A prospective study was carried out to investigate the effectiveness and toxicity of three courses of combination high-dose bolus CDDP and 120-hour continuous infusion 5-FU every three weeks prior to definitive surgery and/or radiation therapy in 35 patients with locally advanced Stage I11 and IV squamous cell carcinoma of the head and neck. Twenty-two patients (63%) achieved a CR and 11 (31%) a PR after three cycles of chemotherapy, for an objective response rate of 94%. Toxicity was clinically acceptable. Nausea and vomiting occurred in 23 of 35 (66%) without any patients discontinuing therapy for this reason. Leukopenia in 13 (37%) and reversible azotemia in six (17%). Following three courses of Chemotherapy, 13 patients had surgical resection and 12 patients had radiation therapy. Ten of these 35 patients had no pathologic evidence of cancer in the surgical specimen or preradiation therapy biopsy. Only two patients of those achieving a complete objective response have relapsed. However, the median follow-up has been short. The authors concluded that three courses of CDDP and 5-FU is a highly effective and safe adjuvant treatment in patients with advanced carcinoma of the head and neck. Cancer 51:1353-1355, 1983.

A review of the trends in the clinical practice of esophageal cancer treatment is presented. The preponderance of evidence indicates that concomitant chemotherapy and radiation is superior to either modality above. Chemotherapy usually, but not invariably, consists of 5-fluorouracil (5-FU) and cisplatin; radiotherapy is usually 50 Gy. Attempts to escalate to higher dose by external-beam boost or brachytherapy is still experimental. Combination treatment with surgery is also successful, but the inclusion of esophagectomy in the treatment is not universally accepted and is unlikely to be tested. A suggestion to base treatment selection on response is proposed.

For more than 15 years, active clinical research and continuing efforts in the field of CT in head and neck cancer have produced a modest but definite progress and achievements in this disease. We are a long way away from producing more definitive and acceptable results and higher cure rates in this disease. The achievements of systemic CT in patients with head and neck cancers are summarized in this review. Continuing efforts and investigation are needed to study the efficacy of systemic CT in patients with resectable head and neck cancer. We are continuing to investigate the best timing and sequence of CT as part of CMT and then the efficacy of such treatment in patients with resectable cancer. Efforts are underway to improve on the results in patients with NPC and patients with unresectable disease with the use of chemotherapy as part of CMT. Efforts are also underway to consolidate and improve on the results obtained with systemic CT to preserve laryngeal function. We strongly believe that with continuation of these serious efforts further achievement and impact can be obtained with systemic CT as part of other modalities in these patients.

The traditional treatment of patients with resectable locally advanced (stages III & IV) squamous cell carcinoma of the head and neck has been surgery (S) followed by post-operative radiotherapy (RT). Usually those who receive postoperative radiotherapy are those with stage IV, nodal involvement, or patients with positive surgical margin(s). The overall results in these patients are poor, more than 60 % will recur loco-regionally in spite of the complete removal of all the disease by the surgeon and the adjuvant RT. Approximately twenty percent of the patients will develop distant metastasis, and 70 % are dead within five years. Not all the remaining living patients (30 %) at five year, are free of disease.

Most patients with head and neck cancers present with locally advanced (stages III and IV) disease. The conventional treatments for these patients are surgery and/or radiotherapy, and the overall results in resectable or unresectable disease are poor and unacceptable. Most of the patients have locoregionally recurrent disease. These poor results led to the investigation of systemic chemotherapy as part of the combined modality treatment for patients with locally advanced head and neck cancers. The achievements of systemic chemotherapy are summarized herein. For instance, active agent(s) and combinations have been identified, as have prognostic factors that influence response rates (overall and complete), and overall results in previously untreated patients. Identification of timing and sequence of chemotherapy as part of combined modality treatment, especially in patients with resectable cancer, has become feasible. Also possible is the prediction of response to subsequent radiotherapy after response to initial induction chemotherapy. This article also discusses the results obtained with concurrent high-dose cisplatin and radiotherapy as total treatment for patients with nasopharyngeal carcinomas and other patients with inoperable and unresectable cancer or in postoperative patients. Results of systemic chemotherapy in laryngeal function preservation is also summarized. Results are also obtained in unresectable patients and organ preservation with induction chemotherapy followed by concurrent chemoradiotherapy. Improved treatment of systemic metastasis and/or survival with maintenance chemotherapy are goals of current trials. We found a decreased incidence of systemic recurrence to be possible with induction and postsurgery chemotherapy. Continued studies are necessary to further improve prognoses in the treatment of head and neck cancers.

