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Japanese Journal of Clinical Oncology Advance Access originally published online on August 11, 2008
Japanese Journal of Clinical Oncology 2008 38(8):521-527; doi:10.1093/jjco/hyn073
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© The Author (2008). Published by Oxford University Press. All rights reserved

Chemoradiotherapy Laryngeal Preservation for Advanced Hypopharyngeal Cancer{dagger}

Shyh-Kuan Tai1,2,4, Muh-Hwa Yang2,5, Ling-Wei Wang3,6, Tung-Lung Tsai1,2, Pen-Yuan Chu1, Yi-Feng Wang1, Jui-Lin Huang1 and Shyue-Yih Chang1,4

1 Department of Otolaryngology, Taipei Veterans General Hospital
2 Institute of Clinical Medicine, National Yang-Ming University
3 The Cancer Center, Taipei Veterans General Hospital
4 Department of Otolaryngology, National Yang-Ming University
5 Division of Medical Oncology, Department of Medicine, Taipei Veterans General Hospital
6 School of Medicine, National Yang-Ming University, Taipei, Taiwan

For reprints and all correspondence: Shyue-Yih Chang, Department of Otolaryngology, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. E-mail: sychang{at}vghtpe.gov.tw

Received May 21, 2008; accepted July 12, 2008


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Objective: Laryngeal preservation is a challenge for the treatment of advanced hypopharyngeal cancer. The objective of this study is to evaluate the results of chemoradiotherapy laryngeal preservation for advanced hypopharyngeal cancer at a single institute and the impact of treatment factors on prognosis.

Methods: The study population consisted of 42 consecutive patients with resectable stage III–IV hypopharyngeal cancer. Patients with T4b tumor, synchronous primary cancer or those treated palliatively were excluded. Induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) was performed in 32 (76.2%) patients, whereas primary CCRT was done in the other 10 (23.8%). Patients were grouped according to the dose intensity of chemotherapy and total dose of radiotherapy (RT).

Results: Grade 3–4 toxicities occurred mostly during CCRT. Thirty-five (83.3%) patients received an optimum dose of cisplatin (CT-optimum), 27 (64.3%) received an optimum dose of RT-optimum and 26 (61.9%) received optimum doses of both (CRT-optimum). CT- and RT-optimum both correlated significantly with better disease-free survival (DFS) (P < 0.001 and = 0.003), overall survival (OS) (P < 0.001 and = 0.004) and laryngeal preservation survival (LPS) (P = 0.01 and 0.04). The 3-year DFS, OS and LPS for CRT-optimum patients were 48.1, 50.0 and 45.6%, respectively.

Conclusions: Achievement of optimum treatment dose remains challenging in chemoradiotherapy laryngeal preservation for advanced hypopharyngeal cancer. Intensive patient care and monitoring by experienced multi-disciplinary teamwork are mandatory. The criteria for selecting patients who will respond to and complete the treatment remain key issues for future investigation.

Key Words: hypopharyngeal cancer • laryngeal preservation • chemotherapy • radiotherapy


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Hypopharyngeal cancer is uncommon, representing ~0.5% of all human malignancies and 4% of head and neck cancers (1). Prognosis for hypopharyngeal cancer is unfavorable due to the tendency of advanced presentation, submucosal extension, early cervical lymph node metastasis and the propensity for distant metastasis. Surgical resection followed by postoperative radiotherapy (RT) has been the mainstay of treatment, which mostly requires total laryngectomy in advanced cases, leading to the loss of natural speech function (2–4).

Progress in non-surgical organ preservation treatment for head and neck cancer began with the milestone clinical trial of the Veterans’ Administration Laryngeal Cancer Study on advanced laryngeal cancer (5). For hypopharyngeal cancer, the European Organization for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Cooperative group conducted an early randomized trial, demonstrating that laryngeal preservation by induction chemotherapy (ICT) followed by definite RT is a safe treatment alternative for patients with T2–T4 tumors (6). Based on these encouraging results, chemoradiotherapy as the definite treatment for advanced head and neck cancer has been studied in the past 15 years, including cancers arising from the hypopharynx (7–10). However, hypopharyngeal cancer was usually a smaller subgroup (5–39%) in most studies, with a relatively poor outcome (11–14). Details of combined chemoradiotherapy for advanced hypopharyngeal cancer were seldom specifically reported.

