Stanley B. Kaye

Viable Malignant Cells After Primary Chemotherapy for Disseminated Nonseminomatous Germ Cell Tumors: Prognostic Factors and Role of Postsurgery Chemotherapy—Results From an International Study Group

PURPOSEnTo assess the value of postsurgery chemotherapy in patients with disseminated nonseminomatous germ-cell tumors (NSGCTs) and viable residual disease after first-line cisplatin-based chemotherapy.nnnPATIENTS AND METHODSnThe outcome of 238 patients was reviewed. Tumor markers had normalized in all patients before resection. A multivariate analysis of survival was performed on 146 patients.nnnRESULTSnThe 5-year progression-free survival (PFS) rate was 64% and the 5-year overall survival (OS) rate was 73%. Three factors were independently associated with both PFS and OS: complete resection (P <.001), < 10% of viable malignant cells (P =.001), and a good International Germ Cell Consensus Classification (IGCCC) group (P =.01). Patients were assigned to one of three risk groups: those with no risk factors (favorable group), those with one risk factor (intermediate group), and those with two or three risk factors (poor-risk group). The 5-year OS rate was 100%, 83%, and 51%, respectively (P <.001). The 5-year PFS rate was 69% (95% confidence interval [CI], 62% to 76%) and 52% (95% CI, 40% to 64%) in postoperative chemotherapy recipients and nonrecipients, respectively (P <.001). No significant difference was detected in 5-year OS rates. After adjustment on the three prognostic factors, postoperative chemotherapy was associated with a significantly better PFS (P <.001) but not with better OS. Patients in the favorable risk group had a 100% 5-year OS, with or without postoperative chemotherapy. Postoperative chemotherapy appeared beneficial in both PFS (P <.001) and OS (P =.02) in the intermediate-risk group but was not statistically beneficial in the poor-risk group.nnnCONCLUSIONnA complete resection may be more critical than recourse to postoperative chemotherapy in the setting of postchemotherapy viable malignant NSGCT. Immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may be reasonable options depending on the completeness of resection, IGCCC group, and percent of viable cells. Validation is necessary.

Clinical trials of nimodipine as a potential neuroprotector in ovarian cancer patients treated with cisplatin

Abstract Our previous randomised trial in patients with advanced ovarian cancer indicated a significant response and survival advantage for those receiving high-dose (100 mg/m2) as compared with low-dose (50 mg/m2) cisplatin in combination with cyclophosphamide (750 mg/m2). However, this was accompanied by more toxicity; peripheral neuropathy was troublesome, with 32% of patients experiencingu2009≥u2009WHO grade 2 at the cisplatin dose of 100 mg/m2. Nimodipine is a calcium-channel antagonist that has provided protection from cisplatin-induced neurotoxicity in a rat model system. We performed a pilot study in 50 patients that demonstrated the feasibility of co-administration of nimodipine in a chronic oral dosing schedule with cisplatin-based chemotherapy in an open-label non-randomised trial. This led us to initiate a double-blind, placebo-controlled, randomised trial in patients with ovarian cancer, which was prematurely discontinued because of problems with nausea and vomiting, leading to poor patient compliance, that were not predicted by the pilot study. These studies did not demonstrate a neuroprotective effect for nimodipine. The primary efficacy variable, i.e, the neurotoxicity score at the end of treatment, gave a significantly lower mean for placebo patients than for nimodipine patients. This report details our experience and discusses the reasons for premature termination of the randomised trial.

929 Clinical phase I trial of PK1 (HPMA co-polymer doxorubicin)

PKI is a novel compound consisting of N-(2-Hydroxypropyl) methacrylamide (HPMA) hompolymer bound to doxorubicin (DOX) via a peptidyl spacer which is cleaved intracellularly by lysosomal proteinases, (once the compound has entered the cell via endocytosis), releasing free DOX intratumourally. Improved antitumour activity compared to free drug has been demonstrated preclinically, especially in solid tumour models. The stability of the linkage in the bloodstream also reduces general toxicities such as cardiotoxicity and myelosuppression in animal studies, and we have therefore initiated a phase I clinical trial. The starting dose in humans was 20xa0mg/m 2 given as an i. v. infusion every 3 weeks. Concurrent pharmacokinetic studies and tumour imaging using radiolabelled drug are also being performed. To date 19 patients have been treated (ages 34–72, mean 57 years). Tumour types are: colorectal 3, ACUP 3, biliary tract 3, head and neck 2, NSCLC 2, breast 2, others 4. Dose levels 20xa0mg/m 2 , 40xa0mg/m 2 and 80xa0mg/m 2 demonstrated CTC grade I nausea, vomiting and anorexia—toxicities also seen at higher dose levels. 3 patients were entered at 120xa0mg/m 2 ; grade I neurotoxicity (paraesthesia) (2/3), grade I hepatotoxicity (reversible transaminase elevations) (2/3) and grade I lethargy (1/3) was observed. Six patients have been entered at 180xa0mg/m 2 . The first developed reversible grade III neurocerebellar toxicity. Other toxicities seen; grade II neutropenia (1/6), grade I mucositis (1/6) and grade II nausea (1/6) requiring prophylactic antiemetics. No alopecia or cardiotoxicity has been observed. One patient has been entered at 240xa0mg/m 2 (3–xa04× the MTD of free DOX) and has experienced grade II anaemia, and grade I emesis to date. There is evidence of antitumour activity, and the study continues to accrue patients.

