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Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3061-3069 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.108 Cisplatin, Fluorouracil, and Leucovorin Induction Chemotherapy Followed by Concurrent Cisplatin Chemoradiotherapy for Organ Preservation and Cure in Patients With Advanced Head and Neck Cancer: Long-Term Follow-UpFrom the Departments of Medical Oncology, Therapeutic Radiology and Otolaryngology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT Address reprint requests to Amanda Psyrri, MD, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520-8032; e-mail: diamando.psyrri{at}yale.edu
PURPOSE: The poor functional outcome in patients with advanced head and neck squamous cell carcinoma (HNSCC) with surgery and radiation has led to alternative approaches to advanced disease. We conducted a phase II study of induction chemotherapy followed by concurrent chemoradiotherapy for organ preservation in patients with advanced resectable and unresectable (nasopharyngeal) tumors. PATIENTS AND METHODS: Forty-two patients with stage III to IV resectable HNSCC and nasopharyngeal tumors received induction chemotherapy with two courses of cisplatin (20 mg/m2/d continuous infusion [CI]), fluorouracil (800 mg/m2/d CI), and leucovorin (500 mg/m2/d CI; PFL) for 4 days followed by concurrent therapy with cisplatin (100 mg/m2/d on days 1 and 22) and approximately 70 Gy of external-beam radiotherapy. RESULTS: Response to induction chemotherapy included partial response rate of 52% and complete response rate of 24%. The most common grade 3 or 4 toxicity was neutropenia (59%). After cisplatin chemoradiotherapy the complete response rate was 67%. Toxicities of cisplatin chemoradiotherapy consisted of grade 3 or 4 mucositis (79%) and neutropenia (51%). At a median follow-up of 71.5 months, 43% of the patients are still alive and disease-free. The 5-year progression-free survival (PFS) rate was 60%, and the 2- and 5-year overall survival (OS) rates were 67% and 52%, respectively. Three patients died of second primaries. Late complications of treatment included xerostomia and hoarseness. One patient had persistent dysphagia and required laser epiglotectomy 108 months after treatment. CONCLUSION: Induction chemotherapy with PFL followed by concurrent cisplatin chemoradiotherapy is well tolerated and results in a good likelihood of organ preservation and excellent PFS and OS.
Until recently, locally advanced squamous cell carcinoma of the head and neck was generally treated with surgery and radiation. However, a low overall cure rate in combination with poor functional outcome in a significant percentage of patients has led to alternative management strategies. Chemotherapy has been incorporated in combined-modality treatment in an effort to improve the outcome of patients with locally advanced disease.1-3 Induction or neoadjuvant chemotherapy has been shown to be associated with decreased rates of distant metastases2,4 but, with the exception of cisplatin and fluorouracil (FU)-based regimens,5 not improved survival or significantly decreased locoregional recurrence. Induction chemotherapy with cisplatin and FU has been shown in meta-analysis to result in a modest increase in survival and to allow for preservation of the larynx without compromising survival in responding patients with larynx or hypopharynx primary tumors. More recently, concurrent chemoradiotherapy has been shown to be superior to radiation alone in several randomized phase III studies6 as well as in meta-analysis.5 In a recent randomized Intergroup trial,6 concurrent radiation and cisplatin were superior to standard radiation in laryngectomy-free survival and time to laryngectomy. Concurrent chemoradiotherapy was also significantly better than induction chemotherapy with cisplatin and FU followed by standard radiation in time to laryngectomy. Although cisplatin remains the standard drug used in combination with radiation, recent studies incorporating other agents in addition to or instead of cisplatin suggest that cure might be achievable in most patients with locally advanced head and neck squamous cell carcinoma (HNSCC).7-9 Importantly, some of these studies found that distant metastasis was a more frequent cause of failure than locoregional recurrence. This observation provides evidence that the use of chemoradiotherapy is changing the natural history of locally advanced disease but at the same time indicates that the type and dose of drugs used to enhance radiation may not be adequate to sterilize micrometastatic disease. Because cure of advanced HNSCC may require separate approaches to prevent locoregional recurrence and metastatic disease, there has recently been an interest in the use of programs in which induction therapy, used to eradicate occult metastatic foci, is followed by concomitant chemoradiotherapy for the sterilization of locoregional disease. This approach seems particularly attractive in tumor sites associated with a high incidence of metastatic disease, such as nasopharyngeal cancer (NPC) and hypopharyngeal cancer. In fact, a variant