Induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal cancer

J. L. Oh1,+, E. E. Vokes1,2, M. S. Kies3, B. B. Mittal4, M. E. Witt1, R. R. Weichselbaum1 and D. J. Haraf1

1 Department of Radiation and Cellular Oncology and 2 Section of Hematology/Oncology, The University of Chicago, Chicago, IL; 3 Department of Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, Houston, TX; 4 Department of Radiation Oncology, Northwestern University, Chicago, IL, USA

Received 19 April 2002; revised 18 November 2002; accepted 3 December 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
Background:

Since 1990, we have treated patients with advanced nasopharyngeal cancer with induction chemotherapy and concomitant chemoradiotherapy. We herein report the results of our experience.

Patients and methods:

From 1990 to 1999, 27 patients with locoregionally advanced nasopharyngeal cancer were treated with induction chemotherapy followed by concomitant chemoradiotherapy. Using the American Joint Committee on Cancer’s 1992 stage classification, all patients were stage III (11%) or IV (89%). By histology, 63% were poorly differentiated carcinoma and 37% squamous cell carcinoma. The median age was 42 years. Three cycles of induction chemotherapy consisting of cisplatin, 5-fluorouracil, leucovorin and interferon-{alpha}2b were administered, followed by concomitant chemoradiotherapy consisting of seven cycles of 5-fluorouracil, hydroxyurea and once-daily radiotherapy (FHX) on a week-on week-off schedule. The median radiotherapy dose was 70 Gy.

Results:

Clinical response to induction chemotherapy was 100%, 54.2% complete response (CR) and 45.8% partial response. Clinical and/or pathological (37% of all patients had post-treatment biopsy with or without neck dissection) CR after FHX was 100%. At a median follow-up of 52 months, three failures were observed. Two patients have died of disease, one of local failure and one of distant metastases. One patient is alive with an isolated rib metastasis. At 5 years, actuarial locoregional control is 93% and actuarial distant control 92%. The overall survival at 3 and 5 years is 88% and 77%, respectively. Four patients died of unrelated illnesses and had no evidence of disease with respect to their nasopharyngeal cancer. The progression-free survival at 3 and 5 years is 92% and 86%, respectively. Thirty-three per cent of patients required a reduction in the chemotherapy dose due to acute toxicity. Chronic toxicity was not observed, with all patients able to eat orally without dietary restrictions.

Conclusions:

Treatment of locoregionally advanced nasopharyngeal cancer with induction chemotherapy followed by concomitant chemoradiotherapy resulted in excellent overall survival with acceptable toxicity. These results are encouraging and warrant further investigation of intensified approaches.

Key words: concomitant chemoradiation therapy, induction chemotherapy, nasopharyngeal cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
In the USA, Western Europe and Japan, nasopharyngeal cancer accounts for fewer than 1% of malignancies, with the average number of cases per 100 000 population per year being 1 (range 1.0–1.5). The average incidence increases 80-fold in Southern China, particularly Hong Kong and Guangzhou, formerly Canton, with an incidence ranging from 10 to 150 cases annually [1]. Due to the anatomical location, nasopharyngeal cancers are considered unresectable and the conventional treatment approach has been radiation. Traditionally, due to high rates of both local and distant failures, patients with advanced nasopharyngeal cancer (stage III–IV) treated with radiation alone have had poor 5-year survival rates of only 10–40% [25]. More recent results, with optimal radiotherapy (RT), have reported improved actuarial survival at 3 and 5 years of 75% and 56%, respectively [6, 7].

In efforts to improve locoregional control and eradicate early micrometastases, several phase II trials have looked at the addition of induction chemotherapy (CT). The favorable results indicate nasopharyngeal cancer is highly sensitive to induction CT with response rates as high as 75–98% [814]. Unfortunately, the response seen in these earlier trials failed to translate into an overall survival (OS) or disease-free survival benefit. However, a recent phase III Intergroup study, comparing concurrent chemoradiotherapy versus RT alone in a US population of patients, is the first randomized trial to demonstrate an OS benefit with concurrent chemoradiotherapy for patients with advanced nasopharyngeal cancer [15].

