Oral 5-FU Alternatives for the Treatment of Head and Neck Cancer

ABSTRACT: The common clinical presentations of head and neck cancer include early (stage I or II) disease, locally or regionally advanced (stage III or IV, M0) disease, and recurrent or metastatic disease (

Introduction

Head and neck cancer occurs at an incidence of approximately 40,000 cases per year. Its primary risk factor is the combination of tobacco smoking and alcohol. The overwhelming majority of cases are of squamous cell histology. The disease is characterized by local and regional presentation. Patients who fail traditional treatment with surgery and/or radiotherapy most frequently fail within the head and neck region.[1] Thus, the primary focus of investigational head and neck cancer therapy is the delivery of more effective local and regional care.

There are three common clinical presentations of head and neck cancer. About one third of patients will present with early stage disease (stage I or II). This is characterized by a small T1 or T2 lesion without clinically overt lymph node involvement or distant metastases. These patients are treated with curative intent, usually consisting of single-modality therapy with either surgery or radiation. Although a small fraction of these patients can develop recurrent disease, the majority are cured. They do, however, remain at significant risk of developing second primary malignancies within the upper aerodigestive tract area.

Approximately two thirds of patients present with locally or regionally advanced disease (stage III or IV, M0). These patients have large primaries and/or lymph node involvement. Historically, they have been treated with surgery (if the disease was resectable) followed by postoperative radiotherapy. Despite this aggressive multi- modality approach, disease recurs in the majority of patients within 2 years in the irradiated field, which underscores the inability of this therapy to eradicate locally or regionally predominant disease.

The third group of patients presents with metastatic disease at the time of initial diagnosis (stage IV, M1); however, this is observed in less than 5% of patients at the time of initial diagnosis. Also included in this group are patients with locoregionally recurrent disease following previous radiotherapy or surgery. These patients are treated with palliative intent, usually consisting of combination chemotherapy with cisplatin and 5-fluorouracil (5-FU).

Current Role of Chemotherapy in Head and Neck Cancer

The use of chemotherapy is considered separately for the three clinical categories described above. Many patients with stage I or II disease are cured following surgery or radiotherapy; therefore, few investigations involving this patient group have used the addition of chemotherapy.

For patients with stage III or IV, M0 locally or regionally advanced disease, chemotherapy has been investigated intensively over the past 20 years. At this time, the use of induction chemotherapy (2 to 3 cycles of cisplatin and 5-FU followed by local therapy with surgery and/or radiotherapy) has not been shown to increase survival; however, it has allowed for larynx preservation.[1-4] When compared with surgery and radiotherapy, patients treated with induction chemotherapy and radiotherapy had no difference in survival, but a large percentage of patients who survived retained a functioning larynx. Thus, induction chemotherapy can be recommended for these patients with the goal of organ preservation, but not the goal of increased survival. The use of simultaneous chemoradiotherapy, on the other hand, has been shown to result in increased locoregional control and survival. This was confirmed by a recent meta-analysis as well as several recent randomized trials comparing radiotherapy alone (or surgery followed by radiotherapy) vs the use of radiotherapy with simultaneous chemotherapy (or surgery followed by simultaneous chemoradiotherapy).[5-10] As a result, the use of concomitant chemoradiotherapy can now be considered a possible standard treatment option for all patients with locoregionally advanced disease.

Finally, patients with recurrent or metastatic disease receive chemotherapy as the primary treatment modality. The goal of treatment is prolongation of life and palliation of symptoms. With currently available regimens, such as cisplatin and 5-FU or cisplatin and paclitaxel, about 30% to 40% of patients will have at least a partial response. However, median survival rates have averaged 6 to 7 months for the last 3 decades.[11-13] The use of newer chemotherapy agents in this disease setting is of great interest. Current investigations looking at paclitaxel, docetaxel, vinorelbine, and gemcitabine as single agents or in combination are in progress.

Oral Chemotherapy in Head and Neck Cancer

Clinical experience with oral administration of chemotherapy in head and neck cancer patients is limited. Nevertheless, given the anatomic location of the disease, its risk factors, and epidemiology, it is clear that some special considerations apply to this patient population (Table 1). Many patients with cancer of the oropharynx, hypopharynx, or oral cavity will present with swallowing dysfunction. This includes initial symptoms of dysphagia or odynophagia due to advanced primary tumor stage. Similar symptoms can occur as a result of radiotherapy or chemoradiotherapy while the patient is undergoing treatment. In more severe cases, patients may aspirate with an associated risk of developing aspiration pneumonia. Mucositis and candidal infections frequently occur during the delivery of radiotherapy. Following completion of radiotherapy, patients experience loss of taste, at least temporarily. In addition, patients suffer from usually life-long xerostomia. All of the above symptoms may interfere with a patient’s ability or willingness to take oral fluids or food. Such patients may also be less willing or able to take medications orally.