The primary treatment for patients with localized squamous cell carcinoma of the head and neck has been surgery and/or radiotherapy. The results of therapy will depend on the clinical stage, and resectability of the disease.

The development of metastatic carcinoma in cervical lymph nodes is a relatively common syndrome. In most patients, meticulous evaluation of the head and neck area and the lungs will identify a primary tumor site. FNA biopsy of the cervical lymph nodes is the recommended initial biopsy technique; open biopsy should be withheld until after a search for the head and neck primary tumor site is completed. In the patient with no identified primary tumor site, prognosis depends on the site and extent of neck involvement. Because comparative trials have not been performed, conclusions regarding optimal therapy must be made by inference from existing data. Patients with N1 disease located in the upper or midcervical lymph nodes have a relatively high cure rate and can usually be treated with a single local treatment modality (radiation therapy or radical neck dissection). Patients with N2 or N3 disease are probably best treated with combined local modalities including surgical resection followed by radiation therapy. Most investigators have recommended high-dose radiation therapy as is used to treat squamous cancer of the head and neck, with inclusion of those areas in the head and neck that may harbor an occult primary tumor site. Limited data exists regarding the benefit of systemic therapy added to local therapy in these patients. However, treatment with cisplatin and fluorouracil before definitive local therapy is reasonable in patients with N3 disease, who have very poor prognoses with local modalities alone.

BACKGROUNDThe efficacy of conventional treatment with surgery and radiation for cancer of the esophagus is limited. The median survival is less than 10 months, and less than 10 percent of patients survive for 5 years. Recent studies have suggested that combined chemotherapy and radiation therapy may result in improved survival.METHODSThis phase III prospective, randomized, and stratified trial was undertaken to evaluate the efficacy of four courses of combined fluorouracil (1000 mg per square meter of body-surface area daily for four days) and cisplatin (75 mg per square meter on the first day) plus 5000 cGy of radiation therapy, as compared with 6400 cGy of radiation therapy alone, in patients with squamous-cell carcinoma or adenocarcinoma of the thoracic esophagus. The trial was stopped after the accumulated results in 121 patients demonstrated a significant advantage for survival in the patients who received chemotherapy and radiation therapy.RESULTSThe median survival was 8.9 months in the radiation-treated patients, as compared with 12.5 months in the patients treated with chemotherapy and radiation therapy. In the former group, the survival rates at 12 and 24 months were 33 percent and 10 percent, respectively, whereas they were 50 percent and 38 percent in the patients receiving combined therapy (P less than 0.001). Seven patients in the radiotherapy group and 25 in the combined-therapy group were alive at the time of the analysis. The patients who received combined treatment had fewer local (P less than 0.02) and fewer distant (P less than 0.01) recurrences. Severe and life-threatening side effects occurred in 44 percent and 20 percent, respectively, of the patients who received combined therapy, as compared with 25 percent and 3 percent of those treated with radiation alone.CONCLUSIONSConcurrent therapy with cisplatin and fluorouracil and radiation is superior to radiation therapy alone in patients with localized carcinoma of the esophagus, as measured by control of local tumors, distant metastases, and survival, but at the cost of increased side effects.

Because of the poor results of standard therapy in patients with locally advanced head and neck cancers, chemotherapy is increasingly used to improve the outcome of these patients. In resectable disease, chemotherapy is being investigated before definitive treatments, after surgery, concurrent with postoperative radiotherapy, after radiotherapy, and for possible laryngeal salvage. In unresectable cancers, chemotherapy before, concurrent with, and following radiotherapy is being investigated.

Cancer of the head and neck is a common cancer worldwide. The majority of patients present with locally advanced disease. Recently a great deal of improvement has been made in multimodality therapy of this disease, warranting more careful consideration of factors affecting quality of life, disease course, and treatment. Infection is clearly a factor. Analysis of 662 hospital admissions of 169 head and neck cancer patients was performed. A definite infection was documented in 86 febrile episodes, pneumonia contributed to 40%, bacteremia to 13%, skin and soft tissue infection to 12%, and tracheobronchitis to 10%. Among the evaluated risk factors, foreign bodies, specifically intravenous (IV) cannulae and gastrostomy tubes, race, performance status, alcohol intake, and nutritional status were statistically significant variables that predicted for or were associated with infection. Infection contributed to 44% of the deaths.

