Clinical Results of Radiotherapy/Chemotherapy Treatment Meyer JL, Vaeth JM (eds): Radiotherapy/Chemotherapy Interactions in Cancer Therapy. Front Radiat Ther Oncol. Basel, Karger, 1992, vol 26, pp 55-63
Concomitant Chemoradiotherapy as Investigational Therapy for Locoregionally Advanced Head and Neck Cancer Everett E. liked Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Ill. USA
Standard therapy for head and neck cancer has traditionally consisted of surgery and/or radiotherapy, reflecting the predominance of locoregional initial presentation. For patients with stage I and II disease either treatment modality used alone will usually result in cure. For patients with stage III and IV disease, however, cure is achieved in a minority of cases only. The cause of failure most commonly is locoregional recurrence, indicating the inability of both surgery and radiotherapy to effectively eradicate locoregionally advanced disease. A much smaller percentage ( < 20%) of patients will develop distant metastases. However, since autopsy series have shown systemic micrometastases in 50% and more of cases [ 1, 2], this distant failure rate could be expected to rise significantly if more effective locoregional therapy would not also address successfully the systemic tumor burden. Efforts at improving surgical and radiotherapeutic techniques, therefore, could result in better regional control but might not improve the overall outcome because of their inherent inability to address systemic disease. Chemotherapy, although systemically active, has not been shown to be curative in this disease [3]. As a single treatment modality it is used to palliate symptomatic patients with recurrent or metastatic disease. For previously untreated patients, it is being investigated for its potential use in multimodality therapy to enhance the cure rate achieved with surgery and/or radiotherapy. The sequential use of chemotherapy prior to or after standard local therapy has consisted in large part of pilot trials using 2-3 cycles of neoadjuvant chemotherapy [4-8]. These trials have shown high overall response rates and complete response (CR) rates of approximately 30%. It has also been shown that patients achieving CR have a good
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
' I wish to thank Susan Jarman for preparation of the manuscript.
Yokes
56
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
prognosis. However, survival data from these studies have mostly indicated that any improvement in overall survival is likely to be very limited in degree. Two trials conducted at our own institution using the combination of cisplatin and continuous infusion 5-FU with or without methotrexate resulted in median survival times of 22 and 20 months, respectively [7, 8]. This is not clearly superior to survival times reported following standard therapy only. Randomized trials have compared neoadjuvant chemotherapy followed by standard therapy to standard therapy alone. However, due to the choice of drugs, the number of cycles administered or the low number of patients enrolled, and the heterogeneity of head and neck cancer, most of these trials are inconclusive; they do not prove or disprove the question they were designed to answer [9]. One notable exception to this is the Veterans Administration Cooperative Study Program trial [ 10]. In this trial, 61 % of patients with advanced laryngeal cancer treated with 3 cycles of neoadjuvant cisplatin and 5-FU were rendered free of disease by chemotherapy and radiotherapy, and did not require laryngectomy. Overall survival, however, was not better than that of patients treated with surgery and radiotherapy but without chemotherapy. Neoadjuvant chemotherapy has, therefore, been shown to have a potential role in organ preservation; whether it can prolong survival remains unknown, but all studies so far suggest that its impact will be limited at best. More recent pilot studies have attempted to define regimens with higher activity, hoping to achieve CR rates exceeding 50% since patients achieving CR have been shown to have a better prognosis. Among these, the combination of cisplatin, 5-FU and leucovorin seems particularly promising, although survival rates have not been reported to date [ 11-13]. Concomitant chemoradiotherapy represents another approach to integrating chemotherapy into the therapy of locoregionally advanced head and neck cancer. Its rationale and possible mechanisms of interaction have recently been reviewed [ 14]. It is a particularly attractive approach to head and neck cancer. It allows one to focus therapy on the locoregional tumor where the bulk of malignant cells is largest, while also allowing for systemic therapy at an earlier time in the natural history of the disease when the number of therapy-resistant cells may be lower. Concomitant chemoradiotherapy has been actively pursued in clinical research for the last three decades. The first clinical trials addressing concomitant chemoradiotherapy for head and neck cancer were designed to not compromise administration of standard radiotherapy. Since standard radiotherapy by itself results in mild to moderate toxicity in many patients, it is difficult to add effective chemotherapy, i.e. high dose multiagent regimens. Instead, single agents were chosen and administered at lower doses several times during the
Chemotherapy for Locoregionally Advanced Head and Neck Cancer
57
Table 1. Selected randomized trials of concomitant chemoradiotherapy Author
Drug
Survival, % chemotherapy
Gupta et al.
methotrexate
Shanta and Krishnamurthi Fu et al.
bleomycin
Eschwege et al.
bleomycin
Lo et al.