of this strategy has been validated in NPC where concurrent cisplatin and radiation followed by cisplatin and FU was shown to be superior to radiation alone.10 In an unpublished study,11 the reverse order of treatment was at least as effective as the latter program. At the time that the current study started, many of the more modern programs of chemoradiotherapy had not yet been published. However, several reports in the literature stimulated the development of our protocol in which induction chemotherapy was followed by concurrent chemoradiotherapy. Dreyfuss et al12 showed that the combination of cisplatin, FU, and leucovorin resulted in a greater than 50% complete response (CR) rate in patients with locally advanced HNSCC. This was the first program to result in a greater than 50% CR rate and suggested the possibility that induction chemotherapy could potentially change the natural history of advanced HNSCC. Later, Ensley13 showed that even though radiation was generally ineffective in patients with induction failure, the addition of cisplatin to radiation in similarly poor responders seemed to partially overcome radiation resistance. Finally, the Radiation Therapy Oncology Group14 showed that in patients with unresectable disease, the combination of concurrent cisplatin and radiation gave superior results compared with a historical control group that was treated with radiation alone. In view of these findings, we performed a study in which induction cisplatin/FU/leucovorin for two courses was followed by concomitant cisplatin plus standard dose radiation. Because we found excessive mucositis in a small pilot group of patients15 treated with the Dreyfuss et al induction program,12 the induction protocol was modified and a formal study was performed. Our major target populations were patients with HNSCC who were poor candidates for resection because of requirement for laryngectomy or total glossectomy and patients with NPC because of the high incidence of metastatic disease.
This study opened in May 1992 and closed to accrual in June 1996. Patients were followed-up through March 2003. Eligible patients had squamous cell carcinoma, poorly differentiated carcinoma, or lymphoepithelioma of the head and neck. Patients had stage III to IV disease and, after evaluation by the Yale Head and Neck tumor board, were considered poor candidates for resection because significant functional impairment would result from laryngectomy or major tongue resection. Patients had Karnofsky performance status greater than 70%. No prior therapy, including chemotherapy, was allowed. Patients with grossly apparent metastatic disease beyond the neck by physical examination or chest x-ray were not eligible; however, patients with questionable abnormalities by computed tomography (CT) scan (ie, small mediastinal lymph nodes or pulmonary nodules of uncertain significance) were eligible. Pretreatment evaluation consisted of a history and physical, measurement of all detectable tumor, chest x-ray, CT scan or magnetic resonance imaging of the head and neck, CT of the chest within the first 2 months of beginning therapy, CBC count with differential count, liver function studies, blood urea nitrogen, creatinine, albumin, calculated creatinine clearance, audiometric testing, and dental examination. Placement of a feeding device was recommended. All patients signed an informed consent before beginning treatment. Our protocol was approved by the Yale Human Investigation Committee on May 2, 1992.
Protocol Treatment
Dose modifications during induction chemotherapy were based on blood counts obtained on the day of treatment. Induction chemotherapy was only administered if WBC  3,000/µL and platelets 100,000/µL. Doses were not modified based on hemoglobin or hematocrit. If a nadir granulocyte count was  1,000/µL or a nadir platelet count was 50,000/µL, then doses of FU were reduced from 800 mg/m2 to 600 mg/m2 for the next cycle of therapy. For grade 3 stomatitis or diarrhea, the FU dose was reduced to 600 mg/m2 in patients older than 60 years. All patients with grade 4 stomatitis or diarrhea underwent FU dose reduction to 600 mg/m2. PFL was held until the serum creatinine was 2 mg/mL and the calculated creatinine clearance was 45 mL/min. If calculated creatinine clearance was less than 45 mL/min, then patients could not receive cisplatin and were taken off study. Cisplatin was given if neurologic toxicities were grade 1 or less. When grade 2 neurotoxicity developed, the next dose of cisplatin was reduced by 20%. Patients with grade 3 neurotoxicity were taken off protocol. When clinical evidence of ototoxicity developed, chemotherapy with PFL or cisplatin (but not radiation therapy) was held until an audiometric evaluation was performed. Patients who were to continue treatment underwent a 20% reduction in the cisplatin dose. Patients who developed grade 3 ototoxicity were taken off protocol. Patients who were removed from protocol during induction chemotherapy secondary to renal, ototoxicity, or neurotoxicity underwent surgery or radiation therapy as recommended by the head and neck cancer tumor board.
