Joseph Kattan

Phase I clinical trial and pharmacokinetic evaluation of doxorubicin carried by polyisohexylcyanoacrylate nanoparticles

SummaryDoxorubicin (DXR) incorporated into biodegradable acrylate nanoparticles such as polyisohexylcyanoacrylate (PIHCA) has been shown to increase DXR cytotoxicity and reduce cardiotoxicity by modifying tissue distribution in preclinical studies. We have conducted a phase I clinical trial of DXR-PIHCA in 21 patients with refractory solid tumors (10 male, 11 female, median age: 53 years, median PS: 1, prior free-DXR therapy: 7 patients). A total of 32 courses at 28 day intervals were administered at 6 dose levels (15, 30, 45, 60, 75 and 90 mg/m2). The drug was given as a 10 minute IV infusion on day 1 to the first 5 patients: 2 of them presented a grade 2 allergic reaction (W.H.O. criteria) during infusion, which was rapidly reversible once drug administration was discontinued. Subsequently, in the other 16 patients, the administration was modified to a 60 minute i.v. perfusion diluted in 250 cc of Dextrose 5%: only 1 patient presented the same allergic reaction. Grade 2 fever and vomiting occurred in 9 patients and 7 patients respectively during the first 24 h after treatment. There was no cardiac toxicity among the 18 evaluable patients. Grade 3 or 4 hematologic toxicity occurred at the 75 and 90 mg/m2 dose level. The dose limiting toxicity was neutropenia. The maximum tolerated dose was 90 mg/m2 and the recommended phase II dose was 75 mg/m2. A pharmacokinetic evaluation of DXR-PIHCA was conducted in 3 patients each at a different dose level (60,60 and 75 mg/m2) and was compared with free DXR given to the same patients in the same conditions.

Penile cancer chemotherapy: Twelve years' experience at Institut Gustave-Roussy

Between 1980 and 1992, 14 patients (median age 50 years) with penile carcinoma were treated with multidrug combination chemotherapy in our institution. Twelve patients had Stage IV (Jackson classification) tumor, 1 patient each had Stage III and Stage II. All patients received cisplatin-based chemotherapy. Cisplatin was associated with either 5-fluorouracil (4 patients), methotrexate and bleomycin (4 patients), methotrexate (3 patients), Adriamycin (1 patient), bleomycin and vinblastine (1 patient), or bleomycin and epirubicin (1 patient). Thirteen patients were evaluable for response. Objective response was encountered in 2 patients (15%) with 1 complete response and 1 partial response. Response duration was difficult to determine because of additive radio-therapy or patient was lost to follow-up. There were 2 patients with long-term evidence of no disease among 12 patients with Stage IV disease. These 2 patients received complementary irradiation in association with the chemotherapy. The response rate was dismal in our series. Methotrexate-based regimens seem to be the most active. The bimodality treatment with multidrug chemotherapy and radiotherapy for advanced penile cancer could offer a survival advantage in the management of these patients.

Evaluation of estramustine phosphate combined with weekly doxorubicin in patients with androgen-independent prostate cancer.

Thirty-one patients with progressive metastatic prostate cancer refractory to first- or second-line hormonal therapy were treated with a combination of daily oral estramustine phosphate (600 mg) and weekly intravenous doxorubicin (20 mg/m2). Eighteen (58%) patients demonstrated a biologic response with a 50% or more serum prostate-specific antigen decline. The median duration of biologic response was three months. Five (45%) of the 11 patients with measurable lesions achieved a partial response in liver or retroperitoneal lymph nodes. The median duration of these objective responses was four months. Of 22 patients who required analgesics at the onset of the study, six (27%) achieved a significant reduction of pain. The combination of doxorubicin and estramustine phosphate was tolerated on an outpatient schedule. The occurrence of severe toxicities required suspension of therapy in six patients. At the end of the observation time, all patients but one had died, 29 of progressive prostatic cancer and one of toxicity. The median survival time from the onset of chemotherapy was 12 months. The administration of weekly doxorubicin with phosphate estramustine appears to be a safe combination for those patients with hormone-resistant prostate cancer who require chemotherapy. The benefit of chemotherapy should be investigated using relevant quality-of-life criteria in future trials.

Adult Wilms' tumour: Review of 22 cases

The Institut Gustave Roussy experience with nephroblastoma in 22 patients older than 16 years during a 19-year period (1973-1992) was retrospectively reviewed. All patients underwent a nephrectomy. There were 4 stage I, 8 stage II, 3 stage III and 7 stage IV patients. Initial postnephrectomy therapy included single modality approach in 7 patients (radiotherapy in 1 and chemotherapy in 6) and combined modality approach (radiotherapy and chemotherapy) in 15 patients. The agents used most often were actinomycin, vincristine and doxorubicin. 2 of 7 (29%) and 7/15 (47%) patients are disease-free survivors after first-line treatment. Salvage chemotherapy was given in 13 patients. Only 1 patient experienced a subsequent sustained complete remission. After a mean follow-up of 100 months (range 10-240), 12/22 patients (55%) are alive, including 10 who are disease-free (45%). We confirm that adult patients are likely to have more advanced disease and poorer prognosis than children. The combined modality approach is more active than one-modality therapy. Aggressive treatment, including the three-drug regimen actinomycin+vincristine+doxorubicin, regardless of stage, associated to irradiation starting from stage II, is recommended.