5-FU
Weissberg
mitomycin C
Haselow
cisplatin
bleomycin
Disease-free survival, % control
43 35 (at 4 years, p = 0.075) 59 23 (at 5 years) 43 24 (at 3 years, p = 0.112) 22 23 (at 5 years) 32 14 (at 5 years, p < 0.05) 48 40 (at 5 years, p > 0.3) (no significant difference)
chemotherapy
control
72 17 (at 5 years) 31 15 (at 3 years, p = 0.024) 22 22 (at 5 years) 49 18 (at 2 years, p < 0.5) 75 55 (at 5 years, p < 0.01)
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
course of radiotherapy. Most active single agents have been studied in this fashion, and have been compared in randomized studies to standard radiotherapy. These have included methotrexate [ 15], bleomycin [ 16-18], cisplatin [19], 5-FU [20], hydroxyurea [21] and mitomycin [22]. Several of these studies are summarized in table 1. Improved disease-free survival has been achieved with bleomycin (although not consistently), mitomycin C, and by subgroup analysis with methotrexate. Improved overall survival has been reported for 5-FU and bleomycin, although the bleomycin trial [ 16] has been criticized for its use of nonstandardized radiotherapy, the nonstandarized route of administration of bleomycin and the lack of survival curves in the actual report. For cisplatin, improved disease-free or overall survival has not been demonstrated. This may be unexpected since cisplatin is a drug with single agent activity comparable to that of methotrexate and has been shown in experimental systems to enhance the activity of radiation [ 14]. It must be pointed out that the doses of cisplatin used in the randomized trial may have been suboptimal to achieve single agent activity or regional enhancement of radiotherapy. Pilot trials using high doses of cisplatin at an intermittent schedule look more promising and randomized studies investigating one of these cisplatin schedules are needed [23, 24]. Acute toxicities were reported to be increased with concomitant chemoradiotherapy in all of these trials. Chronic toxicities, however, do not appear to be significantly increased. While statistically significant, the degree of improvement in disease-free or overall survival is fairly small,
Yokes
58
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
with the great majority of patients not cured of their disease with either standard radiotherapy or radiotherapy with concomitant single agent chemotherapy. In addition, at least for bleomycin, positive trials as well as negative trials have been reported. Why then have none of these concomitant chemoradiotherapy regimens been adopted as standard therapy? The increase in acute toxicity per se does not justify omitting the use of more effective therapy. Cancer chemotherapy has repeatedly been shown to be more effective when used at higher doses (resulting in higher toxicity) and this is readily accepted if cure can be provided. In addition, more aggressive therapy with increased toxicity might also be accepted if surgery could be omitted resulting in organ preservation [25]. In the case of concomitant chemoradiotherapy for head and neck cancer, the difference in disease-free or overall survival may be insufficient to justify the more aggressive approach. The real meaning of these trials may be that they demonstrate the feasibility of the concept and prove that the theoretical potential for improved outcome does exist in clinical practice. These trials do not represent an endpoint but they do call for additional clinical investigation of this approach. During the last decade clinical trials have attempted to use chemotherapy in a more rational way with concomitant radiotherapy. Byfield et al. [26] studied the interaction of 5-FU and radiotherapy in experimental systems and concluded that 5-FU was most effective if present for prolonged periods of time (up to 48 h) following a dose of fractionated radiation and administered at maximally tolerated dose. Due to the short half-life of 5-FU in vivo, prolonged exposure is best achieved by a continuous infusion schedule. In head and neck cancer, clinical trials support an impression of increased activity of 5-FU if administered by that route. Byfield et al. [27] then conducted a clinical phase I trial in patients with stage III and IV head and neck cancer. In this trial, 5-FU was administered continuously over 5 days with concomitant daily radiotherapy followed by 9 days interruption of both chemotherapy and radiotherapy. The dose of 5-FU was increased in cohorts of patients. Mucositis was dose-limiting, which is consistent with the toxicity profile of infusional 5-FU and of radiotherapy. CR was achieved in 9 of 12 patients with Stage IV disease and one of two patients with Stage III disease. Patients treated at higher doses of 5-FU had a higher chance of achieving CR, which was consistent with previous experimental findings and supported the concept of treating patients at the maximally tolerated dose of 5-FU. Also of interest in this trial, protracted radiotherapy (administered over 5 days of every other week) did not appear to result in inferior outcome, as would be expected for radiotherapy administered as a single treatment modality; in the presence of 5-FU, protracted radiotherapy appeared to be feasible.
Chemotherapy for Locoregionally Advanced Head and Neck Cancer
59
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
Clinically, this finding was of significance since it seemed to allow for the interruption of radiotherapy in order to increase the feasibility of administering effective chemotherapy. Subsequent clinical trials expanded on these data and added additional active chemotherapy agents to the treatment schedule. Taylor et al. [28] added to the regimen cisplatin administered in a dose compatible with single agent activity (60 mg/m2 on day 1 of each chemoradiotherapy cycle). This was a logical choice since cisplatin is one of the most active single agents and has been shown to enhance radiotherapy in vitro. When last updated, their trial included 53 patients with advanced or recurrent disease, who were treated for seven cycles (over a 14-week period of time) to a total of 70 Gy. Fifty-five percent of patients achieved CR, and at a median follow-up of 51 months the median survival was 37 months. Only 15% of patients achieving CR developed local recurrence. These encouraging pilot data require confirmation and testing in a randomized trial. Adelstein et al. [29] also used the combination of cisplatin and 5-FU with concomitant radiotherapy. Fifty-four patients were treated with 30 Gy preoperatively (5-FU and cisplatin were given during week 1) followed by a 2-week treatment interruption and a second