Despite advances in surgical technique, head and neck reconstruction, and the delivery of radiotherapy, outcomes for people suffering from head and neck cancer have generally remained poor. With early tumors, a single modality of therapy results in a high rate of cure but with advanced disease, the rates of locoregional recurrence and the development of systemic metastases are unacceptably high despite the use of multi-modality therapy.1, 2 Chemotherapy has been used for head and neck cancer for several decades, but its use has yet to find a universally accepted role. Early experience showed encouraging response rates, but these were short-lived in the setting of advanced disease, and large trials failed to show a survival benefit when chemotherapy was used in the adjuvant setting. Researchers still struggle to demonstrate a clear survival benefit, but the secondary goal of preserving function of the larynx and pharynx without compromising survival can now be successfully achieved. The advent of new drug types, novel ways of combining therapies, and new methods of drug delivery are now producing high rates of organ preservation and are beginning to provide survival benefits in some groups of patients.

Chemotherapy for Recurrent or Metastatic Disease

Chemotherapy was initially used for palliation of advanced, unresectable tumors, and systemic disease. Numerous agents have been found to have activity in this setting, including methotrexate, bleomycin, 5-fluorouracil (5-FU), cisplatin, and carboplatin, with response rates ranging from 10% to 35%. Most of these responses are partial, and few are lasting, with median duration of only 4 to 6 months.^{3, 4} Methotrexate has been used most extensively and despite numerous phase II trials, no other single agent has demonstrated a clear superiority over this drug. One trial has reported an improved response and survival benefit using cisplatin, but the numbers treated and the improvement in overall survival (approximately 2 months) were small.⁵ Newer agents being investigated include the topoisomerase inhibitor, topotecan, and the pyrimidine antimetabolite, gemcitabine. Trials to date have reported modest response rates. Some encouraging results have been seen with the taxanes, paclitaxel and docetaxel, with response rates reported as high as 50%. These drugs may prove useful in combination therapies or as adjuncts to radiotherapy.

It was hoped that the use of drugs in combination would provide a better outcome. Numerous phase II and III trials have been performed using a variety of combinations, but the results have been disappointing. Four multi-institutional trials large enough to detect a significant difference between combination and single-agent chemotherapy have been reported.^6–9 These were all able to demonstrate an improvement in response rates with multiagent treatments, but this was achieved at the cost of greater toxicity without any improvement in median survival. A meta-analysis of trials of combination chemotherapy conducted during the early 1990s found cisplatin to be the most effective single agent, and that the combination of cisplatin and 5-FU was more efficacious than any other single agent or combination.¹⁰ This combination remains the gold standard to which all new combinations are compared. However, even with this combination, responses are seen in about one-third of patients, no more than one-half of which are complete. What is still unknown is whether this group of patients with advanced disease would fare better with good supportive care than with toxic therapies producing responses that are infrequent and of brief duration. One subset of this group in which cisplatin-based combination chemotherapy has produced lasting responses is patients with recurrent undifferentiated nasopharyngeal carcinoma. Higher response rates than at other sites, both complete and partial, are usually reported, and long-term disease-free survival has been reported in a few.^11–13 At most subsites of the head and neck, the role of chemotherapy cannot be considered part of standard management even in its traditional use in incurable disease, outside the context of trials designed to evaluate new therapies.

Chemotherapy for Advanced Resectable Disease

Although the success of chemotherapy in unresectable disease has been modest, encouraging results have been achieved in the setting of locally advanced primary disease. Although the primary goal of cancer therapy remains cure or prolonged survival, an important secondary goal of the use of chemotherapy is the reduction of the morbidity of treatment. In the head and neck, this takes the form of preservation of the organs of speech and swallowing. Three general approaches have been used, alone or in combination: induction therapy, adjuvant therapy, or chemotherapy concomitant with primary radiation.

INDUCTION CHEMOTHERAPY

Induction chemotherapy is given before definitive local therapy in an attempt to downstage local disease and make it more amenable to local therapy, to improve both local recurrence rates, and to treat microscopic systemic disease. This approach is attractive in that the drug is delivered to the tumor bed before it has been interfered with by surgery or radiotherapy and is delivered before the cells have had the chance to develop resistance to therapy. Preliminary studies from single institutions using this approach reported response rates as high as 90% with cisplatin-based regimens, with 40% complete response (CR) rates. Two-thirds of these had a pathologic CR. When followed with definitive radiotherapy, it was found that the response to induction chemotherapy was predictive of the subsequent response to radiation, and ultimately with survival.

Several randomized controlled trials of chemotherapy given before surgery14–18 and before radiation^{19, 20} have been reported. The first of these large multi-institutional studies reported was the Head and Neck Contracts Program. The three arms of this study compared standard surgery and postoperative radiotherapy, induction chemotherapy with a single course of cisplatin and bleomycin before standard treatment, and induction chemotherapy plus standard treatment plus maintenance cisplatin.¹⁴ The overall response rate to the chemotherapy was only 37%, and no survival benefit was demonstrated; however, lower rates of distant metastasis were obtained with chemotherapy, and the disease-free interval was prolonged in those who received maintenance therapy.

