 h after treatment, tumor and kidney tissue were assayed for cellular platinum (atomic absorption spectroscopy, AAS) and DNA platination (immunochemical detection of the four CDDP-DNA adducts). The results were compared with previous data. All tissues showed a linear response to dose with regard to platinum uptake as well as adduct formation, with no quantitative difference being seen between the tumors. Also the relative occurrence of the four adducts was very similar. Between 1 and 24 h, in tumors a substantial decrease occurred in both platinum content and adduct level; the kidneys showed little reduction, if any. At the lower CDDP dose a somewhat larger loss of platinum and removal of DNA adducts was observed for the resistant tumor, but these differences could be explained by "dilution", as this tumor continues to grow after low-dose treatment (about 20% within 24 h). Since the strong difference observed between the tumors in sensitivity to CDDP cannot be attributed to differences in CDDP uptake, efficiency of adduct formation, or repair capability, other mechanisms are held responsible.

Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: The present study investigates the role of short chemotherapy (five cycles) versus prolonged (12 cycles) chemotherapy in small-cell lung cancer (SCLC). PATIENTS AND METHODS: Six hundred eighty-seven patients with SCLC were registered in a multicenter study to receive five cycles of chemotherapy consisting of cyclophosphamide 1 g/m2 on day 1, doxorubicin 45 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1, 3 and 5 (CDE), every 3 weeks. Four hundred thirty-four nonprogressing patients after five cycles of chemotherapy were randomized either to receive seven further cycles of the same chemotherapy or to follow-up. RESULTS: The response rate of 585 assessable patients was 79%, with 36% attaining a complete response. Toxicity was mainly hematologic, with 16 toxic deaths (2.4% of all eligible patients), 13 of which were due to sepsis. Median survival time from registration of all patients was 326 days (396 and 267 days for limited and extensive disease, respectively) with 3.2% of patients alive at 5 years. No difference in survival between the two arms was observed, with the same number of 5-year survivors in both arms. The patients randomized to the maintenance arm had a progression-free survival (PFS) duration approximately 2 months longer than the patients randomized to follow-up (median of 177 days v 114 days from randomization; P = .0004). Among patients with a partial response who were randomized to receive maintenance chemotherapy, 12 achieved a complete response after 12 cycles. More patients in the follow-up arm than in the maintenance arm received subsequent treatment on progression and responded more frequently to that treatment. Twelve patients developed second malignancies (seven non-small-cell lung cancers). CONCLUSION: Prolonged chemotherapy does not offer a better chance of cure than short chemotherapy (five cycles) and does not prolong survival in patients with SCLC. Short, combination chemotherapy appears to be a reasonable choice for standard treatment of SCLC and for attempts to improve the cure rate of this disease.

Comparison of two carboplatin-containing regimens with standard chemotherapy for small cell lung cancer in a randomised phase II study. The EORTC Lung Cancer Cooperative group.

The EORTC Lung Cancer Cooperative group performed a randomised phase II study in patients with small cell lung cancer comparing the standard cyclophosphamide/doxorubicin/etoposide (CDE) regimen with two regimens containing the new and active cisplatin derivative, carboplatin, 400 mg/m2 in combination with ifosfamide, a drug without important myelotoxicity, at a dose of 5 g/m2 (IMP) or the non-myelotoxic drug vincristine twice 2 mg (VP). Of 178 evaluable patients, 63 received CDE [30 limited disease (LD), 33 extensive disease (ED)], 55 received IMP (22 LD, 33 ED) and 60 (26 LD, 34 ED) were treated with VP. The response duration was not statistically different: CDE 31 weeks, IMP 29 weeks and VP 21 weeks. The time to progression after CEE was 28 weeks, IMP 24 weeks and VP 17 weeks. This was significantly shorter after VP than after CDE (P = 0.017). The 60% response rate of the VP combination was low compared with CDE (83%) and IMP (77%). Toxicity of all three regimens was acceptable, and dose reduction for myelosuppression was necessary in only a minority of the patients. We conclude from this study that the combination of carboplatin, at the maximally tolerated dose of 400 mg/m2, in combination with ifosfamide 5 g/m2, is an active regimen with efficacy comparable with the standard CDE regimen.

Long-term follow-up of non-seminomatous testicular cancer patients with mature teratoma or carcinoma at postchemotherapy surgery. EORTC Genitourinary Tract Cancer Cooperative Group (EORTC GU Group)

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.

