RTOG Protocol No:	9111	Protocol Status:
ECOG Protocol No:	R9111	Opened:	August 17, 1992
SWOG Protocol No:	9201	Closed:	May 31, 2000

Title:

Phase III Trial to Preserve the Larynx: Induction Chemotherapy and Radiation Therapy versus Concomitant Chemotherapy and Radiation Therapy versus Radiation Therapy

Patient Population:

Patients with biopsy-proven, previously untreated, stage III and IV squamous cell carcinoma of the glottic and supraglottic larynx. Patients with KPS >60, no distant metastases, and no synchronous primary. Patients must have resectable tumors which are potentially curable with conventional surgery and radiation therapy.

Objectives:

The primary endpoint is survival with preservation of laryngeal function. Other outcomes include: disease-free survival, tumor response, patterns of relapse, incidence of adverse effects, concomitant morbidity of neck dissection and/or laryngeal salvage surgery, and quality of life outcomes.

Schema:

*		R
S	Location:
	1. Glottic	A		CDDP/5-FU
T	2. Supraglottic			CR,PR x 1 Cycle RT
		N
R	T-Stage:		Arm 1:	CDDP/5-FU
	1. T2	D		x 2 Cycles
A	T3, Fixed cord
	2. T3, Fixed cord	O		NR Surgery RT**
T	3. T3, No cord fixation
	4. T4, with base of tongue <1 cm	M
I			Arm 2:	Radiation Therapy* + CDDP
	N-Stage:	I
F	1. N0, N1
	2. N2, N3	Z	Arm 3:	Radiation Therapy*
Y
		E

Chemotherapy

Arm 1: Cisplatin 100 mg/m² over 20-30 minutes followed by 5-FU 1 gm/m²/24 hours by continuous infusion over 120 hours. Administered in three cycles, three weeks apart.

Arm 2: Cisplatin 100 mg/m² over 20-30 minutes administered on days 1, 22, and 43 of RT.

Radiation Therapy

* 70 Gy total dose, 2.0 Gy/5 days a week for seven weeks. Treatment for Arm 1 will begin 3 weeks after the start of the third chemo cycle or 2-3 weeks after surgery as applicable.

** Post-surgical RT: 50-70 Gy total dose, 2.0 Gy x 5 days a week for 5-7 weeks.

Study Chairs:		Patients Entered: 547
Helmut Goepfert, M.D.	(Surgical Oncology)
Randall S. Weber, M.D.	(Surgical Oncology)
George L. Adams, M.D., (ECOG)	(Surgical Oncology)
David Schuller, M.D., (SWOG)	(Surgical Oncology)
Arlene Forastiere, M.D.	(Medical Oncology)
Andrea N. Leaf, M.D. (ECOG)	(Medical Oncology)
John Ensley, M.D. (SWOG)	(Medical Oncology)
Moshe Maor, M.D.	(Radiation Oncology)
Henry Wagner, M.D. (ECOG)	(Radiation Oncology)
Jeffrey Forman, M.D. (SWOG)	(Radiation Oncology)
Jackie Fisher, R.N., B.S.N.	(Quality of Life)

Reference: Weber R, Berkey B, Forastiere A, et al. Outcome of Salvage Total Laryngectomy Following Organ Preservation Therapy: The Radiation Therapy Oncology Group Trial 91-11. Arch Otolary H&N Surg, 129 (Jan 2003):44-49, 2003.

Objective: To evaluate the incidence of morbidity, mortality, and disease control for patients requiring salvage total laryngectomy (TL) following organ preservation therapy.

Design: Patients entered into a 3-arm randomized prospective multi-institutional trial for laryngeal preservation who required TL following initial treatment.

Setting: The Radiation Therapy Oncology Group 91-11 trial for laryngeal preservation.

Patients: From 1992 to 2000, 517 evaluable patients were randomized to receive chemotherapy followed by radiation therapy (arm 1), concomitant chemotherapy and radiation therapy (arm 2), or radiation therapy alone (arm 3).

Results: Overall, TL was required in 129 patients. The incidence was 28%, 16%, and 31% in arms 1, 2, and 3, respectively (P =.002). Of these, 7 patients (5%) required TL for aspiration or necrosis. Following TL, the incidence of major and minor complications ranged from 52% to 59% and did not differ significantly among the 3 arms. Pharyngocutaneous fistula was lowest in arm 3 (15%) and highest in arm 2 (30%) (P>.05). There was 1 perioperative death. Local-regional control following salvage TL was 74% for arms 1 and 2 and 90% for arm 3. At 24 months, the overall survival was 69% (arm 1), 71% (arm 2), and 76% (arm 3) (P>.73).

Conclusions: Laryngectomy following organ preservation treatment is associated with acceptable morbidity. Perioperative mortality is low but up to one third of patients will develop a pharyngocutaneous fistula. Local-regional control is excellent for this group of patients. Survival following salvage TL was not influenced by the initial organ preservation treatment.