Coagulation system abnormalities in patients with malignancy ranges from asymptomatic laboratory abnormalities to overt clinical manifestations. To determine the incidence and significance of clinically manifest thromboembolic phenomena in patients with high-grade gliomas, the records were analyzed of 77 patients that presented between January 1985 and June 1988. Fifteen patients (19%) had clinically manifest deep venous thrombosis and/or pulmonary emboli during the course of their disease. All these patients were ambulatory before and at the time of diagnosis of the event. The thromboembolic episodes occurred at the time of initial management of the primary tumor while there was documented clinical improvement in the functional status of the patient or at the time of progression of the disease. One patient died as a result of a pulmonary embolism; in two others, an embolism was a significant contributor to the patient's death. Anticoagulation resulted in complications in two of eight patients treated. Thromboembolic events occur with high frequency in patients with high-grade gliomas and contribute to the high morbidity and mortality seen in these patients. The optimum approach to screening and the treatment of these events has not been determined.

4'Deoxydoxorubicin was evaluated in patients with advanced renal carcinoma. Only one partial remission was noted, and no significant cardiac toxicity was seen on serial evaluation of ejection fractions. Appropriate dose escalations were performed.

In this issue of the International Journal of Radiation Oncology Biology Physics, Whittington et al. (17) report on a retrospective analysis of the results of single and combined modalities in patients with adenocarcinoma of the esophagus and esophago-gastric (GE) junction. They concluded that combined modality therapy of surgery, radiotherapy, and chemotherapy reduced the risk of local recurrence, and was found to extend the median survival of patients with this disease without excessive toxicity. The results of this important paper will attract attention, considering the poor prognosis reported in this disease, and the ongoing efforts by the cooperative groups to activate protocols investigating the role of combined modality treatment. All the published combined modality trials containing chemotherapy in patients with esophageal cancer are either single institution or cooperative group Phase II studies, or retrospective analyses of the results of various therapeutic approaches in this disease as in the above-mentioned article. Two randomized prospective clinical trials have been conducted: one study was just completed by the Eastern Cooperative Oncology Group (ECOG), and the second trial is ongoing, initiated by the Radiation Therapy Oncology Group (RTOG) and later activated by other cooperative groups. Cancer of the esophagus is a rare tumor in the United States; it represents about 1% of the estimated newly diagnosed cancer cases in 1990 (13). About 10,600 estimated new cases in the United States were diagnosed in 1990, with a male to female ratio of about 2: 1. The estimated death from cancer of the esophagus in 1990 will be about 9,500, which represents 1.8% of the estimated total deaths from cancer in the United States. The most common histopathology is squamous cell cancer, which constitutes about 90% to 95% of all cancer cases. Adenocarcinomas of the esophagus and GE junction represent the rest of the cases. Adenocarcinoma is most common in the distal third of the esophagus (5). The trend of 5-year survival rates of all stages of cancer of the esophagus has not changed between 1960 and 1979; it is about 5% in white patients and 3% in black patients ( 13). The relative 5-year survival rate between 1980-l 985 is estimated to be 8% in white patients and 6% in black patients ( 13). One would wonder if this slight but definite improvement in survival is caused by the introduction of combined treatment modality in this disease, the early diagnosis of the cancer, or both. Survival of patients with esophageal cancer will depend on the stages of the disease at treatment, location of the cancer, histopathology, performance status of these patients, and possibly the type of treatment used. Between 1974 and 1985, the 5-year survival rates of all stages was about 6%; for localized disease it was 13% in white and 10% in black patients, for regional involvement it was about 4%, and in patients with distant metastases it was 1% ( 13). The standard therapy for esophageal cancer is either surgery, radiation therapy, or both. The overall results of such treatments have been poor and not acceptable. The majority of patients with esophageal cancer are considered unresectable, either at the time of preoperative assessment or at surgery. This is because of the poor condition of these patients, cardio-pulmonary problems, location of the cancer, or the regional and/or distant spread of the cancer. The type and extent of surgical resection may differ between investigators, or may depend on the end results of palliation or cure. The morbidity and mortality rates from this procedure are high, and the expected end results of long-range palliation or survival are poor. The two major problems from esophageal resection and anastomosis are leakage and stricture. From review of the literature of patients who had sur-

This Head and Neck Intergroup (Radiation Therapy Oncology Group, Southwest Oncology Group, Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, Northern California Oncology Group, and Southeastern Cancer Study Group) phase 3 randomized prospective trial was opened for registration January 1985. It is an evaluation of the role of chemotherapy for previously untreated advanced stage resectable squamous cell carcinoma of the head and neck. As of March 1, 1988, there has been a total of 535 patients registered. There are 266 patients analyzable with 133 in each treatment group. The surgical, chemotherapy, and radiation therapy toxic reactions are in the tolerable range with the worst toxic reactions reported in those patients receiving both surgery and radiation therapy. Compliance continues to be a major challenge to patient accrual. The most common cause for cases not being randomized involves positive margins of surgical resection. Patient refusal or surgical complications are other common reasons.