Phase I Study of Retelliptine Dihydrochloride (SR 95325 B) Using a Single Two-Hour Intravenous Infusion Schedule

Retelliptine dihydrochloride (SR 95325 B, NSC D-626717-W) is an ellipticine derivative having a very high level of antitumor activity in resistant murine solid tumor models. We studied in a Phase I trial escalating doses of retelliptine using a single 2-hour IV infusion schedule. Data from other Phase I studies allowed a starting dose of 80 mg/m2 and a rapid dose escalation. Included were 15 patients (M/F = 13/2) with a median age of 55 (range: 17–72). There were 22 courses delivered at the following dose levels: 80, 180, 700, 900, 1,200, and 1,500 mg/m2. Primary tumor types were kidney (6 patients), colon (3 patients), pancreas (2 patients), and others (4 patients).Mild dose-related visual troubles (blurring, accommodation troubles, oculomotor paresis) occurred in 9/11 patients starting from 700 mg/m2. Asymptomatic EKG anomalies, including significant prolongation of PR and QRS intervals occurred at 1500 mg/m2 (in 3/3 patients) marking the maximum tolerated dose. Both visual and EKG anomalies were spontaneously reversible few minutes to few hours after the end of infusion. Other possible drug-related toxicity occurred sporadically such as somnolence, bronchospasm, dry mouth, and vomiting (2 patients each). There were no significant laboratory anomalies. Neither drug-related deaths nor objective complete or partial responses were observed. The recommended dose for Phase II trial using the 2-hour intravenous infusion schedule is 1,200 mg/m2.

Acute tumor lysis syndrome in poor-risk germ cell tumors: does it exist?

Acute tumor lysis syndrome (ATLS) is a well-known adverse event described after effective chemotherapy for extensive, highly proliferative, and chemosensitive tumors. While its occurrence with hematological malignancies is frequently described, there have been scattered case reports documenting ATLS in solid tumors. However, such events have not been reported in poor-risk germ cell tumors. We reviewed retrospectively 46 cases of such tumors treated in our department between 1988 and 1993 by aggressive cisplatin-based chemotherapy. All patients received systematically 61/24 h hydration according to the cisplatin-protocol administration. Blood chemistry data for potassium, phosphorus, calcium, alkaline reserve, uric acid, creatinine and lactate dehydrogenase were obtained before treatment and during the 7 days of the induction chemotherapy. No metabolic abnormalities suggestive of ATLS were observed. Nevertheless, 2 patients with bulky disease of the chest experienced early death from respiratory distress complicated by multiorgan failure. ATLS seems to be an unlikely event in poor-risk germ cell tumors and therefore special prophylactic therapy may be unnecessary.

High failure rate of carboplatin-etoposide combination in good risk non-seminomatous germ cell tumours

24 patients with good risk non-seminomatous germ cell tumours (GR-NSGCT) were enrolled in a phase II trial combining carboplatin (C) and etoposide (E). Carboplatin was given at a fixed dose of 450 mg/m2 at d2, and E 120 mg/m2, dl-3, every 4 weeks x 4 cycles (cy). Myelosuppression was the major toxicity with neutropenia grade 4 in 18 cy (19%) and grade 3 in 26 cy (27%). Thrombocytopenia grade 3 and 4 occurred in 7 and 1 cy, respectively. Responses included: 20 complete responses (CR) (83%) with 16 clinical CR and 4 pathological CR; 3 additional patients had complete surgical removal of residual disease (SRRD) with viable tumour (surgical CR); 1 patient progressed during C+E therapy. 5 of the 16 clinical CR relapsed, and all the 3 surgical CR progressed despite post-operative salvage chemotherapy. Adverse events occurred in 9 patients (37.5%; 95% C.I., 19-59%). After a median follow-up of 24 m (range 14 to 38) 4 patients had died [3 progressive disease (PD), 1 suicide while in CR], 3 were alive with PD, and 17 had no evidence of disease. No significant correlation between area under the curve values of carboplatin, overall treatment failure and the platelet nadirs was observed. We conclude that the efficacy of the C+E regimen as given in our protocol is inferior to the standard cisplatin-containing regimens. The low dose-density (D/I) of carboplatin could be responsible for the high failure rate.

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.

Ovarian dysgerminoma metastatic to the breast.

A 16-year-old girl underwent a right salpingo-oophorectomy for a pure dysgerminoma limited to the right ovary. One month later, she developed a right pelvic mass along with abdominal lymphadenopathies, peritoneal carcinomatosis, left breast mass, and left axillary node. Cytology of the breast mass was suggestive of a pure dysgerminoma. Breast metastases of epithelial ovarian carcinoma are uncommon. In the literature, this is the first case of a breast metastasis of an ovarian dysgerminoma.

Long-term results of two VAB-like regimens (vinblastine+actinomycin-D+bleomycin+cyclophosphamide+cisplatin) in malignant germ cell tumours of the ovary

21 patients with malignant germ cell tumours of the ovary were treated with two chemotherapy regimens including vinblastine, actinomycin-D, bleomycin, cyclophosphamide and cisplatin. Chemotherapy was delivered as primary postoperative therapy in 15 patients and for recurrent disease in 6 patients. 3 of 4 patients with pure dysgerminomas and 10 of 17 patients with non-dysgerminomatous tumours are alive without evidence of disease. The overall progression-free survival is 62% (95% confidence interval 45-77) with a median follow-up of 7 years. Two toxic deaths were observed. Less toxicity and better efficacy favour etoposide- and cisplatin-based regimens as standard chemotherapy for germ cell tumours of the ovary.