Treatment of Locally Advanced Head and Neck Cancer: Historical and Critical Review

Muhyi Al-Sarraf, MD, FRCPC, FACP

Disclosures

Cancer Control. 2002;9(5) 

In This Article

Nasopharyngeal Cancer

The results of treatments for patients with nasopharyngeal cancer are considered separately from other head and neck cancer patients due to differences in sex, age, nodal presentation, histopathology, response to radiation therapy and chemotherapy, incidence of systemic metastases, and overall survival.

Nasopharyngeal carcinomas are highly sensitive to radiation therapy ( Table 5 ). Before 1980, radiotherapy was the treatment of choice for all stages of nasopharyngeal cancer. The results in patients with stages I and II disease are excellent, and radiation therapy has remained the initial therapy for these patients.[27,28] However, the majority of the patients with this disease present with locally advanced disease, especially stage IV cancers. Despite the excellent initial tumor clearance with radiation therapy in patients with locally advanced disease (stage III and IV), locoregional recurrence rates are high. Systemic involvement at presentation or later is common in these patients and may exceed 35%. These considerations limit survival, with estimated the 5-year survival rate using radiation therapy alone for patients with stage IV cancer being less than 30%.[27,28]

Nasopharyngeal cancer is also sensitive to chemotherapy ( Table 6 ).[4,27] Compared with single agents, combination chemotherapy produces higher response rates and a longer duration of response, and cisplatin-5FU is the most widely used combination. Because of the poor results obtained with radiation therapy alone in patients with locally advanced disease, induction cisplatin-5FU before radiation therapy has been tested. The overall response rate to cisplatin-5FU is approximately 90%, and about 50% achieved CRs, with improved 5-year survival.[27] Concurrent cisplatinradiation therapy,which has been investigated by us and later by other investigators, produced higher CR rates and better 5-year survival rates.[2,27] Since the introduction of effective chemotherapy as part of the salvage treatment after relapse in these patients with nasopharyngeal cancer, the 5-year survival rate in patients with stage IV disease who received radiation therapy as their initial treatment has risen to the 40% range.[27]

In phase II or III studies reported thus far with the use of limited chemotherapy with radiation therapy, induction only, concomitant only, or adjuvant only, the worldwide 5-year survival rate in patients with stage IV nasopharyngeal cancer has risen to approximately 50% to 55% ( Table 5 ). This is pertinent to the randomized trials reported in this disease.

Nine prospective phase III randomized studies have compared radiation therapy alone to the same radiation therapy with chemotherapy ( Table 7 ).[29,30,31,32,33,34,35,36,37,38,39] One negative adjuvant chemotherapy trial used a noncisplatin combination and was carried on before the introduction of cisplatin-5FU in this disease. Of four induction chemotherapy trials, two used combinations without cisplatin-5FU, and the other two used cisplatin-5FU combinations. None of these four induction randomized studies reported a prolonged overall survival. The two cisplatin-5FU trials, however, reported a difference in overall survival rates of 7% and 12%. Some studies reported improved disease-free survival and/or freedom from local relapse. Several reasons may be cited to explain why these chemotherapy induction trials might not show improvement in overall survival. These include small patient numbers, inclusion of stage II patients, larger numbers of stage III patients, short durations of follow-up, use of only two courses of chemotherapy, a high mortality rate (9%) in one study with non-PF chemotherapy, a low dosage of cisplatin and/or 5FU, and limited chemotherapy given (induction, concurrent, or adjuvant only). A recent phase III randomized study by Chan et al[39] comparing concurrent chemotherapy-radiation therapy to radiation therapy alone reported a 7% difference in progression-free survival, which was not statistically significant because of the small sample of patients included. However, in patients with T3 disease based on the Ho staging system, 40 the difference was 68% vs 46% (P=.0075) favoring the combined treatment group.

We reported on the use of "total" chemotherapyradiation therapy vs radiation therapy alone in patients with locally advanced nasopharyngeal cancer (90% stage IV).[35,36] The experimental arm consisted of concurrent cisplatin given for three courses with radiation therapy followed by three courses of cisplatin-5FU. This study demonstrated a significant difference in 5-year actual overall survival rate (67% vs 37%, P <.001) and progression-free survival (P <.001) in favor of the combined approach. The disease-related 5-year overall survival rates were 76% and 46% (P <.001), respectively. Total chemotherapy-radiation therapy produced significant improvement in the incidence of local and regional control and in the incidence of systemic recurrence.

A meta-analysis comparing combined chemotherapy-radiation therapy vs radiation therapy alone in locally advanced nasopharyngeal cancer included patients from six randomized studies (1,528 patients).[41] The addition of chemotherapy to radiation therapy increased disease-free/progression-free survival by 37% at 2 years, 40% at 3 years, and 34% at 4 years after treatment. Likewise, the overall survival increased by 20%, 19%, and 21%, respectively, with chemotherapy plus radiation therapy.

For the last 10 years in our practice, we have reversed the sequence of chemotherapy and have prescribed three courses of cisplatin-5FU induction followed by concurrent chemotherapy-radiation therapy, with cisplatin for three courses. In this unpublished trial, the 5-year actual overall survival was approximately 90%. Recent reports from other centers indicated approximately the same incidence of overall survival using the same sequence of total chemotherapyradiation therapy.[42] Table 8 shows the change in actual 5-year survival of stage IV patients with nasopharyngeal cancer over the last 20 years.

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