Dose adjustments during cisplatin chemoradiotherapy have previously been described.16 The dose of cisplatin was not modified based on blood counts observed during treatment with PFL. If nadir granulocyte count was
Surgery
Brachytherapy
Quality of Life/Performance Outcome
Second Primaries
Treatment Evaluation and Statistical Considerations This was a phase II study to determine the feasibility of organ preservation in patients with locally advanced HNSCC. Of interest was a 30% prolonged (> 2 years) disease-free survival with the larynx and tongue in place. The null hypothesis of 30% was chosen because it has been previously shown that 20% to 40% of patients with stage III to IV larynx cancer survive 3 years when initially treated with radiation therapy and surgery reserved for salvage after relapse.21-23 To determine whether 30% of patients with poorly resectable disease obtain a CR and remain disease-free, we estimated that at least 25 patients should be treated. A total of 25 patients entered onto the study would ensure that the estimated SE associated with the observed CR rate is 0.10 or less.
A total of 42 patients were registered. The median follow-up time was 71.5 months. The median age was 60.5 years. The baseline characteristics of our patient population are listed in Table 1. The primary site was larynx in 38%, hypopharynx in 24%, BOT in 19%, NPC in 9.5%, tonsil in 7.5%, and unknown in 2%. Twenty-five patients (59%) had stage IV disease, 15 patients (36%) had stage III disease, and two patients (5%) had bulky stage II disease (Table 2). A feeding support device was placed in almost all the patients before initiation of concurrent chemoradiotherapy.
Induction Chemotherapy After induction chemotherapy, 40 patients were evaluated for response. One patient died of pneumococcal pneumonia after two cycles of PFL, and another one did not undergo formal evaluation after two cycles of PFL because of lack of compliance. Overall, 10 (24%) of 42 patients with measurable disease (95% CI, 11% to 37%) had a clinical CR (CR/CRu), 22 (52%; 95% CI, 37% to 68%) had a PR, five patients had stable disease, and three patients had progressive disease (one patient progressed locally and the other two developed pulmonary metastases). The overall response rate was 76% (95% CI, 63% to 89%). Toxicities to induction chemotherapy are listed in Table 3. One patient died of pneumococcal sepsis after the first cycle of treatment but was not neutropenic. Neutropenia was grade 3 or 4 in 41% and 18% of patients, respectively. Granulocyte colony-stimulating factor was not administered. Grade 3 or 4 mucositis was noted in 7% and 3% of patients, respectively. Two patients developed grade 3 motor-sensory neuropathy, one of whom was diabetic. One patient developed grade 3 and another one grade 4 renal toxicity manifested as Fanconi syndrome with refractory hypomagnesemia, hypocalcemia, long QT syndrome, syncope, and seizures. One patient developed grade 4 liver function test abnormalities. The feasibility of administering 2 months of this induction regimen was further evaluated by calculating the dose-intensity. As shown in Table 4, 90% of the patients received more than 80% of the intended PFL dose.
Concomitant Chemoradiotherapy After completion of induction chemotherapy, patients received cisplatin chemoradiotherapy and were evaluated for final response to therapy. From the original cohort of 42 patients, 34 patients received chemoradiotherapy. One patient died of pneumococcal sepsis during induction therapy, three patients did not receive chemoradiotherapy because of disease progression, three patients received radiation therapy alone because of grade 3 or 4 toxicity (two patients developed renal toxicity and one developed motor-sensory neuropathy) during induction therapy, and one patient refused further chemotherapy. Sixty-seven percent (95% CI, 52% to 81%) had a CR or CRu as final response, 12% had a PR, and 2% experienced disease progression (Table 5).
The toxicities of cisplatin radiotherapy are listed in Table 3. Thirty percent developed grade 3 nausea. Mucositis was grade 3 or 4 in 29% and 50%, respectively. Fifty percent developed grade 3 or 4 neutropenia. One patient developed grade 3 neuropathy. Two patients developed grade 3 and one grade 4 renal toxicity. However, as shown in Table 4, the majority of the patients were able to tolerate cisplatin, with less than 20% dose reductions.
