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

Chemotherapy

The two major indications for administering chemotherapy are as a single modality or as concurrent chemotherapy-radiation therapy.

Chemotherapy as a single modality is used for patients with recurrent and/or metastatic tumor, but it is also used for patients with locally advanced cancers. The cisplatin-5FU combination is more effective than the single agents previously used -- methotrexate, bleomycin, and cisplatin. Cisplatin-5FU is now the most commonly used chemotherapy combination,[1,2,4] with the most frequently used treatment regimen consisting of cisplatin 100 mg/m2 given intravenously (IV) on day 1 and 5FU 1,000 mg/m2 given by continuous infusion for 5 days every 3 to 4 weeks. For the last 20 years, efforts have been underway not only to improve on the results obtained with cisplatin-5FU by adding other agents, but also to search for more effective combinations to replace it.

Improvements in cancer therapy would include better antitumor efficacy, fewer side effects, and lower cost and hospitalization rates, thereby being more amenable to patients. Initially, many single agents, eg, bleomycin, methotrexate, and the vinca alkaloids,were added to the cisplatin-5FU regimen. This policy reduced the optimal doses of cisplatin or 5FU or both and increased side effects without increasing efficacy.[2] The addition of leucovorin or interferon or both to the cisplatin-5FU regimen provided similar results. Of the newer active single agents, the taxanes (docetaxel and paclitaxel) have shown the most promise.

The role of taxanes in head and neck cancers have been reviewed by Schrijvers and Vermorken[5] and by Glisson.[6] As single agents, both demonstrate overall response rates that range from 20% to 42% in patients with recurrent and/or metastatic disease. It is noted that most of these patients treated with taxanes in these reports had no previous chemotherapy for recurrent cancers, and some patients with locally advanced head and neck cancers were included in these studies. This may explain the relatively high response rates reported by these investigators. Our experience indicates that the response rate to the taxanes alone after failure of a cisplatin combination is poor. This suggests that the taxanes should be used initially with cisplatin-5FU or as part of newer combination(s) of chemotherapy. Randomized trials comparing cisplatin-5FU to either cisplatin plus paclitaxel[7] or cisplatin plus docetaxel[8] reported no differences in response rates or complete responses (CRs) but some difference in side effects and the cost of each combination.

Efforts are underway to investigate the addition of one of the taxanes to the cisplatin-5FU regimen or to find newer combinations of two or three active agents in patients with recurrent and/or metastatic disease, as well as in patients with previously untreated locally advanced squamous cell carcinoma of the head and neck.[4] One such approach was reported by Posner et al[9] using docetaxel combined with cisplatin-5FU. Synergy has been reported between cisplatin and 5FU, between docetaxel and cisplatin, and between docetaxel and 5FU. In their initial trials, leucovorin was added to docetaxel-cisplatin-5FU, which added to the incidence and severity of oral and oropharyngeal mucositis without appearing to add to the efficacy of this combination. The results from docetaxel-cisplatin-5FU alone suggest a high incidence of response but with appreciable toxicity.[9] Presently, two prospective, randomized phase III trials in patients with recurrent and/or metastatic disease or in patients with previously untreated locally advanced head and neck cancers are comparing three courses of cisplatin-5FU vs docetaxel-cisplatin-5FU in North America. Similar international trials are currently in progress.

Thus, docetaxel-cisplatin-5FU is a promising combination, but the phase III studies are not mature. Our experience indicates that docetaxel-cisplatin-5FU is more toxic than cisplatin-5FU, especially in regard to mucositis, diarrhea, and neutropenia. As a result, we have modified this promising combination in two ways. To reduce cisplatin-related side effects, including renal insufficiency, hearing loss, nausea and vomiting, peripheral neuropathy, and the diuresis associated with use of mannitol,we have substituted carboplatin for cisplatin. Because of the incidence and degree of mucositis, diarrhea, and right-sided abdominal pain, the continuous infusion of 5FU for 96 hours was changed to a schedule of 2,600 mg/m2 as a 24-hour infusion given weekly with docetaxel (75 mg/m2) and carboplatin (300 mg/m2 or an area under the curve [AUC] of 5, depending on creatinine clearance) given every 3 weeks for three courses. Our early experience suggests that this program may be the most effective and "patient friendly" combination we have used in patients with head and neck cancers (unpublished data, 2002).