cycle of chemotherapy (without radiotherapy). Local therapy consisted of surgery (28 patients) and radiotherapy with additional chemotherapy. Fifty-one patients were considered clinically free of disease and the overall survival was 52%. Adelstein et al. [30] have also compared this chemoradiotherapy program to 3 cycles of induction chemotherapy with cisplatin and 5-FU. In 48 patients enrolled, the disease-free survival was statistically superior with concomitant chemoradiotherapy. For overall survival, a similar trend was seen, although statistical significance was not reached. Since two experimental arms are compared in this trial, the superior arm cannot be considered a `standard'; it can only be considered the superior experimental treatment. Furthermore, the low patients numbers accrued and the lack of a clear survival advantage render this trial, ultimately, inconclusive. Biochemical modulation of 5-FU as part of concomitant chemoradiotherapy has also been investigated. Clinically, this 5-FU modulation with leucovorin has been shown to result in superior survival in patients with metastatic colorectal cancer. This pathway can also be modulated with hydroxyurea (HU). HU is a ribonucleotide reductase inhibitor which will deplete the cell of dUMP, the natural substrate for thymidylate synthase. In 1986, we started to investigate the concomitant administration of 5-FU, HU and radiotherapy, because we hoped to identify an active regimen based on the potential for synergy between 5-FU and HU and their known potential to enhance radiotherapy [31]. In a phase I trial, we identified maximally tolerated doses of 5-FU at 800 mg/m2/day x 5 by
Yokes
60
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
continuous intravenous infusion (decreased to 600 mg/m2/day for mucositis > grade 3) and of HU at 1,000 mg administered orally every 12 h for a total of 11 doses, with one daily dose preceding the daily fraction of radiation by 2 h. The dose of HU was adjusted only for myelosuppression _> grade 3. Five days of concomitant chemoradiotherapy were followed by 9 days of no treatment analogous to the schedule by Byfield et al. [26]. Patients who had failed prior radiation were shown to readily achieve CR (6/15) or PR (8/15) and, thus, palliation of symptoms was much more readily achieved than when using chemotherapy alone [11]. This finding has since been confirmed by Guillot et al. [32]. However, the responses in our trial were not durable, possibly as a result of the less than optimal radiotherapy doses and field sizes (only 40-60 Gy were administered on this trial to previously irradiated patients). Of previously unirradiated patients, 12 of 17 evaluable patients achieved CR and 5 achieved PR. This represented a group of patients with a very unfavorable prognosis (distant metastases, failure to respond to neoadjuvant chemotherapy, poor renal and pulmonary functions). However, local recurrence as a cause of failure was seen in only 1 patient of these previously unirradiated patients [33]. We have investigated the further modulation of this regimen with leucovorin. While this trial has not been evaluated for survival due to insufficient follow-up time, the leucovorin greatly increased the severity of mucositis, necessitating 5-FU dose reduction to 300-400 mg/m2/day. We have also attempted to add continuous infusion cisplatin to this regimen, but found cumulative myelosuppression to be prohibitive, probably reflecting insufficient bone marrow recovery time between cycles. Due to these difficulties in adding leucovorin or cisplatin to the combination, we are currently focusing on using 5-FU, HU and concomitant radiotherapy without additional drugs in previously untreated patients. Wendt et al. [ 34] have also investigated 5-FU modulation with concomitant radiotherapy. Sixty-two patients were treated with a complex schedule of cisplatin, 5-FU and leurovorin with concomitant hyperfractionated radiotherapy. Forty-eight achieved clinical CR and 11 clinical PR 3 months after completion of therapy. The median survival was 52% at a median follow-up of 29 months. Other studies using concomitant chemoradiotherapy with 5-FU-based chemotherapy have been reported [35-37]. Another line of research has been the administration of chemotherapy and radiotherapy on a rapidly alternating schedule. This is supported by experimental data by Looney et al. [38]. Clinically, it may be difficult to administer one treatment modality at a time when toxicity from the other is peaking. A few investigators have reported on this approach, including O'Connor et al. [39] and Merlano et al. [40, 41]. Both groups of investigators have compared the rapidly alternating administration of therapy to
Chemotherapy for Locoregionally Advanced Head and Neck Cancer
61
neoadjuvant chemotherapy (with the same drugs) followed by standard radiotherapy [39, 40]. In both trials, the rapidly alternating treatment arm was superior, although statistical significance was only reached in the trial by Merlano et al. [40]. Single agent concomitant chemoradiotherapy has been shown to be superior to standard radiotherapy in randomized trials. Recent trials investigating combination chemotherapy (5-FU based) with concomitant radiotherapy have led to encouraging response and survival data. While additional pilot trials are needed to refine the regimens and doses, it may now be appropriate to compare one of these regimens to standard therapy.
References Kotwall C, Sako K, Razack MS, et al: Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg 1987;1154:439. 2 Zbaeren P, Lehmann W: Frequency and sites of distant metastases in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 1987;113:762-674. 3 likes ΕΕ: Head and neck cancer, in Perry MC (ed): Chemotherapy Source Book, Baltimore, Williams & Wilkins, in press. 4 Hong WK, Shapshay SM, Bhutani R, et al: Induction chemotherapy in advanced squamous head and neck carcinoma with high-dose cis-platinum απd bleomycin infusion. Cancer 1979;44:19-25. 5 Ervin TJ, Clark JR, Weichselbaum RR, 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. 6 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. 7 Vokes ΕΕ, Mick R, Lester EP, Panje WR, Weichselbaum RR: Cisplatin and 5fluorouracil does not yield long-term benefit in locally advanced head and neck cancer: Results from a single institution. J Clin Oncol 1991;9:1376-1384. 8 likes ΕΕ, Moran WJ, Mick R, Weichselbaum RR, Panje WR: Neoadjuvant and adjuvant methotrexate, cisplatin, and fluorouracil in multimodal therapy of head and neck cancer. J Clin mcii 1989;7:838-845. 9 Forastiere AA: Randomized trials of induction chemotherapy: A critical review. Hematol/Oncol Clin N Am 1991;5:725-736. 10 The Department of Veterans Affairs Laryngeal Cancer Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. New Engl J Med 1991;324:1685-1690. 11 likes ΕΕ, Choi ΚΕ, Schilsky RL, et al: Cisplatin, fluorouracil, and high-dose leucovorin for recurrent or metastatic head and neck cancer. J Clin Oncol 1988;6:618626. 12 likes ΕΕ, Schilsky RL, Weichselbaum RR, et al: Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for locally advanced head απd neck cancer: A clinical and pharmacologic analysis. J Clin Oncol 1990;8:241-247. Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
