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SPECIAL FEATURE |
Department of Radiation Oncology, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425-0002
Strategies for combining the different modalities are the focus of this conference. The reason we employ more than one modality is that any one alone is inadequate. The use of each depends on an understanding of the benefits of each modality by itself and the failure of each modality when used alone. The use of more than one modality is costly in terms of both resources and toxicity. At one time, it was fashionable for any one modality to discredit the value of others. Today we seek to find answers on how to use the tools we have today, as we wait for the strategies derived from knowledge about genes and fundamental mechanisms. However, the outcomes with any one modality are not good enough in any stage, or any histology of lung cancer.
Surgery is sensible for localized cancer without regional or distant metastasis. Even in early-stage disease, surgery produces only marginally good results. Unfortunately, some patients die of lung cancer, dominantly distant disease, even after apparent complete resection. In early nodal disease, the addition of radiotherapy has not improved survival. This group has an even larger risk of systemic disease. Consequently, adding local therapy can influence local control, but it is baffling why anyone would expect an additional local therapy to influence clinically undetected systemic disease and survival. Rather than this being a failure of local therapy, it is the frailty in detecting occult disease, and at least until today, the inadequacy of our ability to provide effective systemic therapy.
Chemotherapy remains the treatment centerpiece for small cell lung cancer. It has forged a role in the treatment of stage III disease, either before surgery, before radiotherapy, or together with radiotherapy before surgery. The exact role, what drugs and the timing remain the subject of trials. Platinoid drugs form the foundation of today’s successful chemotherapy combinations. A second drug is almost always added, and there are debates about the value of adding a third, or even fourth drug. For small cell, the second drug is VP-16, etoposide. In non-small cell lung (NSCLC) the second drug commonly begins with the letter "V"—vindesine, vinblastine, VP-16, vinorelbine, but not vincristine, and many argue that VP-16 has a poor response rate as a single agent, even though survival with cisplatin-VP-16 is as good as with any other combination. Other drugs that have been used include ifosfamide and mitomycin C. Others have been tried and were formerly popular, but are no longer regularly used. There are promising new drugs—gemcitabine, the taxanes, topotecan, irinotecan—all have already shown evidence of activity in lung cancers, but their use with radiotherapy is still unfolding.
Radiotherapy is perhaps the most versatile and least understood modality. It has been the treatment of choice for lung cancer when surgery cannot be used. It has been used like surgery, as a local treatment, but also like chemotherapy, as a regional treatment, attempting to include contiguous lymph node-bearing regions. The dose of radiotherapy has been limited by the volume, and an inability to understand three-dimensional dose volume relationships, particularly in tobacco-abusing patients. We do not know how to predict for lung toxicity. A challenge for today is to escalate doses depending on volume of normal tissue irradiated. Radiotherapy had been restricted to doses in the 60-65 Gy in the past, but this was for volumes that included prophylactic treatment of lymph nodes. Re-defining doses and treatment volumes will allow better use of radiotherapy by itself, but, more importantly, as a partner in multimodal therapy.
Timing of the modalities provides a variety of choices, each with different potential benefits and liabilities. The sequential methods have the longest history. Pre-operative radiotherapy is a classic form of sequential therapy. Today we refer to "neoadjuvant" or "proto-adjuvant" therapy relating for the most part to chemotherapy before surgery, or before radiotherapy. Adjuvant therapy, or additional therapy after the more important therapy, has been extensively tested with older chemotherapy combinations and has not demonstrated great improvements in any measure of effectiveness. Post-operative radiotherapy has also not proven beneficial to survival, but there are recent retrospective trials that again raise the issue, and others that underscore the potential toxicity. A study of concurrent chemoradiotherapy in the post-op setting is just completed. It will show that therapy has toxicity, but the improvement in survival, if any, has not yet been detected. Consequently, the post-operative radiotherapy strategy does not enjoy universal popularity today, but there is increased enthusiasm for testing some of the newer drugs in this setting. Sequential therapies allow for assessment of the benefits and risks of each component of therapy.
Concurrent treatment uses at least two modalities at the same time. This strategy invites interactions between the modalities looking for the elusive "synergism" of effects, hopefully exclusively against the cancer, but usually it is less discriminating and causes additive or even synergistic toxicity. Large and unresected tumors harbor resistant cells. It is reasonable to anticipate that these are more likely to require more aggressive approaches.
Alternating modalities in swift sequence of days or weeks was tried in the 1980s with the promise of increasing antitumor effects without excess toxicity. Unfortunately, it seems that the toxic effects were not sufficiently reduced and the antitumor effects were not sufficiently improved. The radiotherapy used in these programs introduces gaps or "splits" in the treatment. These gaps allow for repopulation of tumor, which may explain in part the failed efficacy of this approach.
Small cell proves to be a very responsive tumor to either chemotherapy or radiotherapy. For disease confined to the thorax at presentation, local failure is a surprisingly high first sight of failure, even with the addition of thoracic radiotherapy. For disease disseminated at presentation but achieving a complete response, local failure occurs in 60%. By two meta-analyses, the addition of thoracic radiotherapy causes improved survival (and local control). Although there remains controversy, early and concurrent therapy seems to be associated with better survival than delayed and later treatment with radiotherapy. The role of surgical treatment is limited to odd cases with peripheral nodules without nodal or distant metastases. The problem of local failure needs attention, whether it be with improved drugs, altered thoracic radiotherapy dose or fractionation strategies, or timing of modalities alone or in combination.
Combined modality therapy is better for Stage III-a lung cancer (NSCLC), but Stage III-b remains unsettled. These combined modalities for Stage III provide the setting for clinical trials in the 1990s. Two surgical adjuvant trials have shown that surgery alone is poor treatment, and the standard of radiotherapy alone has fallen to very modest doses, added to only five weeks of chemotherapy before the thoracic radiotherapy. Studies now exist showing reduced systemic failure when even modest doses of chemotherapy are used. Concurrent cisplatin reduced local failure in a few studies but not consistently; a number of studies have shown no benefit. The critical III-a question is the value of surgery in these patients. Surgery trials have selected patients capable of the rigors of surgery, but many try to apply these observations to less-fit patients. We are obliged to clarify these facts by clear clinical trials. These efforts are hampered by the allure of new drugs crying like sirens, seducing us away from our duty to answer difficult questions. New drugs are clearly needed, but so are clarifications of how we combine modalities.
Brain failure and brain prophylaxis pose special questions for combined modality therapists. Judicious use of surgical therapy in select patients is warranted. The value of adjunctive radiotherapy is under test. For patients with multiple metastases, we have little to offer. Prophylactic (PCI) therapy in both small cell and non-small cell are very contentious subjects. There is recent information suggesting a net benefit, and a very modest frequency of late effects when PCI is sequenced after completion of systemic therapy. Also, NSCLC patients completing chemotherapy, radiotherapy, and surgery seem to have a higher-than-expected frequency of brain metastasis. Since these patients have achieved good outcomes, this group might offer a reasonable cohort to test the value of adjuvant brain treatment.
Combined modality management of lung cancer has made major strides in the last decade. There is a great deal of work to do to clarify how best to manage these patients while we await new clues from the bench.
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