Other patients may present with gastric or jejunal feeding tubes to circumvent their inability to swallow sufficient amounts of food. The crushing or need to solubilize oral medications in order to facilitate administration via feeding tube may result in variability in the administered dose and absorption. Finally, head and neck cancer patients may suffer from hepatic dysfunction, low serum albumin, or malnutrition that may alter their ability to handle medications. This latter concern is, however, not unique to orally administered medications.

Table 2 describes oral chemotherapy agents that have been studied in head and neck cancer patients. Of these, hydroxyurea is approved by the US Food and Drug Administration for use as a radiation sensitizer. Most other agents have been studied either infrequently or not at all.

5-FU, Hydroxyurea, and Concomitant Radiotherapy

At the University of Chicago, we have developed a regimen consisting of infusional 5-FU with oral hydroxyurea and concomitant radiation therapy (FHX). This regimen was based on (1) the observed single-agent activity of both chemotherapy agents, (2) the possibility of a synergistic interaction between hydroxyurea and 5-FU based on the intracellular depletion of dUMP leading to enhanced binding of 5-FdUMP to its target enzyme, thymidylate synthase, and (3) the possibility of radiation enhancement by both drugs. The FHX regimen was shown to have high local and regional activity in patients with recurrent disease.[14-16] Since that time, we have studied this regimen in patients with stage II and III disease and have found high locoregional control and survival rates.[17] We have also studied the FHX combination (preceded by induction chemotherapy) in patients with locoregionally advanced stage III and IV disease.[18,19] Again, highly encouraging locoregional and distant control and overall survival rates were achieved.

Eniluracil, 5-FU, and Radiotherapy

Based on this encouraging activity, we wished to explore further the possibility of administering the FHX combination as an all oral chemotherapy (outpatient) regimen. As a first step, we initiated a phase I study of eniluracil 20 mg administered every 12 hours × 14 doses with escalating doses of 5-FU administered twice daily × 10 doses and concurrent, twice-daily radiotherapy (150 cGy/fraction) for 5 consecutive days. This 5-day chemoradiotherapy regimen was repeated every other week until completion of radiotherapy (usually 5 cycles or 75 Gy). A final analysis of this study is currently in progress. Early evaluation suggested that systemic myelosuppression rather than radiation enhancement was dose-limiting.[20] We are, therefore, currently investigating alternative schedules of eniluracil, 5-FU, and concomitant radiotherapy in an effort to decrease myelosuppression while increasing the potential interaction of 5-FU and radiotherapy.

This combination of 5-FU and eniluracil is also currently undergoing clinical evaluation in patients with recurrent or metastatic disease (without concurrent radiotherapy) in a phase II study conducted by the National Cancer Institute of Canada. Patients are treated with palliative intent. Overall response rate is the primary end point of this study.

UFT

UFT (tegafur and uracil) has also been studied in head and neck cancer. Tanaka et al reported on 43 previously treated patients with recurrent head and neck cancer.[21] The overall response rate was 38% with a partial response rate of 19% and complete response rate of 19%. Additional trials have evaluated UFT in combination with cisplatin or carboplatin.[22-24] In a study involving 36 previously untreated head and neck cancer patients, Gonzalez-Baron reported an overall response rate of 94% (22% complete response rate) for the combination of cisplatin and tegafur.[22] The combination of carboplatin and tegafur resulted in an objective response rate of 62% (33% CR) in 22 patients.[23] Additional studies evaluating the combination of carboplatin, tegafur, leucovorin, and cisplatin with UFT have also been reported.

UFT as Radiation Sensitizer

UFT has also been evaluated as a radiation sensitizer. Fifty-two patients with larynx cancer were treated with this combination. Improved disease-free and overall survival was reported as compared with a historical control group of 113 patients treated by the same investigators.[25]

Oral Etoposide

Intravenously administered etoposide has been shown to be minimally active in head and neck cancer. Therefore, oral etoposide has been studied, albeit infrequently. One group of investigators reported on 16 extensively previously treated patients who were administered oral etoposide 100 mg/m²×5 every 3 weeks; no response activity was observed.[26]

Additional Agents

Additional orally administered chemotherapy agents include JM-216, capecitabine, S-1, methotrexate, and cyclophosphamide. No information on the use of these oral agents in head and neck cancer is available at the present time.

Conclusions

Orally administered chemotherapy drugs have been shown to have activity in head and neck cancer. At the present time, the general use of chemotherapy in head and neck cancer is most promising when combined with simultaneous radiotherapy. Therefore, the development of orally administered chemotherapy regimens with simultaneous radiotherapy is of great clinical interest. This might result in the feasibility of administering such regimens more easily on an outpatient basis. However, special considerations do exist, in particular the high likelihood of increased mucocutaneous reaction such as exacerbated mucositis and esophagitis, within the irradiated field. These toxicities and underlying tumor-related symptoms may render the administration of oral chemotherapy difficult. Given the possible interactions between several orally administered drugs, in particular platinum analogues with antimetabolites such as 5-FU, UFT, or capecitabine, and their mutual ability to enhance the activity of radiotherapy, the development of combination chemotherapy regimens with or without concurrent radiotherapy is also of high clinical interest.

