Originally published as JCO Early Release 10.1200/JCO.2005.01.2047 on December 27 2005

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Single-Cycle Induction Chemotherapy Selects Patients With Advanced Laryngeal Cancer for Combined Chemoradiation: A New Treatment Paradigm

From the University of Michigan Comprehensive Cancer Center, Ann Arbor, MI

Address reprint requests to Susan Urba, MD, University of Michigan, C361 MIB 0849, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0848; e-mail: surba{at}umich.edu

	ABSTRACT

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PURPOSE: Primary chemoradiotherapy in patients with advanced laryngeal cancer can achieve high rates of organ preservation without sacrificing survival compared with radiation alone or conventional laryngectomy. Appropriate selection of patients for organ preservation approaches could enhance overall treatment outcome and quality of life. We conducted a phase II organ preservation trial for patients with stage III and IV larynx cancer to determine whether late salvage surgery rates could be decreased and survival improved by selecting patients for organ preservation based on response to a single cycle of induction chemotherapy.

PATIENTS AND METHODS: The chemotherapy was cisplatin 100 mg/m² on day 1 and fluorouracil 1,000 mg/m²/d for 5 days. Patients who achieved less than 50% response had immediate laryngectomy. Patients who achieved more than 50% response went on to concurrent chemoradiotherapy. Histologic complete responders after chemoradiotherapy received two more cycles of chemotherapy. Patients with residual disease after chemoradiotherapy had planned salvage surgery.

RESULTS: Of 97 eligible patients, 73 (75%) achieved more than 50% response and received chemoradiotherapy. A total of 29 patients (30%) had salvage surgery; 19 patients (20%) had early salvage surgery after the single cycle of induction chemotherapy, three patients (3%) had late salvage surgery after chemoradiotherapy, six patients (6%) eventually had salvage surgery for recurrence, and one patient had laryngectomy for chondroradionecrosis. The median follow-up time was 41.9 months. The overall survival rate at 3 years is 85%. The cause-specific survival rate was 87%. Larynx preservation was achieved in 69 patients (70%).

CONCLUSION: These results confirm excellent larynx preservation and improved overall survival rates compared with historical results.

	INTRODUCTION

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Treatment paradigms for patients with head and neck squamous carcinoma are rapidly changing to reflect increasing knowledge of tumor biology. A consistent observation over the last 20 years has been the prognostic importance of tumor response to neoadjuvant chemotherapy in previously untreated patients.^1-5

A major shift in treatment for patients with advanced laryngeal cancer occurred with publication of results indicating that successful organ preservation, with survival rates similar to primary laryngectomy, could be achieved with definitive radiation therapy in patients responding to neoadjuvant chemotherapy.^6,7 Recent randomized trials have indicated that combinations of radiation and concurrent chemotherapy are superior to treatment with radiation alone, both in the definitive^8,9 and the postoperative adjuvant settings.^10,11

We designed a phase II trial to select patients with advanced laryngeal cancer for nonsurgical treatment. Patients who achieved a partial tumor response to a single test cycle of neoadjuvant therapy were selected for definitive chemoradiotherapy. In an effort to reduce disseminated disease, two cycles of adjuvant chemotherapy were added for patients who had no residual disease at the primary site after the completion of chemoradiotherapy. Nonresponders underwent immediate surgery and postoperative radiation. The rationale for this trial design was supported by our previous demonstration that speed of tumor response to neoadjuvant chemotherapy is an important prognostic factor and that successful organ preservation can be predicted based on response to a single cycle of chemotherapy.¹² We wished to reduce overall treatment time to reduce accelerated repopulation of surviving clonogens.¹³ Reported here are the long-term results in these patients.

	PATIENTS AND METHODS

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Eligibility
All patients had pathologically confirmed, resectable, previously untreated stage III or IV squamous cell carcinoma of the larynx. Staging included direct laryngoscopy and contrast-enhanced computed tomography (CT). All patients were candidates for total laryngectomy. Patients were required to have a Karnofsky performance score of 60 and adequate medical and laboratory status to undergo chemotherapy. This protocol was approved by the Institutional Review Board at the University of Michigan (Ann Arbor, MI), and all patients gave documented informed consent.