Although there have been anecdotal reports of cardiac toxicity associated with fluorouracil (5-FU) therapy, this phenomenon has not been studied in a systematic fashion. We prospectively performed continuous ambulatory ECG monitoring on 25 patients undergoing 5-FU infusion for treatment of solid tumors in order to assess the incidence of ischemic ST changes. Patients were monitored for 23 +/- 4 hours before 5-FU infusion, and 98 +/- 9 hours during 5-FU infusion. Anginal episodes were rare: only one patient had angina (during 5-FU infusion). However, asymptomatic ST changes (greater than or equal to 1 mm ST deviation) were common: six of 25 patients (24%) had ST changes before 5-FU infusion v 17 (68%) during 5-FU infusion (P less than .002). The incidence of ischemic episodes per patient per hour was 0.05 +/- 0.02 prior to 5-FU infusion v 0.13 +/- 0.03 during 5-FU infusion (P less than .001); the duration of ECG changes was 0.6 +/- 0.3 minutes per patient per hour before 5-FU v 1.9 +/- 0.5 minutes per patient per hour during 5-FU (P less than .01). ECG changes were more common among patients with known coronary artery disease. There were two cases of sudden death, both of which occurred at the end of the chemotherapy course. We conclude that 5-FU infusion is associated with a significant increase in silent ST segment deviation suggestive of ischemia, particularly among patients with coronary artery disease. The mechanism and clinical significance of these ECG changes remain to be determined.

Four patients with head and neck tumors were observed by serial computed tomography (CT) during treatment. Osseous regeneration was demonstrated at sites of initial osteolytic destruction in two patients who responded to therapy. This regeneration was observed at 4 and 7 months, respectively, after the start of therapy. No such regeneration could be seen in the other two patients who did not respond to treatment. CT may be useful not only in demonstrating initial osseous invasion, but also in monitoring treatment response.

The presence and degree of DNA aneuploidy as measured by the DNA index (DI) and the S phase fraction (SPF) were determined by flow cytometry in 294 specimens from 237 patients with untreated and recurrent squamous cell carcinomas of the head and neck (SCCHN). A descriptive analysis was performed in which the specimen DNA parameters were correlated with stage, size of primary, degree of lymph node involvement, morphological grade, and treatment status of the corresponding patients. Approximately 70% of the previously untreated specimens contained DNA aneuploid populations (DI greater than 1.10) and three quarters had SPF that were above 15%. There was a strong, direct association between DI and SPF (P less than 0.001). There was no correlation of the presence or degree of DNA aneuploidy with the stage of the tumor or the size of the primary or conventional morphological grade of the tumor. Specimens from patients with recurrent tumors and untreated patients with N3 lymph nodes had significantly lower rates of DNA aneuploidy and mean DI. Serial determinations of DNA aneuploidy in patients with SCCHN undergoing cytotoxic therapy are ongoing and may prove useful in the identification and understanding of resistance and response in this tumor.

The feasibility of chemotherapy of three courses of cis-platin and 120-h 5-fluorouracil (5-FU) infusion after definitive surgery, followed by standard radiotherapy, in patients with resectable locally advanced head and neck cancer was carried out in Radiation Therapy Oncology Group (RTOG). Seventy-nine percent of the patients had stage IV cancer, 65% of the tumors were moderately differentiated, and primary sites were 38% oropharynx and 28% larynx. Toxicity to chemotherapy was acceptable, with no life-threatening side effects. Nausea and vomiting were the most common side effects (78%) and were severe in 26%; 30% of patients experienced had leukopenia, 22% had anemia, 13% had thrombocytopenia, and 9% had renal impairment—all of which were mild and reversible. In six patients, chemotherapy was not given for medical conditions or because of patient refusal. Of 23 patients started on cis-platin and 5-FU postsurgery, 18 (78%) completed all three courses. Ninety-six percent of the patients finished adequate radiotherapy according to the protocol. With minimum follow-up of 24 months, 62% of the patients were alive. Of the expired patients, 5 died from other causes, without evidence of recurrence at the time of their death. It is our conclusion that chemotherapy with cis-platin and 5-FU infusion following definitive surgery is feasible on the group level, and a Phase III trial comparing this combined modality therapy to standard treatment of surgery and postoperative radiotherapy is underway by the Head and Neck Cancer Intergroup.