1
Yokes
62
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
13 Dreyfuss AI, Clark JR, Wright JE, Norris CM Jr, Busse PM, Lucarini JW, Fallon BG, Casey D, Andersen JW, Klein R, Rosowsky A, Miller D, Frei E III: Continuous infusion high-dose leucovorin with 5-fluorοuracil and cisplatin for untreated stage IV carcinoma of the head and neck. Ann Intern Med 1990;112:167-172. 14 likes EE and Weichselbaum RR: Concomitant chemoradiotherapy: Rationale and clinical experience in patients with solid tumors. J Clin Oncol 1990;8:911-934. 15 Gupta 1K, Pointon RCS, Wilkinson PM: A randomised clinical trial to contrast radiotherapy with radiotherapy and methotrexate given sychronously in head and neck cancer. Clin Radiol 1987;38:575-581. 16 Shanty V, Krishnamurthi S: Combined bleomycín and radiotherapy in oral cancer. Clin Radiol 1980;31:6l7-620. 17 Fu ΚΚ, Phillips TL, Silverberg IV, et al: Combined radiotherapy and chemotherapy with bleomycín and methotrexate for advanced inoperable head and neck cancer: Update of a Northern California Oncology group randomized trial. J Clin Oncol 1987;5:1410-1418. I8 Eschwege F, Sancho-Gamier Η, Gerard JP, et al: Ten-year results of randomized trial comparing radiotherapy and concomitant bleomycín to radiotherapy alone in epidermoid carcinomas of the oropharynx: Experience of the European Organization for Research and Treatment of Cancer. NCI Monogr 1988;6:275-278. 19 Haselove RE, Warshaw MG, Oken MM, et al: Radiation alone versus radiation plus weekly low-dose cis-platinum in unresectable cancer of the head and neck; in Fee WE Jr, Goepfert Η, Johns ME, et al (eds): Head and Neck Cancer. Toronto/Philadelphia, Decker 1990, vol 2, pp 279-281. 20 Lo TC, Wiley AL Jr., Ansfield FJ, et al: Combined radiation therapy and 5-fluorοuracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: A randomized study. Am J Roentgenol 1976;126:229-235. Richards GJ, Chambers RG: Hydroxyurea: A radiosensitizer in the treatment of neoplasms 21 of the head and neck. Am J Roentgenol Radium Nucl Med 1969;55:555-565. 22 Weissberg JB, Son YH, Papac RJ, et al: Randomized clinical trial of mitomycin-C as an adjunct to radiotherapy in head and neck cancer. Int J Radiat Oncol Biol Phys 1989;17:3-9. 23 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 1990;66:1861 —1868. 24 Wheeler R, Salter M, Stephens S, et al: Simultaneous therapy with high-dose cisplatin and radiation for unresectable squamous cell cancer of the head and neck: A phase I—II study. NCI Monogr 1988;6:339-341. 25 McNeil BJ, Weichselbaum RR, Paoker S: Speech and survival: Tradeoffs between quality and quantity of life in laryngeal cancer. N Engl J Med 1981;305:982-987. Byfield JE, Calabro-Jones P, Klisak I, et al: Pharmacologic requirements for obtaining 26 sensitization of human tumor cells in vitro to combined 5-fluorouracíl or ftorafur and x-rays. Int J Radiat Oncol Bíol Phys 1982;8:1923-1933. Byfield JE, Sharp TR, Frankel SS, et al: Phase I and II trial of five-day infused 27 5-fluorouracíl and radiation in advanced cancer of the head and neck. J Clin Oncol 1984;2:406-413. 28 Taylor SG IV, Murthy AK, Caldarelli DD, et al: Combined simultaneous cisplatin/fluorouracil chemotherapy and split course radiation in head and neck cancer. J Clin Oncol 1989;7:846-856. 29 Adelstein DJ, Sharah VM, Earle AS, et al: Long-term results after chemoradiotherapy for locally confined squamous-cell head and neck cancer. Am J Clin Oncol 1990;13:440447.
Chemotherapy for Locoregionally Advanced Head and Neck Cancer
63
30 Adelstein DJ, Sharan VM, Earle AS, et al: Simultaneous versus sequential combined technique therapy for squamous cell head and neck cancer. Cancer 1990;65:1685-1691. 31 Vokes EE, Panic WR, Schilsky RL, et al: Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head απd neck cancer: A phase I—II Study. J Clin Oncol 1989,7:761-768. 32 Guillot T, Wibault P, Cvitkovic E, Luboinski Β, Tellez-Bernal E, Eschwege F, Schwaab G, Armand JP: Treatment of `favorable' recurrent head απd neck squamous cell with 5 days on/9 days off simultaneous chemoradiotherapy (meeting abstract). Proc Am Soc Clin Oncol 1990;9:Α684. 33 Haraf DJ, Vokes EE, Panic WR, Weichselbaum RR; Survival and analysis of failure following hydroxyurea, 5-fluorouracil απd concomitant radiation therapy in poor prognosis head and neck cancer. Am J Clin Oncol. 1991;14:419-426. 34 Wendt TG, Hartenstein RC, Wustrow TPU, et al: Cisplatin, fluorouracil with leucovorin calcium enhancement, απd synchronous accelerated radiotherapy in the management of locally advanced head and neck cancer: A phase II study. J Clin Oncol 1989;7:471-476. 35 Bo11a M, Borgel J, Guenoun A, Junien-Lavillauroy C, Dionet C, Vrousos C: Chemotherapy with low doses of radiation followed by definitive radiotherapy for advanced unresectable carcinoma of the head and neck. NCI Monogr 1988;6:357-359. 36 Keane TJ, Harwood AR, Beale FA, Cummings BJ, Payne DG, et al: A pilot study of mitomyciπ-C/5-fluorouracil infusion combined with split course radiation therapy for carcinomas of the larynx and hypopharynx. J Otolaryngol 1986;15:286-288. 37 Stryker JA, Harvey HA, Houck JR, Manders EK, Bradfield JJ: Advanced head and neck cancer: Low-dose, split-course radiation therapy απd simultaneous infusion of 5-fluorouracil and cisplatin. Radiology 1990;176:567-571. 38 Looney WB: Special lecture: Alternating chemotherapy and radiotherapy. NCI Monogr 1988;6:85-94. 39 O'Connor D, Clifford P, Edwards WG, et al: Long-term results of IBM and radiotherapy in advanced head and neck cancer. Int J Radiat Oncol Biοl Phys 1982;8:1525-1531. 40 Merlano M, Rosso R, Sertoli MR, et al: Sequential versus alternating chemotherapy απd radiotherapy in stage III—IV squamous cell carcinoma of the head and neck: A phase III study. J Clin Oncol 1988;6:627-632. 41 Merlano M, Grimaldi A, Benasso M, Bacigalupo A, Toma S, Scarpati D, Corvo R, Santelli A, Garaventa G, Rosso R: Alternating cisplatin-5-fluorouracil απd radiotherapy in head and neck cancer. Am J Clin Oncol 1988;11:538-542.