Survival and Pattern of Relapse
Surgery Of the 37 patients with non-NPC primary, 32 did not undergo any surgery at the primary site; 20 patients required no surgery (54%), one patient died after induction therapy, one patient refused surgery, three patients were inoperable, and seven patients developed distant metastases. After local recurrence, salvage procedures were attempted in five patients (Table 6). Four patients underwent total laryngectomy and one glossectomy. All five patients subsequently died of their disease. The overall 2-year and 5-year survival rates with the larynx and tongue in place were 64.3% (95% CI, 50% to 79%) and 52.4% (95% CI, 37% to 68%), respectively. The 5-year laryngectomy-free survival rates were 69% (95% CI, 46% to 91%) for laryngeal and 40% (95% CI, 10% to 70%) for hypopharyngeal cancer. Three patients underwent a neck dissection for presumed residual clinical disease after completion of chemoradiotherapy. Only one of these patients was found to have residual tumor in the pathologic specimen.
Quality of Life/Performance Status We performed a retrospective quality-of-life assessment. Of the 18 patients alive at April 2003, 15 underwent quality-of-life assessment. Two patients had persistent hoarseness, whereas three patients with laryngeal cancer reported improvement in voice quality after treatment. Three patients had persistent dysphagia to solids, one of whom required laser epiglottectomy 108 months after treatment. Nine patients had persistent xerostomia. One patient developed radiation-induced vertebral artery stenosis 36 months after completion of treatment. One patient developed hypothyroidism. None of the patients required a feeding tube for more than 1 year.
This study provides the longest reported follow-up of patients with locally advanced HNSCC and NPC treated with an induction cisplatin/FU-based program followed by concomitant cisplatin/radiation. Our goal was to identify a tolerable regimen that optimizes local and distant control for organ preservation and cure in patients with HNSCC. For this purpose, we used induction chemotherapy followed by concurrent chemoradiotherapy. We modified the PFL regimen for induction because the original PFL doses followed by concurrent cisplatin-radiotherapy resulted in excessive mucositis in our experience. A modified PFL regimen, 2 months instead of 3 months of induction therapy, was also used for two reasons: first, it would decrease the delay to definitive local therapy; second, it would limit the total cumulative dose of cisplatinum to 360 mg/m2 over the entire treatment period. The modified PFL regimen yielded CR and OR rates of 25% and 76%, respectively. These clinical response rates are similar to those reported after three cycles of cisplatin and fluorouracil but were inferior to those reported by Dreyfuss12 with the standard PFL regimen. Neutropenia was the major dose-limiting toxicity. Despite the high incidence of myelosuppression, almost all the patients received more than 80% of the intended PFL dose. The feasibility of administering cisplatin chemoradiotherapy was not significantly compromised by the initial administration of induction PFL. However, the concomitant portion of the program was associated with significant mucositis, and most patients required enteral nutritional support beginning with the fifth week of radiation. As enteral support is not generally required during cisplatin/radiation,6 the latter observation suggests that induction chemotherapy may have potentiated the severity of mucositis during chemoradiotherapy. One patient required enteral feeding 1 year after treatment. The 5-year OS with larynx and tongue in place was excellent. Patients with laryngeal cancer in our study had a 5-year laryngectomy-free survival of 69%, which compares favorably with the 45% reported by the Radiation Therapy Oncology Group 91 to 11 Larynx Intergroup study.6 The results in a small number of patients with hypopharyngeal and BOT cancers were not as good and suggest that these patients may require a more intensive program. Patients with hypopharyngeal cancer had a 5-year laryngectomy free survival, which again is superior to the 17% reported by the European Organization for Research and Treatment of Cancer hypopharynx trial4 of three cycles of induction cisplatin and fluorouracil followed by radiation therapy. Our study, along with others,24,25 clearly showed that patients with laryngeal cancer have a more favorable outcome compared to the other non-NPC head and neck sites. PFS and OS in this trial are encouraging. The survival curves clearly show that the majority of disease-related deaths occur relatively early, within 2 years. Patients who survived past