Until now, the combination of radical surgery and postoperative radiation therapy has usually been considered standard treatment for advanced but resectable oropharyngeal carcinoma, and conventional radiation therapy alone also was standard for advanced unresectable oropharyngeal carcinoma. Although surgical resection and postoperative radiation therapy achieved good results in terms of survival for advanced but resectable oropharyngeal carcinoma, conventional radiation therapy alone gave poor results of 10% to 20% survival at 5 years for advanced resectable and unresectable cancer. 1,2 Radical surgery may require total laryngectomy to avoid aspiration and regional resection of the base of the tongue in many patients with oropharyngeal carcinoma, and therefore might result in more significant impairment of speech and swallowing as well as cosmesis than with radiation therapy alone, 3,4 even if reconstruction using the free-flapping technique is performed. Considering this potential morbidity, some patients may select conventional radiation therapy alone, although the results of radiation therapy alone are suboptimal. 5 It is very important to develop a new approach for obtaining long survival and preservation of organ and function in the treatment of oropharyngeal carcinoma.
One such approach is the combination of radiation therapy and chemotherapy using cisplatin (CDDP). CDDP is active against head and neck cancer, and its toxicity does not overlap with that of radiation therapy. 6 Also, CDDP is a potent radiosensitizer. 7 Douple and Richmond 8 showed that CDDP radiosensitizes tissues by inhibiting the repair of potentially lethal damage. Furthermore, its possible mechanism of action includes inhibition of sublethal damage repair, selective radiosensitization of hypoxic cells, and reduction in tumor burden leading to an improved tumor blood supply, reoxygenation, and redistribution of cells toward a more sensitive cell cycle phase. 9
Given the poor results of radiation therapy alone, several pilot studies have explored the efficacy of induction chemotherapy using CDDP followed by conventional radiation therapy, 10–12 or concurrent chemoradiotherapy for advanced head and neck cancer. 13,14 These protocols were feasible, and some reports have demonstrated favorable results in regard to local control and/or overall survival comparable those with standard surgery followed by radiation therapy. However, reports concentrating on patients with tumors of the oropharynx are few. Pfister et al., 3 in a study on induction chemotherapy using CDDP followed by radiation therapy in patients with advanced oropharyngeal carcinoma, reported that 5-year overall survival was 41% and that organ- and function-preservation rates were good.
The role of chemotherapy and optimal treatment schedules still remains unclear for oropharyngeal carcinoma. We used concurrent chemoradiotherapy using weekly cisplatin for preservation of organ and function in patients with advanced squamous cell carcinoma of the oropharynx. We herein report our results.
PATIENTS AND METHODS
Between January 1986 and June 1998, 31 patients who were referred for definitive radiation therapy from the Department of Otorhinolaryngology to the Department of Radiology in Kyoto University Hospital were retrospectively analyzed. Twenty-five patients were male and six were female. The median age of patients was 61 years old, with a range of 35 to 83 years. All patients had squamous cell carcinoma with pathologic proof. Patient characteristics are shown in Table 1. Six patients underwent hemilateral radical neck dissection after the completion of radiation therapy, with a further one before radiation therapy. Another patient with N3 lymph node enlargement was treated with five sessions of local hyperthermia for the N3 lymph node during radiation therapy. Two patients had a history of esophageal cancer. Primary esophageal cancer and lung cancer was detected during follow-up periods in one patient each. Also, one patient had a newly diagnosed primary buccal carcinoma and esophageal cancer during follow-up periods. The potential and median follow-up periods were 18 and 26 months, respectively.
