Intensive Chemoradiotherapy As a Primary Treatment for Organ

Home , Chemoradiotherapy

ORIGINAL ARTICLE Intensive Chemoradiotherapy as a Primary Treatment for Organ Preservation in Patients With Advanced Cancer of the Head and Neck Efficacy, Toxic Effects, and Limitations

Ehab Hanna, MD; Michael Alexiou, MD; Justin Morgan, MD; Jenny Badley, RNP; Anne Marie Maddox, MD; Jose Penagaricano, MD; Chun-Yang Fan, MD, PhD; Randall Breau, MD; James Suen, MD

Objectives: To evaluate the efficacy and toxic effects of Overall, at mean follow-up of 3 years, local disease con- intensive chemoradiotherapy as a primary modality for or- trol was achieved in 113 patients (89%), and organ pres- gan preservation in patients with advanced squamous cell ervation was possible in 102 patients (80%). Two thirds carcinoma of the head and neck (SCCHN) and to define of all patients (n=83) had clinical N+ disease. Complete the patterns of treatment failure associated with this therapy. clinical response to chemoradiotherapy in the neck was achieved in 57 of these patients (69%). However, com- Design: Retrospective review. plete response to chemoradiotherapy was 93%, 62%, and 47% for N1, N2, and N3 disease, respectively (PϽ.001). Setting: Tertiary care referral center. Patients achieving less than complete clinical response underwent salvage neck dissection. Overall, at an aver- Patients: A total of 127 consecutive patients with ad- age follow-up of 36 months, regional disease control was vanced SCCHN treated with primary concurrent che- achieved in 76 (92%) of the 83 patients with neck me- moradiotherapy. tastasis. Despite this high locoregional control rate, distant metastasis occurred in 18 patients (14%), was the Main Outcome Measures: Efficacy data included the most common site of disease recurrence (53%), and ac- rates of tumor response to therapy, organ preservation, counted for almost 40% of all treatment failures. Severe disease recurrence, overall and disease-specific sur- (grade 3 or 4) mucositis and neutropenia occurred in 33% vival, and patterns of treatment failure. Toxic effect data and 25% of patients, respectively. Two patients (2%) died included the rate and grade of treatment-related compli- of treatment-related toxic effects. At 3-year mean follow- cations and the rate of unscheduled hospital admissions up, disease-specific and overall survival were 72% and for managing treatment-related toxic effects. 57%, respectively. Most deaths were due to distant metastasis, comorbidity, and second primary tumors. Results: Ninety-six patients (76%) were men and 31 (24%) were women. Average age at diagnosis was 62 years Conclusions: High rates of locoregional disease con- (range, 37-85 years). The primary tumor site was the oro- trol and organ preservation are achievable with primary pharynx in 58 patients (46%), the larynx in 36 (28%), chemoradiotherapy in patients with advanced SCCHN, the hypopharynx in 20 (16%), the oral cavity in 10 (8%), but they are associated with severe treatment-related toxic and another site in 3 (2%). Most patients (91%) had stage effects. Despite this effective local and regional disease III or IV disease. Average follow-up was 36 months. Pri- control, improved survival is hampered by the rela- mary chemoradiotherapy achieved complete response at tively high incidence of distant metastasis, second pri- the primary tumor site in 109 patients (86%). Patients mary tumors, and comorbidity. with partial response, stable or progressive disease, or recurrence at the primary site underwent salvage surgery. Arch Otolaryngol Head Neck Surg. 2004;130:861-867

S AN ALTERNATIVE TO SUR- therapy, sequentially or concurrently.1 The gical resection, the inte- sequential regimen, which includes in- gration of chemotherapy duction chemotherapy followed by defini- and radiotherapy is cur- tive irradiation for responders, has been rently being investigated as tested in 2 large randomized trials, one for aA viable treatment option for organ pres- patients with laryngeal cancer2 and the Author affiliations are listed at ervation in patients with advanced squa- other for patients with hypopharyngeal 3 the end of this article. The mous cell carcinoma of the head and neck. cancer. These 2 phase 3 trials demon- authors have no relevant Organ preservation strategies include 2 strated that sequential chemotherapy and financial interest in this article. regimens of chemotherapy and radio- radiotherapy yielded survival rates simi-