the 2-year threshold died of other causes. After a median follow-up of nearly 6 years, 43% of patients are alive without disease. Nondisease-related mortality occurred in one patient of toxicity during treatment and in seven others as a result of second malignancies (three patients) or unrelated causes (four patients). Both the Veterans Affairs Larynx project2 and the European Organization for Research and Treatment of Cancer hypopharynx trial4 showed that there is no significant survival compromise when resection of the primary site is reserved for salvage in patients who experienced treatment failure with induction chemotherapy. In both studies, however, the cure rate of late salvage laryngectomy (after radiation), for persistent or recurrent disease, is not indicated. Surgical salvage was not successful in any of our patients. Clark et al26 reported a 0% and 17% cure rate of salvage procedures for persistent and recurrent disease after induction PFL followed by radiation therapy, respectively. In a Vokes et al27 trial of induction chemotherapy with carboplatin and paclitaxel followed by chemoradiotherapy with paclitaxel, fluorouracil, and hydroxyurea, two patients underwent salvage procedures after chemoradiotherapy; both patients subsequently died of local and distant recurrence. These results indicate that treatment failure after these intensive regimens indicates aggressive, poor-prognosis, chemoresistant disease. A major goal of adding induction chemotherapy to chemoradiotherapy is the eradication of distant micrometastatic disease. The impact of our regimen on distant disease control is difficult to determine. Our distant control rate of 79% is inferior to that reported in most of the trials of induction chemotherapy followed by either radiation alone26 or chemoradiotherapy.27 This result may be explained by our higher proportion of patients with hypopharyngeal tumors; hypopharyngeal location is associated with significantly increased risk of distant metastases.28-30 Another explanation may be the inclusion in our study of three patients with subtle abnormalities on the chest CT, such as subcentimeter pulmonary nodules and indeterminate mediastinal lymph nodes. Only five other patients developed metastatic disease, suggesting that for patients with truly occult micrometastic disease (negative chest CT), our regimen was effective. Better imaging studies, including CT and positron emission tomography,31,32 may more accurately identify patients with metastatic disease at the time of diagnosis. Retrospective evaluation of quality-of-life assessment on a subset of long-term survivors demonstrated the predominant late toxic effect in our study was xerostomia (> 50%). With median follow-up of 71.5 months, our patients had minimal to moderate late toxicity effects and very good quality of life. None of the patients was feeding-tube dependent. Two unusual late complications deserve mention. One patient has required two laser epiglottectomies for strictures at 108 months after treatment. A second patient developed vertebrobasilar artery stenosis 3 years after therapy. These data suggest that long-term follow-up is required for the diagnosis and management of complications after treatment with these very intensive regimens. In this trial, we showed that the combination of induction modified PFL chemotherapy with concurrent cisplatin chemoradiotherapy resulted in excellent organ preservation rate in our group of patients with resectable HNSCC. Given the excellent 5-year survival with larynx and tongue in place, a phase III trial comparing the sequential chemotherapy paradigm of our study with concurrent chemoradiotherapy as an organ-preserving strategy would be appropriate.
The authors indicated no potential conflicts of interest.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
1. Adjuvant chemotherapy for advanced head and neck squamous carcinoma: Final report of the Head and Neck Contracts Program. Cancer 60:301-311, 1987[CrossRef][Medline] 2. 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 324:1685-1690, 1991[Abstract] 3. Al-Sarraf M, Pajak TF, Marcial VA, et al: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck: An RTOG Study. Cancer 59:259-265, 1987[CrossRef][Medline]
4. Lefebvre JL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organization for Research and Treatment of Cancer phase III trial—EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88:890-899, 1996 5. Pignon JP, Bourhis J, Domenge C, et al: 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 355:949-955, 2000[Medline]
6. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003 7. Lo TC, Wiley AL Jr, Ansfield FJ, et al: Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: A randomized study. Am J Roentgenol 126:229-235, 1976[Abstract]