Twenty-eight patients received conventional radiation therapy. The total dose of these patients ranged from 60.0 Gy to 74.0 Gy, with a median dose of 66 Gy in a daily fraction of 2 Gy 5 days a week. However, radiation therapy was given to three patients using a hyperfractionation technique with a range from 65.6 Gy to 74.4 Gy in a fraction of 1.2 Gy twice a day. Radiation therapy was given using opposed lateral ports including the primary tumor and regional lymph nodes in the upper neck area, with matched anterior–posterior supraclavicular and lower neck fields using a shielding block for the spinal cord. Seven patients received upper neck radiation alone, whereas 24 patients received whole neck irradiation; 19 patients were treated simultaneously after 1993 and 5 patients were treated sequentially before 1993. Whole neck irradiation was simultaneously given to all patients after 1993. The spinal cord was excluded at a usual dose of 46 Gy. The overall treatment time (OTT) ranged from 39 to 113 days, with a median of 50 days. Eight patients needed more than 8 weeks for the radiation therapy because of the sequential schedule or healing of mucositis. The median dose to lower neck area was prophylactically 50 Gy with a range from 42 Gy to 56 Gy. No brachytherapy was used.
Twenty patients received intravenous chemotherapy using cisplatin (CDDP) for 2 hours. After 1992, CDDP was concurrently administered in principle, whenever consenting patients had adequate hepatic, renal, and bone marrow functions without any serious disease. Two patients received carboplatin rather than CDDP because of the renal toxicity of CDDP. Another patient treated before 1992 underwent chemotherapy of CDDP combined with pepleomycin. Fourteen patients received concurrent weekly chemotherapy using 50 mg/d CDDP alone three to seven times during radiation therapy.
Statistics and Adverse Effects Evaluation
The cause-specific survival (CSS) rate was calculated and plotted from the first date of starting radiation therapy using the Kaplan-Meier method with significance compared by the log-rank test. Two patients who died of intercurrent disease were censored from analysis. Four patients were considered lost to follow-up. They were also censored from analysis at that point. Acute and late adverse effects were evaluated according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer classification. 15
Among the 31 patients, 28 patients obtained complete remission of the primary tumor on local findings by physical examination. Six of these 28 patients showed a residual neck mass, and therefore, underwent hemilateral radical neck dissection after radiation therapy. They also obtained complete remission of neck lymph node metastasis. Locoregional recurrences were detected 3 to 13 months after radiation therapy in 7 of the 28 patients with complete remission: 4 in the primary site and 3 in regional lymph nodes. The 2-year local control rate was 65%. In the other two patients with complete remission of their primary tumor, distant metastasis developed: liver metastasis 2 months after radiation therapy and lung metastasis 15 months after radiation therapy.
The 5-year overall survival rate and CSS rate were 55% and 62%, respectively.
The 3-year CSS rates were 78% for the patients with stage I-III and 52% for stage IV in Union International Contre le Cancer 1997 classification system, and those of the patients with N0 to N1 and N2 to N3 were 75% and 46%, respectively. Figure 1 shows survival curves according to the clinical stage and N factor. The difference between survival curves was not significant.
The 3-year CSS rate of the 25 patients with lateral or superior wall origin was 71%, whereas that of the 6 patients with anterior or posterior wall origin was 20%. The difference in survival curves according to primary site was significant (Fig. 2, p < 0.05).
The median of OTT in patients receiving chemotherapy was 50 days, and that of patients treated with radiation alone was 62 days. Figure 3 shows survival curves according to the OTT. The 3-year CSS rates were 70% and 76%, respectively, for the patients receiving chemotherapy with less than or more than 50 days of OTT, and 67% and 33% for the patients treated with radiation alone with less than or more than 62 days of OTT. There was no impact of OTT on the CSS rates based on OTT relative to the median (<50 versus ≥50, and <62 versus ≥62).
The 3-year CSS rates of patients treated with whole neck irradiation and upper neck alone irradiation were 53% and 85%, respectively. The difference in survival curves according to radiation fields was not significant.
The 3-year CSS rate of patients who received concurrent weekly chemotherapy using CDDP of 50 mg/d at least three times was 83%, whereas that of the remaining patients was 53% (Fig. 4, p < 0.05).
In 14 patients treated with concurrent chemoradiotherapy, all patients complained of grade II acute mucositis and moderate odynophagia. However, no patient needed a radiation interval of more than 1 week. No grade III hematologic adverse effects were observed. Regarding late complications, grade II xerostomia was seen in all patients. No osteoradionecrosis of the mandible or cartilage necrosis were noted.
