Yung H. Son

Randomized clinical trial of mitomycin c as an adjunct to radiotherapy in head and neck cancer

A randomized prospective clinical trial was carried out to assess the usefulness of the addition of mitomycin C to radiation therapy used alone or in combination with surgery for the treatment of squamous cell carcinoma of the head and neck region. One hundred and twenty patients with biopsy proven tumor of the oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx were randomly assigned to receive or not receive mitomycin C; all other aspects were similar in the two treatment groups. One hundred and seventeen patients were evaluable with a median follow-up time of greater than 5 years. Acute and chronic normal tissue radiation reactions were equivalent in the two treatment groups. Hematologic and pulmonary toxicity were observed in the drug treated patients. Actuarial disease-free survival at 5 years was 49% in the radiation therapy group and 75% in the radiation therapy plus mitomycin C group, p less than 0.07. Local recurrence-free survival was 66% in the radiation therapy group and 87% in the radiation therapy plus mitomycin C group, p less than 0.02. The findings demonstrate that mitomycin C can be administered safely as an adjunct to radiation therapy in the treatment of head and neck cancer. The drug improves local tumor control without enhancing normal tissue radiation reactions.

Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: results of the Yale Mitomycin Randomized Trials.

PURPOSE Two consecutive randomized trials were run at our institution using the bioreductive alkylating agent mitomycin as an adjunct to radiation therapy in an effort to improve outcome in patients with squamous cell carcinoma of the head and neck. METHODS Between 1980 and 1992, two consecutive randomized trials using mitomycin (trial 1) and mitomycin with dicumarol (trial 2) as an adjunct to radiation therapy in patients with squamous cell carcinoma of the head and neck were conducted at our institution. The patients were stratified by intent of therapy, extent of disease, and primary tumor site. Within each strata, patients were randomized to receive radiation therapy with or without mitomycin (trial 1) or mitomycin/dicumarol (trial 2). RESULTS A total of 203 patients were enrolled onto both trials, 195 of whom were eligible for analysis. Patients were equally balanced with respect to sex, age, extent of disease, primary site, radiation dose, and total duration of radiation treatment. Hematologic toxicities were more frequently noted in the drug-treated arms, but were acceptable with no drug-related treatment deaths. Nonhematologic toxicities were acceptable and not significantly different between the two arms. As of September 1995, with a median follow-up of 138 months, a statistically significant benefit occurred in the mitomycin arms with respect to cause-specific survival (0.74 +/- 0.05 v 0.51 +/- 0.05; P = .005), local recurrence-free survival (0.85 +/- 0.04 v 0.66 +/- 0.05; P = .002), and local regional recurrence-free survival (0.76 +/- 0.05 v 0.54 +/- 0.05; P = .003). No statistically significant difference in overall survival was obtained (0.48 +/- 0.05 mitomycin arms v 0.42 +/- 0.05 radiation alone). CONCLUSION The bioreductive alkylating agent mitomycin is a safe and effective adjunct to radiation therapy in the treatment of squamous cell carcinoma of the head and neck. The statistically and clinically significant improvement in local regional relapse and cause-specific survival obtained support the use of mitomycin as an adjunct to radiation therapy in the management of squamous cell carcinoma of the head and neck.

Mitomycin C as an adjunct to postoperative radiation therapy in squamous cell carcinoma of the head and neck: results from two randomized clinical trials.

