The management of advanced supraglottic and

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1 ORIGINAL ARTICLE ORGAN PRESERVATION FOR ADVANCED LARYNGEAL CARCINOMA Robert L. Foote, MD, 1 R. Tyler Foote, 1 Paul D. Brown, MD, 1 Yolanda I. Garces, MD, 1 Scott H. Okuno, MD, 2 Scott E. Strome, MD 3 1 Department of Radiation Oncology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN foote.robert@mayo.edu 2 Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 3 Department of Otorhinolaryngology, University of Maryland, Baltimore, Maryland Accepted 24 October 2005 Published online 17 April 2006 in Wiley InterScience ( DOI: /hed Abstract: Background. Inclusion of patients with mobile vocal cords on larynx preservation trials may lead to overstatement of larynx preservation (LPR) and survival (OS) rates. Methods. This is a retrospective review of patients at our institution who would have been eligible for the Department of Veterans Affairs Laryngeal Cancer Study Group (VA) and Radiation Therapy Oncology Group/Head and Neck Intergroup (RTOG 91-11) clinical trials. No laryngeal conservation procedure could be performed in patients with mobile vocal cords. Results. One hundred one patients at our institution would have been eligible for the VA trial. The 2-year OS was 76% for total laryngectomy and 90% for radiotherapy patients (p ¼.28) compared with 68% reported for the VA trial. Seventy-three patients at our institution would have been eligible for the RTOG trial. The 5-year OS was 52% for total laryngectomy and 63% for radiotherapy patients (p ¼.18) compared with 55% reported for the RTOG trial. Radiotherapy patients had an LPR of 80% (VA trial) and 86% (RTOG trial). Conclusion. It is unlikely that inclusion of patients with mobile vocal cords had a significant impact on OS or LPR for the VA and RTOG larynx preservation trials. VC 2006 Wiley Periodicals, Inc. Head Neck 28: , 2006 Keywords: laryngeal carcinoma; organ preservation; total laryngectomy; chemoradiotherapy Correspondence to: R. L. Foote VC 2006 Wiley Periodicals, Inc. The management of advanced supraglottic and glottic larynx cancer that would require a total laryngectomy has been undergoing an evolution in the United States over the past 20 years. Patients are undergoing total laryngectomy less frequently, and the use of chemoradiotherapy is becoming more common. The Department of Veterans Affairs Laryngeal Cancer Study Group (VA) completed a clinical trial that confirmed that there is no difference in overall survival in patients randomly assigned to total laryngectomy and postoperative radiotherapy or induction chemotherapy followed by radiotherapy in patients who responded to the induction chemotherapy. 1 However, significant differences included preservation of the larynx in 64% of the patients treated with induction chemotherapy and radiotherapy and improved function and quality of life in patients with laryngeal preservation compared with patients undergoing a total laryngectomy. 2,3 Subsequently, the Radiation Therapy Oncology Group and the Head and Neck Intergroup conducted a randomized clinical trial (RTOG 91-11) that revealed that concomitant cisplatin chemoradiotherapy resulted in a better larynx preserva- Organ Preservation for Laryngeal Cancer HEAD & NECK DOI /hed August

2 tion rate than induction chemotherapy followed by radiotherapy or radiotherapy alone. 4 The results of these two landmark clinical trials have not been universally accepted so that the management of advanced larynx cancer remains somewhat controversial. 5 9 The conduct of the preceding clinical trials has been criticized. One such criticism is that many of the patients included in the clinical trials had vocal cords that were mobile. Experienced head and neck cancer surgeons have stated that many of these larynx cancers could have been removed with a conservative procedure less radical than a total laryngectomy, such as transoral laser resection, partial vertical laryngectomy, supraglottic laryngectomy, supracricoid laryngectomy, or near total laryngectomy. It is also argued that many of the patients from the subsequent RTOG trial had earlier, more favorable stage disease than those treated on the original VA larynx preservation trial with an even greater opportunity to perform laryngeal conservation procedures. Therefore, perhaps more larynges could have been preserved with conservation surgical procedures, and perhaps the larynx preservation rates and overall survival reported for the chemoradiotherapy patients