Induction Chemotherapy
For patients with a creatinine clearance of 60 mL/min and hearing loss of 30 dB between 500 and 2,000 Hz, cisplatin (100 mg/m²) was administered on day 1. For patients with a creatinine clearance of 30 to 59 mL/min and hearing loss of more than 30 dB between 500 and 2,000 Hz, carboplatin (area under the curve = 6) was administered on day 1. Fluorouracil (1,000 mg/m²/d) was administered as a 24-hour continuous infusion for 5 days.

Tumor Assessment
All patients were examined by direct laryngoscopy under anesthesia before treatment and 3 weeks after induction chemotherapy to obtain bidimensional measurements of the primary tumor and percent reduction in their product. Response Evaluation Criteria in Solid Tumors, which were not in common use at the time of this trial, were not used.

Patients underwent biopsy after induction chemotherapy, but the results of the biopsy were not used to determine subsequent selection of treatment. In all patients, there was no question as to whether the patient had a partial response (> 50% reduction in bidimensional product) or stable disease. In all patients classified as achieving a partial response, tumor regression was 70% among responders or 50% among nonresponders.

Concurrent Chemoradiotherapy
Radiation. Definitive radiotherapy began within 3 weeks after induction chemotherapy. Large-field treatment included the primary tumor, grossly involved lymph nodes, and electively treated nodes at risk. Usually, a combination of lateral opposed or angled-down fields was initially used, followed by off-cord fields and a final boost to the primary tumor and grossly involved lymph nodes. If parotid-sparing intent demanded a different field arrangement, three-dimensional conformal or multisegmental intensity-modulated irradiation was delivered.¹⁴ Treatment was administered once daily, 5 days per week, at 2 Gy per fraction. The dose to the initial large fields was 46 to 50 Gy, and the dose to tumor and grossly involved lymph nodes was a total of 70 Gy. The spinal cord dose was limited to 46 Gy. Dose homogeneity was ± 10% across the targets.

Chemotherapy. Cisplatin-eligible patients received cisplatin 100 mg/m² on days 1, 22, and 43 concurrent with radiation therapy, with appropriate antiemetics and hydration. Patients who were not eligible for cisplatin received carboplatin (area under the curve = 6) on days 1, 22, and 43, with appropriate antiemetics.

Tumor Assessment After Chemoradiotherapy
Eight weeks after the completion of chemoradiotherapy, tumor evaluation was performed and recorded separately for the primary tumor and regional nodes. CT scan of the neck and direct laryngoscopy were performed, with open biopsy of any persistent neck nodes. Patients who had no residual disease at the primary site were eligible for two cycles of adjuvant chemotherapy. Patients with biopsy-proven disease at the primary site underwent laryngectomy. Patients with no disease at the primary site but with clinical evidence of disease in the neck or with neck nodes more than 3 cm at the time of initial staging underwent either selective or modified radical neck dissection only, as deemed appropriate.

Adjuvant Chemotherapy
Two cycles of adjuvant chemotherapy using cisplatin or carboplatin and fluorouracil were administered every 21 days, beginning 8 weeks after completion of radiation therapy. The regimen was identical to that used for induction chemotherapy.

Salvage Surgery
Total laryngectomy was required in all patients with documented persistent or locally recurrent disease. Bilateral selective neck dissections were performed in conjunction with total laryngectomy for any patient initially staged N0 in the neck. Ipsilateral modified or radical neck dissection was required for any patient initially staged N+ who experienced disease recurrence or persisted with cancer in the neck. At 8 weeks after radiation, neck dissection alone without laryngectomy was required for any patient with an initial staging neck node of more than 3 cm or with biopsy-proven palpable neck disease regardless of initial size.