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
Everett E. Vokes, MD, Associate Professor of Medicine απd Radiation and Cellular Oncology, Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, 5841 S. Maryland Avenue, Box 420, Chicago, IL 60637-1470 (USA)
Concomitant Chemoradiotherapy as Investigational Therapy for Locoregionally Advanced Head and Neck Cancer Everett E. liked Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Ill. USA
Standard therapy for head and neck cancer has traditionally consisted of surgery and/or radiotherapy, reflecting the predominance of locoregional initial presentation. For patients with stage I and II disease either treatment modality used alone will usually result in cure. For patients with stage III and IV disease, however, cure is achieved in a minority of cases only. The cause of failure most commonly is locoregional recurrence, indicating the inability of both surgery and radiotherapy to effectively eradicate locoregionally advanced disease. A much smaller percentage ( < 20%) of patients will develop distant metastases. However, since autopsy series have shown systemic micrometastases in 50% and more of cases [ 1, 2], this distant failure rate could be expected to rise significantly if more effective locoregional therapy would not also address successfully the systemic tumor burden. Efforts at improving surgical and radiotherapeutic techniques, therefore, could result in better regional control but might not improve the overall outcome because of their inherent inability to address systemic disease. Chemotherapy, although systemically active, has not been shown to be curative in this disease [3]. As a single treatment modality it is used to palliate symptomatic patients with recurrent or metastatic disease. For previously untreated patients, it is being investigated for its potential use in multimodality therapy to enhance the cure rate achieved with surgery and/or radiotherapy. The sequential use of chemotherapy prior to or after standard local therapy has consisted in large part of pilot trials using 2-3 cycles of neoadjuvant chemotherapy [4-8]. These trials have shown high overall response rates and complete response (CR) rates of approximately 30%. It has also been shown that patients achieving CR have a good
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
' I wish to thank Susan Jarman for preparation of the manuscript.
Yokes
56
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
prognosis. However, survival data from these studies have mostly indicated that any improvement in overall survival is likely to be very limited in degree. Two trials conducted at our own institution using the combination of cisplatin and continuous infusion 5-FU with or without methotrexate resulted in median survival times of 22 and 20 months, respectively [7, 8]. This is not clearly superior to survival times reported following standard therapy only. Randomized trials have compared neoadjuvant chemotherapy followed by standard therapy to standard therapy alone. However, due to the choice of drugs, the number of cycles administered or the low number of patients enrolled, and the heterogeneity of head and neck cancer, most of these trials are inconclusive; they do not prove or disprove the question they were designed to answer [9]. One notable exception to this is the Veterans Administration Cooperative Study Program trial [ 10]. In this trial, 61 % of patients with advanced laryngeal cancer treated with 3 cycles of neoadjuvant cisplatin and 5-FU were rendered free of disease by chemotherapy and radiotherapy, and did not require laryngectomy. Overall survival, however, was not better than that of patients treated with surgery and radiotherapy but without chemotherapy. Neoadjuvant chemotherapy has, therefore, been shown to have a potential role in organ preservation; whether it can prolong survival remains unknown, but all studies so far suggest that its impact will be limited at best. More recent pilot studies have attempted to define regimens with higher activity, hoping to achieve CR rates exceeding 50% since patients achieving CR have been shown to have a better prognosis. Among these, the combination of cisplatin, 5-FU and leucovorin seems particularly promising, although survival rates have not been reported to date [ 11-13]. Concomitant chemoradiotherapy represents another approach to integrating chemotherapy into the therapy of locoregionally advanced head and neck cancer. Its rationale and possible mechanisms of interaction have recently been reviewed [ 14]. It is a particularly attractive approach to head and neck cancer. It allows one to focus therapy on the locoregional tumor where the bulk of malignant cells is largest, while also allowing for systemic therapy at an earlier time in the natural history of the disease when the number of therapy-resistant cells may be lower. Concomitant chemoradiotherapy has been actively pursued in clinical research for the last three decades. The first clinical trials addressing concomitant chemoradiotherapy for head and neck cancer were designed to not compromise administration of standard radiotherapy. Since standard radiotherapy by itself results in mild to moderate toxicity in many patients, it is difficult to add effective chemotherapy, i.e. high dose multiagent regimens. Instead, single agents were chosen and administered at lower doses several times during the
Chemotherapy for Locoregionally Advanced Head and Neck Cancer
57
Table 1. Selected randomized trials of concomitant chemoradiotherapy Author
Drug
Survival, % chemotherapy
Gupta et al.
methotrexate
Shanta and Krishnamurthi Fu et al.
bleomycin
Eschwege et al.
bleomycin
Lo et al.