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 861

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 lar to those obtained by surgery and irradiation but with specific survival, and patterns of treatment failure. Toxic effect organ preservation in many patients. The response to che- data included the rate and grade of treatment-related compli- motherapy is highly predictive of the response to radio- cations and the rate of unscheduled hospital admissions for the therapy, and, therefore, it is used to select patients for treat- management of treatment-related toxic effects. ment by either surgery or irradiation. Despite a slightly lower rate of distant metastasis, this approach showed no RESULTS improvement in locoregional control or survival. In contrast, growing evidence suggests that concur- PATIENT DEMOGRAPHICS, rent administration of chemoradiotherapy may yield im- PRIMARY TUMOR SITE, AND DISEASE STAGE proved locoregional control, disease-free survival, and overall survival rates compared with the sequential regi- Of the 127 patients, 96 (76%) were men and 31 (24%) men or radiotherapy alone.4-6 A meta-analysis7 of 6 trials were women. Average age at diagnosis was 62 years (range, (861 patients) comparing neoadjuvant chemotherapy fol- 37-85 years). Mean follow-up was 36 months. lowed by radiotherapy with concomitant or alternating The oropharynx was the most common site of pri- radiochemotherapy yielded a hazard ratio of 0.91 (95% mary tumor, followed by the larynx. Of the 127 pa- confidence interval, 0.79-1.06) in favor of concomitant tients, 58 (46%) had cancer of the oropharynx, which or alternating radiochemotherapy. This improvement is originated from the base of the tongue in 30 patients attributed to the radiosensitizing effects of chemo- (24%), the tonsils in 18 (14%), and the oropharyngeal therapy.6 walls in 10 (8%). The larynx was the primary site of tu- Despite these encouraging results, a larger meta- mor in 36 patients (28%) and was classified as glottic in analysis7 of 63 trials (10741 patients) evaluating the effect 23 patients (18%) and supraglottic in 13 (10%). The hy- of chemotherapy added to locoregional treatment on sur- popharynx was the primary site of tumor in 20 patients vival yielded an absolute survival benefit of 4% at 2 and (16%), originating from the piriform sinus. The oral cav- 5 years. In this large meta-analysis, although no signifi- ity was the least frequent site of primary tumor in this cant benefit was associated with adjuvant or neoadju- series, occurring in only 10 patients (8%). Other sites of vant chemotherapy, chemotherapy given concomi- primary tumor involvement, for example, upper esoph- tantly with radiotherapy had substantial benefits, but ageal and sinonasal, occurred in 3 patients (2%). heterogeneity of the results prohibited firm conclu- The American Joint Committee on Cancer TNM stag- sions. In addition, although intensive regimens of con- ing system was used to define the tumor stage in all pa- current chemoradiotherapy may be more effective, they tients. Of the 127 patients, 91 (72%) had advanced pri- result in considerable toxic effects, such as mucositis, xe- mary tumors (55 had T3 and 36 had T4 tumors). The rostomia, dysphagia, weight