The trials that compared various treatment modalities included small numbers of patients with oropharyngeal carcinoma and reached no definitive conclusions regarding the best treatment strategy. 16 In the treatment of advanced head and neck cancers, randomized trials have failed to show a significant survival advantage for patients receiving induction chemotherapy over that obtained with surgery and/or radiation therapy alone. 17 On the other hand, randomized trials that compared concurrent or alternating chemoradiotherapy with radiation therapy alone demonstrated an improvement in survival with chemoradiotherapy, 6,18 although another trial showed a negative impact on survival. 19 Other randomized trials that compared induction chemotherapy versus concurrent or alternating chemoradiotherapy have shown the improvement of the locoregional control rate with the chemoradiotherapy, but these trials have failed to demonstrate a survival benefit of the chemoradiotherapy. 20,21Table 2 shows details of these randomized trials. Radiation therapy was administered in a split course for the chemoradiotherapy, 19–21 and CDDP was not used. 20 These might be the reasons that the concurrent therapy had no impact on survival.
A meta-analysis clearly showed advantages for the combination of chemotherapy and radiation therapy as compared with radiation therapy alone in terms of locoregional control. 22 In patients receiving concurrent chemotherapy, a significant improvement in survival was also demonstrated. The present study reported the sufficient local control and CSS rates. The use of chemotherapy concurrently with radiation therapy is thought to be more reasonable to improve not only the local control rate but also survival. However, it still remains unclear which chemotherapeutic agent and schedule would be best in the combination with radiation therapy: CDDP or taxoids, weekly bolus chemotherapy or protracted infusion chemotherapy. Brockstein et al. 23 showed the benefit of paclitaxel in the phase I study of concurrent chemoradiotherapy for poor-prognosis head and neck cancer. Kyriazis et al. 24 suggested that the antitumor effects were greater when CDDP was administered by continuous infusion because it may be a cell-cycle–phase-specific drug with preferential action on the G1 phase of the cell cycle. It is essential to perform randomized trials to solve these questions.
Another approach to increase the radiation effect is to alter fractionation. Twice a day continuous radiotherapy with no acceleration is considered by many investigators to be a promising modality for irradiation of advanced oropharyngeal cancer, 25,26 although this has not been demonstrated clearly in the survival results of randomized trials. Table 3 shows the results of randomized trials altering fractionation. Pinto et al. 25 reported the significantly higher overall survival rate in patients treated with hyperfractionated radiation therapy, but Horiot et al. 26 demonstrated in the treatment of T2/3N0/1 oropharyngeal carcinoma excluding the base of the tongue that only a trend toward improvement in overall survival with treatment in the hyperfractionation arm was observed. For accelerated fractionation, Horiot et al. 27 failed to show a significant difference between survival curves of patients with advanced head and neck cancer treated with accelerated fractionation and those treated with conventional radiotherapy, although the difference in specific survival curves was borderline significant. Also, continuous, hyperfractionated, accelerated radiotherapy of 54 Gy had no impact on survival in patients with head and neck cancer. 28 The reason for these failures of accelerated fractionation might be that many patients with T1/2 or N0 were included in these trials. The results of the present study were more favorable than these results with low acute adverse effect rates. To obtain higher local control rates, the combination of concurrent chemotherapy with hyperfractionated radiation therapy may be effective. Bensadoun et al. 29 reported that the hyperfractionated radiation therapy of more than 75 Gy combined with CDDP and 5-fluorouracil resulted in 54% for the 2-year overall survival and 72% for specific survival at 20 months. Wendt et al. 30 demonstrated that the 3-year overall survival rate was 48% with concurrent chemotherapy-accelerated radiation therapy, and Jeremic et al. 31 reported that hyperfractionation and concurrent low-dose daily CDDP offered significantly higher survival rates of 68% at 2 years and 46% at 5 years (Table 3). Further investigations regarding these protocols are needed.
Harrison et al. 4 concluded that radiation therapy provided a better performance status than surgery for cancer of the base of the tongue. Our results confirmed this finding. In the present study, the larynx and base of the tongue were preserved in all surviving patients. Although diet was slightly restricted because of xerostomia, all spoke clearly and maintained daily activities. Quality of life in patients treated with chemoradiotherapy was excellent.