Combined modality treatment of head and neck cancers has been studied extensively at The University of Chicago and Northwestern University [16]. From 1990 to 1999, patients presenting with advanced nasopharyngeal cancer have been treated with a novel combination of induction CT followed by concomitant chemoradiotherapy as per our locoregionally advanced head and neck cancer protocol. We herein present our results and compare them with the current published data.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
Patient eligibility
From 1990 to 1999, 27 patients with locoregionally advanced nasopharyngeal cancer were treated at The University of Chicago Hospital, Northwestern Memorial Hospital and Michael Reese Hospital on a joint protocol (University of Chicago Study 6126/5959). This is a site-specific subset analysis from a larger pool of patients treated on the protocol, which included other head and neck cancer sites. Eligible patients required histological diagnosis of squamous cell carcinoma or poorly differentiated carcinoma of the nasopharynx, a performance status (Cancer and Leukemia Group B) of zero to two, tumor and nodal staging determined at a multidisciplinary management conference to be stage III or IV by American Joint Committee on Cancer (AJCC) 1992 classification, and signed, informed consent. The 1992 AJCC staging was used over the more recent 1997 AJCC staging for the purpose of comparison with other published results, which predominantly employ the AJCC 1992 staging system.

Treatment plan
The treatment schema is summarized in Figure 1. The overall treatment plan consisted of induction CT with cisplatin, 5-fluorouracil (5-FU), leucovorin and interferon-{alpha}2b (IFN-{alpha}2b) (PFL-IFN), followed by concomitant chemoradiotherapy with 5-FU and hydroxyurea (FHX). Patients were hydrated over 6 h before commencing the 6-h continuous infusion of cisplatin at 100 mg/m2. This was followed by 5-FU at 640 mg/m2 per day by continuous infusion for 5 days. Leucovorin was started during the hydration period and given at a dose of 300 mg/m2 per day by continuous infusion for 5.5 days [17, 18]. IFN-{alpha}2b was administered subcutaneously 2 h before cisplatin and repeated daily for a total of six doses. This induction CT (PFL-IFN) was administered every 21 days for three cycles.



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Figure 1. Treatment schema. CI, continuous infusion; FHX, 5-fluorouracil (5-FU), hydroxyurea and once-daily radiotherapy; PFL-IFN, cisplatin, 5-FU, leucovorin and interferon-{alpha}2b.

 
Following response evaluation to the induction phase of therapy, seven cycles of FHX were given in a week-on week-off schedule. The patient was routinely admitted on Sunday evening to start the CT and the concurrent radiation commenced Monday morning. One 14-day cycle of treatment consisted of continuous infusion 5-FU 800 mg/m2/day for 5 days, hydroxyurea 1 g administered orally every 12 h for a total of 11 doses with one dose preceding radiation therapy by ~2 h, and a single daily fraction of radiation of 2 Gy. After 5 days of treatment, CT and radiation were withheld for 9 days. Patients received an average of seven cycles of treatment to a median dose of 70 Gy. The treatment plan was to treat gross disease to a minimum of 70 Gy, high-risk microscopic disease to 60 Gy, and low-risk microscopic disease to 50 Gy. During the intervening weeks between treatment, vital signs and electrolytes were routinely monitored and normotonic fluids and/or supplemental potassium or magnesium were provided as needed.

Evaluation of results
Evaluation of response was performed at the end of induction CT and again at the completion of all therapy. Response was assessed clinically by at least two observers and included radiographic evaluation if felt to be appropriate by a physician. Response was recorded as complete response (CR) or partial response (PR). A CR was defined as the complete disappearance of all clinically detectable disease, a PR was an average reduction of all measurable disease by at least 50% and no appearance of new lesions.

Survival and disease control parameters were calculated using Kaplan–Meier actuarial analysis [19]. OS was defined as the time from the first day of treatment until death or time of last contact. Progression-free survival was defined as the time from the first day of treatment until the date of local failure, regional failure, distant failure or treatment-related death. Time to distant failure was defined as the time from the first day of treatment until either distant failure or treatment-related death. Patients dying without evidence of disease recurrence were censored in the analyses of time to progression. Meticulous follow-up was done to be certain that deceased patients marked as having no evidence of disease (NED) had evidence of the medical cause of death. Likewise, patients scored as alive and NED required evidence by direct nasopharyngoscopy examination and/or computed tomography scans at the time of last follow-up.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
Between 1990 and 1999, 27 patients were enrolled into the study. Follow-up data are available through to November 2001. Median follow-up for all patients was 52 months. The median follow-up of surviving patients was 82 months (range 17–139). By American Joint Committee on Cancer 1992 stage classification, all patients were Stage III (11%) or IV (89%). Tx, primary tumor cannot be assessed; T1, tumor limited to one subsite of the nasopharanx; T2, tumor invading more than one subsite of the nasopharanx; T3, tumor invading the nasal vacity and/or oropharanx; T4, tumor invading the skull and/or cranial nerve(s); N0, no regional lymph node metastases; N1, metastases in a single ipsilateral lymph node, <=3cm in size; N2, metastasis is a single ipsilateral lymph node, >3 cm but <=6cm, or bilateral or contralateral lymph nodes; N3; metastasis in a lymph node >6cm. Stage by TNM (tumor–node–metastasis) status is seen in Table 1. By histology, 63% were poorly differentiated carcinoma, 37% squamous cell carcinoma. Median age was 42 years, ranging from 16 to 76 years.