Resistance of in vitro grown IgM immunocytoma cells to cis-diamminedichloroplatinum (II) (cis-DDP) and cross-resistance to other DNA interacting drugs.

Previously, we reported on the resistance to cis-diamminedichloroplatinum(II) (cis-DDP) of tumor cells in IgM immunocytoma tumors. In vitro cell lines were established, from tumors both sensitive and resistant to cis-DDP. The cultured cells obtained from the parent tumor were designated IgM-I, and those from a cis-DDP resistant tumor IgM/cDDP. In vitro dose response studies showed a difference in cis-DDP sensitivity with a resistance factor of approximately 20 at a relative survival of the tumor cells of 50 percent. The resistance factor was determined both in an assay with continuous cis-DDP exposure for 72 h, and in a clonogenic assay after an exposure for 1 h to various dosages of cis-DDP. The IgM/cDDP cells showed cross-resistance, in vitro and in vivo, to the currently used cis-DDP analogs carboplatin (CBDCA or JM8) and iproplatin (CHIP or JM9). Cross-resistance was also observed against the recently developed platinum(IV) compound tetraplatin. In addition, the cell line IgM/cDDP was resistant to other drugs interacting with DNA, such as doxorubicin (DXR), mitomycin C (MMC) and melphalan (L-PAM). For two non DNA-interacting drugs, vincristine (VCR), a mitosis inhibitor, and VP-16, a topoisomerase inhibitor, both cell lines were equally sensitive.

A phase 1 and pharmacokinetic study using the aromatic retinoic acid analogue dichloroetretinate (Ro 12-7554).

A phase I study was carried out with the new aromatic retinoic acid analogue DCE, all-trans-9-(2,6-dichloro-4-methoxy-m-tolyl)-3,7-dimethyl-2,4,6,8- nonatetraenacetylester. Data from preclinical studies show that DCE has a promising anti-tumor effect. Data from others investigators show that when DCE was given to patients in daily doses, the dose-limiting toxicity. This toxicity was comprising considerable muco-cutaneous toxicity, occurred at 40 mg/day. To avoid this dose-limiting toxicity, a weekly oral treatment schedule was tested for toxicity in this study. The starting dose was 40 mg/m2 body surface, and a modified Fibonacci scheme was used for the dose escalations. A total of 20 patients entered this study, and all were evaluable for toxicity. The highest dose was 300 mg/m2. In three patients, completely reversible WHO grade 1 liver toxicity was observed. In contrast to daily doses, a once-a-week schedule produced no mucocutaneous toxicity. Pharmacokinetic measurements showed that absorption was highly unpredictable and did not increase with dose increments. Given the results of the pharmacokinetic determinations, we concluded that escalating the DCE dose would not lead to a recommendable dose for further phase II studies, and the study was subsequently discontinued.

[Cured of testicular cancer; does life just go on?]. / Genezen van zaadbalkanker; gaat het leven gewoon voort?

From 1976 through 1979 we have treated 91 patients with disseminated non-seminomatous testicular cancer with induction chemotherapy comprising cisplatin, vinblastine and bleomycin. After 4 induction cycles complete responders went on to receive maintenance therapy with cisplatin and vinblastine for a median of one year. Fifty-seven patients (63%) are at present alive and free of disease. Seven to ten years after the start of treatment we have investigated their physical, mental and social situation by means of a questionnaire and by collection of data from the charts. It appeared that 90% of the respondents were fully employed. However, over half of the men reported symptoms of polyneuropathy and 40% experienced sexual function disturbances. Part of these problems were due to the maintenance chemotherapy, which has been abandoned in our country since 1982.

Ten-year survival and late sequelae in testicular cancer patients treated with cisplatin, vinblastine, and bleomycin.

This 10-year follow-up study of 91 patients with disseminated testicular nonseminomatous cancer, treated with cisplatin, vinblastine, and bleomycin (PVB) induction chemotherapy and vinblastine plus bleomycin maintenance chemotherapy for a planned period of 2 years, shows a 63% cure rate. The predominant long-term sequelae are neurological and sexual dysfunction in 68% and 40% of patients, respectively. Two patients died of myocardial infarction. Sixteen percent of patients developed hypertension, 23% Raynaud's phenomenon, and 25% ototoxicity. Despite the long-term side effects, 90% of the patients who responded to a questionnaire are fully employed. This study shows that the maintenance chemotherapy has contributed to the incidence and/or degree of neurotoxicity, hypertension, and renal function disturbance.