loss, neutropenia, and sep- remaining 36 patients (28%) had T1 (n=6) and T2 (n=30) sis. These complications may require treatment inter- tumors. Eighty-three patients (65%) had clinical evi- ruption, enteral feeding, and hospital admission for the dence of metastasis in the regional lymph nodes: 27 pa- management of sepsis, malnutrition, and dehydration.8 tients had N1 disease, 39 had N2 disease, and 17 had N3 The objectives of this study are to critically evalu- disease. Only 2 patients (2%) had evidence of distant me- ate the efficacy and toxic effects of intensive concurrent tastasis when first seen. Overall, 116 patients (91%) had chemoradiotherapy as a primary modality for organ pres- either stage III (n=41) or IV (n=75) disease. ervation in patients with advanced squamous cell carcinoma of the head and neck and to define the patterns of TUMOR RESPONSE treatment failure associated with this therapy. Tumor response was assessed in all patients 4 to 6 weeks METHODS after the completion of concurrent chemoradiotherapy. Evaluation of tumor response was performed by a de- A total of 127 consecutive patients with previously untreated tailed clinical examination of the head and neck, includ- squamous cell carcinoma of the head and neck who received ing office endoscopy of the primary tumor site and high- concurrent chemoradiotherapy as their primary treatment be- resolution imaging (computed tomography, magnetic tween 1996 and 2002 were included in this study. This study was approved by the institutional review board of the Univer- resonance imaging, or both) of the primary site and the neck. sity of Arkansas for Medical Sciences, a tertiary care referral Any suspicious findings in the primary tumor site on either center. The medical records of these 127 patients were re- clinical examination or imaging were evaluated by direct viewed for patient demographics, primary tumor site, disease tumor biopsy and histopathologic examination. Any sus- stage, treatment, and follow-up. picious findings in the neck on either clinical examina- All patients received standard fractionation (1 fraction/d, tion or imaging were evaluated by fine-needle aspiration 1.8-2.0 Gy/fraction, 5 d/wk, and a total dose of 66-72 Gy) ra- biopsy, which was image guided when necessary. diotherapy. All patients received at least 2 cycles of cisplatin The following definitions were used to describe tu- and fluorouracil concurrently with radiotherapy. Of the 127 mor response to therapy: (1) complete response is the ab- patients, 44 also received, at the treating physician’s discre- sence of any signs of disease on clinical examination, high- tion, an additional 2 cycles of neoadjuvant chemotherapy before starting concurrent chemoradiotherapy. Patients with less resolution imaging, and histopathologic or cytologic than a complete response to chemoradiotherapy underwent sal- examination; (2) partial response is at least a 50% reduc- vage surgery. tion in tumor size by clinical examination and imaging; Efficacy data included the rates of response to therapy, or- (3) stable disease is a less than 50% reduction or a less gan preservation, disease recurrence, overall and disease- than 25% increase in tumor size by clinical examination