are inflated because of inclusion of favorable early cancers with mobile vocal cords. In an attempt to address the preceding surgical controversies, we reviewed the outcomes of total laryngectomy with or without postoperative adjuvant radiotherapy and radiotherapy with or without concomitant chemotherapy at our institution and compared them with the outcomes of the VA and RTOG trials. The Mayo Clinic has a number of experienced and skilled head and neck cancer surgeons who are adept at appropriate patient selection and excel in performing all types of laryngeal conservation procedures as alternatives to total laryngectomy. Patients referred for radiotherapy or chemoradiotherapy had a total laryngectomy as their only surgical option in this review. MATERIALS AND METHODS This retrospective chart review was approved by the Mayo Foundation Institutional Review Board. In accordance with Minnesota state law, all living patients authorized review of their medical records. Individual patient records were reviewed to identify patients that would have been eligible for the VA and RTOG clinical trials. For these two prospective clinical trials and our retrospective review, all patients were required to have biopsy-proven, previously untreated stage III or IV squamous cell carcinoma of the glottic or supraglottic larynx, according to the 1985 classification system of the American Joint Committee on Cancer. 10 The disease had to be considered curable with surgery and postoperative radiotherapy. Patients with unresectable cancers, distant metastases, previous radiotherapy to the head or neck, or previous cancer were excluded. Patients were required to have no prior cancer except nonmelanoma skin cancer or to be disease-free from cancer for 3 or more years. The required pretreatment laboratory criteria included a Karnofsky performance status score greater than 50 points (VA) or at least 60 points (RTOG 91-11) 11 ; a creatinine clearance of at least 1 ml/second (VA) or 50 ml/min (RTOG 91-11); a white blood cell count of at least 4000/mm 3 (VA) or 3500/mm 3 (RTOG 91-11); a platelet count of at least 100,000/mm 3 ; and adequate auditory, nutritional, pulmonary, and cardiac status. All patients underwent pretreatment endoscopic tumor staging and evaluation. Patients with T1N1 carcinomas were excluded from the VA trial. Patients with T1 disease or large-volume T4 disease (defined as a tumor penetrating through the cartilage or extending more than 1 cm into the base of the tongue) were not eligible for the RTOG trial. For the RTOG trial, the extent of the primary cancer was not amenable to a conservation procedure and required a total laryngectomy. In addition, patients had to have a normal serum calcium level for the RTOG trial. High-resolution CT scanning of the primary tumor and the neck, CT imaging of the chest, barium esophagography, or panendoscopy was performed as clinically indicated. All patients had a chest x-ray performed. The Mayo Clinic in Rochester computerized surgical index database was searched electronically to identify all patients undergoing a total laryngectomy for squamous cell carcinoma of the larynx between January 1985 and May 2000, which was the period encompassed by the VA and RTOG prospective clinical trials. Two hundred eighty-three patients were identified. Eighty-one met the eligibility criteria for the VA larynx preservation trial. The reasons for exclusion of 202 patients are listed in Table 1. Fifty-nine of the 81 patients met the eligibility criteria for the RTOG trial. Twenty-two would have been excluded from the RTOG trial because of an advanced T4 primary tumor. 690 Organ Preservation for Laryngeal Cancer HEAD & NECK DOI /hed August 2006

3 Table 1. Reasons for exclusion of patients with total laryngectomy (n ¼ 202). Exclusion No. of patients Prior RT 91 Prior surgery 6 RT 43 Subglottic primary 28 Stage I/II (T1, T2N0) 22 Synchronous cancer or 11 prior cancer 3 y NED No follow-up* 6 Stage IV (M1) 1 Abbreviations: RT, radiotherapy; NED, no evidence of disease; M1, distant metastases. *Four international patients, two prisoners of the Federal Medical Center. All attempts were made to perform a conservation surgical procedure in the patients treated with total laryngectomy, but the extent of the tumor or pulmonary status of the patient dictated a total laryngectomy in all patients in this study. Forty-nine patients underwent total laryngectomy with (n ¼ 48) or without (n ¼ 1) a neck dissection. Thirty-two patients underwent a total laryngectomy