Jean Pierre Armand

Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5‐fluorouracil, and bleomycin

The authors treated 14 patients with advanced squamous cell carcinoma (SCC) of the skin or lip with one to four cycles of combination chemotherapy consisting of cisplatin by bolus injection, and 5‐fluorouracil (5‐FU) and bleomycin by continuous 5‐day infusion. Objective responses were seen in 11 of the 13 evaluable patients (84%). Four patients had a complete remission (30%) and seven patients, a partial remission (54%). Local control after definitive complementary radiation and/or surgical treatment was achieved in seven patients. Toxic side effects was acceptable; they consisted of nausea and vomiting in all patients, transient skin changes, hematologic (Grade 3/4) abnormalities in four patients, and pulmonary fibrosis in one elderly patient. These results show that this chemotherapy combination could play a role in reducing the tumor mass and in facilitating definitive treatment to obtain better functional and cosmetic results in advanced SCC of the skin.

Phase I and Pharmacokinetic Study of Aplidine, a New Marine Cyclodepsipeptide in Patients With Advanced Malignancies

PURPOSE To establish the safety, pharmacokinetic parameters, maximum-tolerated dose, and recommended dose of aplidine, a novel marine cyclodepsipeptide, in patients with advanced cancer. PATIENTS AND METHODS Using a modified Fibonacci method, we performed a phase I and pharmacokinetic study of aplidine administered as a 24-hour intravenous infusion every 2 weeks. RESULTS Sixty-seven patients received aplidine at a dose ranging from 0.2 to 8 mg/m(2). Dose-limiting myotoxicity corresponding to grade 2 to 3 creatine phosphokinase elevation and grade 1 to 2 myalgia and muscle weakness occurred in two of six patients at 6 mg/m(2). No cardiac toxicity was observed. Electron microscopy analysis showed the disappearance of thick filaments of myosin. Grade 3 muscle toxicity occurred in three of 14 patients at the recommended dose of 5 mg/m(2) and seemed to be more readily reversible with oral carnitine (1 g/10 kg). Therefore, dose escalation was resumed using carnitine prophylactically, allowing an increase in the recommended dose to 7 mg/m(2). Other toxicities were nausea and vomiting, diarrhea, asthenia, and transaminase elevation with mild hematologic toxicity. Aplidine displayed a long half-life (21 to 44 hours), low clearance (45 to 49 L/h), and a high volume of distribution (1,036 to 1,124 L) with high interpatient variability in plasma, whereas in whole blood, clearance ranged from 3.0 to 6.2 L/h. Minor responses and prolonged tumor stabilizations were observed in patients with medullary thyroid carcinoma. CONCLUSION Muscle toxicity was dose limiting in this study. Recommended doses of aplidine were 5 and 7 mg/m(2) without and with carnitine, respectively. The role of carnitine will be further explored in phase II studies.

Drug insight: gastrointestinal and hepatic adverse effects of molecular-targeted agents in cancer therapy.

Recent advances in the understanding of molecular mechanisms of cancer have led to the development of novel compounds that target specific cancer pathways. These drugs encompass monoclonal antibodies and tyrosine and non-tyrosine kinase inhibitors, and have been approved by the FDA and the European Medicines Agency, among others, for cancer treatment. These agents are associated with several toxic effects including potentially unacceptable gastrointestinal adverse effects. Diarrhea and hepatotoxicity, the most common adverse events experienced with these treatments, can frequently lead to treatment discontinuation and consequently decreased cancer control. We review the incidence and clinical patterns of the gastrointestinal and hepatic toxic effects induced by the main molecular-targeted therapies and propose some hypotheses for the causes of each adverse event.

Leukemoid reaction, bone marrow invasion, fever of unknown origin, and metastatic pattern in the natural history of advanced undifferentiated carcinoma of nasopharyngeal type: a review of 255 consecutive cases.

PURPOSE This study is an analysis of frequency and relationship regarding two undifferentiated carcinoma of nasopharyngeal type (UCNT)-associated paraneoplastic syndromes (PNS): leukemoid reaction (LR) and fever of unknown origin (FUO) with bone marrow invasion (BMI) and metastatic pattern. PATIENTS AND METHODS A consecutive UCNT patient cohort (N = 255) with locally advanced (n = 142) or metastatic (n = 113) disease receiving chemotherapy alone or in combination with radiotherapy was studied. All patients had a complete baseline work-up that included bone marrow biopsy. RESULTS UCNT has distinctive features among head and neck squamous cell cancers (HNSCC). These include early subclinical dissemination, with 70% of metastases appearing within 18 months of first symptoms. Metastases are common in bone (65% v 25% in HNSCC), liver (29% v 23%), and lung (18% v 84%), and BMI is observed in 25% of UCNT patients with metastases. Metastases likelihood is related to lymph node involvement, with 64% of patients with metastases having N3 disease. Involved lymph nodes in contrasted CT scans revealed hypodensity in 26% of UCNT patients versus 79% in patients with other HNSCC. Hypercalcemia was observed in one case. LR was identified in 41 patients (16%); in 26 of the 41 patients (64%) it was observed concomitant with N3 and/or metastatic disease. FUO was found in 23 patients (9%) and was associated in four instances with BMI and in 17 with LR (in four instances with both). Brain metastases or meningeal carcinomatosis were not observed despite the high rate of skull base compromise. Paraneoplastic signs were observed in 47 of 255 cases (18.5%) and were more frequent in patients with metastases. However, PNS were observed in 15 patients with negative metastases work-up. CONCLUSION The PNS described could help in the diagnosis and follow-up of UCNT patients because they may be the first manifestation of the disease or may reappear with relapse. BMI is a frequent finding in patients with metastases and is unrelated to PNS.