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 862

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 and imaging; and (4) progressive disease is at least a 25% 80 increase in tumor size by clinical examination and im- 76 aging or the appearance of new lesions. 70

60 Response of the Primary Tumor Site, Salvage Surgery, Local Disease Control, 50

and Organ Preservation 40

Concurrent chemoradiotherapy, with or without induc- Patients, No. 30 26

tion chemotherapy, achieved a complete response at the 20 18 primary tumor site in 109 (86%) of the 127 patients. Pa- tients with less than a complete response, that is, a par- 10 7

tial response (6%) or stable (5%) or progressive (1%) dis- 0 ease at the primary site, underwent salvage surgery, with Loss >4.5 kgUnchanged Gain >4.5 kg Unknown overall initial local disease control being achieved in 119 Weight patients (94%). Tumor response was considered non- evaluable in 3 patients (2%) because they refused to com- Figure 1. Patient weight change during treatment. plete the therapy or they died of toxic effects or unre- lated causes during treatment. Complete response rates Overall, at mean follow-up of 36 months, regional were not statistically significantly different among the vari- disease control was achieved in 76 (92%) of the 83 pa- ous subsites: oropharynx, 86% (50/58); larynx, 92% (33/ tients with neck metastasis. 36); hypopharynx, 85% (17/20); and oral cavity, 80% (8/10). However, the overall sample size does not allow TREATMENT-RELATED TOXIC EFFECTS an adequately powered subset analysis. Of the 119 patients with initial local tumor control, Acute Toxic Effects 9 had local recurrence of disease (7 after an initial complete response to chemoradiotherapy and 2 after initial sal- Approximately 50% of all patients experienced some de- vage surgery). Local control of recurrent disease was gree of neutropenia, and half of these patients experi- achieved in 3 of the 5 patients who underwent salvage sur- enced severe (grade 3-4) neutropenia. Most treatment- gery. The other 4 patients either refused surgery or were related toxic effects, however, were gastrointestinal. At inoperable and died of progressive disease. Overall, at mean least 64% of patients experienced some degree of muco- follow-up of 3 years, local disease control was achieved sitis. The incidence of severe (grade 3-4) mucositis was in 113 (89%) of 127 patients and organ preservation was 33%. Some degree of nausea was experienced by 44% of possible in 102 (80%) of 127 patients. patients, but severe nausea and vomiting occurred in only 15% and 11% of patients, respectively. At least 25% of Response of Tumor in Neck, Neck Dissection, patients developed dehydration and electrolyte imbal- and Regional Disease Control ance that required intravenous or enteral fluid replace- ment. Overall, 93 (73%) of the 127 patients required gas- Eighty-three (65%) of 127 patients were first seen with trostomy tube (G-tube) placement before (n=73), during clinical N1 to N3 disease. Overall, concurrent chemora- (n=17), or after (n=3) treatment for nutritional sup- diotherapy with or without induction chemotherapy port. Despite the frequent use of G-tubes for nutritional achieved a complete response at the neck in 69% of these management, weight loss was a considerable problem in patients (n=57). The complete response rate in the neck, most patients (Figure 1). During treatment, 76 (60%) however, was 93%, 62%, and 47% for N1, N2, and N3 of 127 patients experienced weight loss of more than 4.5 disease, respectively (PϽ.001). The response to chemo- kg (mean, 7.8 kg). Even 1 year after treatment, the av- radiotherapy in the regional lymph nodes could not be erage weight loss was 5.9 kg. Patients with G-tube sup- assessed in 4 patients either because they had a neck dis- port experienced significantly less average weight loss dur- section before chemoradiotherapy or because they died ing treatment (PϽ.05) and a trend toward less average of treatment-related toxic effects or intercurrent illness weight loss 1 year after treatment compared with those before completion of treatment. Patients with less than without G-tube support (Figure 2). a complete response in the neck (n=22) were classified as having a partial response (17%) or stable (6%) or pro- Unscheduled Hospital Admissions gressive (4%) disease. Salvage neck dissections were performed on 19 of these 22 patients; the other 3 patients Unscheduled hospital admissions for the management of refused surgery or were inoperable and died of progres- treatment-related toxic effects were frequent. One, 2, or sive disease. Of the 19 patients who underwent salvage 3 unscheduled hospital admissions were needed for 64 neck dissection, 11 had histopathologically confirmed re- (50%), 25 (20%), and 7 (6%) patients, respectively, for sidual carcinoma in their neck dissection specimens. The the management of treatment-related complications. The other 8 patients had no viable tumor, and the excised most frequent reasons for unscheduled hospitalization lymph nodes showed evidence of extensive necrosis, dense included dehydration and electrolyte imbalance, sepsis, fibrosis, dystrophic calcification, and keratinaceous de- febrile neutropenia, pneumonia, and malnutrition. Place- bris surrounded by macrophage infiltration. ment of a G-tube before initiating therapy had no im-

