RTOG Protocol No: 9914	Protocol Status:
	Opened:	April 24, 2000
	Closed:	November 15, 2000

Title:

A Phase II Trial of Concomitant Boost Radiation and Concurrent Cisplatin for Advanced Head and Neck Carcinomas.

Patient Population:

Patients with histologic proof (from the primary lesion and/or lymph nodes) of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx. Patients should have Stage III or IV disease (M0). Patients must have a life expectancy of at least 6 months and a Zubrod performance status of 0-1. No distant metastatic disease. Patients should have adequate bone marrow function defined as an absolute peripheral granulocyte count (AGC) of > 2000 cells/mm³, platelet count of > 100,000 cells/mm³, adequate hepatic function with bilirubin < 1.5 mg%, serum creatinine < 1.5 mg%, creatinine clearance > 50 ml/min, SGOT or SGPT < 2x the upper limit of normal, and normal serum calcium (without intervention). Creatinine clearance > 50 ml/min determined by 24-h collection or nomogram: CrCl male = (140 - age)x(wt. as kg) / (Serum Cr ml/dl)x72 CrCl female = 0.85x(CrCl male). No symptomatic coronary artery disease (angina) or myocardial infarction within the last 6 months. Patients with a history of non-melanoma skin cancer, or other previous malignancies from which the patient has remained continuously disease free for > 3 years are eligible. Patients must sign a study-specific informed consent form prior to study entry.

Objectives:

1. To determine the rate of local-regional recurrence at one year.
2. To determine the feasibility of treatment delivery, patient tolerance, acute and late toxicities.
3. To determine the overall survival, disease-free survival, and distant relapse rates of patients with relatively advanced HNSCC treated with this regimen.

Schema:

R		R
			72 Gy / 42 fxs / 6 weeks (AFX-CB*) plus cisplatin (100 mg/m2)
E		E	on days 1 and 22 (week 1 and week 4, before initiation of twice a
	Zubrod Status		day irradiation).
C	Zero (0), or	G
	One (1)		* Accelerated Fractionation with Concomitant Boost:
O		I
			a. Large Field:
R		S	32.4 Gy/18 fx/3 ½ weeks
			1.8 Gy/fx/day, 5 days/week
D		T
			b. Concomitant Boost:
		E	1.5 Gy/fx/day to boost field for 18.0 Gy/12 fx > 6 hours after
			large field treatment
		R	Large Field Treatment to receive 21.6 Gy/12 fx, 1.8/fx
			c. Total Dose:
			72.0 Gy/42 fx/6 weeks

Study Chairs:	K. Kian Ang, M.D. (Radiation Oncology)	Total patients entered:84
	Sharon S. Spencer, M.D. (Radiation Oncology)
	Arlene A. Forastiere, M.D. (Medical Oncology)
	Randal S. Weber, M.D. (Surgical Oncology)

Reference: Ang K K, Harris J, et al. Concomitant Boost Radiation And Concurrent Cisplatin For Advanced Head And Neck Carcinomas: Preliminary Results Of A Phase II Trial Of The RTOG (99-14). Proc Am Soc Thera Rad Oncol (ASTRO), Int J Radiat Oncol Biol Phys 54:71, 2002.

Purpose/Objective: A phase II trial was undertaken to assess the feasibility, acute and late toxicity, rate of local-regional control (LRC), and survival of the combination of accelerated fractionation by concomitant boost (AFX-CB) and cisplatin for the treatment of patients with locally advanced head and neck squamous cell carcinomas (HNSCC).

Materials/Methods: Between April and November 2000, 84 patients with histologic proof of stage III or IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and having Zubrod performance status of 0-1 and adequate hematologic, hepatic, and renal functions were registered. Three patients were found to be ineligible, 1 did not receive protocol therapy, and 3 had no follow up data resulting in a total of 77 (92%) analyzable patients. Age ranged from 40 to 76 with a median of 57 years. Sixty-one (79%) patients were men, 51 (66%) had oropharyngeal cancer, 64 (83%) had stage IV disease. The radiation dose was 72 Gy in 42 fractions over 6 weeks, delivered in one daily fraction of 1.8 Gy during the first 3.5 weeks and two fractions per day, 1.8 Gy and 1.5 Gy separated by > 6 h interval, during the last 2.5 weeks. Cisplatin, 100 mg/m2, was given in short iv infusion at week 1 and week 3 or 4. Tumor status and side effects were assessed every 2-3 months the first year and subsequently 3-4 months.

Results: Of the 77 analyzable patients, 92% received radiation dose within 5% of the protocol guideline and 89% received both cycles of cisplatin. Overall, 51 (66%) patients had grade 3 acute reactions, 19 (25%) had grade 4 toxicity, and 3 patients (4%) died of sepsis or pneumonia. Dysphagia, bone morrow suppression, nausea, and vomiting were the most common side effects, which were mainly associated with cisplatin administration. Grade 3 and 4 acute mucositis occurred in 39 (51%) and 2 (3%) patients, respectively. At the time of analysis, 63 (82%) patients were still alive. At a median follow-up of 1 year for patients at risk, the estimated 1-year survival rate was 81.3% (95% confidence interval: 71.8-90.7). Grade 3 and 4 late toxicities developed in 17 (23%) and 6 (8%) patients, respectively, with chronic dysphagia being the leading problem.

Conclusions: Results of phase III trials in patients with locally advanced HNSCC showed that AFX-CB improved the likelihood of LRC and cisplatin given concurrently with SF yielded better LRC and survival rates relative to SF radiotherapy. This phase II study was launched to test the feasibility of combining AFX-CB and cisplatin in patients with advanced HNC. The data showed that the acute and late toxicities of the combination of AFX-CB with cisplatin were similar to those observed with other concurrent radiation-chemotherapy regimens (e.g., cisplatin-5FU given during the boost phase of SF, hydroxyurea-5FU plus split-course radiation, and cisplatin-taxol and SF as studied in RTOG 97-03). The 1-year survival rate of 81.3% is encouraging given that 83% of patients had stage IV disease. Therefore, a phase III trial comparing AFX-CB plus cisplatin with SF plus cisplatin will be activated to test whether accelerated fractionation provides an additional benefit in the concurrent radiation-chemotherapy setting.