ABSTRACT: Although the need to combine thoracic radiotherapy with systemic chemotherapy in the curative treatment of limited small-cell lung cancer is now widely acknowledged, there is substantial disagreement on how best to do this. This paper reviews radiotherapeutic factors but also highlights the important interactions that occur with some classes of chemotherapeutics. Studies examining variables like dose and volume are clearly in order. Concurrent therapy given early has been adopted throughout most of the world, except Europe. The reasons for this are explored. Multiple studies are now showing excellent results with fewer total cycles of chemotherapy. Integrationof newer drugs is another challenge for clinical investigators at the close of this century. [ONCOLOGY 12(Suppl 2):15-18, 1998]
To increase survival, the treatment of small-cell lung cancer depends on effective chemotherapy to control systemic disease and thoracic radiotherapy to reduce local failure. Prophylactic cranial irradiation is employed to reduce the frequency of brain metastasis. The most effective treatment regimen remains contentious, particularly regarding which agents to use and how to blend the local therapy.
Since the advent of new agents with substantial activity, somewhat of a consensus now exists regarding the core agents for systemic therapy. We are uncertain, however, as to how to introduce them into otherwise successful regimens for limited small-cell lung cancer. Debate continues regarding which drugs to add and which old standards to delete. The use of thoracic radiotherapy in limited disease provides benefits in local control and survival, but local failure remains a significant problem. Variables like dose, volume, fractionation, sequence, and timing continue to be contentious issues, but relatively few trials have looked specifically into any of these factors. How much chemotherapy, ie, how many total cycles, and the best timing and sequence of thoracic radiotherapy continue to be debated as the millennium closes and we attempt to move forward with new approaches to treatment.
Complicating the study of these questions is the apparent decline in referral of limited small-cell lung cancer patients to centers that conduct clinical trials. The differences in results between regimens get smaller as more successful treatment results in fewer and later events (deaths and progression), but it has become more difficult to complete the trials with sufficient power in a timely fashion. Fewer patient resources are available to permit researchers to tackle complex questions about either modality. The good news is that large cooperative trials on two continents are reporting 2-year survival rates in excess of 40%,[2,3] a significant gain from the past era.
For many centers around the world, PE (cisplatin [Platinol]/etoposide [VePesid]) is the mainstay of systemic therapy. In some treatment centers, carboplatin (Paraplatin) has replaced cisplatin because of its ease of administration and decreased toxicity. Although carboplatin is more expensive, it can be safely administered on an outpatient basis, without incurring the expense of the hydration protocols needed for cisplatin.
The feasibility of this substitution is bolstered by a trial from Greece, which shows very similar outcomes (response and survival) when a fixed dose (milligrams per square meter as opposed to area under the time-concentration curve) of carboplatin was used. Based on the Hellenic trial, many are moving to substitute carboplatin for cisplatin. Cisplatin is perceived by most oncologists to be more toxic than carboplatin. On the other hand, there may not be as much toxicity or hydration requirement associated with cisplatin when its dose is restricted to
£ 60 mg/m². A considerable advantage of PE over doxorubicin and alkylating agents is its lack of intrinsic toxicity to heart and lungs. Furthermore, PE blends favorably with thoracic radiotherapy and may enhance its antitumor effects. Although significant esophageal toxicity occurs, it is generally limited to 2 to 4 weeks’ duration and rarely causes strictures.
Many clinicians remain steadfast to cyclophosphamide (Cytoxan)-based or doxorubicin-based chemotherapies. Unlike PE, these drugs have underlying cardiac and pulmonary toxicities when used alone and when added to thoracic radiotherapy may produce on net more harm to normal tissues than additive effects against the tumor. When cyclophosphamide-based or doxorubicin-based chemotherapy is used as stand-alone treatment in extensive disease, one could argue that either is acceptable, since neither is curative and there is no need to use thoracic radiotherapy on a routine basis. These agents are relatively inexpensive and can be administered on 1 day without the need for multiple office visits. Problems arise, however, when one attempts to integrate thoracic radiotherapy with any regimen including doxorubicin.
Thoracic radiotherapy has been used in many ways, and the factors influencing its effects require better clarification. Although the importance of variables like dose, volume of radiation exposure, fractionation, and timing has been appreciated for these past 15 years, there remains no consensus on any of these issues. Standard guidelines for determining dose and volume remain elusive and largely reflect the policies of groups or institutions.
Although Papac et al used a thoracic radiotherapy dose of 60 Gy and reported a local failure rate of only 3%, lower doses in the 45- to 50-Gy range are most commonly used. One large study compared once-daily vs twice-daily fractionation. Thus far, the only significant difference observed was in the degree of toxicity, and no significant measure of beneficial effect was reported. Some data are available on the timing of chemotherapy with radiotherapy, using concurrent, sequential, or alternating methods of integration, and the issue of early use of thoracic radiotherapy (ie, before the fourth cycle of systemic therapy) or later use of thoracic radiotherapy (ie, with the fourth cycle or later). However, as with the other factors, worldwide agreement as to what is best is lacking.
For the past 30 years, the dose of thoracic radiotherapy has remained between 40 and 50 Gy in continuous-course treatments for limited small-cell lung cancer. This dose is less than that typically applied for non-small- cell lung cancer, presumably because small-cell lung cancer has been so responsive. Few studies have been conducted to test a higher dose for efficacy.
Choi and Carey retrospectively analyzed data from the Massachusetts General Hospital and found improved local control with doses of 40 and 50 Gy in comparison with lower doses. Doses below 40 Gy were associated with a greater than 50% local failure rate, but doses between 40 and 50 Gy still failed at least 30% of the time.
Local failure has been considered less important than achieving systemic control. However, cure demands both local and systemic control. Clearly, chemotherapy alone produces responses, even complete responses, but the local failure rate is 90% in one large study.
As mentioned above, Papac et al used 60 Gy thoracic radiotherapy, which seemed to produce excellent control with only 3% local failure. However, that work has never been replicated, and, unfortunately, definition and duration of local control were not clearly defined. Surprisingly, few have followed this lead, as Papac’s results clearly suggest that higher dose controls local disease better.
In an attempt to determine a better dose of thoracic radiotherapy, Choi et al and the Cancer and Leukemia Group B (CALGB) have conducted a thoracic radiotherapy dose-seeking phase I study intended to identify the maximum tolerated dose of thoracic radiotherapy. This study used a comparison of twice-daily radiotherapy to once-daily radiotherapy. They were able to achieve total doses of 70 Gy when administered once a day, but only 45 Gy when given twice daily. Rather than defining the dose-limiting toxicity, this trial somewhat arbitrarily selected grade 3 esophageal toxicity as its end point, and this may not be truly dose limiting (grade 3 may reflect use of narcotic analgesics, or requirement for tube feedings for brief interludes without long-term sequelae). The thoracic radiotherapy was integrated concurrently with the fourth cycle, but there was no mention of volume (but the CALGB practice has been to use larger, prechemotherapy volumes). Although each patient category was very small, there were no trends favoring higher doses. A study comparing the established doses of 45 with 50 Gy thoracic radiotherapy vs larger doses will be needed to assess the influence of higher dose on local control and survival vs tolerability.
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