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 863

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 ond primary tumors (n=6; 11%) and treatment-related 11.2 During Treatment toxic effects (n=2; 4%). 1 y After Treatment 9.9

9.0 COMMENT

6.8 6.8 6.3 EFFICACY OF CONCURRENT 5.4 CHEMORADIOTHERAPY

4.5 Weight Loss, kg Weight Locoregional Control and Organ Preservation

2.2 Despite advanced disease stage, concurrent chemoradiotherapy achieved a high complete response rate (86%) at the primary tumor site attributable to the radiosensi- 0 G-tube No G-tube tizing effects of chemotherapy.6 The possible mechanisms of such synergy between chemotherapy and ra- Figure 2. Mean patient weight loss during and 1 year after treatment, with diotherapy are as follows: and without gastrostomy tube (G-tube) support. • Modification of the slope of the dose-response curve pact on the frequency of unscheduled hospital admis- • Decreased accumulation or inhibition of repair of sions. Less frequent reasons for unscheduled hospitalization sublethal damage included airway distress, bleeding, pulmonary embolism, • Inhibition of repair of potentially lethal damage and seizures. • Inhibition of repopulation • Increased proportion of cells in the sensitive cell- Long-term Complications and Functional Deficits cycle phase • Decreased tumor bulk with improved cell oxy- The most common long-term treatment-related compli- genation cation was dysphagia. At least 40% of patients com- • Enhanced drug delivery and uptake plained of dysphagia that was severe enough to require a change in their pretreatment diet. Other long-term treat- Patients with less than a complete response of the ment-related complications included osteoradionecro- primary tumor to chemoradiotherapy underwent sal- sis of the mandible in 2 patients (1 required segmental vage surgery, resulting in an overall initial local disease resection of the mandible and microvascular free flap re- control rate of 94%. This high rate of local disease con- construction) and chondroradionecrosis of the larynx in trol was durable. At mean follow-up of 3 years, the local 3 patients (2 required a total laryngectomy, although they disease control rate was 89%, highlighting the relatively were free of recurrent cancer). Two patients died of treat- low incidence of local disease recurrence. After account- ment-related toxic effects. ing for salvage surgery for nonresponders and those with locally recurrent disease, organ preservation was pos- DISEASE RECURRENCE, PATTERNS OF sible in most patients (80%). TREATMENT FAILURE, AND SURVIVAL The complete response rate of metastatic disease in the regional lymph nodes to chemoradiotherapy (69%) was Overall, 30 (24%) of 127 patients experienced disease re- less than that in the primary tumor site, but it was highly currence, and 12 patients (9%) developed second pri- dependent on the N stage (93%, 62%, and 47% for N1, N2, mary tumors, mostly in the lung. The site of disease re- and N3 disease, respectively). Salvage neck dissection was currence was local in 5 patients, regional in 5, distant in performed in patients with less than a complete response 16, local and regional in 2, and local and distant in 2. in the regional lymph nodes, and it was effective in achiev- Overall, distant metastasis occurred in 14% of patients, ing a durable high rate of regional control (92% at 3-year was the most common site of disease recurrence (53%), mean follow-up). This success underscores the impor- and accounted for almost 40% of all treatment failures. tance of timely salvage neck dissection for patients with N2 Patients who received 2 cycles of induction chemo- or higher disease who have clinical or radiologic evidence therapy before definitive chemoradiotherapy had less in- of persistent disease. However, many of these salvage neck cidence of distant metastasis (9%) than those who re- dissections (8 of 19) revealed no viable tumor. This rate ceived concomitant chemoradiotherapy only (16%), but was similar to that reported in other studies.9 the difference was not statistically significant (P=.29). The optimal treatment for patients with N2 or higher The tumor primary site, disease stage, and length of fol- nodal disease who appear on clinical examination and low-up were not statistically significantly different in pa- high-resolution imaging (computed tomography, mag- tients who did vs did not receive induction chemo- netic resonance imaging, or both) to have achieved a com- therapy. At 3-year mean follow-up, disease-specific and plete clinical response in the neck is not clearly defined. overall survival were 72% and 57%, respectively. Most Recommendations vary from routine performance of a of the 54 deaths were due to distant metastasis (n=17; planned comprehensive or selective neck dissection to 31%), comorbidity (n=18; 34%), and locoregional re- observation and close surveillance. In a study9 from The currence (n=11; 20%). Other deaths were caused by sec- Cleveland Clinic, the rate of occult residual carcinoma