Since 2002, chemoradiotherapy laryngeal preservation was included as one of the treatment choices for advanced hypopharyngeal cancer at the Taipei Veterans General Hospital, a tertiary referral center in Taiwan. This study was conducted to evaluate the results of chemoradiotherapy laryngeal preservation for advanced stage III–IV hypopharyngeal cancer. The toxicities, oncologic results were described and the impacts of treatment factors were explored in an effort to optimize future laryngeal preservation treatment for this poor prognostic malignancy.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study Population
Forty-two consecutive patients treated between January 2002 and July 2004 at our institute were included in this retrospective study. All patients had stage III–IV hypopharyngeal squamous cell carcinoma (SCC) and were treated by combined chemoradiotherapy for curative intent. Those who had T4b tumors or synchronous primary cancers were excluded. Patients with previous primary cancer were also excluded unless disease free for at least 2 years.

Pre-treatment evaluation included physical examination, panendoscopy tumor mapping and biopsy, computed tomography (CT) or magnetic resonance imaging (MRI) of the primary and the neck, chest X-ray or chest CT and routine laboratory studies. All of the patients had Eastern Cooperative Oncology Group performance status of 0–2, with no evidence of distant metastasis, and met the criteria of age younger than 75 years, hemoglobin ≥11 g/dl, leukocyte count ≥4000/mm3, platelet count ≥100 000/mm3, creatinine clearance rate >60 ml/min and serum total bilirubin <2 mg/dl. Patients were staged according to the 2002 criteria of the American Joint Committee on Cancer (15).

Treatment Plan
Each patient was reviewed by the multi-disciplinary head and neck oncology team, which consisted of radiologist, surgical oncologist, radiation oncologist and medical oncologist. Chemoradiotherapy organ preservation was included as one of the treatment choices and was arranged after pre-treatment discussion with the patient and family. The laryngeal preservation protocol consisted of ICT followed by concurrent chemoradiotherapy (CCRT). The treatment schema and chemotherapeutic regimen are summarized in Fig. 1. In each cycle of ICT, cisplatin (25 mg/m2) and 5-fluorouracil (750 mg/m2) were given intravenously on Days 1–4. Methotrexate (40 mg/m2) was also given intravenously on Days 1, 8 and 15. The treatment included two cycles of ICT and response evaluation was conducted at Week 8. Patients who responded to ICT (responder), defined as more than 50% reduction at the primary site or neck, were arranged for definite CCRT treatment. For those who achieved less than 50% reduction (non-responder) at the primary site or neck, immediate surgical treatment was recommended.


Figure 1
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  		Figure 1. Details of treatment schema and chemotherapeutic regimen. ICT, induction chemotherapy; CCRT, concurrent chemoradiotherapy; CDDP, cisplatin; 5-FU, 5-fluorouracil; MTX, methotrexate; RT, radiotherapy.

 
Six cycles of chemotherapy were planned during CCRT (Fig. 1), consisting of intravenous infusion of cisplatin (20 mg/m2) and 5-fluorouracil (400 mg/m2). For simplicity, the cumulative dose of cisplatin was used for dose intensity calculation. The intended cisplatin dose for ICT+CCRT was therefore 320 mg/m2. Ten patients did not undergo ICT, but received primary CCRT (Table 1). The intended cisplatin dose for them was 120 mg/m2. RT was given 5 days per week under conventional RT schedule at 1.8–2.0 Gy per fraction. The intended irradiation dose to the primary site and gross lymphadenopathy (≥1 cm) was 70 Gy, while it was 50 Gy to the N0 neck. RT was given with 6 MV X-rays from the linear accelerator and most of the RT technique used was initial 2-D followed by 3-D boost after 56 Gy. Intensity-modulated RT was done in 10 patients.