8. Vokes EE, Kies MS, Haraf DJ, et al: Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol 18:1652-1661, 2000
9. Kies MS, Haraf DJ, Rosen F, et al: Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer. J Clin Oncol 19:1961-1969, 2001
10. Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310-1317, 1998 11. Al-Sarraf M, Reddy MS: Nasopharyngeal carcinoma. Curr Treat Options Oncol 3:21-32, 2002[Medline] 12. Dreyfuss AI, Clark JR, Wright JE, et al: Continuous infusion high-dose leucovorin with 5-fluorouracil and cisplatin for untreated stage IV carcinoma of the head and neck. Ann Intern Med 112:167-172, 1990 13. Ensley J, Ahmad K, Kish J: Improved response to radiation and concurrent cisplatin in patients with advanced head and neck cancers (SCCHN) that failed induction chemotherapy. Proc Am Soc Clin Oncol 9: 1990 (abstr) 14. Marcial VA, Pajak TF, Mohiuddin M, et al: Concomitant cisplatin chemotherapy and radiotherapy in advanced mucosal squamous cell carcinoma of the head and neck: Long-term results of the Radiation Therapy Oncology Group study 81-17. Cancer 66:1861-1868, 1990[CrossRef][Medline] 15. Psyrri A, Kwong M, Lekakis L, et al: PFL-induction chemotherapy followed by concomitant cisplatin chemoradiotherapy (CRT) for head and neck squamous cell cancer (HNSCC): Long-term follow-up. Proc Am Soc Clin Oncol 22:500, 2003 (abstr 2014) 16. Harrison LB, Pfister DG, Fass DE, et al: Concomitant chemotherapy-radiation therapy followed by hyperfractionated radiation therapy for advanced unresectable head and neck cancer. Int J Radiat Oncol Biol Phys 21:703-708, 1991[Medline] 17. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976[Medline] 18. List MA, D’Antonio LL, Cella DF, et al: The performance status scale for head and neck cancer patients and the Functional Assessment of Cancer Therapy-Head and Neck Scale: A study of utility and validity. Cancer 77:2294-2301, 1996[CrossRef][Medline] 19. List MA, Ritter-Sterr C, Lansky SB: A performance status scale for head and neck cancer patients. Cancer 66:564-569, 1990[CrossRef][Medline] 20. Warren S, Gates O: Multiple primary malignant tumors: A survey of the literature and statistical study. Am J Cancer 51:1358, 1932 21. Karim AB, Kralendonk JH, Njo KH, et al: Radiation therapy for advanced (T3T4N0-N3M0) laryngeal carcinoma: The need for a change of strategy—A radiotherapeutic viewpoint. Int J Radiat Oncol Biol Phys 13:1625-1633, 1987[Medline] 22. Vermund H, Boysen M, Brandenburg JH, et al: Primary irradiation, surgery or combined therapy in squamous cell carcinoma of the larynx: A comparison of treatment results from two centers. Acta Oncol 29:489-503, 1990[Medline] 23. McLean M: Primary management of limited laryngeal cancer by radiotherapy and surgical salvage: Results of 164 cases treated in a district hospital. Clin Oncol (R Coll Radiol) 1:97-100, 1989
24. Hill BT, Price LA, MacRae K: Importance of primary site in assessing chemotherapy response and 7-year survival data in advanced squamous-cell carcinomas of the head and neck treated with initial combination chemotherapy without cisplatin. J Clin Oncol 4:1340-1347, 1986 25. Vokes EE, Schilsky RL, Weichselbaum RR, et al: Cisplatin, 5-fluorouracil, and high-dose oral leucovorin for advanced head and neck cancer. Cancer 63:1048-1053, 1989[CrossRef][Medline] 26. Clark JR, Busse PM, Norris CM Jr, et al: Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for squamous cell carcinoma of the head and neck: Long-term results. J Clin Oncol 15:3100-3110, 1997[Abstract]
27. Vokes EE, Stenson K, Rosen FR, 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 21:320-326, 2003 28. Spector JG, Sessions DG, Haughey BH, et al: Delayed regional metastases, distant metastases, and second primary malignancies in squamous cell carcinomas of the larynx and hypopharynx. Laryngoscope 111:1079-1087, 2001[CrossRef][Medline] 29. Spector GJ: Distant metastases from laryngeal and hypopharyngeal cancer. ORL J Otorhinolaryngol Relat Spec 63:224-228, 2001[Medline] 30. Leon X, Quer M, Orus C, et al: Distant metastases in head and neck cancer patients who achieved loco-regional control. Head Neck 22:680-686, 2000[CrossRef][Medline]
31. Schwartz DL, Rajendran J, Yueh B, et al: Staging of head and neck squamous cell cancer with extended-field FDG-PET. Arch Otolaryngol Head Neck Surg 129:1173-1178, 2003
32. Antoch G, Vogt FM, Freudenberg LS, et al: Whole-body dual-modality PET/CT and whole-body MRI for tumor staging in oncology. JAMA 290:3199-3206, 2003 Submitted January 16, 2004; accepted May 5, 2004. This article has been cited by other articles:
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