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 864

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 in patients with N2 or higher disease who had no clini- fects. Grade 3 to 4 neutropenia and mucositis were expe- cal or radiologic evidence of residual disease and who un- rienced by 25% and 33% of all patients, respectively. Other derwent planned neck dissection was approximately 20%. common complications included nausea, vomiting, dehy- Meanwhile, patients with a similar neck stage (N2 or dration and electrolyte imbalance, and malnutrition. Un- higher) and a complete clinical response who chose not scheduled hospital admissions were frequent and were to have a planned neck dissection were closely ob- necessary in 50% of patients for the management of treat- served. The regional recurrence rate in this group of pa- ment-related toxic effects. The most frequent reasons for tients was 25%, and most of these patients died of pro- unscheduled hospitalization included dehydration and gressive disease in the neck. Based on these results, the electrolyte imbalance, sepsis, febrile neutropenia, pneu- authors9 recommended planned dissection for all pa- monia, and malnutrition. The high incidence of unsched- tients with N2 or N3 disease regardless of the neck re- uled hospitalizations for the management of treatment- sponse because it is difficult to follow patients for recur- related complications highlights not only the considerable rent neck cancer after chemoradiotherapy and because toxic effects associated with intensive chemoradiotherapy salvage is often unsuccessful in these patients. This ap- but also the need for intensive supportive care during treat- proach has also been adopted by some of the largest co- ment. Many patients required multiple hospitalizations for operative clinical trials of organ preservation therapy.6 supportive care during treatment, which has a statistically In our study, however, of 32 patients who had N2 or significant effect on the overall cost of treatment. higher disease and no clinical or radiologic evidence of Placement of a G-tube was necessary for the man- residual tumors, 10 chose to have a planned neck dis- agement of poor oral intake, dehydration, electrolyte im- section (3 patients had occult disease on pathological ex- balance, and malnutrition in 93 patients (73%). Despite amination), and 22 patients were followed with close ob- the frequent use of a G-tube for nutritional management, servation. The regional failure in these 2 groups was not weight loss was a considerable problem in most patients statistically significantly different, but this may be be- during and even 1 year after treatment (Figure 1). How- cause of the small sample size. It remains to be seen ever, patients with G-tube support experienced statisti- whether functional imaging techniques, such as posi- cally significantly less average weight loss during treat- tron emission tomography, can reliably distinguish be- ment and a trend toward less average weight loss 1 year tween residual carcinoma and posttreatment changes and after treatment compared with those without G-tube sup- offer some guidance on whether planned or salvage neck port (Figure 2). These findings coincide with those re- dissection after chemoradiotherapy is indicated for pa- ported by Lee et al8 on the effect of prophylactic G-tube tients with N2 or higher disease. placement in patients undergoing intensive chemoradiotherapy. However, unlike the results of their study, we did Patterns of Treatment Failure and Survival not demonstrate that prophylactic G-tube placement sub- stantially reduced the rate of unscheduled hospital admis- Despite excellent locoregional control, distant metasta- sion. Another disadvantage of routine prophylactic sis occurred in 14% of patients and accounted for more G-tube placement is “defunctioning” of normal degluti- than half of all disease recurrence (53%). Distant metas- tion, which may have a negative effect on the long-term tasis was also the most common cause of treatment fail- outcome of swallowing function. There is some evi- ure (40%) and death (31%). Another statistically signifi- dence10 to suggest that early and intensive swallowing re- cant factor compromising survival was the development habilitation during chemoradiotherapy of the head and of second primary tumors in several patients (9%). Two neck may be associated with less long-term dysphagia and thirds of all treatment failure could be attributed to either G-tube dependence. Therefore, the indiscriminate use of distant metastasis or second primary tumors. Similarly, prophylactic G-tube placement may not be advisable and distant metastasis and second primary tumors com- may be detrimental to swallowing rehabilitation. When bined were responsible for 42% of all deaths. However, G-tube placement is necessary for nutritional manage- the most common cause of death was the presence of co- ment, every effort should be made to continue active swal- morbidity, with 34% of patients dying of causes unre- lowing rehabilitation throughout treatment. lated to cancer. This finding underscores that despite a relatively high disease-specific survival rate (72%), over- Long-term Toxic Effects and Functional Deficits all survival was only 57%. Future strategies to improve survival rates in patients with advanced cancer of the head The most common long-term complication of intensive and neck, therefore, should address the most common chemoradiotherapy of the head and neck is dysphagia. causes of treatment failure and mortality—distant me- In this study, at least 40% of patients complained of dys- tastasis, second primary tumors, and comorbidity. phagia that was serious enough to require a change their pretreatment diet. Dysphagia after intensive chemora- TREATMENT-RELATED TOXIC EFFECTS diotherapy of the head and neck may be caused by stricture formation resulting from severe ulcerative mucosi- Acute Toxic Effects tis during treatment. In some cases, stricture formation may be severe enough to preclude endoscopy or dila- Although the synergy between chemotherapy and radio- tion. In extreme cases, there may be complete oblitera- therapy enhances the efficacy of both modalities com- tion of the hypopharyngeal or esophageal lumen. There- bined, intensive chemoradiotherapy results in statistically fore, in cases of severe ulcerative confluent mucositis of significant acute and delayed treatment-related toxic ef- the hypopharynx or upper esophagus, it may be better

