C. Domenge

Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data

BACKGROUND Despite more than 70 randomised trials, the effect of chemotherapy on non-metastatic head and neck squamous-cell carcinoma remains uncertain. We did three meta-analyses of the impact of survival on chemotherapy added to locoregional treatment. METHODS We updated data on all patients in randomised trials between 1965 and 1993. We included patients with carcinoma of the oropharynx, oral cavity, larynx, or hypopharynx. FINDINGS The main meta-analysis of 63 trials (10,741 patients) of locoregional treatment with or without chemotherapy yielded a pooled hazard ratio of death of 0.90 (95% CI 0.85-0.94, p<0.0001), corresponding to an absolute survival benefit of 4% at 2 and 5 years in favour of chemotherapy. There was no significant benefit associated with adjuvant or neoadjuvant chemotherapy. Chemotherapy given concomitantly to radiotherapy gave significant benefits, but heterogeneity of the results prohibits firm conclusions. Meta-analysis of six trials (861 patients) comparing neoadjuvant chemotherapy plus radiotherapy with concomitant or alternating radiochemotherapy yielded a hazard ratio of 0.91 (0.79-1.06) in favour of concomitant or alternating radiochemotherapy. Three larynx-preservation trials (602 patients) compared radical surgery plus radiotherapy with neoadjuvant chemotherapy plus radiotherapy in responders or radical surgery and radiotherapy in non-responders. The hazard ratio of death in the chemotherapy arm as compared with the control arm was 1.19 (0.97-1.46). INTERPRETATION Because the main meta-analysis showed only a small significant survival benefit in favour of chemotherapy, the routine use of chemotherapy is debatable. For larynx preservation, the non-significant negative effect of chemotherapy in the organ-preservation strategy indicates that this procedure must remain investigational.

Antitumor electrochemotherapy: New advances in the clinical protocol

Electrochemotherapy (ECT) is a new antitumor approach that combines systemic bleomycin (BLM) with electric pulses (EP) delivered locally at the tumor site. These EP permeabilize the cells in the tissue, allow BLM delivery inside the cells, and increase BLM cytotoxicity. As an extension of our initial Phase I trial on patients with head and neck squamous cell carcinoma (HNSCC) permeation nodules, we tested variations of ECT protocol to determine how to improve it.

Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study

Patients who are cured from head and neck carcinomas remain at high risk for developing a second primary in the head and neck area. It is now clear that retinoids exert a prophylactic action on the development of epithelial cancers when tested on laboratory animals and on human premalignant lesions. They are now used in the chemoprevention of epithelial cancers in randomised trials evaluating their efficacy. We prospectively studied 316 patients who developed squamous cell carcinoma of the head and neck, classified as T1/T2, N0/N1 < or 3 cm, M0 according to the UICC TNM classification. Patients were randomly assigned to receive orally, either etretinate (a loading dose of 50 mg/day for the first month, followed by a dose of 25 mg/day in the following months) or a placebo for 24 months. Adjuvant treatment began no later than 15 days after surgery and/or the initiation of radiotherapy. The 5-year survival rate and disease-free survival rate are similar in the two groups. There are no significant differences regarding either local, regional and distant relapses. After a median follow-up of 41 months (range 0-81), 28 patients in the etretinate group and 29 in the placebo group developed a second cancer with, respectively, 12 and 13 in the head and neck region. Adjuvant treatment was definitively discontinued mainly due to toxicity in 33% of patients in the etretinate group versus 23% in the placebo group (P < 0.05). Etretinate, a second-generation retinoid, does not prevent second primary tumours in patients who have been treated for squamous cell carcinoma of the oral cavity and oropharynx.

A phase II study of docetaxel in patients with metastatic squamous cell carcinoma of the head and neck

SummaryThis study was designed to evaluate the activity, safety and tolerance of docetaxel (D) in a selected population with metastatic squamous cell carcinoma of the head and neck (SCCHN). Twenty-four patients with no prior palliative therapy were enrolled and received D 100 mg m–2 by 1 h of infusion, every 3 weeks. All but two patients had been evaluated for efficacy on lung metastatic sites. No prophylactic administration of anti-emetics or growth factors was given. A pharmacokinetic study was performed in 22 patients. Twenty-one patients were assessable for response and 24 for toxicity. One hundred and four cycles were administered with a median of 4.5 (range 1–9) per patient. The median cumulative dose was 449 mg m–2. Partial responses were achieved in five patients with a median duration of 18.7 weeks (range 13.1–50.3). The overall response rate was 20.8% with a median duration of 11.0 weeks (range 2.4–52.6). The most frequent side-effect was neutropenia (79.2% grade IV) but with a short duration (median 4 days) and no febrile neutropenia. The incidence of moderate/severe fluid retention was 29.2% with one treatment discontinuation. Other toxicities (all grades) were common (skin 75%, asthenia 50%, infection 29.2%, nausea 16.7%, diarrhoea 12.5%, stomatitis 16.7%, vomiting 8.3% and HSR 8.3%). A mean clearance of 19.6 l h–1 m–2 and an area under the curve of 6.00 μg ml–1 h–1 was found in the pharmacokinetic analysis. Docetaxel is active in this selected population with metastatic SCCHN, with a good tolerance.

