Neoadjuvant chemotherapy and radiotherapy for the treatment of advanced hypopharyngeal carcinoma

Neoadjuvant Chemotherapy and Radiotherapy for the Treatment of Advanced Hypopharyngeal Carcinoma Kwang Hymn Kim, MD, Myung-Whnn Sung, MD, Chae-Seo Rhee, MD, Ja Won Koo, MD, Tae Yong Koh, MD, Dong Wook Lee, MD, Due Seog Heo, MD, and Churn I1 Park, MD Purpose: To evaluate the efficacy of the neoadjuvant chemotherapy and radiation therapy in treatment of patients with advanced hypopharyngeal cancer, which is notorious for its poor prognosis and severe surgical morbidity with functional deficits. Materials and Methods: Medical records of 62 patients with squamous cell carcinoma of the hypopharynx, Stage III or IV (AJCC, 1992), were retrospectively reviewed. Results: Neoadjuvant chemotherapy showed an overall response rate of 87% and a complete remission (CR) rate was 67% following chemotherapy and radiation therapy. The patients who did not show CR after chemotherapy had a high likelihood of treatment failure, even though they achieved CR following subsequent radiotherapy. Thirteen of 30 patients were able to preserve their larynges for more than 3 years by chemotherapy and radiation. Conclusion: This approach appeared to be as effective as radical surgery with postoperative radiation therapy without comprising survival. To improve the cure rates, we need to develop better strategies to increase CR rates with chemotherapy and determine the best treatment option for patients who are partially or nonresponsive to chemotherapy. Copyright 0 1998 by W.B. Saunders Company.

For patients with advanced squamous cell carcinoma of the hypopharynx, radical surgery and postoperative radiation therapy has been used as a standard treatment. However, about 50% of the patients showed recurrence within the first 2 years of therapy, and 5year survival rates were reported to be between 10% and 50%.lm3 For hypopharyngeal cancer, surgical morbidity is especially high because of wide excision including the larynx, pharynx, and sometimes cervical esophagus, and additional reconstruction procedures performed in many patients. The patients who are fortunate enough to survive their cancer still have lifelong cosmetic deformities and func-

From the Departments of Otolaryngology, Medical Oncology, and Therapeutic Radiology, Seoul National University, College of Medicine, Seoul, Korea. Presented at the Fourth International Conference on Head and Neck Cancer, Toronto, Canada, July 27August 1,1996. Address reprint requests to Kwang Hyun Kim, MD, Department of Otolaryngology, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul, Korea 11 o-744. Copyright o 1998 by W.B. Saunders Company 0196-0709/98/l 901-0008$8.00/O 40

tional impairments. Even though the patients can avoid the surgical morbidity and functional deficit by irradiation alone, the overall cure rate ranges only from 0% to 20%.4 Recently, chemotherapy has widened its application in the treatment of head and neck cancer. Neoadjuvant chemotherapy combined with subsequent radiation therapy emerged as one of the possible treatment options for advanced, but resectable head and neck cancer5q7 For patients with advanced laryngeal cancer, the several multiinstitutional studies showed that this approach could be an alternative approach with the advantages of avoiding surgery and achieving organ preservation in successful cases. The survival rates were comparable with those of standard surgery and postoperative radiation.7-g Neoadjuvant chemotherapy combined with radiation might have more application for patients with hypopharyngeal cancer, who usually face severe surgical morbidity and long hospitalization, if the survival rate is acceptable. However, most reports on the role of neoadjuvant chemotherapy and radiation in head and neck cancer were based on data from

American Journal of Otolatyngology, Vol 19, No 1 (January-February),

1998: pp 40-44

ADVANCED

HYPOPHARYNGEAL

heterogeneous patients, which included cancer of many different anatomic sites, and very few comprehensive data are available for hypopharynx carcinoma so far. Because of the oppressive surgical morbidity and dismal cure rate of hypopharyngeal cancer, we analyzed the treatment results of patients with this particular cancer to evaluate the efficacy of neoadjuvant chemotherapy and subsequent radiation therapy. MATERIALS