and neck dissection followed by postoperative adjuvant radiotherapy. All patients underwent complete resection of the primary tumor and lymph node metastases with negative margins. Postoperative adjuvant radiotherapy was added on an individual basis per physician recommendation. In general, patients with advanced primary tumors with close surgical margins, multiple lymph node metastases, multiple levels of lymph nodes involved, lymph node(s) greater than 3 cm in size, and/or extranodal extension received postoperative adjuvant radiotherapy. In one of these patients, postoperative adjuvant radiotherapy was planned, but the patient had a recurrence before beginning radiotherapy and so was treated with a therapeutic dose of radiotherapy and concomitant chemotherapy. The median overall treatment time was 42 days (range, days). The median total dose was 60 Gy (range, Gy), with a median fraction size of 2.0 Gy (range, Gy). The patient receiving 25.2 Gy stopped treatment early because of nausea, vomiting, and weight loss. The Mayo Clinic in Rochester Department of Radiation Oncology computerized tumor registry was searched electronically to identify all patients undergoing radiotherapy for squamous cell carcinoma of the larynx during the same time period. Two hundred forty-one patients were identified. Twenty met the eligibility criteria for the VA larynx preservation trial. The reasons for exclusion of 221 are indicated in Table 2. Fourteen of the 20 patients met the eligibility criteria for the RTOG trial. Six would have been excluded from the RTOG trial because of an advanced T4 primary tumor. During the study period, the nonsurgical treatment of advanced larynx cancer was undergoing evolution at the Mayo Clinic. In general, early in the study patients were treated with conventionally fractionated radiotherapy alone. Subsequently, altered fractionation schemes including hyperfractionated radiotherapy and accelerated concomitant boost radiotherapy were used. In the later years of the study, concurrent chemotherapy was added to the radiotherapy. Patients treated with radiotherapy with or without concurrent chemotherapy underwent planned posttreatment neck dissection for advanced nodal disease. Fourteen patients were treated with primary radiotherapy with (n ¼ 1) or without (n ¼ 13) a planned postradiotherapy neck dissection. Six were treated with concomitant chemoradiotherapy with (n ¼ 2) or without (n ¼ 4) a planned posttreatment neck dissection. The median overall treatment time was 43.5 days (range, days). The median total dose was 72 Gy (range, Gy). Nine patients were treated with hyperfractionated radiotherapy using 1.2 Gy twice a day. Eight patients were treated with conventional fractionation (six patients, 2.0 Gy per day; two patients, 1.8 Gy per day). Three patients were Table 2. Reasons for exclusion of radiotherapy 6 chemotherapy patients (n ¼ 221). Exclusion No. of patients T1/T2N0 glottic cancer 72 Surgery þ postoperative RT 44 Prior surgery 33 T1/T2N0 supraglottic 20 Prior RT 14 Subglottic 12 Synchronous cancer or 8 prior cancer 3 y NED Stage IV (M1) 6 Medically inoperable/unresectable 5 No follow-up* 3 Carcinoma in situ 2 T1N1 supraglottic 1 T3 supraglottic y 1 Abbreviations: RT, radiotherapy; NED, no evidence of disease; M1, distant metastases. *One international patient, two prisoners of the Federal Medical Center. y Patient was thought to be a candidate for a supraglottic laryngectomy or near total laryngectomy. Organ Preservation for Laryngeal Cancer HEAD & NECK DOI /hed August

4 Characteristic Table 3. Patient characteristics according to treatment group. Total laryngectomy 6 RT (n ¼ 81) RT 6 CT (n ¼ 20) No. of patients (%) All (n ¼ 101) VA (n ¼ 332) RTOG (n ¼ 518) Age, y <60 30 (37) 5 (25) 35 (35) 263 (51) (63) 15 (75) 66 (65) 255 (49) Median 64 y 67 y 65 y 62 y 59 y Range y y y y y Sex Male 68 (84) 14 (70) 82 (81) 321 (97) 401 (77) Female 13 (16) 6 (30) 19 (19) 11 (3) 117 (23) Karnofsky performance score (18) (33) 6 (30) 33 (33) 287 (55) (51) 10 (50) 51 (50) 106 (20) (84) 16 (80) 84 (83) 253 (76) 486 (94) (12) 2 (10) 12 (12) 26 (5) 60 3 (4) 2 (10) 5 (5) 6 (1) <80 13 (16) 4 (20) 17 (17) 79 (24) 32 (6) Site of tumor Supraglottis 46 (57) 13 (65) 59 (58) 208 (63) 356 (69) Glottis 35 (43) 7 (35) 42 (42) 124 (37) 162 (31) American Joint Commission on Cancer stage III 42 (52) 10 (50) 52 (51) 188 (57) 337 (65) IV 39 (48) 10 (50) 49 (49) 144 (43) 181 (35) Tumor-node-metastasis stage T classification T1 0 1 (5) 1 (1) T2 8 (10) 0 8 (8) 31 (9)* 60 (12) T3 