It is well known that prognosis correlates with the primary site of tumors of the oropharynx. Our data confirmed these findings, although the number of anterior/posterior tumors was small. Regarding tumors of the base of the tongue, many studies in which interstitial implantation was used as a final boost after external beam irradiation revealed no improvement in local control compared with results using continuous course external irradiation alone. 2 Combined radiation therapy and have not produced results better than those obtained with radiation therapy alone for carcinoma of the posterior pharyngeal wall. 32
In the treatment of carcinoma of the oropharynx, the OTT was a very important prognostic factor. 33 The difference in survival curves according to OTT between patients treated with radiation alone did not reach a significant level, possibly because of the small number of patients, in our study. Conversely, there was no difference of OTT in patients treated with radiation therapy combined with chemotherapy. The OTT might not be a prognostic factor if chemotherapy is used.
In conclusion, definitive radiation therapy of 66 Gy in a fraction of 2 Gy combined with concurrent weekly chemotherapy using cisplatin of 50 mg/d at least three times for oropharyngeal carcinoma appeared promis-ing. A randomized trial is warranted.
1. Fu KK, Cooper JS, Marcial VA, et al. Evolution of the radiation therapy
Oncology Group clinical trials for head and neck cancer. Int J Radiat Oncol Biol Phys 1996; 35: 425–38.
2. Fein DA, Lee WR, Amos WR, et al. Oropharyngeal carcinoma
treated with radiotherapy: a 30-year experience. Int J Radiat Oncol Biol Phys 1996; 34: 289–96.
3. Pfister DG, Harrison LB, Strong EW, et al. Organ-function preservation in advanced oropharynx cancer: results with induction chemotherapy
and radiation. J Clin Oncol 1995; 13: 671–80.
4. Harrison LB, Zelefsky MJ, Armstrong JG, et al. Performance status after treatment for squamous cell cancer of the base of tongue–a comparison of primary radiation therapy
versus primary surgery. Int J Radiat Oncol Biol Phys 1994; 30: 953–7.
5. McNeil BJ, Weichselbaum RR, Pauker SG. Speech and survival: tradeoffs between quality and quantity of life in laryngeal cancer. N Engl J Med 1981; 305: 982–7.
6. Jeremic B, Shibamoto Y, Stanisavljevic B, et al. Radiation therapy
alone or with concurrent low-dose daily either cisplatin
or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: a prospective randomized trial. Radiother Oncol 1997; 43: 29–37.
7. Dewit L. Combined treatment of radiation and cisdiamminedichloroplatinum (II): a review of experimental and clinical data. Int J Radiat Oncol Biol Phys 1987; 13: 403–26.
8. Douple EB, Richmond RC. Platinum complexes as radiosensitizers of hypoxic mammalian cells. Br J Cancer Suppl 1978; 37: 98–102.
9. Fu KK, Phillips TL. Biologic rationale of combined radiotherapy and chemotherapy
. Hematol Oncol Clin North Am 1991; 5: 725–36.
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. N Engl J Med 1991; 324: 1685–90.
11. Urba SG, Forastiere AA, Wolf GT, et al. Intensive induction chemotherapy
and radiation for organ preservation in patients with advanced resectable head and neck carcinoma. J Clin Oncol 1994; 12: 946–53.
12. Khan A, Spiro JD, Dowsett R, et al. Sequential chemotherapy
and radiotherapy for organ preservation in advanced resectable nonlaryngeal head and neck cancer. Am J Clin Oncol 1999; 22: 403–7.
13. Taylor SG IV, Murthy AK, Caldarelli DD, et al. Combined simultaneous cisplatin
and split course radiation in head and neck cancer. J Clin Oncol 1989; 7: 846–56.
14. Glicksman AS, Slotman G, Doolittle C III, Clark J, Koness J, Coachman N, Posner M, DeRosa E, Wanebo H. Concurrent cis-platinum and radiation with or without surgery for advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1994; 30: 1043–50.