Postoperative Radiation Therapy
The patients were treated with conventional fractionation (2.0 Gy per fraction, 5 fractions per week). The dose to the tumor bed and lymph nodes was 56 to 64 Gy, depending on extranodal extension or close surgical margins. Patients with gross residual disease or positive resection margins received a total of 66 to 70 Gy to the sites of residual disease. Megavoltage equipment ( 6 MeV) with a source to skin distance of 80 to 100 cm or greater was used.

Statistical Methods
² statistics were used to compare the frequency distribution of induction chemotherapy response between T3 and T4 classes, between glottic and supraglottic tumors, and between stage III and IV patients. Survival end points included overall survival, cause-specific survival, disease-free survival, and laryngectomy-free survival. Overall survival considered all deaths as events. Cause-specific survival defined event as head and neck cancer–related death. Disease-free survival was defined as the time to recurrence.

Laryngectomy-free survival was defined as the time to laryngectomy, recurrence, or death. Protocol-planned laryngectomy, late salvage laryngectomy, cancer recurrence, and death from cancer were counted as events. Laryngectomy-free survival takes into consideration both larynx preservation and patient status at last follow-up to give the proportion of people who are alive, free of cancer, and with intact larynx. Kaplan-Meier survival curves and CIs at 2 and 3 years are reported.

	RESULTS

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Patient Characteristics
Between September 15, 1995 and May 15, 2000, 100 patients were enrolled, of whom 97 were eligible. Seventy-seven patients were male, and 20 were female. Table 1 lists the patients characteristics. All T4 tumors were advanced lesions that were high volume or deeply invasive. A total of 23 (71%) of 32 patients had gross cartilage invasion on CT scanning, and 13 (41%) of 32 patients had extension through cartilage to grossly involve the strap muscles and soft tissues of the neck. Forty-one percent of patients also had obstructing lesions that required prior tracheostomy. Most T4 tumors were transglottic with fixed cords (19 of 32 patients, 59%) or were massive supraglottic tumors with extension to the tongue base and lateral oropharynx.

There was no difference in tumor response by tumor class (73% of patients with T3 cancers and 78% of patients with T4 cancers showed response; P = .7), tumor stage (P = .8), or site (glottic v supraglottic; P = .96). Seventy-three patients were eligible to receive definitive chemoradiotherapy. Of these patients, 70 received chemoradiotherapy, and three received radiation alone because of toxicities.

Decisions for laryngectomy after radiation were made if any histologically positive cancer cells were detected on primary site biopsy performed at laryngoscopy after chemoradiotherapy. Compliance with the timing of this endoscopy was good. Viability of cells was not considered in making this decision. In all patients, the final pathology report from the resected specimen confirmed residual cancer. Sixty-seven patients (92%) had documented histologic complete response after radiation. Four patients (5%) had residual cancer in the biopsy, and one patient had a complete clinical response, but the biopsy was omitted in error. Therefore, 68 patients (70% of all patients) were eligible for adjuvant chemotherapy.

Toxicity and Feasibility
All 97 patients received one cycle of induction chemotherapy. Seventy-three (75%) of 97 patients went on to definitive chemoradiotherapy. The numbers of cycles of concurrent chemotherapy delivered were as follows: three cycles, 63%; two cycles, 30%; one cycle, 3%; and zero cycles, 4%.

Sixty-eight patients (70%) were eligible to receive adjuvant chemotherapy. The numbers of cycles received were as follows: two cycles, 28%; one cycle, 25%; and zero cycles, 47%. Reasons for receiving less chemotherapy than initially planned were primarily grade 3 and 4 toxicities, as listed in Table 2.

Survival
Overall survival. Seventy-two patients (74%) are alive and disease free, three patients (3%) are alive with disease, and 22 patients (23%) are dead. Median follow-up time is 41.9 months. The estimated survival rate at 2 and 3 years is 88% and 85%, respectively (Fig 1).