AND METHODS

The authors retrospectively records of 62 patients with

noma of the hypopharynx,

41

CARCINOMA

reviewed medical squamous cell carci-

Stage III or IV (AJCC,

1992), treated in Seoul National University Hospital from March 1987 to December 1995. Patients who did not complete at least one of the planned modalities (ie, chemotherapy, surgery, or radiation, or patients with distant metastasis at diagnosis) were excluded. There were 60 men and 2 women. The average age was 61, with a range of 30 to 80 years. Duration of follow-up was from 2 to 75 months (median, 26 months). All patients were stage III (n = 8) or IV (n = 54) without any evidence of distant metastasis at the time of initial treatment. The sites of primary tumor were as follows: pyriform sinus (52), posterior pharyngeal wall, (7) and postcricoid area (3). The 62 patients were initially treated with one of three modalities: chemotherapy (n = 37), surgery (n = 18), or radiation (n = 7). The patients who underwent radiation only were excluded from detailed analysis because of their small number. In the surgery group, 17 patients completed postoperative radiation. Neoadjuvant chemotherapy consisted of cisplatin, 100 mg/m2 with intravenous bolus on day one, followed by 5-fluorouracil(5-FU), 1,000 mg/m2 with continuous infusion for 24 hours, from day 1 through day 5. Courses were repeated every 3 weeks for a total of three cycles. Radiation therapy was delivered to the primary site and neck for patients initially treated with chemotherapy with a total dose of 65 to 70 Gy. For surgical patients, a total dose of 60 Gy was irradiated to the surgical bed. Two experienced head and neck surgeons examined patients before and after each treatment and assessed the response. Following the third cycle of chemotherapy and completion of radiotherapy, the response was evaluated by physical examination and computed tomography scans. A complete response (CR) was defined as no visible and palpable disease. A partial response (PR) was defined as more than 50% decrease in size compared with the initial measurements. No response (NR) was defined as stationary or progressive disease. We compared the treatment results of neoadjuvant chemotherapy with radiation therapy (n = 30),

with those postoperative

of conventional radical surgery with radiation therapy (n = 17). Survival

rates were calculated using the life-table method and the log-rank

test.

RESULTS Thirty-seven patients were initially treated with chemotherapy. Overview of treatment and survival status in this group is shown in Fig 1. After two or three cycles of chemotherapy, 9 patients (24.3%) achieved CR in the primary site and neck nodes, and 23 (62.2%) had PR. After subsequent radiation therapy, a total of 20 patients showed CR (67%; * in Fig 1). All patients in the CR group (n = 9), received radiation therapy after chemotherapy as scheduled. Seven patients showed no evidence of disease (NED) over 3 years, and one patient had a nodal recurrence after 15 months but was successfully treated with a salvage neck dissection. He was disease-free for over 3 years with his larynx preserved. Among patients with PR after chemotherapy (n = 23), 18 patients underwent subsequent radiation therapy with 10 (56%) achieving CR. Four of 10 showed NED over 3 years, and another four had a recurrence. Three patients received salvage treatment for recurrence at primary site, and two of those had NED over 3 years. All patients (n = 8) who failed to achieve CR after radiation resulted in unsuccessful

Fig 1. Overview of treatments and survival status. Boxes at the bottom row describe the status of the patients after follow-up of 3 years. Asterisk denotes CR after chemotherapy plus radiation therapy. Plus sign indicates patients who preserved their larynges over 3 years without disease. Abbreviations: NED, no evidence of disease; NT, no further treatment; CR, complete remission; PR, partial remission; NR, no response; C, chemotherapy; OP, operation; RT, radiation therapy; Ret, recurrence.

KIM

42

outcomes. After 3 years, only 6 of 18 partial responders to chemotherapy showed NED. Three patients who underwent surgery, because of PR with initial neoadjuvant chemotherapy, died of distant metastases. The treatment results of neoadjuvant chemotherapy with radiotherapy (n = 30) were compared with those of radical surgery with postoperative radiation (n = 17). Patient profiles in each treatment arm are summarized in Table 1. To decide the treatment option, we discussed the pros and cons of both treatments in detail with the patient and allowed the patient to choose in most of the cases. We found no significant differences in pretreatment states of both groups despite a lack of prospective randomization. We had two patients that were less than T3 in each treatment arm. One patient in the chemotherapy and radiation group had a TZNl tumor, and after treatment, he showed NED for 28 months. The other one in the surgery and radiation group had a TlNl tumor, which involved the medial wall of the pyriform sinus. After total laryngectomy, neck dissection, and irradiation, he has been free of disease for more than 3 years. Local and regional control rate after 3 years were comparable between the two groups (Table 2). The group that had surgery with radiation therapy showed a 3-year disease-free survival rate of Sl%, and group that had chemotherapy with radiotherapy group had 52%. These numbers did not show a statistiTABLE 1. Chemotherapy

Comparison of Patient Characteristics of Plus Radiation and Surgery Plus Radiation Chemotherapy + RT (n = 30)

Characteristic Male:Female Age, years Range Mean Stage III/IV Primary site (T~/T~ITZYT~) Nodal disease (NO/Nl/NZN3) Primary site Pyriform sinus Posterior pharyngeal wall Postcricoid area Median follow-up (mo) ECOG performance status (0 or 1) Abbreviations: RT, radiation

ECOG, therapy.