PURPOSE This study was undertaken to assess the benefit of mitomycin C as an adjunct to postoperative radiation therapy in patients with operable squamous cell carcinoma of the head and neck. METHODS AND MATERIALS Between May 1980 and May 1991, 182 patients have been enrolled in two consecutive randomized clinical trials testing mitomycin C as an adjunct to radiation therapy in squamous cell carcinoma of the head and neck. In both trials, patients were stratified by stage, disease site and intent of therapy. This subset analysis includes 113 patients entered into these two randomized trials treated with surgery and postoperative radiation therapy. In the first trial, patients were randomized to receive standard postoperative radiation therapy alone compared with postoperative radiation therapy with concomitant mitomycin C. In the second trial, patients were randomized to postoperative radiation therapy or postoperative radiation therapy with concomitant mitomycin C plus dicoumarol. RESULTS As of November 1991, the 113 patients treated with surgery and postoperative radiation therapy in both trials had a median follow-up of 93 months. There have been a total of 12 local recurrences in the radiation therapy alone arm compared to 0 local recurrences in the radiation therapy/mitomycin C arm. There were eight regional recurrences in the radiation therapy alone arm compared with five regional recurrences in the mitomycin C arm. Patients in the mitomycin C arm experienced a superior 5-year actuarial local regional control rate (87% vs. 67%, p < .015) and a statistically significant disease-free survival benefit (67% vs. 44%, p < .03). Overall survival difference between the two arms (56% vs. 41%) has not reached statistical significance. CONCLUSIONS We conclude from these prospectively designed randomized clinical trials that in patients with operable head and neck cancer treated with surgery and postoperative radiation therapy, concomitant administration of mitomycin C with radiation therapy will result in a statistically significant disease-free survival and local regional control benefit. We are currently investigating the value of other bioreductive alkylating agents as adjuncts to radiation therapy in patients with squamous cell carcinoma of the head and neck.

Management of carotid artery rupture by monitored endovascular therapeutic occlusion (1988‐1994)

The reported mortality (40%) and neurologic morbidity (25%) rates for carotid rupture remain unacceptably high. This study was conducted to assess the impact of endovascular detachable balloon occlusion and the changing characteristics of carotid rupture in head and neck surgery. Between January 1, 1988, and June 30, 1994, 18 carotid ruptures were identified in 15 patients. Etiologic factors included radical surgery, radiation therapy, wound complications, and recurrent or persistent carcinoma. In 15 of 18 instances of carotid rupture, patients survived without major neurologic sequelae. After the introduction of endovascular techniques in 1991, the 12 patients whose hemorrhage was definitively managed through permanent balloon occlusion survived without significant neurologic sequelae. Endovascular occlusion techniques in the monitored patient may significantly improve the outcome after carotid rupture.

Cisplatin, Fluorouracil, and Leucovorin Induction Chemotherapy Followed by Concurrent Cisplatin Chemoradiotherapy for Organ Preservation and Cure in Patients With Advanced Head and Neck Cancer: Long-Term Follow-Up

PURPOSE The poor functional outcome in patients with advanced head and neck squamous cell carcinoma (HNSCC) with surgery and radiation has led to alternative approaches to advanced disease. We conducted a phase II study of induction chemotherapy followed by concurrent chemoradiotherapy for organ preservation in patients with advanced resectable and unresectable (nasopharyngeal) tumors. PATIENTS AND METHODS Forty-two patients with stage III to IV resectable HNSCC and nasopharyngeal tumors received induction chemotherapy with two courses of cisplatin (20 mg/m2/d continuous infusion [CI]), fluorouracil (800 mg/m2/d CI), and leucovorin (500 mg/m2/d CI; PFL) for 4 days followed by concurrent therapy with cisplatin (100 mg/m2/d on days 1 and 22) and approximately 70 Gy of external-beam radiotherapy. RESULTS Response to induction chemotherapy included partial response rate of 52% and complete response rate of 24%. The most common grade 3 or 4 toxicity was neutropenia (59%). After cisplatin chemoradiotherapy the complete response rate was 67%. Toxicities of cisplatin chemoradiotherapy consisted of grade 3 or 4 mucositis (79%) and neutropenia (51%). At a median follow-up of 71.5 months, 43% of the patients are still alive and disease-free. The 5-year progression-free survival (PFS) rate was 60%, and the 2- and 5-year overall survival (OS) rates were 67% and 52%, respectively. Three patients died of second primaries. Late complications of treatment included xerostomia and hoarseness. One patient had persistent dysphagia and required laser epiglotectomy 108 months after treatment. CONCLUSION Induction chemotherapy with PFL followed by concurrent cisplatin chemoradiotherapy is well tolerated and results in a good likelihood of organ preservation and excellent PFS and OS.

