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

Locally Advanced Resectable Cancer

The "standard" treatment for patients with locally advanced tumor stages (stage III and IV) has been surgery followed by radiation therapy. The radiation was given as an adjuvant to reduce the incidence of local failure, but this approach has not been investigated in prospective, randomized studies to show improvement in overall survival. Despite adequate surgical resection with negative margins and the addition of adjuvant radiation therapy, the 5-year survival rate for these patients is usually less than 30%. Induction chemotherapy has not gained scientific support, since any reduction of the tumor bulk would not change tumor resection margins. Induction chemotherapy has been investigated in patients with resectable cancers where planned surgery was performed on all patients, and the results were negative. This resulted in a sense that induction chemotherapy is ineffective in patients with locally advanced disease regardless of their resectability or operability. However, this observation may not be correct.

Postoperative concurrent chemotherapy-radiation therapy with cisplatin given every 3 weeks for three courses was investigated by the RTOG in a phase II study.[2] Patients with positive surgical margins and/or stage IV disease were treated with cisplatin 100 mg/m2 on days 1, 22, and 43 during radiation therapy. These patients were compared to an historically matched group with the same stage and site of cancers but with negative surgical margins. The local control rate was better in the patients treated with the combined chemotherapy-radiation therapy. Two randomized trials have also addressed this question.[2,4,15] Both were posi- September/October 2002, Vol. 9, No.5 Cancer Control 391 tive, thus supporting the addition of chemotherapy concomitantly with radiation therapy in locally advanced cancers. The most recent EORTC trial compared patients treated with postoperative radiation therapy alone vs postoperative chemotherapy-radiation therapy and reported a 3-year disease-free survival of 41% vs 59% (P=.0096) and overall survival of 49% vs 65% (P=.0057), respectively.

Postoperative chemotherapy followed by radiation therapy alone was investigated by the Detroit group[2] and found to be feasible. Three courses of cisplatin-5FU were administered without additional side effects or progression of the disease, and then radiation therapy was given. The sequence was tested by RTOG, and the feasibility of our local study was confirmed. Large prospective, randomized phase III trials were activated by RTOG and joined by other cooperative groups to compare surgery plus radiation therapy to surgery plus chemotherapy-radiation therapy. Local control and the incidence of systemic recurrences improved. However, the overall survival was not affected by the addition of chemotherapy, despite approximately a 2-year improvement in median survival and about a 9% difference in the actual 5-year survival rate in favor of the chemotherapy group.[5] The lack of statistical significance of benefit reflect the relatively small number of patients included in these trials.

At least six meta-analyses have examined the addition of induction chemotherapy to local definitive therapy in patients with locally advanced cancer. The results differ depending on the type and the year of the studies included in these analyses. Study reports before the use of cisplatin-5FU in this population showed no benefit for induction chemotherapy. The meta-analyses that included studies after 1980s, especially those using cisplatin-5FU chemotherapy, showed superiority of chemotherapy followed by radiation therapy vs radiation therapy alone.[16] All of the meta-analyses reported the superiority of concurrent chemotherapy-radiation therapy over radiation therapy alone; however, Pignon et al[16] updated three meta-analyses from 63 randomized trials performed between 1965 and 1993 involving 10,741 patients. This meta-analysis confirmed the superiority of the overall use of chemotherapy, especially the concomitant use of chemotherapy-radiation therapy over radiation therapy only. The authors also reported the superiority of cisplatin-5FU administration as either induction or adjuvant therapy in these patients.

Recently, Browman et al[17] reported a metaanalysis including 18 trials with 3,192 patients, in which concurrent chemotherapy-radiation therapy was compared to radiation therapy alone ( Table 3 ). Overall, the chemotherapy-radiation therapy arm was again superior to radiation therapy alone (P <.00001). Single fraction,two fractions a day irradiation, single agents, combination chemotherapy, and especially cisplatin-5FU provided statistically significant results. Only platinum-based chemotherapy plus radiation therapy was highly significant (P <.0001), while mitomycin C-based treatment was moderately significant (P=.032). Thus, we believe that single-agent cisplatin or carboplatin with radiation therapy should be the current standard treatment approach in patients with locally advanced cancers.

For the last 10 years, our approach to treatment for patients with stage IV disease or for those with stage III disease (only T3 N1 M0) after their planned surgery who are not on study has been to prescribe chemotherapy using three courses of cisplatin-5FU followed by concurrent chemotherapy-radiation therapy. This treatment is tolerable and feasible,and it gives patients time to recover from their surgical resection before beginning the concomitant chemotherapy-radiation therapy treatment. The effectiveness of this specific approach needs to be confirmed by prospective, randomized trials.

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