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Table 1. Stage at diagnosis (numbers of patients)
 
Response to sequential treatments
Dose intensity was maintained in this study, as 89% of patients (24 of 27) completed all three cycles of induction CT. Compliance to this regimen proved to be highly effective. The response rate to induction CT was 100%, 54% achieving a CR and 46% a PR. After the completion of concomitant chemoradiotherapy, the CR rate increased to 100%. This was confirmed pathologically by biopsy or neck dissection in 33% of patients.

Progression-free survival and overall survival
At a median follow-up of 5 years, three failures and six deaths were observed. Two patients died of disease, one of local failure and one of distant metastases. One patient is alive with an isolated rib metastasis and is responding to additional CT. Four patients died of unrelated illnesses and were NED with respect to their nasopharyngeal cancer. The causes of death were pneumonia, multiple sclerosis, a cerebral vascular accident and cardiac disease. The OS at 3 and 5 years is 88% and 77%, respectively. Progression-free survival at 3 and 5 years is 92% and 86%, respectively (Figure 2).



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Figure 2. Overall survival and progression-free survival.

 
Locoregional and distant control
One local failure and two distant failures were observed. At 5 years, the actuarial locoregional and distant control are 93% and 92%, respectively. The single patient with local failure received only 63 Gy, considerably less than the 70 Gy average radiation dose. The average dose was not completed due to the patient’s non-compliance. This patient had stage IV (T4N2cM0) disease and died of disease 4 years after initiation of treatment. Two distant failures were observed. One patient developed simultaneous metastases to the lung and liver 16 months after initiation of treatment, and died of disease 5 months later. The second patient developed a bone metastasis to a rib 27 months after initiation of treatment and is responding to additional CT.

Causes of death
At a median follow-up of 52 months, two of the six deaths were due to nasopharyngeal cancer. The remaining four deaths were elderly patients (ages 62, 63, 76 and 57) who died of complications from pneumonia, multiple sclerosis, a cerebral vascular accident and cardiac disease, respectively. All four patients were NED with respect to their nasopharyngeal cancer at the time of death. This was meticulously confirmed by recent follow-up physician notes, radiological reports and direct communication with family members by telephone.

Toxicity
Acute toxicity was observed in 33% of patients, requiring a reduction in the CT dose due to leukopenia, thrombocytopenia, nausea, vomiting or mucositis. The most common dose modification was a 20% reduction in the PFL-IFN induction phase, with only one patient requiring dose reduction during the FHX therapy. The mucositis for some required supportive care including analgesics, supplemental feedings and attention to infections such as thrush. Chronic toxicity was not observed, as all patients resumed normal diets after completion of therapy. No patient required a permanent feeding tube. There were no radiation treatment delays or treatment-related deaths.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
Carcinoma of the nasopharynx is an uncommon malignancy in the USA, with incidence less than 1%. Therefore, the experience of the average radiation oncologist is limited, even at large cancer centers. These factors explain, in part, the relative paucity of large, randomized clinical trials comparing treatment modalities for advanced nasopharyngeal cancer. In the 1980s, advanced nasopharyngeal cancer patients treated with RT alone reported 5-year survival ranging from 30% to 55%. The largest study, by Qin et al. [20], analyzed 1379 patients treated with RT alone and reported a 5-year survival of 41% for patients with stages III and IV. More recent results, with optimal RT, have reported improved actuarial survival at 3 and 5 years of 75% and 56%, respectively [6, 7].