with fixed cord 41 (51) 7 (35) 48 (48) 240 (46) T3 without cord fixation 6 (7) 5 (25) 11 (11) 216 (65) y 167 (32) T4 26 (32) 7 (35) 33 (33) 85 (26) 51 (10) N classification N0 46 (57) 13 (65) 59 (58) 180 (54) 260 (50) N1 15 (19) 0 15 (15) 60 (18) 109 (21) N2a 1 (1) 0 1 (1) 12 (2) N2b 2 (2) 5 (25) 7 (7) 37 (11) { 43 (8) N2c 15 (19) 2 (10) 17 (17) 85 (16) N3 2 (2) 0 2 (2) 55 (17) 9 (2) Eligible for VA trial Yes 81 (100) 20 (100) 101 (100) No Eligible for RTOG trial Yes 59 (73) 14 (70) 73 (72) No 22 (27) 6 (30) 28 (28) Abbreviations: RT, radiotherapy; CT, chemotherapy; T, tumor; N, node. *T1 and T2. y T3 with or without fixed cord. { N2a, N2b, and N2c. The designation T4 was limited to low-volume disease that did not extend into the tongue base by more than 1 cm or penetrate through cartilage on the RTOG Clinical Trial. treated using an accelerated concomitant boost fractionation schedule consisting of 1.8 Gy per day for the first 3.5 weeks of treatment and then 1.8 Gy to a large field each morning and 1.5 Gy to a boost field each afternoon for the last 2.5 weeks of treatment. Two patients were treated with intraarterial cisplatin chemotherapy 150 mg/m 2 weekly for the first 4 weeks of treatment. 12 Both patients received three of the four planned cycles. One patient was treated with cisplatin 100 mg/m 2 repeated every 21 days during radiation therapy. This patient received two of the three planned 692 Organ Preservation for Laryngeal Cancer HEAD & NECK DOI /hed August 2006

5 Cause Table 4. Causes of death according to treatment group. Total laryngectomy 6 RT (n ¼ 81) No. of patients (%) RT 6 CT (n ¼ 20) VA surgery (n ¼ 66) VA CT (n ¼ 166) Laryngeal cancer 15 (19) 2 (10) 38 (23) 42 (25) Complications of treatment (2) 4 (2) Other 20 (25) 7 (35) 14 (8) 13 (8) Unknown 21 (26) 3 (15) 2 (1) 6 (4) All 56 (69) 12 (60) 58 (35) 65 (39) Abbreviations: RT, radiotherapy; CT, chemotherapy. cycles and then was switched to daily cisplatin at a dose of 5 mg/m 2 for 5 days because of poor tolerance. One patient was treated with daily cisplatin at 5 mg/m 2 for 22 days and was switched to carboplatin 25 mg/m 2 /day because of poor tolerance but received just 1 day of treatment. One patient was treated with daily cisplatin 5 mg/m 2 and received 33 days of treatment. One patient was treated with weekly cisplatin at 25 mg/m 2 and received 5 weeks of treatment. The indications for total laryngectomy in the 20 patients electing to undergo concomitant chemoradiotherapy were as follows: extent of the primary laryngeal tumor in 14, poor pulmonary function in four, extent of the primary tumor and poor pulmonary function in one, and prior laryngeal surgery in one. The characteristics of the patients according to treatment group are summarized in Table 3. The median follow-up of all patients is 59 months (range, months). Two patients in the total laryngectomy group were lost to follow-up at 5.4 and 18 months. Data on these patients were censored from the survival analysis at the time of the last follow-up. A salvage total laryngectomy was performed in patients who had histologically proven persistent or recurrent carcinoma after the completion of radiotherapy with or without chemotherapy. In general, all patients were seen 4 to 6 weeks after completion of their treatment. They were then seen every 3 months for the first 2 years, every 6 months for another 3 years, and then once a year after 5 years. The primary endpoints of this study were overall survival and larynx preservation. All events were measured from the date of the total laryngectomy or first day of radiotherapy to the date of their occurrence or the date of the last follow-up. The Kaplan Meier method was used to calculate the survival curves and comparisons were made using the log-rank test. 13 All p values correspond to two-sided testing for significance. A p value.05 was considered significant. RESULTS Sixty-eight patients have died, 56 in the total laryngectomy group (69%) and 12 in the radiotherapy group (60%). The most frequent cause of death was causes other than larynx cancer (Table 4). For the 101 patients who would have been eligible for the VA trial, the estimated 2- year and 5-year overall survival was 76% (95% confidence interval [CI], 65 85%) and 51% (95% CI, 42 64%) for the total laryngectomy group and 90% (95% CI, %) and 59% (95% CI, 38 78%) for the radiotherapy group (p ¼.28; Figure 1). For the 73 patients who were eligible for the RTOG trial, the estimated 2-year and 5-year overall survival was 76% (95% CI, 65 85%) and 52% (95% CI, 40 65%) for the total laryngectomy group and 93% (95% CI, %); and 63% (95% CI, 36 85%) for the radiotherapy group (p ¼.18; Figure 2). Overall rates of recurrence did not differ significantly between treatment groups, but there FIGURE 1. Overall survival for the 101 patients who would have been eligible for the Department of Veterans Affairs Laryngeal Cancer Study Group trial by treatment group (total laryngectomy 6 neck dissection 6 radiation therapy (RT) versus RT 6 chemotherapy). Organ Preservation for Laryngeal Cancer HEAD & NECK DOI /hed August

