An Intergroup Phase III Comparison of Standard Radiation Therapy and Two Schedules of Concurrent Chemoradiotherapy in Patients With Unresectable Squamous Cell Head and Neck Cancer

Authors: Adelstein D, Li Y, Adams G, et al.
Source:Journal of Clinical Oncology 2003; 21 (1): 92-98

Background

Radiotherapy (RT) is the standard of care for unresectable squamous cell carcinomas of the Head and Neck, but the overall survival has been relatively poor, usually less than 25%. Efforts have been made to improve these results, including altered RT fractionation and using chemotherapy with RT, especially concurrently. There have been several studies looking at using cisplatin based chemotherapy concurrent with standard and altered fractionation RT, and they have shown promising results, with 4yr overall survival of 34-49%. Based on these studies, the authors started a study using a control arm of standard RT compared to two arms: standard RT with weekly high dose cisplatin, and split course RT with concurrent 5FU and cisplatin.

Methods

• 295 patients were randomized to standard RT (group A), standard RT with high dose cisplatin (group B), or split course RT with concurrent 5FU and cisplatin (group C).
• Stage III or IV patients who were deemed unresectable were accepted onto study.
• Patients well balanced with regard to age, sex, race, performance status, primary tumor site, and differentiation.
• Chemotherapy consisted of: B- cisplatin 100mg/m2 d 1,22,43, C- cisplatin 75 mg/m2 q 4wks x 3 and 5FU 1000mg/m2 continuous infusion over 4d.
• Radiation therapy consisted of: A,B - 2Gy qD to 70 Gy; C - 2Gy qD to 30 Gy, 4 week break, then 2Gy qD to 30-40 Gy.
• Tumors had to be unresectable prior to therapy, and those in group C were reassessed for resectability during their mid-treatment break. If they were unresectable or had a complete response, they received 40 Gy with concurrent chemo. If they had a partial response and were resectable, they received surgery and then the third course of chemo with 30 Gy. If they had progressive disease, they were removed from the trial.
• Salvage surgery was allowed for pts in all three groups if there was still residual disease after treatment.

Results

• 271 pts were analyzable for the study.
• Group B had higher toxicity for N&V, and groups B&C had higher myelosuppression than the control arm.
• There was a significantly better response rate in group C pts vs group A (49% vs 27%, p=0.002).
• The 3 yr OS was significantly better in group B compared to group A (p=0.014).
• There was an equal proportion of pts getting surgery in all three arms - about 20%. Neck dissection alone was performed in 56% of pts.

Author's Conclusions

• This study demonstrates the superiority of single agent cisplatin with radiation vs radiation alone for advanced unresectable squamous cell head and neck cancer.
• Toxicity was greater with chemotherapy, but it was manageable.

Discussion

This study reports on a randomized trial investigating the use of chemotherapy in addition to radiation for unresectable squamous cell carcinomas of the head and neck. There was a significant survival benefit between the high dose cisplatin and control arm, but the study was underpowered and because of this used a one-sided p-value instead of the standard two-sided for their analysis. Therefore, this puts the survival benefit seen into some question.

The group C pts (split course with cisplatin/5FU) did not do as well as expected. One reason might be that during the break, not that many patients went to surgery, which was the main purpose of the break. It is known that doing split course radiotherapy is suboptimal in general, so this might have cancelled out any benefit that could be gained from surgery.

Before this study, high dose cisplatin was thought to be too toxic for oncologists to administer in a community setting, but this study shows the toxicity is manageable. This study and others support the belief that adding cisplatin to radiation is better than radiation alone. However, carboplatin is more widely used today (because of the decreased toxicity), without much supportive scientific evidence.