Given these suboptimal results and because the majority of patients present with advanced disease, studies looking at the benefit of adjuvant CT have evolved. The use of neoadjuvant CT in head and neck cancers has been investigated extensively and the combination of cisplatin and continuous infusion of 5-FU has resulted in consistently high response rates [2128]. While phase II trials are promising in terms of high rates of response to induction CT, earlier phase III randomized trials did not demonstrate improved survival [14, 2932]. However, because CT given upfront has better drug delivery to an untreated tumor in its native vascular bed, induction CT could optimize the likelihood of reducing tumor bulk, ultimately leading to better local control.

Furthermore, CT early in the course of treatment would address micrometastatic disease when it is at its smallest volume and most curable state. While the aforementioned Intergroup study by Sarraf demonstrated a reduction in locoregional and distant metastases in the chemoradiotherapy arm, these patients still had a 23% failure (10% local and/or nodal, 13% distant). Al-Sarraf comments, "Due to the high incidence of late systemic recurrences in these patients, additional effective CT is needed to improve the results of the combined modality treatment in advanced nasopharyngeal cancers" [15]. The fact that patients in head and neck cancer trials have historically been reluctant to complete the adjuvant CT portion of studies makes this risk of distant failure a particular challenge. For example, the Intergroup trial reported a 63% compliance to the initial chemoradiotherapy treatment and a 55% compliance to the adjuvant CT. Reasons for non-compliance were primarily due to toxicity, but patient refusal unrelated to toxicity was also observed. In our study, which delivered the CT upfront, the rate of patient compliance was 89% for the induction phase and 96% for the concomitant chemoradiotherapy treatment. Only one patient was non-compliant with the combined modality phase and went on to experience failure after receiving only 63 Gy of the 70 Gy prescribed dose.

Therefore, in efforts to optimize both local and distant disease with high compliance, The University of Chicago protocol continues to use induction CT in the treatment of patients with advanced nasopharyngeal cancer. The drugs of choice, however, have evolved over time. Specifically, the use of IFN at the time of this study was based on the assumption that IFN-{alpha} modulates the effect of CT, as in vitro data (5-FU) and xenograft data (cisplatin) support this. However, the only phase III trial comparing cisplatin and 5-FU with or without the addition of IFN was performed in patients with recurrent or metastatic squamous cell carcinomas of the head and neck, and apart from increased toxicity, IFN failed to demonstrate any differences in outcome [33]. Therefore, IFN is no longer used as part of the induction regimen.

One may argue against the use of induction CT based on a multicenter randomized trial conducted by the Asian-Oceanian Clinical Oncology Association (AOCOA) [34]. This trial compared induction CT followed by RT versus RT alone in patients with locoregionally advanced nasopharyngeal carcinoma. They found no significant difference in 5-year actuarial survival between the sequential chemoradiotherapy arm and RT alone arm (70% versus 67%, respectively; P = 0.68). However, the induction CT used consisted of two or three cycles of cisplatin at 60 mg/m2 and epirubicin at 110 mg/m2 on day 1. This dose of cisplatin is close to a 50% reduction to the usual dose of 100 mg/m2 per cycle, as prescribed in our study. The authors, Chua et al. propose several possible reasons why the neoadjuvant CT was not more effective, "First, three cycles of neoadjuvant CT may not have been sufficient to eradicate all the distant metastases. Second, the chemotherapeutic agents and the dose we administered may have been inadequate. Third, many of our patients had both advanced T and N classifications, and the subsequent clinical course may have been dominated by the status of local disease" [34]. For the reasons specified by the author, this cannot be compared to our induction CT (PFL-IFN). AOCOA results from both the induction CT arm and the RT alone arm found very high rates of distant metastases, 44% in the CT arm and 43% in the RT arm. Their rate of distant failure is higher than seen in our study and highlights the need for intensive systemic therapy. Although the OS in the AOCOA trial was equivalent, the relapse-free survival (RFS) did reveal a trend towards significance, in favor of induction CT (53% versus 42% RFS; P = 0.13). We feel that the gain of induction CT is yet to be determined and in view of the high rate of distant metastases in these patients, deserves further investigation.

At 52 months of follow-up, our results following this approach of induction CT (PFL-IFN) followed by chemoradiotherapy (FHX) are promising. Evaluation after induction CT revealed a CR rate of 54.2% and PR rate of 45.8%. The final response after the concomitant FHX phase reached 100% CR. Only one local failure and two distant failures were observed. Actuarial locoregional and distant control were 93% and 92%, respectively. While six deaths were observed, only two died of disease, yielding 3- and 5-year progression-free survivals of 92% and 86%, respectively. Three- and 5-year OS were also encouraging at 88% and 77%, respectively. Among the 21 surviving patients, only one has experienced distant failure and is responding to additional CT. These results compare favorably with the Intergroup study, which at 3 years reported superior median progression-free survival of 69% versus 24% (P <0.001) and OS of 78 versus 47% (P = 0.005) for patients in the chemoradiotherapy arm.