6 FIGURE 2. Overall survival for the 73 patients who would have been eligible for the Radiation Therapy Oncology Group/Head and Neck Intergroup trial by treatment group (total laryngectomy 6 neck dissection 6 radiation therapy (RT) versus RT 6 chemotherapy 6 neck dissection). were differences in the patterns of tumor relapse (Table 5). Recurrences at the site of the primary tumor or stoma were less frequent in the total laryngectomy group (7%) than in the radiotherapy group (15%). Recurrence within the neck was less frequent in the radiotherapy group (0%) than in the total laryngectomy group (19%). There was no difference in the incidence of distant metastatic disease. The larynx was preserved in 16 of the 20 patients eligible for the VA trial receiving radiotherapy or chemoradiotherapy (80%). Two patients underwent a total laryngectomy for recurrent disease at 19 and 21 months. Two underwent a total laryngectomy for an incompetent larynx at 20 and 22 months. One had previously undergone a transoral laser resection of a recurrence within the epiglottis. The median time to laryngectomy was 20 months (range, months). The larynx preservation rate at 2 years and 5 years was 80% (95% CI, 56 94%) for the 20 patients eligible for the VA trial and 86% (95% CI, 58 96%) for the 14 patients eligible for the RTOG trial. All 81 patients undergoing a total laryngectomy had a permanent tracheostoma. In 39 patients (48%), the preoperative clinical notes and surgical listing included conservation laryngeal procedures such as transoral laser resection, partial vertical laryngectomy, supraglottic laryngectomy, supracricoid laryngectomy, and near total laryngectomy in addition to total laryngectomy as potential surgical options. However, intraoperative frozen section pathologic findings of invasive cancer or carcinoma in situ involving the interarytenoid or postcricoid mucosa precluded any procedure less than a total laryngectomy. The method of communication is listed in Table 6. Five had a percutaneous endoscopic gastrostomy (PEG) tube at the time of their last follow-up. The swallowing status was unknown in seven patients. For the 20 patients undergoing larynx preservation treatment with radiotherapy or concurrent chemoradiotherapy, four had a permanent tracheostoma after a total laryngectomy for recurrence (n ¼ 2) or for an incompetent larynx (n ¼ 2). In addition, two patients had tracheostomy tubes at the time of their last follow-up. The method of communication is listed in Table 6. Four patients had PEG tubes at the time of their last follow-up. DISCUSSION The VA and RTOG larynx preservation trials have been criticized because they included many larynx cancers with mobile vocal cords that perhaps could have been removed by a laryngeal conservation procedure such as transoral laser resection, partial vertical laryngectomy, supraglottic laryngectomy, supracricoid laryngectomy, or near total laryngectomy rather than a total laryngectomy. Inclusion of these more favorable Site of recurrence Table 5. Patterns of cancer recurrence according to treatment group. Total laryngectomy 6 RT (n ¼ 81) No. of patients (%) RT 6 CT (n ¼ 20) VA surgery (n ¼ 166) VA CT (n ¼ 166) Primary/stomal 6 (7) 3 (15) 4 (2) 20 (12) Nodal 15 (19) 0 9 (5) 14 (8) Distant 14 (17) 3 (15) 29 (17) 18 (11) All 23 (28) 5 (25) 42 (25) 52 (31) Abbreviations: RT, radiotherapy; CT, chemotherapy. Most patients had more than one site of recurrence. For the total laryngectomy 6 RT group, one patient had a stomal recurrence only, two had a stomal and neck recurrence and distant metastasis, three had a stomal and neck recurrence, three had neck recurrence and distant metastasis, and nine had distant metastasis only. For the RT þ CT group, two had a local recurrence only, two had distant metastasis only, and one had both a local recurrence and distant metastasis. 694 Organ Preservation for Laryngeal Cancer HEAD & NECK DOI /hed August 2006