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 865

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 to use a nasogastric tube instead of a G-tube for nutri- moradiotherapy. Such patients are probably better served tional support because the former has the advantage of with initial surgical resection to minimize unnecessary mor- maintaining a patent lumen, which could subsequently bidity and delay in effective tumor control. Therefore, it be dilated. More commonly, however, dysphagia after che- is critical to identify accurate and reliable molecular pre- moradiotherapy of the head and neck is due to general- dictors of tumor response to chemoradiotherapy.16-20 The ized weakness and lack of coordination of degluti- evolution of global gene expression analysis using gene tion.10-14 The exact mechanisms underlying these deficits arrays and the ability to simultaneously study the expres- are not well defined and may include direct neuromus- sion of specific genes in a large number of tumor speci- cular toxic effects or fibrosis of the muscles of degluti- mens using tissue arrays provide a unique opportunity to tion.10,11 The combined effect of weakness and lack of sen- identify molecular markers of tumor response to therapy. sation may lead to considerable pharyngeal dysmotility, Recently, using Atlas complementary DNA microarray (At- aspiration, or both. Other less common long-term com- las; BD Biosciences, San Jose, Calif), Hanna et al21 identi- plications included osteoradionecrosis of the mandible fied gene expression patterns that may be associated with and chondroradionecrosis of the larynx. Treatment of response or resistance to chemoradiotherapy. It is hoped these complications may involve radical surgery, such as that these “molecular signatures” of tumor response or re- segmental mandibulectomy or total laryngectomy. sistance to therapy may optimize treatment selection for The frequency and severity of long-term complica- patients with cancer of the head and neck. tions after intensive chemoradiotherapy highlight that organ preservation does not necessarily result in func- CONCLUSIONS tional preservation. The impact of these long-term complications and functional deficits, particularly dys- High rates of locoregional disease control and organ pres- phagia, on patients’ quality of life must be critically evalu- ervation are achievable with primary chemoradio- ated. In a recent study, Hanna et al15 found no substan- therapy in patients with advanced squamous cell carci- tial differences in the overall quality of life of patients with noma of the head and neck, but they are associated with advanced laryngeal cancer treated with total laryngec- severe treatment-related toxic effects. Despite effective tomy or laryngeal preservation. local and regional disease control, improved survival is hampered by the relatively high incidence of distant me- FUTURE DIRECTIONS tastasis, second primary tumors, and comorbidity. Fu- ture treatment strategies should focus on improving sur- Future strategies of intensive chemoradiotherapy for pa- vival by reducing the rate of distant metastasis and second tients with advanced cancer of the head and neck must ad- primary tumors. Strategies to reduce treatment-related dress the most common causes of treatment failure: dis- toxic effects and to improve the functional outcome of tant metastasis, comorbidity, and second primary tumors. the “preserved” organ should be developed. Finally, fu- In this study, patients who received 2 cycles of induction ture research should also focus on identifying reliable chemotherapy before definitive chemoradiotherapy had less markers of tumor response to various treatments to fa- incidence of distant metastasis (9%) than those who re- cilitate selecting the optimal therapy for each patient. ceived concomitant chemoradiotherapy only (16%). Al- though the difference was not statistically significant, this Submitted for publication April 30, 2003; final revision re- trend needs further evaluation in a larger prospective study. ceived January 26, 2004; accepted March 1, 2004. The lower distant metastatic rate associated with neoad- From the Departments of Otolaryngology–Head and juvant chemotherapy before concurrent chemoradio- Neck Surgery (Drs Hanna, Alexiou, Morgan, Breau, and therapy may be attributed to (1) a higher total number of Suen and Ms Badley), Medical Oncology (Dr Maddox), chemotherapy treatment cycles (4-5 cycles in patients Radiation Oncology (Dr Penagaricano), and Pathology treated with induction chemotherapy followed by chemo- (Dr Fan), the Arkansas Cancer Research Center, Univer- radiotherapy vs 2-3 cycles in those undergoing chemora- sity of Arkansas for Medical Sciences, Little Rock. Dr diotherapy only), (2) earlier “triage” of nonresponders to Hanna is now with the Department of Head and Neck Sur- surgical salvage, avoiding unnecessary delay in definitive gery, The University of Texas MD Anderson Cancer Cen- locoregional therapy, or (3) both. The possible benefits of ter, Houston. induction chemotherapy in select patients for subsequent This study was presented at the American Head and concurrent chemoradiotherapy needs further study. Fu- Neck Society Annual Meeting; May 5, 2003; Nashville, Tenn. ture strategies should also focus on long-term adjuvant Correspondence: Ehab Hanna, MD, Department of Head therapy to lower the incidence of late distant metastasis and and Neck Surgery, The University of Texas M. D. Ander- for the chemoprevention of second primary tumors. son Cancer Center, 1515 Holcombe Blvd, Unit 441, Hous- Treatment-related toxic effects remain an impor- ton, TX 77030-4009 ([email protected]). tant problem in patients undergoing intensive chemoradiotherapy. Future research should focus on novel agents with less toxicity and on mucosal protectants. The REFERENCES long-term functional deficits of intensive chemoradiotherapy should be carefully assessed, and its impact on 1. Wolf GT, Forastiere A, Ang K, et al. Workshop report: organ preservation strat- patients’ quality of life should be critically evaluated. egies in advanced head and neck cancer: current status and future directions. Finally, despite its efficacy, there remains a subset of Head Neck. 1999;21:689-693. patients whose tumors do not respond to intensive che- 2. Induction chemotherapy plus radiation compared with surgery plus radiation in