    Conclusions
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
To date, the highest rate of OS for patients presenting with advanced stage nasopharyngeal carcinoma is achieved with concomitant chemoradiotherapy as demonstrated by the Intergroup study and supported by our results. The choice of radiosensitizing CT agent(s) is less clear but cisplatin and 5-FU as components of therapy have historically shown high response rates and were common to both the Intergroup and our own study. The timing of adjuvant CT before or after chemoradiotherapy is an area of research. At The University of Chicago and Northwestern University, the advanced head and neck protocol employs induction CT with excellent compliance and encouraging results. Although our study of 27 patients is small, its superior results, with acceptable toxicity, suggest that a further increase in survival rate is possible with intensified approaches. Our results warrant further investigation in a randomized setting to further outline the optimum treatment of these patients.


    Acknowledgements
 
This work was supported in part by the Velda and Robert Svendsen Foundation, Chicago, IL and the Geraldi Norton Memorial Corporation, Chicago, IL.


    Footnotes
 
+ Correspondence to: Dr J. L. Oh, The University of Chicago, 5758 South Maryland Avenue, MC 9006, Chicago, IL 60637, USA. Tel: +1-773-702-6860; Fax: +1-773-834-7340; E-mail: jlo91{at}hotmail.com Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
1. Cheng H. Nasopharyngeal cancer and the Southeast Asian patient. Am Fam Physician 2001; 63: 1776–1782.[ISI][Medline]

2. Ahmad A, Stefani S. Distant metastases of nasopharyngeal carcinoma: a study of 256 male patients. J Surg Oncol 1986; 33: 184–197.

3. Cvitkovic E, Bachouchi M, Arman JP. Nasopharyngeal carcinoma biology, natural history and therapeutic implications. Hematol Oncol Clin North Am 1991; 5: 821–839.[ISI][Medline]

4. Qin D, Hu Y, Yan J et al. Analysis of 1379 patients with nasopharyngeal carcinoma treated by radiation. Cancer 1988; 61: 1117–1124.[ISI][Medline]

5. Teo P, Tsao SY, Shiu W et al. A clinical study of 407 cases of nasopharyngeal carcinoma in Hong Kong. Int J Radiat Oncol Biol Phys 1989; 17: 515–530.[ISI][Medline]

6. Ma J, Mai H, Hong M et al. Results of a prospective randomized trial comparing neoadjuvant chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma. J Clin Oncol 2001; 19: 1350–1357.[Abstract/Free Full Text]

7. Kraiphibul P, Atichartakarn V, Clongsusuek P et al. Nasopharyngeal carcinoma: results of treatment by radiotherapy versus chemotherapy plus radiotherapy. J Med Assoc Thai 1991; 74: 391–396.[Medline]

8. Atichartakarn V, Kraiphibul P, Clongsusuek P et al. Nasopharyngeal carcinoma: result of treatment with cis-diamminedichloroplatinum II, 5-fluorouracil, and radiation therapy. Int J Radiat Oncol Biol Phys 1988; 14: 461–469.[ISI][Medline]

9. Bachouchi M, Cvitkovic E, Azli N et al. High complete response in advanced nasopharyngeal carcinoma with bleomycin, epirubicin, and cisplatin before radiotherapy. J Natl Cancer Inst 1990; 82: 616–620.[Abstract]

10. Clark JR, Norris CM, Dreyfuss AI et al. Nasopharyngeal carcinoma: the Dana-Farber Cancer Institute experience with 24 patients treated with induction chemotherapy and radiotherapy. Ann Otol Rhinol Laryngol 1987; 96: 608–614.[ISI][Medline]

11. Dimery I, Peters LJ, Goepfert H et al. Effectiveness of combined induction chemotherapy and radiotherapy in advanced nasopharyngeal carcinoma. J Clin Oncol 1993; 11: 1919–1928.[Abstract]

12. Galligioni E, Carbone A, Tirelli U et al. Combined chemotherapy with doxorubicin, bleomycin, vinblastine, dacarbazine, and radiotherapy for advanced lymphoepithelioma. Cancer Treat Rep 1982; 66: 1207–1210.[ISI][Medline]