In the past, radiotherapy alone was the "traditional" single treatment for patients with unresectable and/or inoperable locally advanced head and neck cancers. Because of the poor results obtained with this approach in these patients, concurrent chemotherapyradiation therapy has been investigated since the 1960s.[1,2,4,10,11] The rationale for such treatment is to increase local control by overcoming radioresistance and to eradicate systemic micrometastasis. The most significant potential mechanisms of interaction between chemotherapy and radiation therapy are summarized in Table 2 .

Initially, agents like methotrexate, hydroxyurea, 5FU, or bleomycin were tested in combination with radiation therapy. Since each of these drugs produces mucositis and stomatitis, the local side effects of radiation therapy on the oral and oropharynx mucosa were increased, which resulted in poor patient compliance, more interruptions of therapy, and no improvement in overall survival when compared to radiation therapy alone. Cisplatin does not induce mucositis and does not increase the local toxicity of radiation therapy in patients with head and neck cancers. It is probably the best currently available radiosensitizer, and it possesses all the mechanisms of interaction with radiation therapy that are summarized in Table 2 . The clinical CR rate obtained with concurrent cisplatin and radiation therapy (single daily fraction) in patients with locally advanced head and neck cancers is in the range of 65% to 70%.[2,4,10,11] The majority of the patients in these studies had stage IV disease. Cisplatin has been administered in various schedules: weekly, daily, days 1-5 every 4 weeks, and every 3 weeks. One randomized ECOGRTOG trial with weekly administration of cisplatin at 20 mg/m2 during radiation therapy vs radiation therapy in locally advanced patients was negative. One positive randomized trial with the weekly schedule has been reported from Europe.[12] The addition of another agent or agents in combination with cisplatin (eg, 5FU or taxanes) concomitant with radiation therapy did not add to the clinical CR rate but increased local side effects, especially mucositis.[4,5,6,10] Thus, cisplatin alone appears to be the chemotherapeutic drug of choice for concurrent chemotherapy with radiation therapy in patients with head and neck cancers. At the present time, cisplatin alone given on a 3-week schedule is the most widely used in the United States.

Carboplatin, the second-generation platinum drug, possesses all of the radiopotentiation properties of cisplatin but has a different side effect profile. Carboplatin is used in a weekly schedule concurrent with radiation therapy in patients with head and neck cancers. The clinical CR rate reported in phase II studies with concomitant carboplatin and radiation therapy (single daily fraction) is in the range of 65% and 70%, which is similar to the clinical CR rate reported with cisplatin and radiation therapy.[2,4] For the last 7 years, our personal practice has been to use carboplatin rather than cisplatin in our concurrent chemotherapyradiation treatment, using a weekly dose of 100 mg/m2 or at an AUC of 1.5. In a comparison of radiation therapy alone or with either cisplatin or carboplatin in these patients, two randomized trials reported the superiority of either combination arm to the radiation therapy alone arm, with no statistical difference between the two combination arms.[13,14]

Mitomycin C also possesses most of the radiopotentiation mechanisms of interaction with radiation therapy ( Table 2 ). Randomized trials comparing radiation therapy with or without mitomycin C showed improved local control but no differences in overall survival between the two groups.[4] More recently, gemcitabine and the taxanes have been tested for their radiosensitizing effects. The clinical CR rate for the combination of taxanes alone or with other agents given concurrently with radiation therapy is approximately 65%.[4,5,6] However, the local side effects, especially mucositis, are problematic.

Gemcitabine plus radiation therapy in phase I-II studies produced a high CR rate in the primary tumor site but had a high incidence of grade 3-4 local toxicities, especially pharyngeal scarring and stenosis.[4] The combination of 5FU and hydroxyurea concomitant with radiation therapy is effective, but again, the local side effects are severe.[4] The addition of cisplatin or paclitaxel increased the effectiveness of the combination of 5FU and hydroxyurea, but the clinical CR rate was similar to that reported with radiation therapy plus cisplatin or carboplatin.

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