Changes in the incidence and mortality of testicular cancer in Scotland with particular reference to the outcome of older patients treated for non-seminomatous germ cell tumours

This paper describes the temporal pattern of germ cell testicular cancer in Scotland between 1960 and 1990. The effect of age on the prognosis of patients with non-seminomatous germ cell tumours (NSGCT) has been assessed by studying all patients presenting in the West of Scotland between 1975 and 1989. Between 1960 and 1990, the number of testicular germ cell tumours registered has increased more than 2-fold; mortality rates have declined equally dramatically. Univariate and multivariate analysis of the data obtained on 440 patients with NSGCT showed age was not a prognostic factor influencing survival. 52 were patients over 40 years at presentation; their 5 years survival was 71% compared with 79% in the younger patients (n = 388). This small survival difference is probably explained by the higher proportion of older patients treated before 1980. Treatment for this older group should be approached with the same curative intent as for younger patients and the same expectation of success.

Malignant pineal teratomas : a report on three patients and the case for craniospinal irradiation following chemotherapy

Malignant pineal teratomas carry a poor prognosis. We describe a long-term survivor after chemotherapy and craniospinal irradiation, and another who achieved only transient disease control with chemotherapy and cranial irradiation. Spinal cord spread occurred in first patient and long-term survivors have been reported following surgery and craniospinal irradiation alone, suggesting a role for craniospinal irradiation following chemotherapy.

The importance of added albumin during continuous intravenous infusion of interleukin-2 with alpha-interferon

We treated 14 patients (4 malignant melanoma/10 renal carcinoma) with a combination of continuous infusion interleukin-2 (IL-2) and subcutaneous alpha-interferon. Variable concentrations of albumin were added to the infusion of IL-2. The toxicity of this regimen seems to be related to the percentage of albumin added to the IL-2 infusion. Partial responses were observed in 3 cases. Interestingly, 1 patients response appeared dependent on the addition of human serum albumin. The mechanism of these effects is unknown, but the use of albumin with IL-2 should be carefully investigated in future studies.

Colonic adenocarcinoma associated ectopic ACTH secretion: a case history.

A 57-year-old woman developed features of Cushings syndrome after resection of a Dukes C adenocarcinoma of the sigmoid colon. Biochemical and endocrine investigation indicated ectopic production of adrenocorticotrophic hormone (ACTH) as the cause for her condition. Hepatic metastases were detected by computed tomography (CT) scan. Histology of the original tumour displayed neuroendocrine characteristics but no definite evidence of ACTH synthesis. Treatment was instituted to control her hypercortisolism, and chemotherapy initiated to reduce the production of ectopic hormone. A clinical, biochemical and radiological response was obtained with complete resolution of her Cushings syndrome. The tumour relapsed after several months with distant metastases, but no further endocrine abnormality was noted. A review of ectopic ACTH producing adenocarcinoma is given along with a discussion of the major pathological and therapeutic features of the case.

How should nausea be assessed in patients receiving chemotherapy

lthough myelosuppression is considered to be the major dose-limiting toxic effect of :ytostatic chemotherapy, when patients are asked which adverse event affects them most lausea and vomiting is generally the most common reply (6). Chemotherapy most often nduces nausea and vomiting within 1 2 h of treatment and the acute emesis usually lasts or 24 h (15). Most studies of anti-emetic treatments have examined emesis control in this )eriod. The best treatment available betbre the advent of the 5-HT3 receptor antagonists, ligh-dose metoclopramide, is only partially effective in patients receiving highly emeto,~enic chemotherapy such as high-dose cisplatin even when used in combination with )ther agents. Complete anti-emetic control in the acute period is important. The main :onsequence of poor initial control is that 1-57°,, o of patients will suffer from anticipatory lausea, depending on the emetogenicity of their chemotherapy regimen, which may lead o refusal of further potentially curative courses of chemotherapy (3, 26, 27). The medical complications of persistent vomiting include: dehydration, electrolyte mbalance, metabolic alkalosis, decreased renal elimination of drugs, malnutrition, vitamin teficiencies, oesophageal tears, aspiration pneumonia and pathological fractures (21). In tddition, patients receiving monthly cycles of chemotherapy may experience delayed ~ausea and vomiting tbr up to 3 weeks out of every 4, and the effects of this on their tuality oflit~ include anxiety, depression, restriction of social life, job loss and even suicide 21, 34). Thus, there is clearly a need for anti-emetics which a~e not only effective tgainst vomiting, but also proved to be effective against nausea because the mechanisms mderlying the development of nausea may be substantially different from those involved n vomiting. The identification of such treatments will require a standardized, simple, ~ccurate and reproducible method tbr assessing the patients experience of nausea and the mpact of anti-emetic treatment on it.

Phase I clinical study of LL-D49194α1 with retrospective pharmacokinetic investigations in mice and humans

SummaryLL-D49194α1 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m2. One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D49194α1 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial.

928 Phase I trial of the topoisomerase I inhibitor GG211 as a 72-hour infusion

In a Phase I trial of the water soluble camptothecin analog GG211, 44 patients received a 72-hour infusion at doses ranging from 0.25 to 2.5xa0mg/m 2 /day. Myelosuppression is dose limiting. At doses ≥xa02.0xa0mg/m 2 /day, 6 of 14 patients experienced grade 4 granulocytopenia and 2 of 14 grade 4 thrombocytopenia. Additional side effects (≥xa0grade 2) included nausea, vomiting, anorexia, diarrhea, fatigue, and phlebitis. One patient at the highest dose had grade 3 mucositis in association with myelosuppression. Partial responses have been observed in ovarian, colon, and breast cancers and hepatoma. Additional minor responses have been observed in colon cancer. Whole blood GG211 lactone C SS concentrations increased linearly with dose. The mean terminal half life was 7.5xa0±xa03.5 hrs, and mean clearance 922xa0±xa0292 ml/min/m 2 . Pharmacodynamic analyses demonstrated that steady-state concentrations were predictive of toxicity. Phase II studies with this novel compound are in progress.