View larger version (14K): [in this window] [in a new window]   Fig 1. Overall survival.

Disease-free survival. Of the 97 patients enrolled, 20 have experienced recurrence of disease, and five were never disease free. Among the 20 patients with recurrence, six underwent laryngectomy after recurrence, and one experienced recurrence after laryngectomy. The estimated disease-free survival rates at 2 and 3 years are 80% and 78%, respectively (Fig 2).

View larger version (14K): [in this window] [in a new window]   Fig 2. Disease-free survival.

Larynx Preservation
Twenty-nine patients (30%) underwent laryngectomy. Nineteen laryngectomies were performed after planned response assessment after one cycle of induction chemotherapy. Three laryngectomies were performed for residual disease at the planned assessment after completion of chemoradiotherapy. Six laryngectomies were performed for eventual recurrence of cancer at the primary site. One laryngectomy was performed for persistent severe dysphagia and chondroradionecrosis; no cancer was found in the surgical specimen. The overall rate of larynx preservation was 70% (68 of 97 patients). The laryngectomy-free survival rates at 2 and 3 years were 63% and 61%, respectively (Fig 3). The overall survival rate of patients requiring planned early laryngectomy was similar to the survival rate for patients with successful organ preservation (Fig 4).

View larger version (15K): [in this window] [in a new window]   Fig 3. Survival of patients with larynx and free of disease.

View larger version (13K): [in this window] [in a new window]   Fig 4. Survival of patients with organ preservation versus laryngectomy.

	DISCUSSION

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The results of this study demonstrate that one cycle of induction chemotherapy identifies a group of patients whose laryngeal cancer is highly likely to be successfully treated with definitive chemoradiotherapy, achieving a 70% larynx preservation rate and excellent function. A major finding was the high rates of overall and cause-specific survival achieved with this integrated approach. The 3-year overall, disease-free, and cause-specific survival rates all showed a more than 50% reduction in risk of death compared with our prior phase II trial¹² in patients with less advanced laryngeal cancers. In the Veterans Affairs’ larynx trial,⁶ patients received three cycles of induction chemotherapy and definitive radiation. Surgical salvage therapy was reserved for patients whose disease failed to respond to neoadjuvant therapy or who experienced recurrence. The 3-year cause-specific and overall survival rates were 76% and 69%, respectively, compared with rates of 87% and 85%, respectively, in our trial. Median follow-up time for both trials was in excess of 40 months.

We realize that it is not possible to conclude a true survival advantage from a phase II trial. However, we are encouraged that our results seem to be promising compared with the results reported in recently completed multi-institutional trials. The Veterans Affairs’ larynx trial reported a 3-year survival rate of 54%, and the recently completed Radiation Therapy Oncology Group (RTOG) 91-11 Intergroup study estimated a 3-year survival rate of greater than 70% for all treatment arms.^6,9 Long-term follow-up on the latter trial has not yet been reported. Compared with both national studies, our current cohort of patients included a much higher percentage of patients with T4 primary tumors and tumors arising in the supraglottis, which are associated with poorer survival rates.

The rate of laryngeal preservation in our trial was 70% at 3 years compared with 64% in the Veterans Affairs’ larynx trial. The data from the RTOG trial was reported at 2 years; at that time, the laryngeal preservation rate was 75% in the induction chemotherapy arm and 88% in the concurrent chemoradiotherapy arm (the best arm in the trial). Three-year data are not yet reported from that trial. Our laryngectomy-free survival rate of 63% at 2 years is similar to the best arm of RTOG 91-11 (66%). Our overall survival rate of 88% at 2 years is better than the best arm of 91-11 (74%).

Our overall 3-year survival rates compare favorably to historical survival rates reported with radiation in patients with T1 or T2 laryngeal cancers¹⁵ and are better than results reported for T3N0 glottic cancer patients treated with primary surgery.¹⁶ These survival rates are also superior to other previously reported, single-institution, 2-year survival results with induction chemotherapy for laryngeal preservation, which ranged from 58% to 71%.^17,18

We believe the excellent survival results achieved with a targeted approach to patient selection may be a result of the early selection for laryngectomy of patients likely to fail chemoradiotherapy. Timely integration of surgery may be a critical component in maintaining overall survival rates that are comparable to the results of primary surgery.