Reference: Maor M, Berkey B, Forastiere A, et al. Larynx preservation and tumor control in stage III and IV laryngeal cancer: a three-arm randomized intergroup trial; RTOG 91–11. Proc Am Soc Thera Rad Oncol (ASTRO), New Orleans, LA, Int J Radiat Oncol Biol Phys, [54] (2) pg. 2-3, Abs. #4, P., 2002.

Purpose/Objective: To evaluate induction chemotherapy followed by radiation (control) versus concomitant chemotherapy and radiotherapy versus radiation therapy alone in the treatment of stage III and low-volume stage IV glottic and supraglottic cancers. Endpoints for evaluating the trial were laryngectomy free-survival (LFS), laryngectomy preservation rate (LPR), patterns of relapse, treatment-related adverse events, and overall survival.

Materials/Methods: Between August 1992 and May 2000, 547 patients were enrolled in our study. Patients were eligible for the study if they had a new diagnosis of a potentially resectable stage III or IV squamous carcinoma of the glottic or supraglottic region; patients with a T1 or a high-volume T4 tumor were excluded from the study. Patients were randomly assigned to 3 treatment arms. Patients in arm 1 received 3 cycles of induction cisplatin 100 mg/m2 once and 5-fluorouracil 1000 mg/m2 /day for 5 days every 3 weeks. In responding patients, this treatment was followed by 70 Gy of radiation in 35 fractions for 49 days. Patients in arm 2 received concurrent cisplatin 100 mg/m2 on days 1, 22, and 43 of radiation treatment (70 Gy/35 fractions for 49 days). Patients in arm 3 received radiation only at 70 Gy/35 fractions for 49 days. Patients with a neck node > 3 cm or with multiple neck nodes underwent a neck dissection 8 weeks after completion of therapy. After excluding 30 patients from the study, 517 remained for analysis (173 in arm 1, 172 in arm 2, and 172 in 3). Sixty eight percent of the 517 patients had supraglottic cancer. Pretreatment patient and tumor characteristics were very similar in the 3 treatment arms.

Results: At 2 years, LFS for the patients treated with concomitant chemotherapy and radiotherapy was significantly better than for patients treated with radiotherapy alone (p = 0.018). The LPR was significantly greater in arm 2 compared with arms 1 and 3. The number of laryngectomies at 2 years was 43, 21, and 49 for the induction, concomitant and radiotherapy arms respectively. Loco-regional control at 2 years for patients in arm 2 (78%) was significantly better than either arm 1 (61%), or arm 3 (56%), p < 0.01. Ten patients in the study died of treatment toxicity; 5 died in the induction chemotherapy arm and 5 died in the concomitant chemotherapy and radiation arm. Acute grade 4 and 5 toxicity was 31%, 21%, and 5% in treatment arms 1, 2, and 3 respectively (<0.0001). Late grade 4 and 5 toxicity was 9%, 8% and 10% in the 3 arms (not significant). Overall survival was very similar for the patients in the 3 treatment arms (~75% at 2 years).

Conclusions: Concomitant chemotherapy and radiotherapy was superior for LPR and loco-regional control compared with induction chemotherapy followed by radiotherapy and compared to radiotherapy alone. Patients on concomitant treatment had a superior LFS compared to patients treated with radiation alone. There was no significant difference between induction chemotherapy and radiotherapy alone using these criteria. Better local control with the concomitant treatment arm did not improve survival.

Reference: Forastiere A, Berkey, B, et al. Phase III Trial to Preserve the Larynx: Induction Chemotherapy and Radiotherapy Versus Concomitant Chemoradiotherapy Versus Radiotherapy Alone, Intergroup Trial R91-11. J Clin Oncol 20: 2a, 2001.

From Aug 1992 to May 2000, 547 pts with stage III & IV potentially respectable cancer of the larynx were randomized to receive: Arm A-induction cisplatin 100 mg/m2 + 5-FU 1000 mg/m2/day x 120 hrs (CF) for 3 cycles followed by RT in responding pts, Arm B-concurrent cisplatin (C) 100 mg/m2 days 1, 22, 43 and RT or Arm C-RT alone. RT total dose was 70 Gy in 7 wks, 2 Gy/fx for all three arms. Arm A served as the control; the primary endpoint was laryngectomy-free survival (LFS). Characteristics of 497 analyzable pts were: median age 59 yrs; KPS [greater than or equal to] 80%-94%; site: glottis 32%, supraglottis-68%; T2/T3/T4-11%/79%/10%; N0-1/N2/N3 - 72%/26%/2%. Results: The 2-year LFS rates for the 3 treatments are: A-58%, B-66%, C-52%. There is no significant difference in LFS or overall survival comparing Arms B or C to control Arm A. Time to laryngectomy (TTL) is significantly better for Arm B compared to Arm A, p=0094. Secondary analysis comparing Arm B to Arm C demonstrates a significant difference in LFS (p=.02) and TTL (p=.00035). Conclusion: No significant differences were found comparing induction CF+RT to RT alone. Concurrent C+RT significantly increases the TTL.