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  		Table 1. Patient characteristics (n = 42)

 
Treatment Evaluation
Toxic effects of the treatment were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0. Response evaluation was based on the RECIST criteria (16). After treatment completion, patients entered a program of follow-up at monthly intervals for the first year and every 3 months thereafter. CT or MRI of the neck and chest was arranged at 3- to 6-month intervals for the first year. Direct laryngoscopy with biopsy was performed if there was suspicion of persistence or recurrence. Laryngeal preservation result was evaluated at least 1 year after treatment completion. Successful laryngeal preservation was considered when all three requirements were met: (i) no evidence of local failure; (ii) no need of feeding tube or tracheostomy and (iii) no subsequent total laryngectomy (6).

According to the dose intensity of cisplatin and the total dose of RT, patients were grouped as ‘CT-optimum’ when cumulative cisplatin dose exceeded 80% of the intended dose (256 mg/m2 for ICT+CCRT, and 96 mg/m2 for primary CCRT). ‘RT-optimum’ was defined as a cumulative irradiation dose exceeding 90% of the intended dose (63 Gy at primary tumor and N+neck, 45 Gy at N0 neck). Patients who completed the optimum dose of both cisplatin and RT were grouped as ‘CRT-optimum’.

Statistical Analysis
Local and regional controls were defined as no evidence of disease at the primary site and the neck, respectively. The categorical variables were analyzed with Chi-square or Fisher’s exact test. Multivariate analyses were done using logistic regression, by inclusion of the significant and borderline significant factors (P < 0.10) in univariate analyses.

Disease-free survival (DFS), overall survival (OS) and laryngeal preservation survival (LPS) were calculated with the Kaplan–Meier method and compared by log-rank test. Follow-up times were defined as the duration between the date of treatment initiation and the events or last contact. For DFS calculation, patients were censored if recurrence or metastasis had not occurred. For LPS, an event was defined as failure of successful laryngeal preservation as previously described. The Cox proportional hazards model was used to identify multivariate risk factors for survival results. All of the tests were two-sided, and P ≤ 0.05 was considered to be statistically significant. Statistical analyses were carried out by using Statistical Package of Social Sciences software version 12.0 (SPSS, Inc., Chicago, IL, USA).


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 References
 
Patient Characteristics
Patient characteristics were summarized in Table 1. The median follow-up time was 42.9 months (range, 25.8–59.1 months) for surviving patients. Thirty-three patients (78.6%) had stage IV disease and 14 (33.3%) had T4 primary tumors. The mean courses of chemotherapy during CCRT were 6.4 cycles for the 32 patients (76.2%) who underwent ICT+CCRT and 6.0 cycles for the other 10 patients (23.8%) who underwent primary CCRT.

According to the treatment dose received, 35 patients (83.3%) were grouped as CT-optimum, 27 (64.3%) as RT-optimum and 26 (61.9%) as CRT-optimum. The dose intensity of cisplatin and the total dose of RT in each group were summarized in Table 2. CT- or RT-optimum was not correlated with T, N classifications, or treatment types (ICT+CCRT or primary CCRT). However, CT-optimum patients showed a higher rate of being RT-optimum, compared with non-CT-optimum patients (74.3 versus 14.3%; P = 0.005).


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  		Table 2. Treatment dose of cisplatin and RT of 42 patients

 
Most RT dose reductions and some of chemotherapy dose reductions are due to the intolerable grade 3–4 mucositis, neutropenia or skin reaction nearly the end of CCRT. In some patients, scheduled chemotherapy course was skipped as mucositis or neurotropenia got severe during CCRT, so as to avoid interruption of RT.

Toxic Effects
Acute grade 3–4 toxic effects were rare during ICT. However, toxic effects were obvious during CCRT, with grade 3–4 mucositis occurred in 63.4% of the patients, severe neutropenia in 41.5%, and anemia in 31.7%. One fatal complication occurred due to dehydration-induced acute renal failure during ICT. Two fatal complications developed during CCRT, including sudden-onset airway obstruction at 18.0 Gy in one patient and sepsis associated with alcohol withdrawal at 30.6 Gy in the other. The types of toxic effects were detailed in Table 3.