Myelodysplastic syndrome and acute leukaemia following treatment of soft tissue sarcoma.

The incidence of secondary myelodysplastic syndromes (MDS) and acute leukaemias (AL) after chemotherapy and/or radiotherapy is increasing. Most cases have been described in patients with Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, polycythemia vera, ovarian cancer and breast cancer. We report 2 patients with secondary MDS and acute myeloblastic leukaemia after combined chemotherapy and radiotherapy for soft tissue sarcoma. Five more cases have been described in the literature. The data of all patients are summarized. The occurrence of secondary MDS/AL in patients with soft tissue sarcoma may become a problem, in particular in children, who have been cured after combined radiotherapy and chemotherapy.

Platinum concentrations and DNA adduct levels in tumors and organs of cisplatin-treated LOU/M rats inoculated with cisplatin-sensitive or -resistant immunoglobulin M immunocytoma.

Female LOU/M rats, bearing either a cisplatin (cisDDP)-sensitive or -resistant IgM immunocytoma, were sacrificed at 1 or 24 h after cisDDP administration (i.v., 10 mg/kg of body weight). Platinum levels, determined with atomic absorption spectroscopy, were in the order kidney much greater than liver greater than tumor greater than spleen in the 1-h samples. In the 24-h samples, more platinum was found in spleens than in tumors; the levels in the kidneys were the same as those measured at 1 h, in the spleens they were higher, and in livers and tumors they were lower than at 1 h after the injection; the greatest decrease occurred in the resistant tumor. cisDDP-DNA adducts were detected after chromatography of digested DNA samples isolated from these tissues and from blood cells. The quantitation of the four cisDDP-DNA adducts (Pt-G, Pt-AG, Pt-GG, G-Pt-G, the same as found previously in cisDDP-reacted DNA) was performed with specific antibodies, in the competitive enzyme-linked immunosorbent assay. The cisDDP-DNA adduct levels in the various 1-h tissue samples showed the same ranking order as the platinum levels. The blood samples contained the lowest amount of adducts. Because of the high platinum level in the kidneys (26 mg/kg of wet tissue), the adducts in this organ also could be determined with atomic absorption spectroscopy (the four adducts comprised about 400 fmol/micrograms of DNA). Comparison of the atomic absorption spectroscopy and enzyme-linked immunosorbent assay data showed excellent agreement. Except for the kidney, all samples showed a decrease in adduct level between 1 and 24 h after cisDDP treatment. The data on the tumors indicated that the difference in susceptibility to cisDDP between the sensitive and resistant tumors is not due to a decreased platinum content or reduced DNA adduct formation in the resistant tumor.

Resistance and cross-resistance of the IgM immunocytoma in the LOU/M Wsl rat for cisplatin, carboplatin, and iproplatin.

We investigated the antitumor activity of cis-diammine[1,1-cyclobutanedicarboxylato]platinum(II) (CBDCA, JM8) and cis-dichloro-trans-dihydroxybis(isopropylammine)platinum(IV) (CHIP, JM9) for the cis-DDP-sensitive and -resistant IgM immunocytoma in the LOU/M Wsl rat. The optimal dose for the antitumor effect of cis-diamminedichloroplatinum (cis-DDP) in this tumor model is 1 mg/kg body weight. In order to determine the dose range for antitumor activity of JM8 and JM9, tumor-bearing rats were treated i.p. (twice weekly) with 2, 4, 8, 16, or 32 mg/kg JM8 or with 2, 4, or 8 mg/kg JM9. The maximal antitumor activity of JM8 was found at a dose of 4-8 mg/kg and that of JM9, at 4 mg/kg. Doses of 16 or 32 mg/kg JM8 did not increase the antitumor activity. Recurrence of tumors was observed in JM8- and JM9-treated rats. It was demonstrated that these relapses during treatment with JM8 or JM9 involved tumor cell populations almost completely resistant against therapy with the respective drugs. The growth of cis-DDP-resistant tumors was not influenced by the analog JM9 (4 and 8 mg/kg). Only a high dose of JM8 (32 mg/kg) caused growth retardation of the cis-DDP-resistant IgM subline. The JM8-resistant tumor was resistant to treatment with cis-DDP (1 and 2 mg/kg). The JM9-resistant tumor was also resistant to this treatment (1 mg/kg); however, at a dose of 2 mg/kg cis-DDP, growth retardation of the tumor occurred. We conclude that cis-DDP, JM8, and JM9 induce resistance in the IgM immunocytoma tumor system; tumors resistant for cis-DDP were not sensitive to the treatment with JM8 or JM9. Although JM9 reacts in vitro distinctly differently with DNA than cis-DDP and JM8, no differences were found in the induction of Pt resistance. In this study tumor cells were readily made resistant, which allows us to study in more detail the induction of (cross-) resistance by cis-DDP, JM8, and JM9.