The Southwest Oncology Group investigated three preoperative cycles of cisplatin, bleomycin, methotrexate, and vincristine. No significant difference in survival rate was demonstrated with survival favoring the standard arm, but the rate of distant metastases was lower in those receiving chemotherapy.¹⁶

Perhaps the most successful trial of neoadjuvant therapy was reported by the Veterans’ Affairs (VA) Laryngeal Cancer Study Group.¹⁹ This trial compared intravenous cisplatin and 5-FU given before definitive radiotherapy with total laryngectomy. Patients were assessed after two courses of chemotherapy. If a significant response was not seen, the patient underwent total laryngectomy. If a good response was seen, the patient received a third cycle of chemotherapy and then underwent definitive radiotherapy. No difference in survival was seen between the two groups. Significantly, the survival was not compromised in the group receiving chemotherapy, yet two-thirds of patients surviving in this group retained a functioning larynx. Again, there was a reduction in the rate of systemic metastases in the chemotherapy group. It remains debatable as to whether this effect is durable, with some believing that the differences in the rates of distant metastases in the two groups become more similar with more prolonged follow-up.^{21, 22} The VA study did establish induction chemotherapy followed by definitive radiotherapy as a standard treatment option in advanced carcinoma of the larynx.

Positive findings in these studies were that high response rates to induction chemotherapy could be achieved, a significant proportion of which were complete, and that survival times were increased in those that did respond. Chemotherapy response predicted response to subsequent radiotherapy, and rates of distant metastases were significantly lowered in the groups receiving chemotherapy. The induction chemotherapy did not increase complications from subsequent surgery or radiotherapy. Perhaps most importantly, laryngeal preservation could be achieved without compromising survival. Despite this good evidence of the drugs’ activity, the trials were disappointing because the responses were translated neither into an increase in locoregional control, nor an increase in overall survival. A subset analysis of the Head and Neck Contracts Program study did, however, demonstrate an improvement in survival in oral cavity carcinomas and in those with limited neck disease.²³ Concerns have been raised about the adverse effects of delaying definitive therapy in those who do not respond.^{24, 25} Ameta-analysis of early trials showed a nonsignificant trend to the harmful effects of the addition of chemotherapy.²⁶

Organ Preservation

The success of the VA Laryngeal Cancer Study has established induction chemotherapy and definitive radiotherapy as a standard treatment option in laryngeal cancer, allowing preservation of laryngeal speech in most patients. This approach has been applied to advanced primary tumors of the oropharynx and hypopharynx in which total laryngectomy would be required as part of standard therapy. A large randomized trial by the European Organization for Research and Treatment of Cancer (EORTC) applied the VA protocol to patients with piriform sinus cancer. As with the laryngeal experience, survival was not compromised by a trial of induction chemotherapy, and 42% of patients in the experimental arm had a functioning larynx at 3 years.²⁷ This protocol is now considered the standard therapy arm in ongoing EORTC trials. The addition of chemotherapy to other forms of definitive therapy comes at the cost of significant morbidity. Despite the success of organ preservation studies, chemotherapy is used as part of initial definitive therapy of head and neck cancer in only about 6% of cases in the United States, although its use appears to be increasing in the treatment of advanced cancer.²⁸ The actual contribution made by chemotherapy in these trials is controversial. Large studies employing radiation alone have yielded disease specific survival rates similar to those achieved in induction chemotherapy trials^{29, 30} and improved survival of induction chemotherapy over radiation alone has yet to be established in a randomized trial.

ADJUVANT CHEMOTHERAPY

The use of chemotherapy as an adjuvant after definitive local therapy has some theoretical advantage over induction chemotherapy in that definitive therapy is not delayed and the potential to underestimate tumor margins after a clinical response is avoided. Two large trials evaluated the effects of adjuvant chemotherapy and again no differences in survival have been demonstrated.^{31, 32} In the first study,³¹ a longer survival was reported in the control arm. The study conducted by Rossi et al.³² of nasopharyngeal carcinoma reported no difference in survival with the addition of vincristine, cyclophosphamide, and doxorubicin after definitive radiotherapy.

A large intergroup study compared the addition of cisplatin and 5-FU after resection, but before radiotherapy.20 No survival difference was observed, but the pattern of failure was different between the two groups, with the patients receiving chemotherapy showing a lower incidence of distant metastases. An interesting finding was that a group with high-risk pathologic findings seemed to benefit from the systemic therapy. Induction chemotherapy trials have also included adjuvant arms. The Head and Neck Contracts Program¹⁴ included an arm with adjuvant cisplatin for 6 months. There was no difference in survival and very poor compliance with the chemotherapy. There was again a decrease in the rate of distant metastases.

In another induction trial, by Ervin et al.,³³ patients who responded to induction chemotherapy were randomized to receive maintenance therapy or not. Disease-free survival on the maintenance arm was significantly greater at 3 years (88% vs 57%). A significant improvement in survival was demonstrated in only one small trial of patients with oral cavity carcinoma.³⁴ The results suggest that chemotherapy can affect the rate of distant metastases, and survival may be improved. Problems with adjuvant trials are that it is difficult to administer therapy after surgery or radiotherapy because of greater toxicity of drugs after local treatment and lack of motivation in patients who have no clinical evidence of disease. There may be a role for adjuvant therapy in patients with high-risk pathologic features who are well motivated, but the overall disappointing results and high toxicity prevent this approach from becoming a standard therapy.

CONCOMITANT CHEMO- AND RADIOTHERAPY

Although chemotherapy has been demonstrated to have systemic activity against metastatic disease, improvements in overall survival are unlikely to be seen without improvements in rates of local and regional control.³⁵

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