Long-term follow-up of chemotherapy in advanced head and neck cancer

We treated 94 patients with advanced head and neck cancer with a combined-modality protocol that included induction chemotherapy followed by surgery with and without radiotherapy. With a minimum follow-up of 3 1/2 years, 33 (35%) of the patients were alive and disease free. Thirty (32%) of the patients died of recurrent head and neck cancer. Complete response to chemotherapy and initial tumor bulk correlated with prolonged disease-free survival. Site of disease had no effect. There appeared to be no advantage to the use of routine postoperative radiotherapy in these advanced tumors.     

Current role for induction chemotherapy in head and neck tumors

According to recent publications in the New England Journal of Medicine (TAX323, TAX324) of the study groups around Jan Vermorken and Marshall Posner induction chemotherapy in squamous cell carcinomas of the head-neck area (in the closer: Oro-hypopharynx, oral cavity and larynx) currently seems to generate a worldwide renaissance. Renaissance, because in the last few decades, induction chemo therapy in this group of tumors after lack of survival improvement in the vast majority of studies was again abandoned. The new data raise the question for which entities induction chemo therapy can be recommended (actually, a combination of docetaxel, cisplatin and 5-fluorouracil; TPF)? The unbroken high value of primary surgery with adjuvant radiation or chemo radiation was complementary to primary radio chemotherapy for non resectable tumors until today worldwide. Running studies are sorting out the role of induction chemotherapy in the current context of clarifying optimal multimodal treatment.     

Current use of chemotherapy for head and neck cancer

A postal survey of 100 members of the Association of Head and Neck Oncologists of Great Britain was conducted in the first 6 months of 1983. The sample consisted principally of Otolaryngologists (50 per cent), Radiotherapists (14 per cent), Medical Oncologists (10 per cent), Oral Surgeons (10 per cent) and Plastic Surgeons (10 per cent). More than 80 per cent of those who completed the questionnaire used chemotherapy for Head and Neck cancer (72 per cent used it for palliation, and 64 per cent as part of combined modality therapy). There was great variation in the chemotherapeutic regimens used by the various responders. Furthermore, most responders used more than one regimen. Methotrexate was the agent most frequently used. No specific regimen, either single-agent or multiple-agent, enjoyed universal acceptance, although the combination of Vincristine, Bleomycin and Methotrexate was popular. Chemotherapy was thought by most responders to have a useful but as yet undefined place in the management of Head and Neck cancer. This survey underlines the need for prospective, controlled, clinical trials into the efficacy of cytotoxic chemotherapy for Head and Neck cancer.     

Pretreatment with chemotherapy in patients with advanced head and neck cancer

Average survival for advanced head and neck cancer (AHNC) is 18 months. In an attempt to improve this we treated 29 AHNC patients between 1978-82 with two courses of chemotherapy. Chemotherapy consisted of cyclophosphamide, methotrexate, 5 fluorouracil and bleomycin; or bleomycin, cisplatinum and methotrexate. Chemotherapy was given prior to definitive therapy of radiotherapy or radiotherapy and surgery. All patients were stage 3 or 4. All patients were Eastern Co-operative Oncology Group status performance 0 or 1. Response to chemotherapy did not improve survival. Pretreatment with chemotherapy should be investigational until increased survival has been documented.     

Organ preservation in locally advanced head and neck cancer of the larynx using induction chemotherapy followed by improved radiation schemes

The present prospective study seeks to evaluate overall and disease free survival, response and organ preservation rate, and toxicity of an intensive chemotherapy regimen (CT) followed by unconventional radiotherapy (RT) in patients with locally advanced operable head and neck cancer. Between January 1998 and December 2006 (June 2005), 115 patients with locally advanced, operable head and neck cancer were evaluated. A total of 333 cycles of neoadjuvant CT (cisplatin–5FU, days 1, 14, 28) followed by hyperfractionated/accelerated radiotherapy were given to 108 patients. A total of 108 patients were evaluable and received the planned CT–RT treatment. Two months after the end of RT, 97.2% of patients had a clinical complete remission of the primary and 67.5% of the neck node site. The overall survival was 55% and cause-specific survival was 73% at 5 years. Of the 33 relapsed patients, 12 recurred only at the primary site and 10 patients had distant metastases. The overall organ preservation rate was 73.5%. The chemotherapy regimen reported an overall cardiotoxicity from 5FU in 14% of patients, with severe toxicity in 3%. The radiotherapy schedule developed 84% of Grade 3–4 mucositis in the observed patients. The accelerated CT–RT regimen is able to achieve a high rate of larynx preservation, a good tolerability, and a satisfactory cause-specific overall survival.     

