Full dose reirradiation combined with chemotherapy after salvage surgery in head and neck carcinoma.

BACKGROUND: The purpose of this study was to analyze the tolerance and efficacy of full dose reirradiation combined with chemotherapy in patients with head and neck carcinoma (HNC) with a high risk of recurrence after salvage surgery. METHODS: Between 1991 and 1996, 25 patients having a recurrence or a second primary tumor in a previously irradiated area (> 45 grays [Gy]) were entered in this prospective study. All of them received salvage surgery and had a positive surgical margin and/or lymph node involvement with capsular rupture (N+R+). Adjuvant radiochemotherapy was given, delivering 60 Gy per 30 fractions with concomitant hydroxyurea and 5-fluorouracil. The median total cumulative dose of the 2 irradiations was 118 Gy. The median follow-up after the second irradiation was 66 months. RESULTS: During the reirradiation course, Grade 3 and 4 mucositis were observed in 40% and 12%, respectively. Analysis of late effects (> 6 months after reirradiation) showed that 16% of the patients had osteoradionecrosis and 40% had Grade 2-3 cervical fibrosis (Radiation Therapy Oncology Group scoring system). The patterns of failure were as follows: local only (n = 9), lymph node only (n = 2), local and lymph node only (n = 1), and metastatic (n = 4). The 4-year survival rate after reirradiation was 43% (95% confidence interval, 25-62). CONCLUSIONS: Full dose reirradiation combined with chemotherapy after salvage surgery in high risk patients with HNC was feasible with an "acceptable" toxicity and led to a relatively good 5-year survival rate. These results prompted the authors to initiate a multicentric randomized trial that is ongoing (GETTEC-GORTEC 99-01) to evaluate the benefit of adjuvant radiochemotherapy in these types of patients.

Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. French Groupe d'Etude des Tumeurs de la Tête et du Cou (GETTEC).

The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer. Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric randomized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy. The loco-regional treatment consisted either of surgery plus plus radiotherapy or of radiotherapy alone. Three cycles of chemotherapy consisting of Cisplatin (100 mg/m2) on day 1 followed by a 24-hour i.v. infusion of fluorouracil (1000 mg/m2/day) for 5 days were delivered every 21 days. 2-3 weeks after the end of chemotherapy, local treatment was performed. The trial was conducted by the Groupe d'Etude des Tumeurs de la Tête Et du Cou (GETTEC). A total of 318 patients were enrolled in the study between 1986 and 1992. Overall survival was significantly better (P = 0.03) in the neoadjuvant chemotherapy group than in the control group, with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group. The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance (P = 0.11). Stratification of the results on the type of local treatment, surgery plus radiotherapy or radiotherapy alone, did not reveal any heterogeneity in the effect of chemotherapy.

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.

Antitumor electrochemotherapy: new advances in the clinical protocol.

BACKGROUND: 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. METHODS: Seven patients with multiple and/or large permeation nodules of HNSCC or of salivary or breast adenocarcinoma were treated in 10 sessions. They received BLM followed by runs of four or eight short (100 microseconds) and intense (1000 or 1300 V/cm-1) EP delivered at adjacent positions on the nodules to cover all of the tumor surface. RESULTS: We determined the therapeutic window for EP delivery to be between 8 and 28 minutes after BLM intravenous injection. We showed patient tolerance to a high number of EP, along with ECT feasibility after BLM intraarterial injection or on adenocarcinoma nodules. Clear antitumor effects were obtained, especially in the small nodules. In the largest nodules we observed extended tumor necrosis. CONCLUSIONS: Relatively efficient ECT can be performed for large and think nodules, and ECT remains safe even when a large number of EP are delivered. However, in this study, ECT's effectiveness on large nodules was lower than on the previously treated small nodules, probably due to external electrodes inadequacy. The data reported stimulated us to design a new device for EP delivery.

[Perioperative chemotherapy of squamous cell carcinoma of the hypopharynx]. / Chimiothérapie périopératoire des carcinomes épidermoïdes de I'hypopharynx.

The aim of this prospective study was to decrease the rate of locoregional recurrence (LRR) and distant metastasis (DM) with a multi-modality approach in hypopharyngeal squamous cell carcinoma (HSCC). Patients presenting with squamous cell carcinoma of the pyriform sinus, epilarynx or postcricoid area with indication of pharyngolaryngectomy, without previous treatment, distant metastasis, multiple primaries or general contraindications for surgery and chemotherapy were included in the study. Patients received three consecutive cycles of chemotherapy (CDDP cisplatinium 100 mg/m2 D1, 5-FU 1 g/m2 D1 to D5) before surgery, then two postoperative courses of the same chemotherapy at day 10 and 31 after surgery. Postoperative radiotherapy was initiated at day 50. Between 1986 and 1989, of 198 patients with HSCC, 60 were included in this study. Tumour response of the induction chemotherapy was: no response (NR): 22; partial response (PR): 25; complete response (CR): 11; non evaluable: 2. Forty-seven patients underwent surgery. Only two patients had no viable tumour in the surgical specimen and two others only keratin debris. Of 39 patients in which protocol treatment was respected, 4 LRR, 4 LRR + DM, 8 DM, three second head and neck primaries, and one acute myeloblastic leukemia were observed. Results were compared with those of historical series, with the same mean delay of follow up. The rate of survival at 2 and 5 years was 78% and 42% in the present series, while it was 77% and 33% in the control group, respectively (NS).

