Synchronous chemoradiation for squamous carcinomas

For many decades the primary treatment for common cancers has mostly been radical surgical resection (for example, for cancers of the large bowel, lung (non-small cell), kidney) or radical radiotherapy for inoperable cases or when tissue preservation is desirable and the cancer sufficiently radiosensitive (for example, cancers of the head and neck, notably larynx). Surgery and radical radiotherapy are sometimes competitors, but in other cancers (such as breast cancer) limited surgical intervention and radiotherapy used conjointly can offer the best compromise between the twin requirements of excellent local control with tissue preservation and near perfect cosmesis. Over the past few years a quiet revolution has been taking place, dramatically altering the treatment options in a surprisingly large proportion of patients with solid tumours. For patients with a squamous primary cancer at most of the common sites it is increasingly clear that traditional treatment with surgical excision, radiation therapy—or both—no longer offers the best possible choice.

Giving chemotherapy in the adjuvant setting—shortly after completion of primary surgery or radiation therapy—has often been regarded as the best possible use of this valuable but demanding form of treatment. However, only recently has synchronous chemoradiation therapy been seriously assessed in the common squamous cancers. A simple but fundamentally important shift in timing has brought the use of chemotherapy alongside the radical radiation.

In the United Kingdom one of the most influential trials was in a relatively uncommon cancer, squamous carcinoma of the anus, which attracted a remarkable degree of participation in 1993-5.¹ Use of synchronous chemoradiation therapy with mitomycin C and fluorouracil proved much more effective than radiation alone, with dramatic improvement in avoidance of salvage surgery (permanent colostomy) and even in cause specific survival. In oesophageal cancer the results of radical chemoradiation have been equally impressive, again proving clearly better than radiation alone, even when the radiation dose was deliberately reduced in the combined therapy arm for fear of unacceptable toxicity.² With modern imaging the precision of therapy can be increased still further, so dose reduction of this kind no longer seems necessary.

In cancer of the cervix, another common tumour where treatment failure often leads to appalling complications, the results of three radical chemoradiation studies led the New England Journal of Medicine to post the trial results on the web before the articles appeared in print, to avoid criticism that important new findings were being deliberately withheld.^3–5 In squamous cancer of the vulva there are fewer studies of radiochemotherapy, largely because it affects mainly older patients. However, many centres now treat this disease in much the same way as anal cancer, because of similarities in aetiology, low pelvic location, and modes of spread. The results of chemoradiation have been so encouraging that this approach has even been proposed as an alternative to radical surgical resection.⁶

Improvements in both local control and overall survival, much harder to achieve, have now been shown in nearly all these cancers—cervix, oesophagus, anus, and head and neck.^1–7 It remains unclear whether synchronous chemotherapy acts chiefly as a radiosensitiser or is independently cytotoxic in producing the additional benefit,⁸ but the former explanation seems more likely since the timing of the chemoradiation interaction is so crucial. Neither neoadjuvant (given before radiation therapy) nor subsequent chemotherapy (after completion of the radiation programme) seems anything like as beneficial, at least for head and neck sites⁷ and cervix, despite the often dramatic tumour shrinkage seen when chemotherapy is given first.

In head and neck cancer a comprehensive meta-analysis published last year suggested an overall improvement in survival of 8% from synchronous chemoradiation therapy.⁷ It had already been known since the mid-1980s that such treatment dramatically improved local control,⁹ which is especially valuable in these cancers since recurrences after radiation require major salvage surgery for any prospect of cure. Laryngectomy, glossectomy, or complex resections all lead to unavoidable, often permanent, difficulties in speech, swallowing, or oral function. Even in carcinoma of the bronchus, where studies have been more delayed, several trials have now suggested that radical synchronous chemoradiation therapy for inoperable cases (non-small cell) is a better bet than radiation therapy alone or radiation followed by chemotherapy.¹⁰,¹¹

Many important issues need clarifying. In future studies of squamous carcinoma arising from the major anatomical primary sites, can the radiation alone control arm now be abandoned? We believe it can and should, providing impetus for more intensive radiation or chemotherapy programmes to be randomised against current standards. A good example might be the use of more compressed regimens of radiation therapy for head and neck cancer,¹² alongside synchronous chemotherapy. Earlier this year a large Danish study showed clear benefit from adding a single additional fraction of radiation therapy once a week (6 rather than 5 per week), reducing the overall treatment time by one week.¹² Twice daily radiotherapy should not tax the resources of even busy departments, if given on only a single day a week. Certainly the continuous hyperfractionated accelerated radiotherapy (CHART) programme has proved logistically too difficult for most departments to implement, despite its benefit in local control and even survival in patients with squamous carcinoma of the lung.¹³ Chemoradiation therapy will probably prove a more feasible and practical means of achieving similar benefit. These questions must be urgently addressed since it is clear that synchronous chemoradiation therapy is here to stay. It represents the most exciting advance in solid tumour oncology over the past decade.