The chemotherapy of head and neck cancer

Chemotherapy in head and neck cancer can be given in metastatic disease at presentation, in locally far advanced disease not amendable for curative treatment with surgery and/or radiotherapy, in the neo-adjuvant setting, in recurrent disease after previous surgery and radiotherapy and either concurrent or alternating with radiotherapy. Most data are gathered in the recurrent and locally far advanced disease setting. Combination therapy (with agents such as cisplatinum, 5-FU and methotrexate) have shown some improvements in response rate, however no obvious survival advantage over monotherapy in the treatment of patients with metastatic or advanced locoregional cancer of the head and neck has been observed. In the neo-adjuvant setting, chemotherapy is helpful in preserving the larynx and hypopharynx but has no proven impact (positive or negative) on survival. New compounds and approaches are needed to improve survival in head and neck cancer. Among the new options for chemotherapy in metastatic/recurrent disease are the taxanes. With monotherapy docetaxel, response rates of 23%-42% are seen, and, when used in combination with cisplatinum and 5-FU, response rates of 52-100% have been reported in phase I/II trials. A phase III trial of the addition of docetaxel to standard neo-adjuvant therapy with cisplatinum and 5-FU is now underway.     

Polymer chemotherapy for head and neck cancer

OBJECTIVES: To study a new method of delivery of chemotherapy for the treatment of squamous cell carcinomas (SCCs) of the head and neck, to evaluate the pharmacokinetics of four anticancer agents (cisplatin, fluorouracil [5-FU], methotrexate [MTX], and paclitaxel) loaded into the biodegradable polymer, polyanhydride polymer poly(FAD:SA), and to evaluate the effectiveness and toxicity of the drug-polymer combination against human SCCs, both in vitro and in vivo. STUDY DESIGN: Poly(FAD:SA) was loaded with different chemotherapeutic drugs and its in vitro and in vivo drug release and tissue penetration characteristics were studied. The biocompatibility and toxicity of the polymer-drug combination were determined. The effectiveness of the drug-polymer was evaluated against three different human SCCs (larynx O11, pharynx FADU, and floor of mouth UM- SCC1) cultured in vitro and in nude mice carrying human SCC xenografts. METHODS: The in vitro drug release pharmacokinetics of the drugs were performed using atomic absorption spectrometry for cisplatin and high-pressure liquid chromatography for the 5-FU, MTX, and paclitaxel studies. In vitro tumor cytotoxicity was assessed by growth assay. In vivo cytotoxicity was assessed by growth rate inhibition in a nude mouse model. RESULTS: All four chemotherapy drugs demonstrated a continuous release that followed first-order kinetics from the polymer. More than 95% of the MTX and 5-FU, 70% of the cisplatin, and 20% of the paclitaxel was released within the 10 days of the assay. Tumor cytotoxicity revealed that the polymer was very effective against the human SCCs O11, FADU, and UM- SCC1 in vitro. When a small amount of polymer (1-2 g) was added to the cell culture and left for 7 days, 96.6% of the UM-SCC1 cells, 86.9% of the FADU cells, and 94.6% of the O11 cells were killed. When the culture medium was then changed every 2 days to remove the effect of nutrient depletion or chemicals released by the degrading polymer, 74% of the UM-SCC1 cells, 94.5% of the FADU cells, and 66.1% of the O11 cells were killed at 7 days. The tumor animal model was the nude mouse carrying human floor of mouth SCC xenografts. Different amounts of cisplatin were incorporated into the polymers (5% and 7% drug/polymer at a weight/weight [wt/wt] load). Thirty-five days after implantation of the polymer in nude mice, the mean treated tumor size was 65.5% of controls in the 5% group and 31.8% in the 7% group. Seventy days after implantation the mean treated tumor size was 41.4% of controls in the 5% group and 38.1% in the 7% group, indicating a statistically significant delay of tumor growth compared with controls or with intraperitoneally injected cisplatin. The blank polymer was well tolerated by the mouse and had no effect on tumor growth. CONCLUSIONS: The study results indicate that polymer chemotherapy is effective against a variety of SCCs of the head and neck, both in vitro and in vivo, and may become a useful therapeutic option for head and neck cancer.     

A preliminary report on the combination of initial chemotherapy and radiotherapy for advanced head and neck cancer

A RETROSPECTIVE review of 45 patients with advanced squamous cell carcinoma of the head and neck treated by a combination of initial chemotherpy (Price and Hill Schedule A) followed by radiotherapy is presented. The regime produced excellent immediate palliation with a tumour control of 50 per cent, and a disease-free survival of 33 per cent at one year and 27 per cent at two years. Treatment morbidity was minimal in an aged patient group.     