We do not believe that adjuvant chemotherapy significantly affected the study outcome because only 28% of patients received the planned two cycles of chemotherapy, and 47% received no adjuvant chemotherapy at all. Therefore, in future trial design, chemotherapy should be delivered either as induction treatment or concurrent with radiation. The high rate of refusal for postradiation chemotherapy and the inability of the patient to receive it as a result of poor physical condition after chemoradiotherapy make it difficult to ensure compliance.

Before this study, no organ-preservation approach using combined chemoradiotherapy has demonstrated survival rates better than those achieved with primary surgery. Support for the role of timely salvage surgery is demonstrated by the excellent survival of nonresponders undergoing planned early laryngectomy in our trial. This is contrary to considerable historical evidence that nonresponders to neoadjuvant chemotherapy have a significantly worse overall survival when compared with responders. It also differs from the results of surgical salvage therapy reported by the RTOG 91-11 study, in which survival rates were less favorable for the surgical salvage group compared with the organ preservation group.¹⁹

Studies of larger numbers of patients will be necessary to demonstrate further significant improvements in the 3-year survival rate, which is now approaching 90%. A randomized, multi-institutional study is needed to compare this treatment paradigm to current standards of concurrent chemoradiotherapy in which surgery is held in reserve for patients with subsequent locoregional failures. Quality-of-life parameters, such as surgical complication rates and long-term swallowing function, are important variables to be assessed in such studies.

The design of this new paradigm may be considered controversial because of the concern that some patients might have achieved a partial response if they had received two or three cycles of neoadjuvant chemotherapy. The complete and partial response rate after one cycle in our University of Michigan trial was 75%, and the response rate after two cycles of chemotherapy in the Veteran Affairs’ larynx trial was only 85%; organ preservation rates were 71% and 66%, respectively.⁶ In the more recent RTOG 91-11 trial, the complete or partial response rate for the patients treated with induction chemotherapy was identical to the Veterans Affairs’ larynx trial (85%).¹⁹ The modestly higher response rates in these trials using multiple cycles of neoadjuvant chemotherapy would have to be accompanied by high rates of successful salvage surgery in patients expected to experience late failures. Surgical salvage for patients experiencing late treatment failure is a difficult undertaking, with increased wound-healing problems and higher likelihood of incomplete tumor resections. We believe that improved laryngectomy-free and overall survival can be achieved by early selection of patients for definitive chemoradiotherapy. Early selection also allows salvage surgery for the nonresponders within a month of entering the trial.

In summary, the current cornerstone of therapy for patients with locally advanced laryngeal cancer has been concurrent chemoradiotherapy. One course of neoadjuvant chemotherapy is able to identify cancer patients who are highly likely to be successfully treated with chemoradiotherapy. Salvage surgery is a critically important part of this integrated treatment regimen, and our approach contributed to promising laryngectomy-free and overall survival rates. Induction chemotherapy to select for chemoradiotherapy should be a treatment strategy considered for other tumor sites in patients with advanced head and neck cancer who face radical cancer surgery with associated morbidity and impact on quality of life.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Conception and design: Susan Urba, Gregory Wolf

Provision of study materials or patients: Susan Urba, Gregory Wolf, Avraham Eisbruch, Francis Worden, Carol Bradford, Theodoros Teknos, Douglas Chepeha, Mark Prince, Norman Hogikyan

Collection and assembly of data: Julia Lee, Jeremy Taylor

Data analysis and interpretation: Susan Urba, Gregory Wolf, Avraham Eisbruch, Jeremy Taylor