7 Communication method Table 6. Method of communication. No. of patients Total laryngectomy 6 RT (n ¼ 81) RT 6 CT (n ¼ 20) Larynx 0 16 Electrolarynx 35 2 TEP 18 1 Unknown 7 Handwriting 5 Electrolarynx and 4 handwriting Electrolarynx and 3 esophagus Esophageal speech 3 Palatal prothesis 1 Electrolarynx and TEP 1 Electrolarynx and 1 mouthing No communication 3 1 Abbreviations: RT, radiotherapy; CT, chemotherapy; TEP, tracheoesophageal puncture. cancers may have artificially inflated the larynx preservation rates and overall survival in patients treated with radiotherapy alone or combined with chemotherapy. Including these more favorable cancers may have also diminished the role that laryngeal conservation procedures may play in selected patients in preserving laryngeal function. We found that nearly half (48%) of the patients undergoing total laryngectomy at the Mayo Clinic in Rochester who would have been eligible for the VA or RTOG larynx preservation trials had consented and been listed for both a laryngeal conservation procedure and a total laryngectomy, indicating that attempts were made to preserve laryngeal function. Nevertheless, all patients ultimately underwent a total laryngectomy because of tumor extent or pulmonary function status. Because we required patients included in our review to be eligible for the VA and/or RTOG larynx preservation trials, our patient characteristics were quite similar to those of the patients treated in the prospective clinical trials (Table 3). The VA trial did include a lower proportion of female patients and more patients with N3 nodal disease. However, the proportion of patients with N2 and N3 disease was very similar in the Mayo surgical group, the Mayo radiation therapy with radiotherapy group, VA trial, and RTOG trial. The RTOG trial did have a higher proportion of patients with stage III disease because of the exclusion of most T4 primary tumors. However, the proportion of patients with T3 and T4 tumors was remarkably similar in the Mayo surgical group, the Mayo radiotherapy group, and the VA trial. The patients on the RTOG trial tended to be younger and have a better performance status. The 2-year overall survival for our 81 patients treated with total laryngectomy with or without postoperative adjuvant radiotherapy is remarkably similar to the 2-year overall survival for patients treated on the VA and RTOG larynx preservation trials and our patients treated with radiotherapy or chemoradiotherapy (76%, 68%, 75%, and 90%, respectively). 1,4 The 5-year overall survival for our patients with total laryngectomy who were eligible for the RTOG trial was 52% compared with 55% for the patients treated with radiotherapy alone or combined with induction or concomitant chemotherapy on the RTOG trial and 63% for our patients treated with radiotherapy or chemoradiotherapy. 4 This would seem to indicate that there was no significant increase in survival for patients treated on the VA and RTOG larynx preservation trials because of inclusion of more favorable laryngeal cancers. The same proportion of patients died of larynx cancer treated at our institution as the patients treated on the VA larynx preservation trial (Table 4). A greater proportion of our patients have died of other or unknown causes because our follow-up is longer (median, 59 months vs 33 months). The pattern of cancer recurrence is also remarkably similar between our patients treated with total laryngectomy with or without postoperative radiotherapy compared with patients treated on the VA trial (Table 5). This would suggest that there was no significant alteration of cancer-related death, tumor control, or patterns of cancer recurrence for patients treated on the VA and RTOG larynx preservation trials because of inclusion of more favorable laryngeal cancers. All of the preceding suggests that even at an institution like the Mayo Clinic with a historical surgical bias, there is no significant difference in overall survival for patients treated with a total laryngectomy and neck dissection with or without postoperative radiotherapy compared with a nonsurgical larynx preservation technique such as radiotherapy alone or with induction or concomitant chemotherapy. Indirectly, the data suggest the patients with mobile vocal cords included on the VA and RTOG larynx preservation trials did, indeed, have advanced disease requiring a total laryngectomy, because the patient characteristics and clinical outcomes were quite similar between treatment groups. Our own limited expe- Organ Preservation for Laryngeal Cancer HEAD & NECK DOI /hed August