Multivariate analysis of prognostic factors in patients with disseminated nonseminomatous testicular cancer: results from a European Organization for Research on Treatment of Cancer Multiinstitutional Phase III Study.

Univariate and multivariate linear logistic regression analyses of potential prognostic variables have been performed for 163 patients with disseminated nonseminomatous testicular cancer, treated with cisplatin, vinblastine, and bleomycin in a multicenter study of the European Organization for Research on Treatment of Cancer Genito-Urinary Tract Cancer Cooperative Group. With a multivariate analysis, four prognostic groups with complete responder rates of 100, 89, 41, and 18%, respectively, were identified based on three prognostic factors: trophoblastic elements in the primary tumor, serum concentration of alpha-fetoprotein, and lung metastases by size and number. However, with a univariate analysis the logarithm of the beta subunit of human chorionic gonadotrophin (BHCG) was the single most important factor. This model aids the physician in selecting prospectively good risk patients who are candidates for low toxicity chemotherapy and poor risk patients with whom innovative treatment should be attempted.

High-dose versus low-dose vinblastine in cisplatin-vinblastine-bleomycin combination chemotherapy of non-seminomatous testicular cancer: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group.

Two hundred fourteen patients with disseminated non-seminomatous testicular cancer were randomized to receive induction chemotherapy with cisplatin, vinblastine, and bleomycin (PVB). The randomization was for vinblastine 0.4 mg/kg/cycle or 0.3 mg/kg/cycle. The complete response (CR) rates to both regimens were identical: 68% and 71%, respectively. In addition, there was no significant difference in disease-free and overall survival. There was a significant decrease in the incidence of WBC nadirs below 1,000/microL: 29% and 13%, respectively (P = .01). Of the non-hematologic toxicities, there was a significant reduction in the incidence of mucositis: 53% and 37%, respectively (P = .006). The major prognostic factor was tumor volume. This study confirms that vinblastine 0.3 mg/kg/cycle in PVB chemotherapy is as effective and less toxic than vinblastine 0.4 mg/kg/cycle.

EORTC Genito-Urinary Group studies in advanced testicular cancer--past and future.

Two hundred and twenty-eight patients with advanced testicular cancer were entered into a randomized study of chemotherapy comprising cis-platinum (P) 20 mg/m2-, days 1-5 every 3 weeks for four courses, bleomycin (B) 30 mg weekly for 12 weeks, and vinblastine (V) at either the low dose of 0.15 mg/kg or the high dose of 0.20 mg/kg on days 1 and 2 every 3 weeks for four courses. In this interim analysis, 64 patients were randomized to high dose PVB. Forty-five (71%) achieved a complete response, and 13 (25%) a partial response. Seventy patients received low dose PVB of whom 50 (71%) achieved a complete response and 16 (23%) a partial response. Thus there is no difference in the efficacy of this combination chemotherapy with respect to the dose of vinblastine, but the low dose schedule was less toxic (particularly to bone marrow). It was also apparent that the response rate varied with the volume of metastatic disease, irrespective of the dose of vinblastine. Patients with low volume metastases had a complete response rate (CR) of 88%, while those with high volume had a CR rate of 60%. In a second randomization, 68 patients achieving CR were randomized to receive either 1 year of further (maintenance) chemotherapy with cis-platinum and vinblastine, or no further chemotherapy. One of 37 patients (3%) receiving treatment and 2 of 31 patients (6%) not receiving treatment relapsed, with a follow-up of at least 10 months. Thus maintenance chemotherapy appears not to be necessary in the treatment of advanced testicular cancer.