RTOG Protocol No: 9501	Protocol Status:
ECOG: R9501	Opened:	September 5, 1995
SWOG: 9515	Closed:	April 28, 2000

Title:

Phase III Intergroup Trial of Surgery Followed by (1) Radiotherapy vs. (2) Radiochemotherapy for Resectable High Risk Squamous Cell Carcinoma of the Head and Neck

Patient Population:

Biopsy-proven squamous cell carcinoma of the oval cavity, oropharynx, hypopharynx, or larynx. For additional requirements, see the protocol.

Objectives:

1. To determine the efficacy of concurrent cisplatin and radiotherapy following surgical resection in patients who have advanced squamous cell carcinoma of the head and neck region.
2. To test whether the use of concurrent chemoradiotherapy following surgery increases locoregional control rates.
3. To determine if the patterns of first failure are changed by the use of concurrent chemoradiotherapy.
4. To determine whether the use of concurrent chemoradiotherapy prolongs disease-free survival and/or overall survival.
5. To compare the toxicity of concurrent chemoradiotherapy vs. radiation alone in the postoperative setting.

Schema:

SURGERY:

S	Age	R	Arm 1
T	1. <70	A	RT - 60 Gy in 6 weeks (2 Gy once a day, 5 x a week)
R	2. >70	N
A		D
T	Risk Category*	O	Arm 2
I	1. Positive Margins	M	RT - 60 Gy in 6 weeks (2 Gy once a day, 5 x a week)
F	2. High Risk (> 2 positive nodes	I	plus
Y	or extranodal capsular spread)	Z	Cisplatin-100 mg/m2 i.v. on days 1, 22 and 43 with
		E	RT.

* If both are present, stratify as "positive margins"

Study Chairs:	Jay Cooper, M.D.	Total Patients Entered: 459
	Arlene Forastiere, M.D.

Reference: Cooper J, Pajak T, et al. Postoperative Concurrent Radiochemotherapy In High-Risk SCCA of The Head And Neck: Initial Report Of RTOG 95-01/Intergroup Phase III Trial. Proceeding from Am Soc Clin Oncol (ASCO), Orlando, FL, J Clin Oncol, 21: pg. 226a, Abs. #903, 2002.

Purpose: Despite resection and postoperative irradiation, high-risk (2 or more involved lymph nodes, extra-capsular disease and/or microscopically involved mucosal margins of resection) squamous cell carcinomas (SCCAs) of the head and neck (H&N) frequently recur in the tumor bed. We sought to learn if the concurrent administration of cisplatin (CDDP) with postoperative radiation therapy (RT) would improve local-regional control.

Methods: Between 9/95 and 4/00, 459 patients who had high-risk SCCAs of the H&N were enrolled in a prospectively randomized phase III trial. Following resection of all detectable disease, 231 patients were randomly assigned to RT (60 - 66 Gy /30 - 33 fx/ 6 - 6.6 weeks) and 228 patients were randomly assigned to identical RT plus CDDP (100 mg/m2 i.v. on days 1, 22 & 43). The primary outcome endpoint was local-regional control.

Results: At a median follow-up of 26.6 months (range: 2.5-62.2), the 2-year local-regional control rate is 73.8% for those assigned to RT and 79.2% for the RT plus CDDP group (p=0.16). Two-year overall survival was 56.6 % and 62.9% (p=0.51) and disease-free survival was 42.5% and 54.2% respectively (p=0.049). The incidence of grade 3+ (1) acute toxicity was 32.8% for RT and 74.9% for RT plus CDDP (p < 0.0001, mostly from hematologic, mucous membrane and/or gastrointestinal toxicity from chemotherapy), (2) late toxicity was 15.3% for RT and 19.2% for RT plus CDDP (p = 0.16), and (3) total worst toxicity was 43.6% for RT and 76.4% for RT plus CDDP (p < 0.0001).

Conclusion: In the post-operative adjuvant setting, this preliminary analysis demonstrated no significant improvement of local-regional control or overall survival of these high-risk patients from the addition of concurrent cisplatin to radiotherapy. However, disease-free survival was significantly improved, at the cost of significantly increased acute and total toxicity.

Reference: Cooper J, Pajak T, et al. Patterns of Failure for Resected Advanced Head & Neck Cancer Treated By Concurrent Chemotherapy and Radiation Therapy: An Analysis of RTOG 95-01/Intergroup Phase III Trial. Proc Am Soc Thera Rad Oncol (ASTRO), New Orleans, LA, Int J Radiat Oncol Biol Phys, [54] (2) pg. 2, Abs. #3, P., 2002.

Purpose/Objective: Local-regional recurrence of disease has been the most common mode of failure of treatment of advanced, head and neck cancer despite grossly or microscopically complete surgical resection and post-operative radiation therapy. We primarily sought to learn whether the addition of concurrent cisplatin (CDDP) chemotherapy to radiation therapy (RT) would improve the likelihood of local-regional control of disease. Associated secondary endpoints measured the anatomic pattern of first failure and the time course of local-regional relapse.

Materials/Methods: Between 9/95 and 4/00, 459 patients who had resected, high-risk (2 or more involved lymph nodes, extra-capsular disease and/or microscopically involved mucosal margins of resection) squamous cell carcinomas of the head and neck region were enrolled in a prospectively randomized phase III trial. Following gross total resection of all visible and/or palpable disease, 231 patients were randomly assigned to RT alone (60–66 Gy /30–33 fractions/ 6–6.6 weeks) and 228 patients were randomly assigned to identical RT plus CDDP (100 mg/m2 i.v. on days 1, 22 & 43). Local-regional (L-R) recurrence of disease was the primary endpoint of this study.

Results: With a median follow-up of 26.6 months, the 2-year L-R control rate is 74% for those assigned to RT and 79% for the RT plus CDDP group (p=0.16). Ninety-six patients are alive at 3 years; 81 of the 96 (84%) do not have local-regional recurrence. Local-regional recurrence as the first site of treatment failure decreased from 25% in the group receiving RT only to 17% in the group receiving concurrent therapy (p=0.041, crude incidence). Distant metastasis as the first site of failure occurred in 22% and 15% respectively (p=0.076, crude incidence). The two-year actuarial estimate of disease-free survival was significantly improved (43% vs. 54%, P=0.049), but overall survival was not (57 % vs. 63%, P=0.51). None of the patients treated by RT experienced protocol-related fatal toxicity, whereas 3% of the patients treated with concurrent chemoradiotherapy did.

The risk of local-regional recurrence began to favor combined therapy only after six months of follow-up had passed. No local-regional recurrences were observed after 36 months of follow-up.

Conclusions: The concurrent addition of single agent cisplatin chemotherapy to post-operative radiation therapy (without any subsequent adjuvant chemotherapy) decreases local-regional recurrence as the first evidence of treatment failure and decreases distant recurrence to almost the same degree. Our findings also suggest that three-year follow-up may be adequate to assess the ultimate rate of local-regional recurrence when concurrent chemotherapy and radiation therapy are used post-operatively.