Adjusting for patient selection suggests the addition of docetaxel to 5-fluorouracil-cisplatin induction therapy may offer survival benefit in squamous cell cancer of the head and neck.

When induction chemotherapy is used in locally advanced squamous cell cancer of the head and neck (SCCHN), patients often receive cisplatin–5-fluorouracil (PF) followed by radical loco-regional therapy. Phase II studies of docetaxel–cisplatin–5-fluorouracil (TPF) induction therapy, with or without leucovorin (L), have achieved high survival rates versus those reported in phase III PF trials. However, the distribution of prognostic factors may vary between phase II and phase III study populations, making the extrapolation of phase II TPF/L results to phase III PF populations difficult. This study used a patient selection standardization method and Cox model to adjust for potential selection bias. Thus, the survival benefit from adding docetaxel into PF induction regimens in SCCHN could be more accurately assessed. The TPF/L dataset comprised 195 patients from six phase II trials. The PF dataset of 585 patients was derived from five large randomized trials included in the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) database. TPF/L and PF datasets differed significantly concerning the distribution of several prognostic factors. Adjusting for these differences, the relative risk of death in the PF versus TPF/L datasets was 1.85 (95% confidence interval 1.37–2.49), corresponding to a 20% 2-year survival benefit (p<0.0001). Sensitivity analyses confirmed that this improved 2-year survival rate of TPF/L over PF was robust, irrespective of the distribution of studied prognostic factors between treatment datasets. We conclude that this improved survival might be due either to docetaxels pharmacologic effect or to uncontrolled prognostic factors.

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.

Recurrent and/or metastatic head and neck squamous cell carcinoma: A clinical, univariate and multivariate analysis of response and survival with cisplatin-based chemotherapy†

One hundred two patients with recurrent and/or metastatic head and neck squamous cell cancer were entered into four consecutive phase II trials, all cis‐platinum (C‐DDP, 100 mg/m2/cycle)‐based. The two combinations tried were C‐DDP, bleomycin, and fluo‐rouracil (CFB) on 54 patients, and cisplatinum and vindesin in 36 patients (CV). The CFB combination was given with C‐DDP by continuous infusion over 96 hours (23 patients) or on day 1 (31 patients). The CV regimen was also given in two different schedules, with VDS at 3 mg/m2/g weekly (12 patients) or by a 96‐hour continuous infusion (0.6 to 1.0 mg/m2/d) in 24 patients. The following variables: sex, age, performance status, previous therapy, local recurrence, length of disease‐free interval (DFI), distant metasta‐ses, weight loss, primary site, histological differentiation, type of chemotherapy, previous chemotherapy, evaluable/measurable disease, erythrosedi‐mentation rate, and their relation with response to chemotherapy (WHO) and survival were submitted to both univariate and multivariate analysis (Cox). Overall response rate (RR:CR+PR) was 25 (28%) of 90. In the CFB protocols, RR was 12 (22%) of 54 us. 13 (38%) of 36 (P = 0.15, NS) in the CV combination group. For the four different combinations the RR was CFB C‐DDPci 7 (30%) of 23, CFB C‐DDP 1 hour 5 (16%) of 31, CV VDS weekly 2 (17%) of 12, CV VDSci 11 (45%) of 24. The patient populations were very different, with the latest combination consisting of metastatic patients exclusively. Univariate analysis of multiple variables showed age <60 years, PS:0 or 1, no previous therapy, absence of local relapse, metastatic disease, long DFI, and that measurable disease was significant for the probability of response. Median survival was 7 months for the 90 evaluated patients, 5 months for nonresponders, and 9 months for responders (P = 0.01). In the univariate analysis, significant factors for survival were PS:0 or 1, a weight loss below 10%, long DFI, response to chemotherapy, erythro‐sedimentation rate (ESR) of <30 mm/lst hr, presence of bone metastasis, and the number of metastases. Multivariate analysis shows PS, the absence of local relapse, and disease‐free interval as significant prognostic factors for response. Multivariate analysis factors of significance for survival were PS, weight loss, and response to chemotherapy. The analysis of the clinical pattern showed an evolution in RR from 3 (8%) of 36 on previously irradiated local recurrent disease to 8 (73%) of 11 in previously untreated patients with metastatic disease at presentation.