References:

References

1. Vokes EE, Weichselbaum RR, Lippman S, et al: Head and neck cancer. N Engl J Med 328:184-194, 1993.

2. Collins S, Stupp R, Dougherty M, et al: Head and Neck Cancer, in Abeloff, Armitage, Lichter, Niederhuber (eds): Clinical Oncology, pp 961-1022. New York, Churchill Livingstone, 1995.

3. 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.

4. Lefebvre JL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European organization for research and treatment of cancer phase III trial. J Natl Cancer Inst 88:890-899, 1996.

5. El-Sayed S, Nelson N: Adjuvant and adjuvantive 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 14:838-847, 1996.

6. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338(25):1798-1804, 1998.

7. Wendt TG, Grabenbauer GG, Rödel CM, et al: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: A randomized multicenter study. J Clin Oncol 16(4):1318-1324, 1998.

8. Al-Sarraf M, LeBlanc M, Shanker PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16(4):1310-1317, 1998.

9. Browman GP, Cripps C, Hodson I, et al: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy and locally advanced head and neck cancer. J Clin Oncol 12:2648-2653, 1994.

10. Haffty BG, Son YH, Papac R, et al: Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: Results of the Yale Mitomycin Randomized Trials. J Clin Oncol 15(1):268-276, 1997.

11. Jacobs C, Lyman G, Velez-Garcia E, et al: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10:257-263, 1992.

12. Vokes EE, Panje WR, Schilsky RL, et al: Hydroxyurea, fluorouracil, and concomitant radiotherapy in poor-prognosis head and neck cancer: A phase I-II study. J Clin Oncol 7:761-768, 1989.

13. Schrijvers D, Johnson J, Jiminez U, et al: Phase III trial of modulation of cisplatin/ fluorouracil chemotherapy by interferon alfa-2b in patients with recurrent or metastatic head and neck cancer. J Clin Oncol 16:1054-1059, 1998.

14. Forastiere AA, Metch B, Schuller DE, et al: Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group study. J Clin Oncol 10:1245-1251, 1992.

15. Vokes EE, Haraf DJ, Mick R, et al: Intensified concomitant chemoradiotherpay with and without filgrastim for poor prognosis head and neck cancer. J Clin Oncol 12:2351-2359, 1994.

16. Haraf DJ, Weichselbaum RR, Vokes EE: Re-irradiation with concomitant chemotherapy of unresectable recurrent head and neck cancer: A potentially curable disease. Ann Oncol 7:913-918, 1996.

17. Vokes E, Haraf D, Weichselbaum R, et al: Fluorouracil, hydroxyurea and concomitant radiotherapy for stage II and III head and neck cancer. Fourth International Congress on Anti-Cancer Chemotherapy, Paris, p 67, 1993.

18. Vokes EE, Kies MK, Haraf DJ, et al: Induction chemotherapy followed by concomitant chemoradiotherapy for advanced head and neck cancer: Impact on the natural history of the disease. J Clin Oncol 13:876-883, 1995.

19. Kies MS, Haraf DJ, Athanasiadis I, et al: Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: Improved disease control and survival. J Clin Oncol 16(8):2715-2721, 1998.

20. Humerickhouse R, Dolan E, Brockstein B, et al: Phase I study of a novel DPD inhibitor GW776C85 and oral 5-FU with RT in recurrent or advanced head and neck cancer (abstract 1521). Proc Am Soc Clin Oncol 17:394a, 1998.

21. Tanaka J, Inuyama Y, Fujii M, et al: Clinical trials on UFT in the treatment of head and neck cancer. Auris Nasus Larynx 12:S261-S266, 1985.

22. Gonzalez-Baron M, Vicente J, Tomas M, et al: Phase II trial of cisplatin and tegafur (Ftorafur) as initial therapy in squamous-cell carcinoma of the head and neck. Am J Clin Oncol 13:312-314, 1990.

23. Feliu J, Gonzalez-Baron M, Zamara P, et al: Experience of Oncopaz cooperative group with oral fluoropyrimidines in tumors of the stomach, lung, head and neck and breast. Oncology 54:30-37, 1997.

24. Gonzalez-Larriba JL, Carbonero IG, Valera JS, et al: Neoadjuvant therapy with cisplatin/ fluorouracil vs cisplatin/UFT in locally advanced squamous cell head and neck cancer. Oncology 11:90-97, 1997.

25. Takahashi H, Yao K, Sawaki S, et al: Investigation of UFT and radiation combination therapy of head and neck cancer—mainly in laryngeal cancer. Gan To Kagaku Ryoho 17:2037-2042, 1990.

26. Grunberg SM, Felman IE, Gala KV, et al: Phase II study of etoposide (VP-16) in the treatment of advanced head and neck cancer. Am J Clin Oncol 8:393-395, 1985.