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

Unresectable Cancers

In the past, the treatment of choice for patients with unresectable or inoperable head and neck cancers was radiation therapy alone. Despite the initial response and high local control rates with radiation therapy,more than 80% of these patients recurred within 2 years, and the 5-year survival was poor. Thus,induction chemotherapy and later concurrent chemotherapy-radiation therapy were investigated.

One prospective, randomized study comparing induction chemotherapy with cisplatin-5FU followed by radiation therapy vs radiation therapy alone was positive, with significant improvement in local, regional, and distant control rates as well as in disease-free and overall survival in the combination arm.[4]

Concomitant chemotherapy-radiation therapy appears to be effective in phase II trials. At least seven prospective phase III trials comparing concurrent chemotherapy-radiation therapy vs radiation therapy have been reported ( Table 4 ).[18,19,20,21,22,23,24] All were positive in favor of the combined-therapy arm. The majority of these randomized trials used hyperfractionated radiation therapy as the standard arm and in combination with chemotherapy, despite previous reports of no improvement in overall survival when daily irradiation was compared with twice-a-day radiation therapy.[4] Also, the majority of these randomized studies used the combination of cisplatin-5FU with radiation therapy as the experimental arm, despite the previously reported phase II trials indicating a CR rate of approximately 65% to 70% using cisplatin-5FU concurrently with radiation therapy. This result was no different than administering cisplatin or carboplatin alone concurrently with radiation therapy. In the Intergroup study (SWOG and ECOG)[23] for locally advanced and unresectable head and neck cancers, patients were randomized into three arms: (1) single-agent cisplatin every 3 weeks during radiation therapy, (2) cisplatin-5FU with radiation therapy, or (3) radiation therapy alone. Standard daily fraction radiation therapy was given to all patient groups. The 3-year survival rates were 37%, 29%, and 20%, respectively. The difference was only statistically significant (P=.016) between cisplatin plus radiation therapy and radiation therapy alone.

Thus, concurrent chemotherapy-radiation therapy is the "new" standard therapy for patients with locally advanced disease who are not undergoing a planned surgical resection. The main question remains as to whether two fractions per day of radiation therapy or once-daily radiation with chemotherapy is the preferred schedule. Another question is whether a single agent or a combination of agents should be given concomitantly with radiation therapy. Radiation alone is inadequate therapy.

As previously mentioned, our practice for patients with locally advanced and resectable tumors is to provide induction chemotherapy first, followed by concomitant chemotherapy-radiation therapy. Other centers have reported the same practice.[10] Limited concurrent chemotherapy with radiation therapy is superior to induction chemotherapy followed by radiation therapy. By giving induction chemotherapy first, the cancer is downstaged in approximately 90% of patients, and up to 50% may achieve a clinical CR. Also,nutrition and nitrogen balance can be improved in these patients so they can better tolerate the chemotherapy-radiation therapy program, and they will have dental care without delay of therapy. After downstaging the disease, the concurrent chemotherapy-radiation therapy theoretically should be more effective in eradicating the remaining locoregional cancer. Also, giving effective chemotherapy first will reduce the incidence of systemic micrometastasis. These considerations contribute to improved disease-free survival and overall survival of patients treated with this "total chemotherapy-radiation therapy."

To achieve the maximal desired results from chemotherapy in patients who have locally advanced disease, a third course of chemotherapy is recommended if a response occurs after two courses of treatment. At the end of the third course, disease is re-staged, and the degree of response is documented. This may include re-biopsy of the primary disease. Response to induction chemotherapy is an important prognostic factor and may determine the sequence and timing of the next planned local definitive therapy. Patients with excellent response, high partial response, and especially clinical CR or histological CR (by biopsy) may avoid surgery and receive concurrent chemotherapy-radiation therapy. Patients with a lesser response will require surgical resection of all the disease or the remaining disease, followed by postoperative chemotherapy-radiation therapy. Computed tomography or magnetic resonance imaging may not be accurate in assessing CR in patients presenting with T3 or T4 cancer. Imaging abnormalities may persist, even in patients with histologically negative biopsies or in those who underwent surgical resection.

In patients with recurrent and metastatic cancers, chemotherapy should be administered to maximal response, followed by an assessment of salvage local therapy of surgery and/or re-radiation concomitant with chemotherapy. At the end of the salvage local therapy, an additional three to six courses of chemotherapy should be considered to try to increase the incidence and the durability of this salvage measure. If a clinical CR or stable partial response is achieved, a positron emission tomography scan, along with the usual re-staging evaluation, may be considered, with a repeat of the study after three to six courses of the same chemotherapy. For patients with locally recurrent disease beyond local treatment of surgery and/or radiation therapy, biopsy of the disease is recommended after achieving a clinical CR. An additional three courses of the same chemotherapy is recommended with two negative biopsies before treatment is stopped.

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