5-FU
Weissberg
mitomycin C
Haselow
cisplatin
bleomycin
Disease-free survival, % control
43 35 (at 4 years, p = 0.075) 59 23 (at 5 years) 43 24 (at 3 years, p = 0.112) 22 23 (at 5 years) 32 14 (at 5 years, p < 0.05) 48 40 (at 5 years, p > 0.3) (no significant difference)
chemotherapy
control
72 17 (at 5 years) 31 15 (at 3 years, p = 0.024) 22 22 (at 5 years) 49 18 (at 2 years, p < 0.5) 75 55 (at 5 years, p < 0.01)
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
course of radiotherapy. Most active single agents have been studied in this fashion, and have been compared in randomized studies to standard radiotherapy. These have included methotrexate [ 15], bleomycin [ 16-18], cisplatin [19], 5-FU [20], hydroxyurea [21] and mitomycin [22]. Several of these studies are summarized in table 1. Improved disease-free survival has been achieved with bleomycin (although not consistently), mitomycin C, and by subgroup analysis with methotrexate. Improved overall survival has been reported for 5-FU and bleomycin, although the bleomycin trial [ 16] has been criticized for its use of nonstandardized radiotherapy, the nonstandarized route of administration of bleomycin and the lack of survival curves in the actual report. For cisplatin, improved disease-free or overall survival has not been demonstrated. This may be unexpected since cisplatin is a drug with single agent activity comparable to that of methotrexate and has been shown in experimental systems to enhance the activity of radiation [ 14]. It must be pointed out that the doses of cisplatin used in the randomized trial may have been suboptimal to achieve single agent activity or regional enhancement of radiotherapy. Pilot trials using high doses of cisplatin at an intermittent schedule look more promising and randomized studies investigating one of these cisplatin schedules are needed [23, 24]. Acute toxicities were reported to be increased with concomitant chemoradiotherapy in all of these trials. Chronic toxicities, however, do not appear to be significantly increased. While statistically significant, the degree of improvement in disease-free or overall survival is fairly small,
Yokes
58
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
with the great majority of patients not cured of their disease with either standard radiotherapy or radiotherapy with concomitant single agent chemotherapy. In addition, at least for bleomycin, positive trials as well as negative trials have been reported. Why then have none of these concomitant chemoradiotherapy regimens been adopted as standard therapy? The increase in acute toxicity per se does not justify omitting the use of more effective therapy. Cancer chemotherapy has repeatedly been shown to be more effective when used at higher doses (resulting in higher toxicity) and this is readily accepted if cure can be provided. In addition, more aggressive therapy with increased toxicity might also be accepted if surgery could be omitted resulting in organ preservation [25]. In the case of concomitant chemoradiotherapy for head and neck cancer, the difference in disease-free or overall survival may be insufficient to justify the more aggressive approach. The real meaning of these trials may be that they demonstrate the feasibility of the concept and prove that the theoretical potential for improved outcome does exist in clinical practice. These trials do not represent an endpoint but they do call for additional clinical investigation of this approach. During the last decade clinical trials have attempted to use chemotherapy in a more rational way with concomitant radiotherapy. Byfield et al. [26] studied the interaction of 5-FU and radiotherapy in experimental systems and concluded that 5-FU was most effective if present for prolonged periods of time (up to 48 h) following a dose of fractionated radiation and administered at maximally tolerated dose. Due to the short half-life of 5-FU in vivo, prolonged exposure is best achieved by a continuous infusion schedule. In head and neck cancer, clinical trials support an impression of increased activity of 5-FU if administered by that route. Byfield et al. [27] then conducted a clinical phase I trial in patients with stage III and IV head and neck cancer. In this trial, 5-FU was administered continuously over 5 days with concomitant daily radiotherapy followed by 9 days interruption of both chemotherapy and radiotherapy. The dose of 5-FU was increased in cohorts of patients. Mucositis was dose-limiting, which is consistent with the toxicity profile of infusional 5-FU and of radiotherapy. CR was achieved in 9 of 12 patients with Stage IV disease and one of two patients with Stage III disease. Patients treated at higher doses of 5-FU had a higher chance of achieving CR, which was consistent with previous experimental findings and supported the concept of treating patients at the maximally tolerated dose of 5-FU. Also of interest in this trial, protracted radiotherapy (administered over 5 days of every other week) did not appear to result in inferior outcome, as would be expected for radiotherapy administered as a single treatment modality; in the presence of 5-FU, protracted radiotherapy appeared to be feasible.
Chemotherapy for Locoregionally Advanced Head and Neck Cancer
59
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
Clinically, this finding was of significance since it seemed to allow for the interruption of radiotherapy in order to increase the feasibility of administering effective chemotherapy. Subsequent clinical trials expanded on these data and added additional active chemotherapy agents to the treatment schedule. Taylor et al. [28] added to the regimen cisplatin administered in a dose compatible with single agent activity (60 mg/m2 on day 1 of each chemoradiotherapy cycle). This was a logical choice since cisplatin is one of the most active single agents and has been shown to enhance radiotherapy in vitro. When last updated, their trial included 53 patients with advanced or recurrent disease, who were treated for seven cycles (over a 14-week period of time) to a total of 70 Gy. Fifty-five percent of patients achieved CR, and at a median follow-up of 51 months the median survival was 37 months. Only 15% of patients achieving CR developed local recurrence. These encouraging pilot data require confirmation and testing in a randomized trial. Adelstein et al. [29] also used the combination of cisplatin and 5-FU with concomitant radiotherapy. Fifty-four patients were treated with 30 Gy preoperatively (5-FU and cisplatin were given during week 1) followed by a 2-week treatment interruption and a second cycle of chemotherapy (without radiotherapy). Local therapy consisted of surgery (28 patients) and