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 866

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 patients with advanced laryngeal cancer: the Department of Veterans Affairs La- 12. Newman LA, Robbins KT, Logemann JA, et al. Swallowing and speech ability ryngeal Cancer Study Group. N Engl J Med. 1991;324:1685-1690. after treatment for head and neck cancer with targeted intraarterial versus intra- 3. Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. Lar- venous chemoradiation. Head Neck. 2002;24:68-77. ynx preservation in pyriform sinus cancer: preliminary results of a European Or- 13. Watkin KL, Diouf I, Gallagher TM, Logemann JA, Rademaker AW, Ettema SL. ganization for Research and Treatment of Cancer phase III trial: EORTC Head Ultrasonic quantification of geniohyoid cross-sectional area and tissue compo- and Neck Cancer Cooperative Group. J Natl Cancer Inst. 1996;88:890-899. sition: a preliminary study of age and radiation effects. Head Neck. 2001;23:467- 4. Adelstein DJ, Sharan VM, Earle AS, et al. Simultaneous versus sequential com- 474. bined technique therapy for squamous cell head and neck cancer. Cancer. 1990; 14. Lazarus CL, Logemann JA, Pauloski BR, et al. Swallowing and tongue function 65:1685-1691. following treatment for oral and oropharyngeal cancer. J Speech Lang Hear Res. 5. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus 2000;43:1011-1023. concomitant chemotherapy and radiation therapy for advanced-stage orophar- 15. Hanna E, Cash D, Adams DC, Vural E, Fan CY, Sherman AC. Quality of life for ynx carcinoma. J Natl Cancer Inst. 1999;91:2081-2086. patients following total laryngectomy versus chemoradiation for laryngeal pres- 6. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radio- ervation. Abstract presented at: American Head and Neck Society Annual Meet- therapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003; ing; May 4-6, 2003; Nashville, Tenn. 349:2091-2098. 16. Bradford CR, Wolf GT, Carey TE, et al. Predictive markers for response to che- 7. Pignon JP, Bourhis J, Domenge C, Designe L, MACH-NC Collaborative Group. motherapy, organ preservation, and survival in patients with advanced laryn- Chemotherapy added to locoregional treatment for head and neck squamous- geal carcinoma. Otolaryngol Head Neck Surg. 1999;121:534-538. cell carcinoma: three meta-analyses of updated individual data. Lancet. 2000; 17. Costa A, Licitra L, Veneroni S, et al. Biological markers as indicators of patho- 355:949-955. logical response to primary chemotherapy in oral-cavity cancers. Int J Cancer. 8. Lee JH, Machtay M, Unger LD, et al. Prophylactic gastrostomy tubes in patients 1998;79:619-623. undergoing intensive irradiation for cancer of the head and neck. Arch Otolaryn- 18. Koukourakis MI, Giatromanolaki A, Fountzilas G, Sivridis E, Gatter KC, Harris AL. gol Head Neck Surg. 1998;124:871-875. Angiogenesis, thymidine phosphorylase, and resistance of squamous cell head 9. Lavertu P, Adelstein DJ, Saxton JP, et al. Management of the neck in a random- and neck cancer to cytotoxic and radiation therapy. Clin Cancer Res. 2000;6: ized trial comparing concurrent chemotherapy and radiotherapy with radio- 381-389. therapy alone in resectable stage III and IV squamous cell head and neck can- 19. Vural E, Alexiou M, Hunt J, Korourian S, Hanna E. Is glutathione-S-transferase-pi cer. Head Neck. 1997;19:559-566. expression a reliable predictor of chemoradiation response in cancer of the head 10. Mittal BB, Pauloski BR, Haraf DJ, et al. Swallowing dysfunction: preventative and and neck? Am J Otolaryngol. 2001;22:257-260. rehabilitation strategies in patients with head-and-neck cancers treated with sur- 20. Warnakulasuriya S, Jia C, Johnson N, Houghton J. p53 and P-glycoprotein ex- gery, radiotherapy, and chemotherapy: a critical review. Int J Radiat Oncol Biol pression are significant prognostic markers in advanced head and neck cancer Phys. 2003;57:1219-1230. treated with chemo/radiotherapy. J Pathol. 2000;191:33-38. 11. Pauloski BR, Rademaker AW, Logemann JA, Colangelo LA. Speech and swal- 21. Hanna E, Shrieve DC, Ratanatharathorn V, et al. A novel alternative approach for lowing in irradiated and nonirradiated postsurgical oral cancer patients. Oto- prediction of radiation response of squamous cell carcinoma of head and neck. laryngol Head Neck Surg. 1998;118:616-624. Cancer Res. 2001;61:2376-2380.

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 867