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  		Table 3. Severe Grade 3–4 acute toxic effects

 
Response to ICT
The primary tumor responded to ICT in 19 (70.4%) patients, and five (18.5%) achieved a complete response (Table 4). Of the eight non-responders, seven (87.5%) refused surgery and proceeded with CCRT. The primary site responders showed a significantly lower rate of distant metastasis (26.3 versus 75.0%; P = 0.03) and a better 3-year OS (47.4 versus 25.0%; P = 0.05), compared with the primary site non-responders. Metastatic neck disease responded to ICT in 13 (65.0%) patients, and three (15.0%) achieved a complete response. Of the seven non-responders of the N+neck, five (71.4%) proceeded with CCRT. The neck responders also showed a better 3-year DFS (37.6 versus 14.3%; P = 0.03) and OS (44.0 versus 14.3%; P = 0.03), compared with the non-responders.


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  		Table 4. Response to ICT

 
Disease Control
Local control was achieved in 23 patients (54.8%). Salvage surgery was feasible in four (21.1%) of the nine patients with local recurrence, but only one (25%) achieved ultimate local control. CT-optimum patients showed a significantly better local control rate than non-CT-optimum patients (Table 5). In multivariate analysis, CT-optimum (P = 0.03) and T1–2 classification (P = 0.04) remained significant predictors of better local control. Regional control was achieved in 27 patients (64.3%). Salvage neck dissection was done in four (26.7%) of the 15 patients with regional recurrence, and two (50.0%) achieved ultimate regional control. A trend towards better regional control was observed in both CT- and RT-optimum patients (Tables 4 and 5). In multivariate analysis, N0–1 classification (P = 0.03) and CT-optimum (P = 0.03) remained two independent predictors of better regional control.


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  		Table 5. Oncologic outcomes in relation to cisplatin dose intensity

 
Distant metastasis developed in 14 patients (33.3%) during the follow-up period. The most common site of distant metastasis is the lung (13/14, 92.9%). Regional recurrence was the only factor correlated with the development of distant metastasis (P = 0.04). Distant metastasis as the only relapse occurred in only four patients (9.5%). Comparing the outcomes between the two treatment types (ICT+CCRT or primary CCRT), there was no difference in local, regional control or distant metastasis in this study.

Survival
The 3-year DFS of all 42 patients was 33.1%. Both CT- and RT-optimum patients showed a significantly higher 3-year DFS than their non-optimum counterparts (Tables 5 and 6). Using a multivariate Cox proportional hazard analysis, CT-optimum remained an independent predictor (P < 0.001). In CRT-optimum patients, the 3-year DFS estimate was 48.1% (Fig. 2). The 3-year OS of all eligible patients was 35.3%. Significant predictors for better OS included local control (P < 0.001), regional control (P < 0.001) and no distant metastasis (P = 0.004). In addition, both CT- and RT-optimum patients showed a significantly better 3-year OS rate than their non-optimum counterparts (Tables 5 and 6). In multivariate analysis, RT-optimum remained an independent predictors (P = 0.003). The 3-year OS estimate for CRT-optimum patients was 50.0% (Fig. 3).


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  		Table 6. Oncologic outcomes in relation to total dose of RT

 

Figure 2
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  		Figure 2. Kaplan–Meier projected disease-free survival (DFS).

 

Figure 3
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  		Figure 3. Kaplan–Meier projected overall survival (OS).

 
About the laryngeal preservation outcomes, the 3-year LPS was 33.9%. Both CT- and RT-optimum patients showed a significantly better 3-year LPS than their non-optimum counterparts (Tables 5 and 6). In multivariate analysis, CT-optimum remained an independent predictor (P = 0.019). The 3-year LPS estimate for CRT-optimum patients was 45.6% (Fig. 4). Comparing the survival results between the two treatment types (ICT+CCRT or primary CCRT), there was also no difference in terms of DFS, OS or LPS.


Figure 4
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  		Figure 4. Kaplan–Meier projected laryngeal preservation survival (LPS).