radiotherapy with additional chemotherapy. Fifty-one patients were considered clinically free of disease and the overall survival was 52%. Adelstein et al. [30] have also compared this chemoradiotherapy program to 3 cycles of induction chemotherapy with cisplatin and 5-FU. In 48 patients enrolled, the disease-free survival was statistically superior with concomitant chemoradiotherapy. For overall survival, a similar trend was seen, although statistical significance was not reached. Since two experimental arms are compared in this trial, the superior arm cannot be considered a `standard'; it can only be considered the superior experimental treatment. Furthermore, the low patients numbers accrued and the lack of a clear survival advantage render this trial, ultimately, inconclusive. Biochemical modulation of 5-FU as part of concomitant chemoradiotherapy has also been investigated. Clinically, this 5-FU modulation with leucovorin has been shown to result in superior survival in patients with metastatic colorectal cancer. This pathway can also be modulated with hydroxyurea (HU). HU is a ribonucleotide reductase inhibitor which will deplete the cell of dUMP, the natural substrate for thymidylate synthase. In 1986, we started to investigate the concomitant administration of 5-FU, HU and radiotherapy, because we hoped to identify an active regimen based on the potential for synergy between 5-FU and HU and their known potential to enhance radiotherapy [31]. In a phase I trial, we identified maximally tolerated doses of 5-FU at 800 mg/m2/day x 5 by
Yokes
60
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
continuous intravenous infusion (decreased to 600 mg/m2/day for mucositis > grade 3) and of HU at 1,000 mg administered orally every 12 h for a total of 11 doses, with one daily dose preceding the daily fraction of radiation by 2 h. The dose of HU was adjusted only for myelosuppression _> grade 3. Five days of concomitant chemoradiotherapy were followed by 9 days of no treatment analogous to the schedule by Byfield et al. [26]. Patients who had failed prior radiation were shown to readily achieve CR (6/15) or PR (8/15) and, thus, palliation of symptoms was much more readily achieved than when using chemotherapy alone [11]. This finding has since been confirmed by Guillot et al. [32]. However, the responses in our trial were not durable, possibly as a result of the less than optimal radiotherapy doses and field sizes (only 40-60 Gy were administered on this trial to previously irradiated patients). Of previously unirradiated patients, 12 of 17 evaluable patients achieved CR and 5 achieved PR. This represented a group of patients with a very unfavorable prognosis (distant metastases, failure to respond to neoadjuvant chemotherapy, poor renal and pulmonary functions). However, local recurrence as a cause of failure was seen in only 1 patient of these previously unirradiated patients [33]. We have investigated the further modulation of this regimen with leucovorin. While this trial has not been evaluated for survival due to insufficient follow-up time, the leucovorin greatly increased the severity of mucositis, necessitating 5-FU dose reduction to 300-400 mg/m2/day. We have also attempted to add continuous infusion cisplatin to this regimen, but found cumulative myelosuppression to be prohibitive, probably reflecting insufficient bone marrow recovery time between cycles. Due to these difficulties in adding leucovorin or cisplatin to the combination, we are currently focusing on using 5-FU, HU and concomitant radiotherapy without additional drugs in previously untreated patients. Wendt et al. [ 34] have also investigated 5-FU modulation with concomitant radiotherapy. Sixty-two patients were treated with a complex schedule of cisplatin, 5-FU and leurovorin with concomitant hyperfractionated radiotherapy. Forty-eight achieved clinical CR and 11 clinical PR 3 months after completion of therapy. The median survival was 52% at a median follow-up of 29 months. Other studies using concomitant chemoradiotherapy with 5-FU-based chemotherapy have been reported [35-37]. Another line of research has been the administration of chemotherapy and radiotherapy on a rapidly alternating schedule. This is supported by experimental data by Looney et al. [38]. Clinically, it may be difficult to administer one treatment modality at a time when toxicity from the other is peaking. A few investigators have reported on this approach, including O'Connor et al. [39] and Merlano et al. [40, 41]. Both groups of investigators have compared the rapidly alternating administration of therapy to
Chemotherapy for Locoregionally Advanced Head and Neck Cancer
61
neoadjuvant chemotherapy (with the same drugs) followed by standard radiotherapy [39, 40]. In both trials, the rapidly alternating treatment arm was superior, although statistical significance was only reached in the trial by Merlano et al. [40]. Single agent concomitant chemoradiotherapy has been shown to be superior to standard radiotherapy in randomized trials. Recent trials investigating combination chemotherapy (5-FU based) with concomitant radiotherapy have led to encouraging response and survival data. While additional pilot trials are needed to refine the regimens and doses, it may now be appropriate to compare one of these regimens to standard therapy.
References Kotwall C, Sako K, Razack MS, et al: Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg 1987;1154:439. 2 Zbaeren P, Lehmann W: Frequency and sites of distant metastases in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 1987;113:762-674. 3 likes ΕΕ: Head and neck cancer, in Perry MC (ed): Chemotherapy Source Book, Baltimore, Williams & Wilkins, in press. 4 Hong WK, Shapshay SM, Bhutani R, et al: Induction chemotherapy in advanced squamous head and neck carcinoma with high-dose cis-platinum απd bleomycin infusion. Cancer 1979;44:19-25. 5 Ervin TJ, Clark JR, Weichselbaum RR, 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. 6 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. 7 Vokes ΕΕ, Mick R, Lester EP, Panje WR, Weichselbaum RR: Cisplatin and 5fluorouracil does not yield long-term benefit in locally advanced head and neck cancer: Results from a single institution. J Clin Oncol 1991;9:1376-1384. 8 likes ΕΕ, Moran WJ, Mick R, Weichselbaum RR, Panje WR: Neoadjuvant and adjuvant methotrexate, cisplatin, and fluorouracil in multimodal therapy of head and neck cancer. J Clin mcii 1989;7:838-845. 9 Forastiere AA: Randomized trials of induction chemotherapy: A critical review. Hematol/Oncol Clin N Am 1991;5:725-736. 10 The Department of Veterans Affairs Laryngeal Cancer Study Group: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. New Engl J Med 1991;324:1685-1690. 11 likes ΕΕ, Choi ΚΕ, Schilsky RL, et al: Cisplatin, fluorouracil, and high-dose leucovorin for recurrent or metastatic head and neck cancer. J Clin Oncol 1988;6:618626. 12 likes ΕΕ, Schilsky RL, Weichselbaum RR, et al: Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for locally advanced head απd neck cancer: A clinical and pharmacologic analysis. J Clin Oncol 1990;8:241-247. Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