13. Tannock I, Payne D, Cummings B et al. Sequential chemotherapy and radiation for nasopharyngeal cancer: absence of long-term benefit despite a high rate of tumor response to chemotherapy. J Clin Oncol 1987; 5: 629–634.[Abstract]

14. Chan A, Teo P, Leung T et al. A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1995; 33: 569–577.[ISI][Medline]

15. Al-Sarraf M, LeBlanc M, Shanker PG et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup Study 0099. J Clin Oncol 1998; 16: 1310–1317.[Abstract]

16. Stupp R, Weichselbaum R, Vokes E. Combined modality therapy of head and neck cancer. Semin Oncol 1994; 21: 349–358.[ISI][Medline]

17. Kies M, Haraf D, Athanasiasdis I et al. Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: improved disease control and survival. J Clin Oncol 1998; 16: 2715–2721.[Abstract]

18. Vokes E, Kies M, Haraf D et al. Induction chemotherapy followed by concomitant chemoradiotherapy for advanced head and neck cancer: impact on the natural history of the disease. J Clin Oncol 1995; 13: 876–883.[Abstract]

19. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[ISI]

20. Qin D, Hu Y, Yan J et al. Analysis of 1379 patients with nasopharyngeal carcinoma treated by radiation. Cancer 1988; 61: 1117–1124.[ISI][Medline]

21. Al-Kourainy K, Kish J, Ensley J et al. Achievement of superior survival for histologically negative versus histologically positive clinically complete responders to cisplatin combination in patients with locally advanced head and neck cancer. Cancer 1987; 59: 233–238.[ISI][Medline]

22. Al-Sarraf M. Head and neck cancer: chemotherapy concepts. Semin Oncol 1988; 15: 70–85.[ISI][Medline]

23. Bernal A, Cruz J, Sanchez P et al. Four-day continuous infusion of cisplatin and 5-fluorouracil in head and neck cancer. Cancer 1989; 63: 1927–1930.[ISI][Medline]

24. Cripps C, Odell P, Danjoux C et al. Pretreatment with chemotherapy in patients with advanced head and neck cancer. J Otolaryngol 1985; 14: 391–393.[ISI][Medline]

25. Ervin T, Clark J, Weichselbaum R et al. An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous cell carcinoma of the head and neck. J Clin Oncol 1987; 5: 10–20.[Abstract]

26. Jacobs C, Goffinet D, Goffinet L et al. Chemotherapy as a substitute for surgery in the treatment of advanced resectable head and neck cancer. Cancer 1987; 60: 1178–1183.[ISI][Medline]

27. Kish J, Drelichman A, Jacobs J et al. Clinical trial of cisplatin and 5-FU infusion as initial treatment for advanced squamous cell carcinoma of the head and neck. Cancer Treat Rep 1982; 66: 471–474.[ISI][Medline]

28. Rooney M, Kish J, Jacobs J et al. Improved complete response rate and survival in advanced head and neck cancer after three-course induction therapy with 120-hour 5-FU infusion and cisplatin. Cancer 1985; 55: 1123–1128.[ISI][Medline]

29. Jaulerrry C, Mosseri V, Brunin F et al. Induction chemotherapy in advanced head and neck cancer. Preliminary results of a randomized trial. Acta Oncol 1989; 28: 61–65.[ISI][Medline]

30. Paccagnella A, Orlando A, Marchiori C et al. Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: a study by the Gruppo de Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 1994; 86: 265–272.[Abstract]

31. Toohill R, Anderson T, Byhardt R et al. Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer. Arch Otolaryngol Head Neck Surg 1987; 113: 758–761.

32. Vokes E, Weichselbaum R, Lippman S, Hong W. Head and neck cancer. N Engl J Med 1993; 328: 184–194.[Free Full Text]

33. Schrijvers D, Johnson J, Jiminez U et al. Phase III trial of modulation of cisplatin/fluorouracil chemotherapy by interferon alfa-2b in patients with recurrent of metastatic head and neck cancer. Head and Neck Interferon Cooperative Study Group. J Clin Oncol 1998; 16: 1054–1059.[Abstract]

34. Chua D, Sham J, Choy D et al. Patterns of failure after induction chemotherapy and radiotherapy for locoregionally advanced nasopharyngeal carcinoma: the Queen Mary Hospital experience. Int J Radiat Oncol Biol Phys 2001; 49: 1219–1228.[ISI][Medline]