Marwane Ghosn

Chemotherapy in metastatic nonanaplastic thyroid cancer: experience at the Institut Gustave-Roussy.

Forty-nine patients with metastatic nonanaplastic thyroid carcinoma were treated over a 10-year period. Five successive chemotherapeutic protocols were used: a combination of doxorubicin, etoposide, 5-fluorouracil and cyclophosphamide; elliptinium acetate; doxorubicin; cispiatin; and the combination of doxorubicin and cispiatin. Results obtained with the different protocols were very disappointing, with only two objective responses (3%). Phase II trials with new chemotherapeutic agents are warranted in selected cases of nonanaplastic metastatic thyroid carcinoma.

Prognostic factors in advanced nonseminomatous testicular cancer. A multivariate logistic regression analysis.

In order to define prognostic factors for advanced stage of nonseminomatous germ cell tumors (NSGCT) of the testis, the authors reviewed 84 patients treated from 1978 through 1985. The survival rate was 51% at 3 years. Patients with elevated seric levels of human chorionic gonadotropin (HCG) and/or alpha‐fetoprotein (AFP), or the presence of an abdominal mass had significantly worse survival. Only HCG and AFP levels retained their significance when multivariate Cox analysis was performed. The probability that a patient achieves a complete remission (CR) was assessed by a function of certain patient characteristics using a multivariate logistic regression analysis. The significant variables were a function of HCG and AFP values. Since both variables are related to the CR rate and survival the authors define the obtention of a CR as a unique outcome of interest. The probability of a CR greater than 70% adequately separates the patients into two prognostic subgroups. This model currently is being used to enrole NSGCT patients in a prospective modulated clinical trial according to these prognostic factors.

Long-term survivors after salvage high dose chemotherapy with bone marrow rescue in refractory germ cell cancer

Between April 1984 and May 1985, 17 heavily pretreated patients with relapsing or refractory germ cell tumours were treated with cisplatin 40 mg/m2/day, days 1-5; etoposide 350 mg/m2/day, days 1-5; cyclophosphamide 1600 mg/m2/day, days 2-5 and autologous bone marrow transplantation on day 8 as consolidation of conventional salvage chemotherapy. None of the 11 refractory patients and 4 of the 6 responders to prior salvage treatment are long-term survivors at 68, 72, 74 and 74 months. Mean aplasia duration was 17 days and there were 7 documented episodes of septicaemia in 17 febrile patients. 1 patient died of treatment. Among the 4 survivors, 2 patients have a sustained grade II invalidating neuropathy. We conclude that this regimen is not recommended as salvage therapy in refractory patients but may be a useful consolidation treatment in patients responding to conventional salvage chemotherapy.

Salvage chemotherapy in refractory germ cell tumors with etoposide (vp-16) plus ifosfamide plus high-dose cisplatin. A vihp regimen

Twenty‐one patients with refractory germ cell tumors were treated with a chemotherapy regimen containing etoposide (VP‐16) (V) 75 mg/m2/day (days 1 to 5), ifosfamide (I) 3 g/m2/day (days 1 and 2) with a 3.6 g/m2 continuous infusion of mesna (days 1 and 2), and high‐dose cisplatin (hP) 40 mg/m2/day (days 1 to 5). The regimen is referred to as VIhP. Nineteen patients were evaluable for response. Five patients (26%) achieved a complete remission (CR) with chemotherapy alone, and three patients (16%) were in CR after resection of a residual nonactive tumoral mass (e.g., necrosis and/or fibrosis and/or mature teratoma). Thus, a CR rate of 42% was achieved with the entire treatment. One additional patient achieved a CR after resection of active, bulky disease. Among the responders, five patients (26%) are still alive and disease‐free at 6, 7, 9, 10, and 18 months after the initiation of the chemotherapy. However, toxicity was heavy in this protocol. Severe myelosuppression was observed with 10 patients developing aplasia and six patients documented sepsis. Reversible Grade 1–2 renal toxicity occurred in 14 patients, and Grade 2–3 peripheral neurotoxicity occurred in six patients. No hemorrhagic cystitis was encountered. We conclude that a VIhP regimen seems to play an active role in refractory germ cell tumors although the presence of high‐dose cisplatin in this regimen does not appear to improve the response rate compared to that of a conventional dose. Toxicity, which seems to be enhanced, is currently under detailed study. However, the contribution of VIhP as a first‐line treatment in poor prognosis, advanced germ cell tumors warrants further study.