Very accelerated radiation therapy: Preliminary results in locally unresectable head and neck carcinomas

PURPOSE To report preliminary results of a very accelerated radiation therapy Phase I/II trial in locally advanced head and squamous cell carcinomas (HNSCC). METHODS AND MATERIALS Between 01/92 and 06/93, 35 patients with an unresectable HNSCC were entered in this study. Thirty-two (91%) had Stage IV, and 3 had Stage III disease. The mean nodal diameter, in patients with clinically involved nodes (83%), was 6.3 cm. The median Karnovsky performance status was 70. The treatment consisted of a twice daily schedule (BID) giving 62 Gy in 20 days. RESULTS In all cases, confluent mucositis was observed, which started about day 15 and resolved within 6 to 10 weeks. Eighty percent of patients had enteral nutritional support. The nasogastric tube or gastrostomy was maintained in these patients for a mean duration of 51.8 days. Eighteen patients (53%) were hospitalized during the course of treatment due to a poor medical status or because they lived far from the center (mean 25 days). Nineteen patients (56%) (some of whom were initially in-patients) were hospitalized posttreatment for toxicity (mean 13 days). Five patients (15%) were never hospitalized. During the follow-up period, 12 local and/or regional failures were observed. The actuarial 18-month loco-regional control rate was 59% (95% confidence interval, 45-73%). CONCLUSIONS The dramatic shortening of radiation therapy compared to conventional schedules in our series of very advanced HNSCC resulted in: (a) severe acute mucosal toxicity, which was manageable but required intensive nutritional support in all cases; and (b) high loco-regional response rates, strongly suggesting that the time factor is likely to be critical for tumor control in this type of cancer.

Palliative treatment with low-dose continuous infusion 5-fluorouracil in recurrent and/or metastatic undifferentiated nasopharyngeal carcinoma type

Low‐dose protracted continuous infusion (CI) 5‐fluorouracil (5‐FU), as proposed by Lokich et al, has been reported to be active and well tolerated in colorectal and breast cancers. We initiated a phase II trial with CI 5‐FU in heavily pretreated undifferentiated carcinoma of the nasopharyngeal type (UCNT) patients in February 1989.

Phase I–IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours

PURPOSE BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514. PATIENTS AND METHODS In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD. RESULTS In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (≥4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways. CONCLUSION This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib.

A phase I, dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours

Background:Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours.Methods:Sunitinib was initially administered once daily at 37.5 mg per day on days 1–14 of a 21-day cycle, in which irinotecan 250 mg m−2 was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies.Results:In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug–drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1–14) with irinotecan 250 mg m−2 (day 1), but no activity was observed at this dose.Conclusion:Although a higher sunitinib dose of 37.5 mg per day (days 1–14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies.

Nasopharyngeal cancer, undifferentiated type: The medical oncologist’s viewpoint

Nasopharyngeal carcinoma (NPC) has been dealt with separately by head and neck specialists ever since the description of its particular histopathologic characteristics simultaneously, but separately, by Schmincke [1] and Regaud and Reverchon [2].

Phase I-II Trial of Recombinant Interferon Alpha-2b with Cisplatin and 5-Fluorouracil in Recurrent and/or Metastatic Carcinoma of Head and Neck

The aims of this study were to establish the feasibility and toxicity of the biochemical modulation of the cisplatin (CDDP)-5FU combination by interferon alpha-2b (INF), and to assess its therapeutic efficacy in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The mandatory eligibility criteria included histologically proven SCCHN; a performance status <2; adequate bone marrow, hepatic, renal, and cardiac functions; and measurable and/or evaluable disease. The protocol was CDDP, 100 mg/m2 i.v. day 1; 5-FU, 1,000 mg/m2 in a c.i.v. infusion over 96 h; and INF 3.10(6) U/day s.c., begun 2 h before cisplatinum for 5 consecutive days, repeated every 3 weeks. Twenty patients were included and received 76 cycles (median number cycles/patient = three). Eighteen patients were evaluable for activity with an overall response rate (RR) of 30% [2 complete responses (CR) + 4 partial responses (PR)], which was 55% (5/9) in previously untreated and 9% (1/11) in previously treated patients. Myelosuppression (50%), mucositis (40%), loss of electrolytes (15%), and asthenia (20%) were the most frequent severe toxic effects. Notwithstanding, the protocol was feasible and well tolerated in this overall population with a poor prognosis. Median duration of response was 8 months, and median survival for the overall population was 8.5 months. This schedule is the test arm of an ongoing international multicentric phase III trial versus standard CDDP-5FU in the same SCCHN population.