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
References
 
Considering the advanced disease status and unfavorable prognosis, we performed ICT prior to CCRT in the majority of patients in the study period, although such a sequential treatment approach is still not a standard for organ preservation (17). It has been known that early hypopharyngeal cancer can be effectively treated by RT alone (18,19) or CCRT (20). For advanced hypopharyngeal cancer, our study showed that chemoradiotherapy laryngeal preservation is frequently difficult under regular clinical practice. The local and regional control rates (54.8 and 64.3%), and the 3-year DFS, OS and LPS (33.1, 35.3 and 33.9%, respectively) of all 42 patients are not satisfactory compared with the reported data of several clinical trials (6,11,13).

Increased toxic effects with the combination of chemotherapy and RT remain major concerns in chemoradiotherapy organ preservation (21,22). In each cycle of ICT in this study, a total of 100 mg cisplatin was divided into 4 days to decrease the cisplatin-related acute toxicity, with reference to the previous reports (9). During CCRT, the cisplatin/5-FU combination regimen was applied to enhance the efficacy according to previous experiences in upper aerodigestive tract cancers (23–25). The cisplatin dose was also divided during CCRT (i.e. 20 mg/m2 weekly) in order to minimize the toxicity (9,26). Nevertheless, toxic effects were still obvious during CCRT, leading to non-optimum treatment dose (non-CRT-optimum) in 16 (38.1%) of the 42 patients. Because CCRT has been demonstrated to be the favorable combination of chemoradiotherapy for advanced head and neck cancers (27–29), optimizing the compliance of CCRT while keeping adequate treatment dose remains challenging for advanced hypopharyngeal cancer.

The oncologic analyses in this study, however, revealed the importance of optimum treatment dose. Both cisplatin dose intensity and the total dose of RT showed significant impacts (Tables 5 and 6). In CRT-optimum patients, the 3-year DFS, OS and survival LPS estimates were 48.1, 50.0 and 45.6%, respectively (Figs 2, 3 and 4), comparable to the results of the chemotherapy arm of the EORTC hypopharynx trial (43, 57 and 42% respectively) (6). Given the advanced disease status, and patients with partial response to ICT were treated by CCRT in this study, the results of our CRT-optimum patients were actually encouraging. Because of a higher percentage of non-RT-optimum patients (35.7%) compared with non-CT-optimum patients (16.7%) in this study (Table 2), we speculate that measures to optimize the RT dose during CCRT might noticeably improve the outcomes.

To optimize the treatment outcomes, proper patient selection is mandatory under an off-study clinical practice. However, no pretreatment parameter was found predictive for CT- or RT-optimum in this study, including T, N classifications or treatment types. Only CT-optimum was correlated with RT-optimum (P = 0.005). Because 76.2% of the patients underwent ICT before definite CCRT, this observation might imply that the compliance of ICT could be predictive for the compliance of subsequent CCRT. This assumption, however, still needs further evaluation in a larger patient population. Another important issue in optimizing the treatment outcomes is toxicity management. In this study, the discomforts from toxicities frequently led to the decision from the patients and family for early treatment termination. These highlighted the importance of experienced multi-disciplinary teamwork approach in patient selection, pre-treatment counseling and toxicity managements. Weekly check-up, including blood routine, renal and liver function survey, is important during the later part of CCRT for early detection and management of toxicities. Granulocyte colony-stimulating factor (G-CSF) should be given for grade 3–4 neutropenia. Recording of fluid input and output should be arranged when mucositis developed. Aggressive nutritional and hydration support should also be arranged through the insertion of nasogastric or percutaneous gastrostomy tube whenever needed.

The attempt of using ICT response as a selection tool for CCRT was not successful in this study because most non-responders refused immediate surgical salvage owing to a sense of improvement after ICT. On the other hand, all the oncologic and survival results did not reveal significant difference between patients treated by ICT+CCRT or primary CCRT. Therefore, the role of ICT in chemoradiotherapy laryngeal preservation is not obvious in this study. Nevertheless, by analyzing the subgroup undergoing ICT, the primary site responders did show better in terms of lower distant metastasis rate and a better OS, compared with non-responders. The neck responders to ICT also showed a significantly better DFS and OS. These results might suggest that ICT could bear a potential therapeutic role in responders. However, in non-responders, the relatively worse survival results might indicate a liability from ICT because of the delay in definite treatment (17,30). We therefore tended to perform primary CCRT after this study period for chemoradiotherapy laryngeal preservation.