Eastern

Surgery + RT (n = 17)

28:2

17:o

30-80 58

47-71 60

5125 O/l I1 613 3/6/l 516

2l15 1 /0/5/11 2/4/8/3

Cooperative

25 2 3 35 29

TABLE 2. Chemotherapy

Comparison of Treatment Plus RT and Surgery

Characteristic Ultimate outcome of patients with CR Local recurrence Regional recurrence Distant metastasis 3-year disease-free survival rate 3-year overall survival rate Larynx preservation Abbreviation:

RT, radiation

ET AL

Results of Plus RT

Chemotherapy + RT

Surgery + RT

P Value

3120 2120 O/20

l/17 l/17 3117

>.05 >.05 >.05

52%

61%

>.05

65% 13130

72% o/17

>.05 .0015

therapy.

tally significant difference (P > .05) (Fig 2). The 3-year overall survival rates also showed 72% in the surgery group and 65% in the chemotherapy group without a statistically significant difference (Fig 3). However, 13 of 30 patients were able to preserve their larynges for more than 3 years by chemotherapy and radiation (+ in Fig 1). Median survival period of these patients was 51 months (Table 2). No patient in the chemotherapy and radiotherapy group developed distant metastasis for 3 years, whereas 3 patients in the surgery group died of distant metastasis (Table 2). Instead, 5 patients with CR after chemotherapy and radiotherapy had locoregional recurrence. Among them, 4 patients underwent salvage treatment and of these, 3 were diseasefree for more than 3 years. Toxicities of FP chemotherapy were reversible and tolerable in most patients, but 5 patients omitted the third cycle of chemotherapy because of toxicity. They failed to achieve CR after radiotherapy and could not survive the disease.

15 2 43 17 Oncology

Group;

Fig 2. Three-year (P > .05). Abbreviations: therapy.

disease-free OP, operation;

survival RT,

rates radiation

ADVANCED

HYPOPHARYNGEAL

Fig 3. Three-year overall Abbreviations: OP, operation;

CARCINOMA

survival rates (P > .05). RT, radiation therapy.

No apparent increase in postoperative complications, especially pharyngocutaneous fistula, was observed in surgically salvaged group. The results of each treatment are summarized in Table 2. DISCUSSION The role of neoadjuvant chemotherapy in head and neck cancer has been intensively studied in recent years. The cisplatin and 5-FU regimen that we have used is one of the most active combinations with response rates, ranging from 31% to 98%.7,g-12 Toxicity was acceptable with this induction regimen without an increased number of complications from subsequent surgery or radiation therapy. In our study, we obtained an overall response rate of 87% after FP neoadjuvant chemotherapy, and a CR rate of 67% following chemotherapy and radiation therapy. In addition, the patients with CR after neoadjuvant chemotherapy had higher chances of cure, with 7 of 9 patients being disease-free for more than 3 years, which was compatible with other observations.4,11,13,14 However, the patients who did not show CR after chemotherapy had a high likelihood of treatment failure, even though they achieved CR following subsequent radiotherapy. About 50% of the patients achieved CR with subsequent radiation, but only 25% remained disease-free after 3 years. Increasing the CR rate by neoadjuvant chemotherapy could be critical to improve the total survival rate. Various trials have been attempted to improve the response to chemotherapy. With many modifications of drug combinations, cisplatin and 5-FU has been generally accepted as the regimen of choice, so

43

far.12 However, given that of the 5 patients who were switched to radiation therapy before completion of the third cycle of chemotherapy due to toxicity, only one was able to achieve CR in our study, it seems to be important to develop new regimens to improve the response rate with lesser toxicity. Clinical trial of FP chemotherapy combined with leucovorin or interferon-alpha also failed to modify the course of disease.15J6 A protocol using alternative chemotherapy and radiation starting on the same day was recently tried and reported to achieve a higher response rate than the sequential method of chemotherapy and radiation.17 Unfortunately, in our series, all patients who underwent surgery for PR after chemotherapy died of disease, and only i’ of 21 patients who were treated with subsequent radiotherapy showed NED after 3 years. The conversion rate to CR from PR of the patients who received radiation was also low (11 of Zl), and the recurrence rate was high (4 of ll), even when clinical CR was achieved following radiation. The question of treatment option for patients with PR by chemotherapy is a very important issue to improve the cure rate. The most important advantage of neoadjuvant chemotherapy and subsequent radiotherapy is organ preservation with a better survival rate than that of irradiation alone.4l18 In our series, at least 13 of 30 patients (43%) who completed therapy could retain their larynges for more than 3 years. Our data also suggest a potential benefit of neoadjuvant chemotherapy in reducing distant metastases, which is currently the main cause of failure in head and neck cancer treatment. Several other randomized trials in laryngeal cancer showed reduced metastases in chemotherapy arms.1g,20 Even though this is not a randomized control study some observations can be made. Neoadjuvant chemotherapy with radiotherapy appear to be as effective as radical surgery with postoperative radiation without compromising survival. It also provides the important merit of preserving the larynx and a possibility of lengthening the survival by reducing the risk of distant metastasis, which might be supplemented with improved locoregional control in the future. Salvage laryngectomy or neck dissection can be reserved for locoregionally