1
Yokes
62
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
13 Dreyfuss AI, Clark JR, Wright JE, Norris CM Jr, Busse PM, Lucarini JW, Fallon BG, Casey D, Andersen JW, Klein R, Rosowsky A, Miller D, Frei E III: Continuous infusion high-dose leucovorin with 5-fluorοuracil and cisplatin for untreated stage IV carcinoma of the head and neck. Ann Intern Med 1990;112:167-172. 14 likes EE and Weichselbaum RR: Concomitant chemoradiotherapy: Rationale and clinical experience in patients with solid tumors. J Clin Oncol 1990;8:911-934. 15 Gupta 1K, Pointon RCS, Wilkinson PM: A randomised clinical trial to contrast radiotherapy with radiotherapy and methotrexate given sychronously in head and neck cancer. Clin Radiol 1987;38:575-581. 16 Shanty V, Krishnamurthi S: Combined bleomycín and radiotherapy in oral cancer. Clin Radiol 1980;31:6l7-620. 17 Fu ΚΚ, Phillips TL, Silverberg IV, et al: Combined radiotherapy and chemotherapy with bleomycín and methotrexate for advanced inoperable head and neck cancer: Update of a Northern California Oncology group randomized trial. J Clin Oncol 1987;5:1410-1418. I8 Eschwege F, Sancho-Gamier Η, Gerard JP, et al: Ten-year results of randomized trial comparing radiotherapy and concomitant bleomycín to radiotherapy alone in epidermoid carcinomas of the oropharynx: Experience of the European Organization for Research and Treatment of Cancer. NCI Monogr 1988;6:275-278. 19 Haselove RE, Warshaw MG, Oken MM, et al: Radiation alone versus radiation plus weekly low-dose cis-platinum in unresectable cancer of the head and neck; in Fee WE Jr, Goepfert Η, Johns ME, et al (eds): Head and Neck Cancer. Toronto/Philadelphia, Decker 1990, vol 2, pp 279-281. 20 Lo TC, Wiley AL Jr., Ansfield FJ, et al: Combined radiation therapy and 5-fluorοuracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: A randomized study. Am J Roentgenol 1976;126:229-235. Richards GJ, Chambers RG: Hydroxyurea: A radiosensitizer in the treatment of neoplasms 21 of the head and neck. Am J Roentgenol Radium Nucl Med 1969;55:555-565. 22 Weissberg JB, Son YH, Papac RJ, et al: Randomized clinical trial of mitomycin-C as an adjunct to radiotherapy in head and neck cancer. Int J Radiat Oncol Biol Phys 1989;17:3-9. 23 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 1990;66:1861 —1868. 24 Wheeler R, Salter M, Stephens S, et al: Simultaneous therapy with high-dose cisplatin and radiation for unresectable squamous cell cancer of the head and neck: A phase I—II study. NCI Monogr 1988;6:339-341. 25 McNeil BJ, Weichselbaum RR, Paoker S: Speech and survival: Tradeoffs between quality and quantity of life in laryngeal cancer. N Engl J Med 1981;305:982-987. Byfield JE, Calabro-Jones P, Klisak I, et al: Pharmacologic requirements for obtaining 26 sensitization of human tumor cells in vitro to combined 5-fluorouracíl or ftorafur and x-rays. Int J Radiat Oncol Bíol Phys 1982;8:1923-1933. Byfield JE, Sharp TR, Frankel SS, et al: Phase I and II trial of five-day infused 27 5-fluorouracíl and radiation in advanced cancer of the head and neck. J Clin Oncol 1984;2:406-413. 28 Taylor SG IV, Murthy AK, Caldarelli DD, et al: Combined simultaneous cisplatin/fluorouracil chemotherapy and split course radiation in head and neck cancer. J Clin Oncol 1989;7:846-856. 29 Adelstein DJ, Sharah VM, Earle AS, et al: Long-term results after chemoradiotherapy for locally confined squamous-cell head and neck cancer. Am J Clin Oncol 1990;13:440447.
Chemotherapy for Locoregionally Advanced Head and Neck Cancer
63
30 Adelstein DJ, Sharan VM, Earle AS, et al: Simultaneous versus sequential combined technique therapy for squamous cell head and neck cancer. Cancer 1990;65:1685-1691. 31 Vokes EE, Panic WR, Schilsky RL, et al: Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head απd neck cancer: A phase I—II Study. J Clin Oncol 1989,7:761-768. 32 Guillot T, Wibault P, Cvitkovic E, Luboinski Β, Tellez-Bernal E, Eschwege F, Schwaab G, Armand JP: Treatment of `favorable' recurrent head απd neck squamous cell with 5 days on/9 days off simultaneous chemoradiotherapy (meeting abstract). Proc Am Soc Clin Oncol 1990;9:Α684. 33 Haraf DJ, Vokes EE, Panic WR, Weichselbaum RR; Survival and analysis of failure following hydroxyurea, 5-fluorouracil απd concomitant radiation therapy in poor prognosis head and neck cancer. Am J Clin Oncol. 1991;14:419-426. 34 Wendt TG, Hartenstein RC, Wustrow TPU, et al: Cisplatin, fluorouracil with leucovorin calcium enhancement, απd synchronous accelerated radiotherapy in the management of locally advanced head and neck cancer: A phase II study. J Clin Oncol 1989;7:471-476. 35 Bo11a M, Borgel J, Guenoun A, Junien-Lavillauroy C, Dionet C, Vrousos C: Chemotherapy with low doses of radiation followed by definitive radiotherapy for advanced unresectable carcinoma of the head and neck. NCI Monogr 1988;6:357-359. 36 Keane TJ, Harwood AR, Beale FA, Cummings BJ, Payne DG, et al: A pilot study of mitomyciπ-C/5-fluorouracil infusion combined with split course radiation therapy for carcinomas of the larynx and hypopharynx. J Otolaryngol 1986;15:286-288. 37 Stryker JA, Harvey HA, Houck JR, Manders EK, Bradfield JJ: Advanced head and neck cancer: Low-dose, split-course radiation therapy απd simultaneous infusion of 5-fluorouracil and cisplatin. Radiology 1990;176:567-571. 38 Looney WB: Special lecture: Alternating chemotherapy and radiotherapy. NCI Monogr 1988;6:85-94. 39 O'Connor D, Clifford P, Edwards WG, et al: Long-term results of IBM and radiotherapy in advanced head and neck cancer. Int J Radiat Oncol Biοl Phys 1982;8:1525-1531. 40 Merlano M, Rosso R, Sertoli MR, et al: Sequential versus alternating chemotherapy απd radiotherapy in stage III—IV squamous cell carcinoma of the head and neck: A phase III study. J Clin Oncol 1988;6:627-632. 41 Merlano M, Grimaldi A, Benasso M, Bacigalupo A, Toma S, Scarpati D, Corvo R, Santelli A, Garaventa G, Rosso R: Alternating cisplatin-5-fluorouracil απd radiotherapy in head and neck cancer. Am J Clin Oncol 1988;11:538-542.
Downloaded by: Université de Paris 193.51.85.197 - 2/8/2020 7:36:45 PM
Everett E. Vokes, MD, Associate Professor of Medicine απd Radiation and Cellular Oncology, Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, 5841 S. Maryland Avenue, Box 420, Chicago, IL 60637-1470 (USA)