In conclusion, successful chemoradiotherapy laryngeal preservation for advanced hypopharyngeal cancer remains difficult to achieve and should be performed with caution. CCRT toxicities frequently lead to early treatment termination under regular clinical practice, whereas dose intensity of cisplatin and the total dose of RT are both important predictors of better survival and laryngeal preservation results. Experienced multi-disciplinary teamwork approach is therefore mandatory and the importance of detailed pre-treatment counseling cannot be overstated. The roles of ICT are still controversial and require further investigation. The criteria for selecting patients who will most likely respond to and complete the treatment remain key issues to be explored in the future. For advanced cases with obvious cartilage, cervical esophagus or extralaryngeal soft tissue involvement, chemoradiotherapy organ preservation is not a treatment option in our current policy.

Conflict of interest statement

None declared.


   Footnotes
 
{dagger} Presented at the 8th Taiwan–Japan Conference in Otolaryngology Head and Neck Surgery, Taipei, Taiwan, December 16–18, 2005. Back


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
1 Hoffman HT, Karnell LH, Funk GF, Robinson RA, Menck HR. The National Cancer Data Base report on cancer of the head and neck. Arch Otolaryngol Head Neck Surg (1998) 124:951–62.[Abstract/Free Full Text]

2 Hoffman HT, Karnell LH, Shah JP, Ariyan S, Brown GS, Fee WE, et al. Hypopharyngeal cancer patient care evaluation. Laryngoscope (1997) 107:1005–17.[CrossRef][Web of Science][Medline]

3 Bova R, Goh R, Poulson M, Coman WB. Total pharyngolaryngectomy for squamous cell carcinoma of the hypopharynx: a review. Laryngoscope (2005) 115:864–9.[CrossRef][Web of Science][Medline]

4 Chu PY, Wang LW, Chang SY. Surgical treatment of squamous cell carcinoma of the hypopharynx: analysis of treatment results, failure patterns, and prognostic factors. J Laryngol Otol (2004) 118:443–9.[Web of Science][Medline]

5 Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med (1991) 324:1685–90.[Abstract]

6 Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. 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 (1996) 88:890–9.[Abstract/Free Full Text]

7 Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol (2003) 21:92–8.[Abstract/Free Full Text]

8 Vokes EE, Kies MS, Haraf DJ, Stenson K, List M, Humerickhouse R, et al. Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol (2000) 18:1652–61.[Abstract/Free Full Text]

9 Altundag O, Gullu I, Altundag K, Yalcin S, Ozyar E, Cengiz M, et al. Induction chemotherapy with cisplatin and 5-fluorouracil followed by chemoradiotherapy or radiotherapy alone in the treatment of locoregionally advanced resectable cancers of the larynx and hypopharynx: Results of single-center study of 45 patients. Head Neck (2005) 27:15–21.[CrossRef][Web of Science][Medline]

10 Shin DM, Glisson BS, Khuri FR, Lippman SM, Ginsberg L, Diaz E Jr, et al. Phase II study of induction chemotherapy with paclitaxel, ifosfamide, and carboplatin (TIC) for patients with locally advanced squamous cell carcinoma of the head and neck. Cancer (2002) 95:322–30.[CrossRef][Web of Science][Medline]

11 Urba SG, Wolf GT, Bradford CR, Thornton AF, Eisbruch A, Terrell JE, et al. Neoadjuvant therapy for organ preservation in head and neck cancer. Laryngoscope (2000) 110:2074–80.[CrossRef][Web of Science][Medline]

12 Adelstein DJ, Saxton JP, Rybicki LA, Esclamado RM, Wood BG, Strome M, et al. Multiagent concurrent chemoradiotherapy for locoregionally advanced squamous cell head and neck cancer: mature results from a single institution. J Clin Oncol (2006) 24:1064–71.[Abstract/Free Full Text]

13 Urba SG, Moon J, Giri PG, Adelstein DJ, Hanna E, Yoo GH, et al. Organ preservation for advanced resectable cancer of the base of tongue and hypopharynx: a Southwest Oncology Group Trial. J Clin Oncol (2005) 23:88–95.[Abstract/Free Full Text]

14 Vokes EE, Stenson K, Rosen FR, Kies MS, Rademaker AW, Witt ME, et al. Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol (2003) 21:320–6.[Abstract/Free Full Text]

15 Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, et al. AJCC cancer staging manual. (2002) 6th edn. New York, NY: Springer.