44

recurrent patients. Salvage neck dissection might have an important role in improving regional control, especially in patients with advanced nodal disease following chemotherapy and radiation. Compared with laryngeal cancer, which has a better prognosis with standard therapy, this approach might be more meaningful for hypopharyngeal cancer because of its worse prognosis by standard therapy and severe surgical morbidity. To improve the overall cure rates, we specifically need to develop better strategies to increase CR rates with chemotherapy, and determine the best treatment option for patients who are partially or nonresponsive to chemotherapy. REFERENCES 1. Arrigada R, Eschwege F, Cachin Y, et al: The value of combining radiotherapy with surgery in the treatment of hypopharynx cancer. Cancer 51:1819-1825,1983 2. Razak M, Sako K, Marchetta F, et al: Carcinoma of the hypopharynx: Success and failure. Am J Surg 134:489491,1977 3. Marcia1 VA, Pajak TF, Kramer S, et al: Radiation therapy oncology group studies in head and neck cancer. Semin Oncol15:39-60,1988 4. Castellanos PF, Spector JG, Kaiser TN: Tumors of the larynx and laryngopharynx, in Ballenger JJ, Snow JB Jr (eds): Otorhinolaryngology Head and Neck Surgery (ed 15). Baltimore, MD, Williams&Wilkins, 1995, pp 585-652 5. Arlene AF: Cisplatin and radiation therapy in the management of locallv advanced head and neck cancer. Int J Radiat Oncol BioiPhys 27:465-470,1993 6. Pfister DG. Strong E. Harrison L. et al: Larvnx preservation with combmed chemotherapy and radiation therapy in advanced but resectable head and neck cancer. J Clin Oncol9:850-859,199l 7. Shirinian MH, Weber RS, Lippman SM, et al: Larynx preservation by induction chemotherapy plus radiotheranv in locallv advanced head and neck cancer. Head Neck-1’6:39-44,1994 8. Jacob HE: Current role of chemotherapy in the management of head and neck cancer, in Myers EN (ed): Advances in Otolaryngology-Head Neck Surgery, ~019. St Louis, MO, Mosby, 1995, pp 197-226

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9. 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 324:1685-1690, 1991 10. Toohill RJ, Anderson T, Byhardt RW, et al: Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer. Arch Otolaryngol Head Neck Surg 113:758-761, 1987 11. Jacobs C, Goffinet DR, Goffinet L, et al: Chemotherapy as a substitute for surgery in the treatment of advanced resectable head and neck cancer. Cancer 60:11781183,1987 12. Clavel M, Cappelare P, Cognetti F, et al: Comparison between cisplatin alone, two cisplatin containing multiple drug regimens: CAB0 (Cisplatin, methotrexate, bleomycin, oncovin) and CF (cisplatin and 5-FU) in advanced head and neck carcinoma. Report on a randomized EORTC trial 24842 including 380 patients. Cancer Chemother Pharmacol23:c73-(A292s), 1989 (suppl2) 13. 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 Oncoj 5:10-20,1987 14. Kies MS, Gordon LI, Hauck WW, et al: Analvsisi of complete responders after initial treatment with chemotherapy in head and neck cancer. Otolaryngol Head Neck Surg 93:199-205,1985 15. Lehmann OA, Santos RL, Butagelj E, et al: Cisplatin and fluorouracil versus cisplatin, fluorouracil and leucovorin in advanced head and neck cancer. Proc ASCO 13:927, 1994 16. Arquette MA, Mortimer JE, Loehrer PJ, et al: Phase II Hoosier Oncology Group Trial of interferon alpha-2B added to cisplatin and 5-fluorouracil in recurrent or metastatic head and neck cancer. Proc ASCO 13:901,1994 (abstr) 17. Koch WM, Lee DJ, Eisele DW, et al: Chemoradiotherapy for organ preservation in oral and pharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 121:974-980, 1995 18. Ogura JH, Marks JE, Freeman RB: Results for conservative surgery for cancers of the supraglottis and pyriform sinus. Laryngoscope 90:591-600, 1980 19. Head and Neck Contracts Program: Adjuvant chemotherapy in advanced head and neck squamous carcinoma. Cancer 60:300-311,1987 20. Schuller DE, Metch B, Maltox D, et al: Prospective chemotherapy in advanced resectable head and neck cancer. Final report of the Southwest Oncology Group. Laryngoscope 98:1205-1211,1988