Electrochemotherapy, a new antitumor treatment. First clinical phase I-II trial.

BACKGROUND: Electrochemotherapy is a new antitumor treatment consisting of electrical pulses administered to the tumor several minutes after intravenous injection of bleomycin. In mice, important antitumor effects were observed on subcutaneously transplanted tumors and on spontaneously occurring mammary carcinomas. Cures were obtained after one single treatment combining bleomycin and electric pulses. In humans, permeation nodules seemed an adequate oncologic situation to assay this new procedure. The authors report the first Phase I-II trial of electrochemotherapy. METHODS: Eight patients with 40 permeation nodules of head and neck squamous cell carcinomas were treated with 10 mg/m2 bleomycin intravenous bolus, followed by four or eight short (100 microseconds) and intense (1300 V/cm) pulses administered through two external electrodes located on each side of the treated nodule. RESULTS: An instantaneous painless contraction of the underlying muscles was regularly observed. Neither local nor general side effects were observed, and electrochemotherapy was well tolerated. In addition, a clear local antitumor efficacy was found: 23 (57%) nodules were in clinical complete response within a few days. CONCLUSION: The absence of toxicity, the good tolerance by the patients, and the net antitumor effects observed are encouraging for additional electrochemotherapy developments in clinical oncology.

Correlation between nodal density in contrasted scans and response to cisplatin-based chemotherapy in head and neck squamous cell cancer: a prospective validation.

This prospective study was done to validate an earlier retrospective study demonstrating a relationship between complete response to chemotherapy and nodal density as estimated in contrasted computed tomography (CT scans) in head and neck squamous cell carcinoma (HNSCC). CT scans of 36 patients were evaluated by two radiologists blinded to therapeutic outcome. The density of the largest node (> 2 cm) was compared to that of nuchal muscles. A node was classified as hypodense if more than 33% of the nodal surface area consisted of hypodense zones. Density and nodal staging were related: 67% (10 of 15) of patients with N3 disease but only 29% (six of 21) with N1-N2 exhibited isodensity, p < 0.05. Complete response to chemotherapy was noted in 63% (10 of 16) of the isodense group but only in 15% (three of 20) of the hypodense group, p < 0.01. We believe that nodal density can be used for therapeutic decision-making in high nodal volume HNSCC.

Neoadjuvant chemotherapy in multiple synchronous head and neck and esophagus squamous cell carcinomas.

A consecutive series of 22 patients with multiple synchronous squamous cell carcinomas of the upper aerodigestive tract was retrospectively reviewed. These patients were treated initially with cis-platinum combination chemotherapy before definitive locoregional therapy (surgery and/or radiation therapy). Sixteen of 21 patients had simultaneous head and neck and esophageal primaries, 3 patients had multiple synchronous head and neck primaries, 2 patients had head and neck (HN) and a bronchial epidermoid cancer, and 1 patient had simultaneous esophageal and bronchial carcinomas of epidermoid lineage. Sixteen (77%) of the 21 patients responded to chemotherapy in all the tumor sites evaluated, and a clinically complete response was obtained in 6 (29%). After definitive locoregional treatment, the complete local control rate was 68%, with 34 complete responses for 50 primary tumor sites in 21 patients. Twelve patients were free of disease after locoregional treatment. Six patients are still alive 27 to 57 months after complementary definitive locoregional treatment and a minimum follow-up of 27 months. Median survival for the overall group is 17 months. The response to chemotherapy is remarkable, which may be due to the small tumoral volume present in many of the cases (T1 to T2). Nevertheless, the present report stresses the importance of an aggressive combined therapeutic approach in this difficult clinical situation.

[Electrochemotherapy, a new antitumor treatment: first clinical trial]. / L'électrochimiothérapie, un nouveau traitement antitumoral: premier essai clinique.

Electrochemotherapy (ECT) is a new antitumor treatment which consists in delivering electric pulses to the tumor some minutes after an intravenous injection of bleomycin. We report here the first clinical trial of ECT, applied to patients with permeation nodules of head and neck squamous carcinomas. ECT was well tolerated by patients, no serious incident occurred and a clear antitumor efficiency was found.