16 Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst (2000) 92:205–16.[Abstract/Free Full Text]

17 Adelstein DJ, Leblanc M. Does induction chemotherapy have a role in the management of locoregionally advanced squamous cell head and neck cancer? J Clin Oncol (2006) 24:2624–8.[Abstract/Free Full Text]

18 Amdur RJ, Mendenhall WM, Stringer SP, Villaret DB, Cassisi NJ. Organ preservation with radiotherapy for T1-T2 carcinoma of the pyriform sinus. Head Neck (2001) 23:353–62.[CrossRef][Web of Science][Medline]

19 Garden AS, Morrison WH, Clayman GL, Ang KK, Peters LJ. Early squamous cell carcinoma of the hypopharynx: outcomes of treatment with radiation alone to the primary disease. Head Neck (1996) 18:317–22.[CrossRef][Web of Science][Medline]

20 Nakamura K, Shioyama Y, Sasaki T, Ohga S, Saku M, Urashima Y, et al. Chemoradiation therapy with or without salvage surgery for early squamous cell carcinoma of the hypopharynx. Int J Radiat Oncol Biol Phys (2005) 62:680–3.[CrossRef][Web of Science][Medline]

21 Lee WT, Akst LM, Adelstein DJ, Saxton JP, Wood BG, Strome M, et al. Risk factors for hypopharyngeal/upper esophageal stricture formation after concurrent chemoradiation. Head Neck (2006) 28:808–12.[CrossRef][Web of Science][Medline]

22 Hanna E, Alexiou M, Morgan J, Badley J, Maddox AM, Penagaricano J, et al. Intensive chemoradiotherapy as a primary treatment for organ preservation in patients with advanced cancer of the head and neck: efficacy, toxic effects, and limitations. Arch Otolaryngol Head Neck Surg (2004) 130:861–7.[Abstract/Free Full Text]

23 Crehange G, Maingon P, Peignaux K, N’Guyen T D, Mirabel X, Marchal C, et al. Phase III trial of protracted compared with split-course chemoradiation for esophageal carcinoma: Federation Francophone de Cancerologie Digestive 9102. J Clin Oncol (2007) 25:4895–901.[Abstract/Free Full Text]

24 Fujiwara Y, Kamikonya N, Inoue T, Koishi K, Yoshikawa R, Nakao K, et al. Chemoradiotherapy for T3 and T4 squamous cell carcinoma of the esophagus using low-dose FP and radiation: a preliminary report. Oncol Rep (2005) 14:1177–82.[Web of Science][Medline]

25 Shimoyama S, Konishi T, Kawahara M, Kaminishi M, Ito A, Hojo K, et al. Pre-operative chemoradiation therapy with 5-fluorouracil and low-dose daily cisplatin for esophageal cancer: a preliminary report. Jpn J Clin Oncol (1999) 29:132–6.[Abstract/Free Full Text]

26 Fountzilas G, Tolis C, Kalogera-Fountzila A, Misailidou D, Tsekeris P, Karina M, et al. Paclitaxel, cisplatin, leucovorin, and continuous infusion fluorouracil followed by concomitant chemoradiotherapy for locally advanced squamous cell carcinoma of the head and neck: a Hellenic Cooperative Oncology Group Phase II Study. Med Oncol (2005) 22:269–79.[CrossRef][Web of Science][Medline]

27 Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med (2003) 349:2091–8.[Abstract/Free Full Text]

28 Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet (2000) 355:949–55.[Web of Science][Medline]

29 Adelstein DJ, Saxton JP, Lavertu P, Tuason L, Wood BG, Wanamaker JR, et al. A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck (1997) 19:567–75.[CrossRef][Web of Science][Medline]

30 Pfister DG, Ridge JA. Induction chemotherapy for larynx preservation: patient selection or therapeutic effect? J Clin Oncol (2006) 24:540–3.[Free Full Text]


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