Induction chemotherapy in advanced head and neck cancer. A Radiation Therapy Oncology Group Study

Cisplatin (cis-platinum, 100 mg/m2) and fluorouracil (1000 mg/m2/d), for 120 hours' infusion every three weeks for three courses, produced a 93% overall response rate and a 54% complete clinical response at the single-institution level. The same combination was tested in the Radiation Therapy Oncology Group to evaluate the effectiveness and feasibility of this combination. An overall response rate of 86% was obtained, with a 38% complete clinical response. Only 27 of 42 patients completed planned surgery. Compliance with chemotherapy and radiation therapy was substantially better. No additional morbidity after surgical resection or postoperative radiation therapy was identified as secondary to the induction chemotherapy. We conclude that the combination of cisplatin and fluorouracil infusion is effective, with high complete clinical response rate in patients with advanced, previously untreated head and neck carcinoma.     

Preoperative chemotherapy in advanced resectable head and neck cancer: final report of the Southwest Oncology Group

In 1980, the Southwest Oncology Group instituted a multi-institutional, prospective, randomized phase III trial to evaluate whether inductive chemotherapy improved survival in patients with advanced stage resectable squamous cell carcinoma of the head and neck. From a group of 158 eligible patients, 76 were randomized to conventional treatment (surgery and postoperative radiotherapy), and 82 were assigned to experimental treatment (induction chemotherapy, surgery, postoperative radiotherapy). Median follow-up for living patients was approximately 5 years. These analyses include chemotherapy responses and toxicities, surgical complications, radiotherapy toxicities, patient compliance, survival time, and patterns of treatment failure. Overall chemotherapy response was 0.70 (0.19 CR, 0.51 PR). The median survival time for conventional treatment was longer than the time for patients receiving preoperative chemotherapy, although the survival time differences were not statistically significant. This final analysis demonstrates no benefit in survival using preoperative chemotherapy for advanced stage, resectable head and neck squamous cell carcinoma.     

Current concepts of chemotherapy combined with other modalities for head and neck cancer.

This paper presents an overview of studies of therapy of head and neck squamous cell carcinoma in which chemotherapy was combined with other modalities. The rationale for using chemotherapy with surgery is discussed, but ststematic studies of this combination of modalities have not been reported. Systemic chemotherapy plus radiation therapy has been studied using hydrozyurea, t-fluorouracil (5-FU), and methotrexate (MTX). Uncontrolled studies with hydroxyurea report favorable results, but a well-controlled study gave negative results. Controlled studies with 5-FU have given favorable results in certain tumor stages and sites of origin. MTX plus radiation in a small series produced slightly better survival than radiation alone. Intra-arterial chemotherapy plus radiation therapy has been the subject of exploratory studies but no firm conclusions can be drawn from these studies. Chemotherapy plus immunotherapy has been explored and merits further study. Based on the studies reported to date one can suggest the need for large-scale randomized control studies of long-term chemotherapy combined with other modalities.     

The prognostic influence of induction chemotherapy on advanced head and neck carcinoma

We examined the influence of induction chemotherapy integrated with surgery and postoperative radiotherapy on 5-year treatment results of 107 patients suffering from advanced head and neck carcinomas. The chemotherapy regimen consisted of one to three cycles of a combination of cisplatin, methotrexate and bleomycin. The overall response rate to induction chemotherapy was 58% with a 26% complete response rate. Using actuarial life tables, survival was 44% for all patients. The initial tumor stages were found to be predictive for patients' responses to chemotherapy as well as for their survivals. The overall response rate was 65% for T-3 tumors vs 29% for T-4 tumors. Five-year survival was 54% for T-3 vs 24% for T-4 tumors. The other predictive factor for survival was response to chemotherapy. Five-year survival was 73% for those patients achieving a complete response vs 17%-37% for patients with any residual disease after drug treatment. Since a favorable response to chemotherapy was strongly associated with a lesser T-stage as well as with significantly better survival of patients in our study, we conclude that induction chemotherapy may best benefit those patients with smaller tumors. Our findings show that a complete response to chemotherapy can also serve as a good prognostic sign, although an a priori better prognosis is still associated with patients who have smaller tumors.     

Treatment of the clinically negative neck in advanced cancer of the head and neck

The proper management of the clinically negative neck in primary squamous cell carcinomas of the head and neck remains controversial. Although many clinicians believe that elective neck dissection or neck irradiation are equally effective for controlling subclinical disease, previous studies have not directly addressed this question. The charts of 195 patients with advanced primary squamous carcinoma, yet with clinically negative necks, were reviewed. There were no significant differences in the rates of neck cancer recurrence among the elective neck irradiation, dissection, and combined treatment groups. Elective neck irradiation and neck dissection in patients with clinically negative nodes seemed equivalent in their ability to control neck disease. The decision as to which form of therapy is preferable must therefore be based on other criteria.