Prognostic Significance of Cyclooxygenase-2 in Oropharyngeal Squamous Cell Carcinoma

Purpose: To determine the relative prognostic significance of cyclooxygenase (COX)-2 expression in patients with oropharyngeal squamous cell carcinoma (SCC). Experimental Design: This retrospective cohort study included 82 patients with SCC referred to the Department of Therapeutic Radiology at Yale-New Haven Hospital (Connecticut) between 1980 and 1999 who were treated with primary external beam radiotherapy or gross total surgical resection and postoperative radiotherapy. A microarray of archival tumor tissue was constructed and stained with monoclonal antibodies directed against COX-2 and scored for intensity by a pathologist blinded to the clinical outcomes of the patients. COX-2 immunoreactivity and clinicopathological data were analyzed with respect to survival endpoints using bivariate and multivariate techniques. Results: Frequency of COX-2 overexpression was 45%. In multivariate analysis, COX-2 positivity predicted poor 3-year survival (P = 0.02; odds ratio = 0.41; 95% confidence interval, 0.20–0.84). Increasing age was significantly associated with increased 3-year survival (P = 0.03; odds ratio = 1.04; 95% confidence interval, 1.004–1.09). Positive COX-2 status trended toward predicting decreased 3-year disease-free survival. Conclusions: COX-2 was the most important predictor of poor survival in this patient cohort. In patients with oropharyngeal SCC treated with external-beam radiation therapy, overexpression of COX-2 may affect clinical outcome, and COX-2 may therefore prove valuable both as a prognostic factor and as a therapeutic target.

Randomized trial of conventional versus high fractional dose radiation therapy in the treatment of advanced head and neck cancer

A prospectively randomized clinical trial was undertaken to compare conventionally fractionated radiation therapy and high fractional dose irradiation in the treatment of advanced, surgically unresectable head and neck squamous cell carcinoma. Sixty-four patients were entered into the study between 1973 and 1979 and were randomized to receive either 200 rad daily to total tumor doses of 6000-7000 rad in 6-7 weeks, or 400 rad daily to a total of approximately 4400 rad in 2-3 weeks. The distribution of patients between the two fractionation schedules was comparable regarding site of the primary tumor, extent of disease, degree of histologic differentiation and performance status. Twenty-nine of 31 (94%) patients in the 200 rad group and 29 of 33 (88%) in the 400 rad group has Stage IV disease. Twenty-six in the former group and 30 in the latter completed radiation therapy as planned. Acute skin and mucosal reactions occurred earlier in patients treated with 400 rad daily, but were of equivalent intensity and well within acceptable levels in both groups. No increase in late adverse effects was seen with high daily doses. Palliation of tumor-related symptoms and extent of tumor control were comparable in the two groups. Actuarial five year disease-free survival rates were approximately 10% in both treatment groups with a mean follow-up period of 5 1/2 years. We conclude that high fractional dose irradiation is equivalent to conventionally fractionated radiation therapy in the treatment of advanced head and neck cancer.

Microsurgical free flap reconstruction outcomes in head and neck cancer patients after surgical extirpation and intraoperative brachytherapy.

Objectives: The management of recurrent or persistent head and neck cancer poses a challenging problem. Salvage surgery for these individuals consists of ablative surgery, interstitial brachytherapy, and microsurgical free flap reconstruction. This study reviews complications after such reconstruction.

Intraoperative adjuvant radiotherapy for advanced cancers of the head and neck: Preliminary report☆

We have reported the early local control and survival results of treatment of recurrent or metastatic head and neck tumors with intraoperative brachytherapy. All six patients were locally free of disease after curative surgery and intraoperative brachytherapy for 4 months to 1 year, whereas two of eight patients were alive at last follow-up at 7 and 8 months with some complications after palliative surgery and intraoperative brachytherapy. We advocate such a technique not only in hopelessly advanced tumors but also in less advanced tumors, as well as a definitively integrated plan of management. Doses of iodine-125 of up to 15,000 rads are safe and well tolerated, even in the presence of a past history of radiotherapy.

Crossing and looping methods in radical interstitial therapy for lateral and posterior oro-, hypopharyngeal tumors.

192Ir looping and crossing methods as a means of megavoltage tumor dose boosting have been applied for Stage II and III lateral and posterior oro-, hypopharyngeal tumors. A megavoltage and interstitial combined dose in excess of 9000 rad resulted in a soft tissue injury in two patients. Nevertheless, all five patients are alive without residual tumor at 8-38 months. We believe that a megavoltage dose of 5200 rad plus interstitial doses of 3000-3500 rad with a four week rest period intervening may improve cure rate at an acceptable injury rate.