Elsevier

The Lancet Oncology

Volume 7, Issue 7, July 2006, Pages 565-574
The Lancet Oncology

Review
Reassessment of the role of induction chemotherapy for head and neck cancer

https://doi.org/10.1016/S1470-2045(06)70757-4Get rights and content

Summary

Head and neck cancers are a complex group of diseases defined by variations in histological features, anatomical location, and cause. Once the realm of surgeons and radiation oncologists, the treatment of locally advanced disease now involves medical oncologists. Major developments include primary chemoradiotherapy for unresectable disease and organ preservation, the addition of chemotherapy to adjuvant radiotherapy, improvement in surgical and radiation techniques, and biological therapies. Concomitant chemoradiotherapy consistently improves locoregional control. However, control of distant metastases is poor, resulting in an increasing proportion of deaths from systemic recurrence. Given this shift in site of recurrence, therapeutic strategies to suppress distant metastases may be the next goal for further improvement of survival. One approach that merits reassessment is the use of induction chemotherapy in the setting of locally advanced disease—both resectable and unresectable. In this review we summarise data for the use of induction chemotherapy to define better which patients will likely benefit from this approach now and which questions are important in the design of future clinical trials.

Introduction

Head and neck cancers are a complex group of diseases defined by variations in histological features, anatomical location, and cause (figure 1).1 There are about 500 000 new cases per year worldwide, fewer than 10% of which occur in the USA.2 Given the heterogeneity of head and neck cancer, decision-making to select treatment is complicated. About 60% of patients have locally advanced disease (ie, stages III or IV, according to the AJCC [American Joint Committee on Cancer] system) at diagnosis. The precise definition of advanced-stage disease varies with subsite; most patients have a large primary tumour (ie, >4 cm) and involvement of regional nodes. Stage IV disease is classified as resectable, unresectable, or metastatic, with only about 5% of patients in the latter group at presentation.

Although treatment of head and neck cancer was once the realm of surgeons and radiation oncologists, over the past two decades medical oncologists have become an integral part of the treatment team. Improvements in radiotherapy and reconstructive surgical techniques as well as effective non-surgical curative treatment approaches have relegated radical surgeries that left patients with severe cosmetic deformity, functional impairment, and attendant psychosocial sequelae to the past. Current best practices need a multidisciplinary team approach that uses sequenced and concurrent combinations of the three modalities.

The results of these advances are site-specific and stage-specific, and include improvements in survival and quality of life through organ preservation. Current standards of care include primary chemoradiotherapy for unresectable disease, advanced nasopharyngeal cancer, and resectable disease where organ preservation is desirable; chemotherapy is added to postoperative radiotherapy for patients with high-risk pathological features.

Section snippets

Epidemiology and Survival

Historical survival data suggest that multimodality treatments cure at most 50% of patients with locally advanced disease. About 35% of patients have local recurrence and die from complications of locoregional disease; the remaining 15% die of distant disease. Although these numbers are sobering, they perhaps do not represent effects of recent shifts in the epidemiology of head and neck squamous-cell cancer and recent improvements in treatment.

More recent survival analyses incorporate

Improvement in treatment approach

Given both the increased complexity and potential toxic effects of combined treatment,12, 13 historical and current data must be analysed to determine how to become more selective when applying treatments. Characteristics of both the patient and the tumour—eg, tumour stage, location, and biology and host pharmacogenomics—may be used for this purpose.

Selection of patients and treatments can be optimised for the use of induction chemotherapy added to chemoradiotherapy in the setting of locally

Treatment of locally advanced disease

The first step in the development of multimodality care involved the use of postoperative radiotherapy in patients with adverse pathological features (ie, involved regional nodes; positive resection margin; and perineural, lymphatic, or vascular invasion). Although not proven with randomised studies, the approach has long been the standard of care since work by Lundahl and Huang.21 Variations in radiotherapy dosing, fractionation, and scheduling were also tested, but standard treatment remains

Rationale for induction chemotherapy

There are several theoretical advantages to preceding definitive local treatment (ie, chemoradiotherapy or surgery) with induction chemotherapy, including the potential of systemic treatment to suppress development of distant metastases, and the hypothesis that subsequent local treatment is more effective after reduction of tumour volume. Together, these benefits lower the risk of recurrence. Cisplatin-based induction chemotherapy leads to high objective responses, including complete responses

Induction chemotherapy in practice

Randomised studies of induction chemotherapy followed by surgery or radiotherapy compared with definitive local treatment alone date back two decades (table 1). They are numerous, but the results are easily summarised. Apart from two published trials,19, 20 induction chemotherapy had no benefit in survival compared with local treatment (surgery, radiotherapy, or chemoradiotherapy) alone, although many reported a reduction in distant metastases in patients allocated chemotherapy (table 1). By

Future directions

After several decades of studies involving thousands of patients, the role of induction chemotherapy remains controversial. The current interest in reassessing induction chemotherapy, however, is in the context of adding a more effective three-drug regimen of a taxane, cisplatin, and fluorouracil to a treatment that improves locoregional control—specifically, chemoradiotherapy. Before incorporating this treatment into clinical practice, it is imperative that a gain in survival is shown.

Conclusion

In the 1980s, induction chemotherapy before surgery or radiotherapy was the focus for integration of chemotherapy into the management of newly diagnosed patients. These studies, in the main, showed that local control was not improved, but that chemotherapy did suppress metastases. Although survival was not improved, it also was not jeopardised and larynx preservation was established. Clinical research initiatives in the 1990s investigated concurrent platinum-based chemoradiotherapy. This

Search strategy and selection criteria

Data for this review were identified by searches of PubMed and selected references from relevant articles with the search terms “head neck cancer”, “induction”, “chemotherapy”, “radiation”, “radiotherapy”, “randomised”, “chemoradiotherapy”, “organ preservation”, “neoadjuvant”. The same terms were used in a search limited to “reviews”. Abstracts from the American Society of Clinical Oncology Annual Meetings (2001–05) were also searched for these terms. Papers published from 1984 onwards

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