Manuscript writing: Susan Urba, Gregory Wolf, Avraham Eisbruch

Final approval of manuscript: Susan Urba, Gregory Wolf, Avraham Eisbruch, Francis Worden, Julia Lee, Carol Bradford, Theodoros Teknos, Douglas Chepeha, Mark Prince, Norman Hogikyan, Jeremy Taylor

	NOTES

 
Supported in part by the University of Michigan Cancer Center, Specialized Program of Research Excellence (Grant No. 1P50CA/DE97248), The Molecular Basis of Head and Neck Cancer Therapy, and the Diane and Sinabaldo Tozzi Research Fund.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Schuller DE, Metch B, Stein D, et al: Preoperative chemotherapy in advanced resectable head and neck cancer: Final Report of the Southwest Oncology Group. Laryngoscope 98:1205-1211, 1988[Medline]

2. Jacobs C, Goffinet DR: Goffinett L, et al: Chemotherapy as a substitute for surgery in the treatment of advanced resectable head and neck cancer. Cancer 60:1178-1183, 1987[CrossRef][Medline]

3. Hong WK, Bronner RH, Amato DA, et al: Patterns of relapse in locally advanced head and neck cancer patients who achieved complete remission after combined modality therapy. Cancer 56:1242-1245, 1985[CrossRef][Medline]

4. Ensley JF, Jacobs JR, Weaver A, et al: Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancers of the head and neck. Cancer 54:811-814, 1984[CrossRef][Medline]

5. Spaulding MB, Fischer SG, Wolf GT, et al: Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. J Clin Oncol 12:1592-1599, 1994[Abstract/Free Full Text]

6. The Department of Veterans Affairs’ Laryngeal Cancer Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 324:1685-1690, 1991[Abstract]

7. Lefebrve J, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial—EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88:890-899, 1996[Abstract/Free Full Text]

8. Brizel D, Albers N, Fisher S, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798-1804, 1998[Abstract/Free Full Text]

9. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003[Abstract/Free Full Text]

10. Cooper JS, Pajak TF, Forastiere AF, et al: Postoperative concurrent radiotherapy and chemotherapy for high risk squamous cell carcinoma of the head and neck. N Engl J Med 350:1937-1944, 2004[Abstract/Free Full Text]

11. Bernier J, Domenge C, Ozsahin M, et al: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350:1945-1952, 2004[Abstract/Free Full Text]

12. Eisbruch A, Thornton AF, Urba S, et al: Chemotherapy followed by accelerated fractionated radiation for larynx preservation in patients with advanced laryngeal cancer. J Clin Oncol 14:2322-2330, 1996[Abstract]

13. Withers HR, Taylor JM, Maciejewski B: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 27:131-146, 1988[Medline]

14. Eisbruch A, Marsh LH, Martel MK, et al: Comprehensive irradiation of head and neck cancer using conformal multisegmental fields: Assessment of target coverage and noninvolved tissue sparing. Int J Radiat Oncol Biol Phys 41:559-568, 1998[CrossRef][Medline]

15. Franch G, Minatel E, Gobitt, et al: Radiotherapy for patients with early-stage glottic carcinoma. Cancer 98:765-772, 2003[CrossRef][Medline]

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17. Pfister DG, Strong E, Harrison L, et al: Larynx preservation with combined chemotherapy and radiation therapy in advanced but respectable head and neck cancer. J Clin Oncol 9:850-859, 1991[Abstract]

18. Shirinian MH, Weber RG, Lippman SM, et al: Laryngeal preservation by induction chemotherapy plus radiotherapy in locally advanced head and neck cancer: The M.D. Anderson Cancer Center experience. Head Neck 16:39-44, 1994[Medline]

19. Weber RS, Berkey BA, Forastiere AF, et al: Outcome of salvage total laryngectomy following organ preservation therapy: The Radiation Therapy Oncology Group Trial 91-11. Arch Otolaryngol Head Neck Surg 129:44-49, 2003[Abstract/Free Full Text]

Submitted January 19, 2005; accepted November 10, 2005.

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