Inappropriate antidiuretic hormone secretion induced by ifosfamide

THE SYNDROME of inappropriate antidiuretic hormone secretion (SIADH) has been described as a paraneoplastic entity or an anticancer drug-related side-effect [ 11. Vincristine, cyclophosphamide [l] and in one case vinblastine [2] and cisplatin [3] have been incriminated. We report a case of SIADH induced by ifosfamide in a patient with a prostatic cancer and bone metastases. A histologically proven metastatic well-differentiated adenocarcinoma of the prostate was diagnosed in January 1986 in a 77year-old man. The primary treatment was bilateral orchiectomy which yielded an objective stabilization according to NPCP criteria for 9 months. In October 1986 the disease progressed and the patient received successively cyproterone acetate, aminoglutethimide and flutamide. He was referred to us in August 1988. The disease was confined to the bone, without major biological disturbances. He was receiving flutamide 150 mg per day, as well as nifedipine 30 mg and metoprolol 200 mg daily for coronary insufficiency. He did not receive corticosteroids or diuretics. The patient was included in a phase II trial of chemotherapy with ifosfamide 2 g/m2 and mesna 2.4 g/m2 per day for 2 days in a continuous infusion every 3 weeks. Before the second cycle, clinical examination and biological values were normal. 12 h after the completion of the first infusion, the patient developed drowsiness and muscle twitching with no evidence of localized neurological abnormalities, hypovolaemia or heart failure. Blood pressure was normal. Serum electrolytes (mmol/l) were: sodium 113, potassium 3.4, bicarbonate 24.5. Proteinaemia 12.4 mmolil, glycaemia 12.2 mmolil and blood urea nitrogen 6.0 mmolil caused serum osmolality of 250 mmolil. Renal function was normal with serum creatinine 73 p_molil and creatinine clearance 52 mlimin. Diuresis was 1700 ml/24 h without loss of water and electrolytes by other means than renal excretion. The 24 h inputs were 4000 ml of dextrose 5% with 16 g NaCl and 6 g KC1 during the 2 day treatment. Urinalysis showed (mm01124 h): sodium 143, potassium 95, urea 326, and glucose 83. Urinary osmolality was 5 10 mmol/l. Cerebral computerised tomography was normal and an electro-encephalogram showed diffuse slow waves without evidence of any specific pattern of encephalopathy. Plasma cortisol and thyroid-stimulating hormone were, respectively, 0.41 nmol/l (normal 0.3-0.7 nmolil) and 0.12 ml U/l (normal 0.05-0.2 ml U/l). After treatment by sodium and water restriction the patient recovered in 1 day. Plasma sodium was 140 mmolil on the second day of this regimen. The clinical and biological features of this episode are consistent with a SIADH [4]. No other drug-related aetiology could be

Phase II trial of combination chemotherapy with dacarbazine, cyclophosphamide, cisplatin, doxorubicin, and vindesine (DECAV) in advanced renal cell cancer

Eighteen patients with advanced renal cell cancer were evaluated for objective response to a combination chemotherapy regimen twenty-eight-day (d) cycles, with dacarbazine (200 mg/sq m/d, d1,2,3); cyclophosphamide (400 mg/sq m/d, d1); cisplatin (100 mg/sq m/d, d1); doxorubicin (50 mg/sq m/d, d1); vindesine (1.5 mg/sq m/d, d1,2) (DECAV). One response in 16 patients was observed (6.25%; 95% confidence limits are 0-30%). No major toxicity occurred. An important point is that the only complete remission was observed in a patient with sarcomatoid cell renal cancer. At this dose with this schedule this combination regimen appears to have no activity in renal cell carcinoma.