Intensive concomitant chemoradiotherapy in locally advanced unresectable squamous cell carcinoma of the head and neck: a phase II study of radiotherapy with cisplatin and 7-week continuous infusional fluorouracil.

PURPOSE To evaluate an intensive concomitant chemoradiotherapy protocol of conventional radiotherapy with intermittent cisplatin (CDDP) and continuous-infusion fluorouracil (5-FU) in unresectable, locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Fifty-seven patients with unresectable stage IV MO disease (International Union Against Cancer [UICC]/American Joint Committee on Cancer [AJCC], 1987) received radiotherapy 70 Gy followed by CDDP 80 mg/m2 and 5-FU 300 mg/m2/d. Response was assessed 2 months after treatment completion. RESULTS Thirty patients (52%) received the full treatment schedule; 53 (93%) received full-dose radiotherapy, while 48 (84%) were given at least 75% of the planned chemotherapy doses. Severe mucositis (World Health Organization [WHO]) grade 3 to 4 was the limiting toxicity and was seen in 79% of patients. The median time for mucositis resolution was 8 weeks. Other toxicities were generally manageable, but there were four treatment related deaths (7%). Fifty patients were assessable for activity, with an overall response rate of 70% (95% confidence interval [CI], 58% to 82%). Complete response (CR) and partial response (PR) rates were 42% and 28%, respectively. CONCLUSION This simultaneous combined-modality regimen was feasible at the cost of severe mucosal toxicity, which required hospitalization with nutritional, parenteral, and hydroelectrolytic support. The high response rate achieved (70%) did not translate into improved survival, probably due to patient eligibility. The likelihood of cure of this high-tumoral-volume patient population remains low (approximately 10%), despite the association of two therapeutic modalities at full standard therapeutic intensity.

A comparative study of the efficacy and safety of fluconazole oral suspension and amphotericin B oral suspension in cancer patients with mucositis

This randomized study compared the efficacy and safety of fluconazole suspension with that of amphotericin B suspension in patients with head and neck cancer who were suffering from candidiasis during cancer treatment with radiotherapy and/or chemotherapy. A total of 123 evaluable patients received 50 mg fluconazole once daily and 120 evaluable patients received 0.5 g amphotericin B thrice daily for 7-14 days depending on clinical response. A positive culture result was obtained in 121 of 264 (46%) patients; Candida albicans was most common. At the end of treatment, fluconazole and amphotericin B were equivalent (CI(90) of -10.7 to +14.9) in terms of clinical cure and improvement, but the rate of mycologic cure was higher for fluconazole (48%) than amphotericin B (35%). The incidence of adverse events was 39% for fluconazole and 44% for amphotericin B. Fluconazole suspension appeared effective and safe.

Salvage chemotherapy in recurrent head and neck cancer: The institut gustave roussy experience

Despite the development of innovative approaches (ie, hyperfractionated radiotherapy, and neoadjuvant or adjuvant chemotherapy) the natural history of squamous cell head and neck cancer (SCHNC) has not changed appreciably. The majority of patients are free of distant metastasis at the time of diagnosis but still present with advanced local disease (stage III or IV). Radical surgery followed by radiotherapy is the standard curative approach for patients with resectable disease (5-year survival >80% in early-stage lesions). The remaining patients, who present with locally advanced disease, have a high probability of relapse within 2 years after the initial treatment (which often includes active chemotherapy). Sixty percent to 70% of relapses are locoregional and 20% to 30% show distant metastases. The patients with recurrent SCHNC are generally offered treatment with chemotherapy. The objective response rates reported vary between 15% to SO%, but median survival does not exceed 9 months, This dismal prognosis reinforces the need to consider patient symptoms and quality of life as essential endpoints of treatment. The approach to recurrent SCHNC must be multidisciplinary to identify (1) which patients are still amenable to curative treatment with surgery, external radiotherapy, and/or brachytherapy, alone or in combination, (2) which patients could benefit from aggressive locoregional therapy, and (3) which patients are can