15. Perez CA, Brady LW. Overview. In: Perez CA, Brady LW, editors. Principles and practice of radiation oncology. 2nd ed. Philadelphia: JB Lippincott, 1992: 51—5.
16. Kramer S, Gelber RD, Snow JB, et al. Combined radiation therapy
and surgery in the management of advanced head and neck cancer: final report of study 73–03 of the Radiation Therapy
Oncology Group. Head Neck Surg 1987; 10: 19–30.
17. Vokes EE, Weichselbaum RR, Lipman SM, et al. Head and neck cancer. N Engl J Med 1993; 328: 184–93.
18. Merlano M, Vitale V, Rosso R, et al. Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy
and radiotherapy. N Engl J Med 1992; 327: 1115–21.
19. Keane TJ, Cummings BJ, O’Sullivan B, et al. A randomized trial of radiation therapy
compared to split course radiation therapy
combined with mitomycin-C and 5-fluorouracil as initial treatment for advanced laryngeal and hypopharyngeal squamous carcinoma. Int J Radiat Oncol Biol Phys 1993; 25: 613–8.
20. Adelstein DJ, Sharan VM, Earle AS, et al. Simultaneous versus sequential combined technique therapy for squamous cell head and neck cancer. Cancer 1990; 65: 1685–91.
21. Merlano M, Rosso R, Sertoli MR, et al. Sequential versus alternating chemotherapy
and radiotherapy in stage III-IV squamous cell carcinoma of the head and neck: a phase III study. J Clin Oncol 1988; 6: 627–32.
22. El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy
in the management of squamous cell carcinoma of the head and neck region. A meta-analysis of prospective and randomized trials. J Clin Oncol 1996; 14: 838–47.
23. Brockstein B, Haraf DJ, Stenson K, et al. Phase I study of concomitant chemo-radiotherapy with paclitaxel, fluorouracil, and hydroxyurea with granulocyte colony-stimulating factor support for patients with poor-prognosis cancer of the head and neck. J Clin Oncol 1998; 16: 735–44.
24. Kyriazis AP, Yagoda A, Kereiakes JG, et al. Experimental studies on the radiation-modifying effect of cis-diamminedichloroplatinum II (DDP) in human bladder transitional cell carcinomas grown in nude mice. Cancer 1983; 52: 452–7.
25. Pinto LH, Canary PC, Araujo CM, et al. Prospective randomized trial comparing hyperfractionated versus conventional radiotherapy in stages III and IV oropharyngeal carcinoma
. Int J Radiat Oncol Biol Phys 1991; 21: 557–62.
26. Horiot JC, Le Fur R, N’Guyen T, et al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma
: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 1992; 25: 231–41.
27. Horiot JC, Bontemps P, van den Bogaert W, et al. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial. Radiother Oncol 1997; 44: 111–21.
28. Dische S, Saunders M, Barrett A, et al. A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997; 44: 123–36.
29. Bensadoun RJ, Etienne MC, Dassonville O, et al. Concomitant b.i.d. radiotherapy and chemotherapy
and 5-fluorouracil in unresectable squamous-cell carcinoma of the pharynx: clinical and pharmacological data of a French multicenter phase II study. Int J Radiat Oncol Biol Phys 1998; 42: 237–45.
30. Wendt TG, Grabenbauer GG, Rodel CM, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998; 16: 1318–24.
31. Jeremic B, Shibamoto Y, Milicic B, et al. Hyperfractionated radiation therapy
with or without concurrent low-dose cisplatin
in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 2000; 18: 1458–64.
32. Meoz-Mendez RT, Fletcher GH, Guillamondegui OM, et al. Analysis of the results of irradiation in the treatment of squamous cell carcinomas of the pharyngeal walls. Int J Radiat Oncol Biol Phys 1978; 4: 579–85.
33. Benzen SM, Johansen LV, Overgaard J, et al. Clinical radiobiology of squamous cell carcinoma of the oropharynx. Int J Radiat Oncol Biol Phys 1991; 20: 1197–206.