Sarcoidosis and Testicular Germ Cell Tumor

The authors describe the case of a patient with stage II non seminomatous germinal cell tumor of the testis with a generalized sarcoidosis. They review the existing literature and discuss the problem of diagnosis.

Phase II Trial of Ifosfamide in the Treatment of Metastatic Hormone-Refractory Patients with Prostatic Cancer

Cyclophosphamide has been considered one of the reference drugs of chemotherapy in randomized trials in hormone-refractory prostate cancer by the National Prostatic Cancer Project (NPCP). Ifosfamide, another oxazaphosphorine agent, and an analog of cyclophosphamide, appears to be more active and less toxic in a broad spectrum of tumors. Fifteen patients with metastatic hormone-refractory prostate cancer were treated with continuous infusion of ifosfamide 2 g/m2 per day for 2 days, together with the uroepithelial protective agent Mesna 2.4 g/m2 per day for 2 days, both to be repeated every 3 weeks. All patients have failed on previous hormonal therapy and 7 patients had received previous chemotherapy. The median age was 66 years. Fourteen patients were evaluable; none of whom achieved an objective response. Four patients were stabilized and 10 had disease progression while on chemotherapy. Major toxicity included 2 reversible encephalopathy, 3 grade I reversible renal toxicity, and 1 hemorrhagic cystitis. We concluded that ifosfamide given in this schedule in this group of patients is not an active agent in prostate cancer.

Super-high-risk germ-cell tumors: a clinical entity

Among patients suffering from nonseminomatous germ-cell tumor, with a poor prognosis, a subset underwent respiratory failure and died very early in the course of their treatment. Between 1982 and 1989, 11 out of 56 such patients (20%) died within the first 5 weeks of chemotherapy. The clinical, radiological, biological and infectious characteristics of these patients were analyzed. Nine patients had extensive pulmonary metastases and the 2 others presented a bulky mediastinal mass with pleural effusion. All patients experienced acute respiratory distress during chemotherapy and underwent mechanical ventilation. All patients were febrile, and septicemia was documented in 7 cases. WHO grade 4 and grade 1–2 renal toxicities occurred in 3 and 4 patients respectively. There was no tumor lysis syndrome. All patients died within 35 days from the start of therapy; 4 were autopsied. These 11 patients represent a clinical entity, having what we called super-high-risk germ cell tumors. Early death is related to pulmonary distress within the first 5 weeks of therapy. The origin of the pulmonary distress is multifactorial: bulky disease of the chest, infection, and interstitial fibrosis. Immediate full-dose standard chemotherapy in association with intensive supportive care is recommended in the management of these patients.

Phase II trial of pirarubicin in the treatment of advanced bladder cancer.

SummaryDoxorubicin is one of the standard drugs in the chemotherapy of advanced urothelial tumors. Pirarubicin, a new anthracycline, turned out to be equally active and less toxic than its parent compound in preclinical studies. Twenty one patients with either metastatic or inoperable locally advanced bladder carcinoma were treated with intravenous infusion of pirarubicin: 25 mg/m2/day for 3 days every 4 weeks in the first 15 patients and 20 mg/m2/day for 3 days every 3 weeks in the others. Fifteen patients were not pretreated and 6 received prior chemotherapy (5 patients with doxorubicin containing regimen). Twenty patients were evaluable for response; there were 2 partial response, 8 stable disease and 10 progressive disease. All pretreated patients progressed. Hematological toxicity was moderate, however there was one toxic death with grade 4 neutropenia which occured in a heavily pretreated patient receiving a dose of 25 mg/m2/day for 3 days. There was no clinical cardiac toxicity. Single agent Pirarubicin displays an objective response rate of 10% (95% of CI 0 to 23%) which reaches 14% (95% CI 0 to 29%) when non pretreated patients are analyzed separately. This rate is in the range of doxorubicin activity.