8 rience with 20 patients treated with radiotherapy alone or combined with concurrent chemotherapy in which the extent of disease would have required a total laryngectomy and who would have been eligible for the VA and/or RTOG trial would suggest there are no differences in overall survival compared with total laryngectomy. Our larynx preservation rate was 80% at 2 and 5 years for patients who would have been eligible for the VA larynx preservation trial and 86% for patients who would have been eligible for the RTOG trial. These patients were referred by our head and neck surgeons for radiotherapy or chemoradiotherapy because total laryngectomy was the only surgical option. This result is consistent with those reported on the RTOG trial. 4 Head and neck cancer surgeons often propose tracheoesophageal puncture (TEP) as a useful and convenient means of communication, yet even at a large tertiary cancer center practice with dedicated and experienced head and neck cancer surgeons and speech pathologists, only a small minority of patients were able to use a functioning TEP. Although lung-powered laryngeal speech can be preserved in most patients undergoing radiotherapy alone or combined with chemotherapy with no detrimental impact on survival, there can be significant problems with swallowing function. Four of our patients treated with radiotherapy alone or combined with chemotherapy had a PEG tube at the time of their last follow-up ( months). Although no difference in swallowing function or quality of life was noted in the VA larynx preservation trial, continued efforts should be made to minimize swallowing dysfunction. This may be accomplished through exploring altered fractionation schemes; reducing the dose to the esophagus by intensity-modulated radiotherapy, tomotherapy, or proton beam therapy; by the use of less toxic chemotherapeutic regimens; by earlier and more aggressive swallowing therapy; and by eliminating neck dissection in complete responders. 14 In summary, there does not seem to be a detrimental effect on survival when patients are treated with radiotherapy alone or combined with chemotherapy for advanced laryngeal cancer requiring a total laryngectomy compared with patients undergoing surgery. It is unlikely that inclusion of larynx cancers with mobile vocal cords had a significant impact on the survival or larynx preservation outcome on the VA and RTOG larynx preservation trials. Laryngeal speech can be preserved in most patients. Attempts at minimizing swallowing dysfunction should be further investigated. REFERENCES 1. Wolf GT, Hong WK, Fisher SG, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324: Terrell JE, Fisher SG, Wolf GT. Long-term quality of life after treatment of laryngeal cancer. Arch Otolaryngol Head Neck Surg 1998;124: Hillman RE, Walsh MJ, Wolf GT, et al. Functional outcomes following treatment for advanced laryngeal cancer. Ann Otol Rhinol Laryngol 1998;107: Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349: Weinstein GS, Myers EN, Shapshay SM, et al. Nonsurgical treatment of laryngeal cancer. N Engl J Med 2004;350: DeSanto LW, Lillie JC, Devine KD. Surgical salvage after radiation for laryngeal cancer. Laryngoscope 1976;86: DeSanto LW. T3 glottic cancer: options and consequences of the options. Laryngoscope 1984;94: Weber RS, Forastiere A, Rosenthal DI, Laccourreye O. Controversies in the management of advanced laryngeal squamous cell carcinoma. Cancer 2004;101: Richard JM, Sancho-Garnier H, Pessey JJ, et al. Randomized trial of induction chemotherapy in larynx carcinoma. Oral Oncology 1998;34: Beahrs OH, Myers MH. Manual for staging of cancer (2 nd ed), American Joint Committee on Cancer. Philadelphia, PA: J.B. Lippincott Company; Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutics in cancer. In: MacLeod CM, editor. Evaluation of chemotherapeutic agents. New York: Columbia Press; p Foote RL, Kasperbauer JL, Okuno SH, et al. A pilot study of high-dose intraarterial cisplatin chemotherapy with concomitant accelerated radiotherapy for patients with previously untreated T4 and selected patients with T3N0-3M0 squamous cell carcinoma of the upper aerodigestive tract. Cancer 2005;103: Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53: Graner DE, Foote RL, Kasperbauer JL, et al. Swallow function in patients before and after intra-arterial chemoradiation. Laryngoscope 2003;113: Organ Preservation for Laryngeal Cancer HEAD & NECK DOI /hed August 2006