Concurrent Chemoradiotherapy for Limited Small-Cell Lung Cancer

Introduction

Since the mid- to late 1970s, computed tomography (CT) scans have provided the means to assess tumor involvement, particularly central nodal involvement in patients with small-cell lung cancer (SCLC), which has improved our ability to select patients for therapy. Since that time, CT has profoundly improved our ability to target lesions and apply radiotherapy planning and treatment in more precise ways.

Today, we have newer imaging modalities, such as positron emission tomography (PET) scans,[1] tagged radiolabeled monoclonal antibody scans (Verluma scans, DuPont Pharma, Wilmington, Delaware), that may more clearly define extensive and limited disease and also provide better methods for following patients. Despite their costs, these technologies may save patients fruitless and ineffective testing and provide answers more efficiently, thus leading to lower overall costs. However, many pessimistically emphasize that these advantages of imaging have improved the selection of patients (so-called stage migration). These improved results may be attributed to the illusions caused by the staging rather than results of better treatment.

This paper will provide an overview of the current concepts of chemoradiotherapy and the results of its application in current clincial trials. It will also highlight the promise and pitfalls of this therapy over the next decade.

Rationale for Chemoradiotherapy

Local failure as a component of first failure and the inability of therapy to salvage patients after local recurrence motivated reincorporation of thoracic radiotherapy (TRT) into the clinical treatment of patients with limited small-cell lung cancer. The late 1970s spawned many studies, predominantly involving cyclophosphamide(Drug information on cyclophosphamide)- or doxorubicin(Drug information on doxorubicin)-based chemotherapy, commonly combined with TRT doses in the 30- to 40-Gy range. Although there was disparity among the study results, a recent international meta-analysis of these mainly cyclophosphamide- and doxorubicin-based trials showed a significant benefit afforded by the addition of thoracic radiotherapy.[2]

This benefit of thoracic irradiation was balanced by increased toxicity, commonly hematologic and esophageal, but a proportion also due to pulmonary toxicity. Late esophageal strictures were too frequent to be considered acceptable for standard therapy.[3] Nevertheless, a small but unequivocal survival advantage accrued to those who received thoracic radiotherapy.[2]

In patients with limited small-cell lung cancer the integration of radiotherapy with chemotherapy poses challenges. Issues about radiation dose, fractionation, the intensity and schedule of radiotherapy, and the intensity and duration or total cycles of chemotherapy require consideration. The potential for toxicity must be balanced against the prospect of improved cancer cell kill. Each chemotherapeutic agent must be understood in light of the fact that irradiating the target volume may augment intrinsic chemotoxicity or increase damage to normal tissue that has been sensitized by chemotherapy.

Thoracic radiotherapy is used routinely in limited small-cell lung cancer but less commonly in extensive disease, because the focus is on the need for systemic treatment. Interestingly, patients with extensive small-cell lung cancer who achieve a complete response have been reported to have local failure rates of 60%.[4] This may point to a role for thoracic radiotherapy, but local control may improve even if survival is only modestly affected.

Not until the 1980s was cisplatin(Drug information on cisplatin)/etoposide introduced and used for the initial treatment of small-cell lung cancer. Ihde and colleagues published results show that higher doses of both cisplatin and etoposide(Drug information on etoposide) increase toxicity and also offer no therapeutic advantage over less toxic, standard doses.[5] Etoposide must be administered orally or intravenously, on more than one or two occasions-with lower doses (80 mg/m²) for 5-day schedules and no more than 120-mg/m² doses for 3-day schedules. Furthermore, whether the addition of the other active agents, such as cyclophosphamide and especially doxorubicin (which causes clinical synergistic toxicity with radiotherapy), improve response, disease-free survival, overall survival, or local control, is not yet clear.

Radiotherapy Factors

Focusing on radiotherapy factors may provide avenues for improving treatment. Radiotherapy factors may influence toxicity, response, survival, and local control. The factors usually considered include: (1) total and daily radiation dose; (2) volume to be irradiated; (3) fractionation; (4) timing of radiation in relation to chemotherapy; (5) continuous vs split-course radiation; and (6) whether radiation should be given immediately or postponed until a later chemotherapy course.

Dose

Total physical dose measures how much radiation has been deposited in the tissue. The biologic dose can be calculated based on such factors as the addition of modifying agents and the methods (time, fractionation, volume) of administering the radiation that may profoundly alter the observed effects. When combined-modality regimens are used or compared, physical doses are one consideration, but results may depend on these other variables as well.

Defining a Dose-Response Relationship—In attempting to define a dose-response relationship, Choi and Carey retrospectively analyzed patients treated at the Massachusetts General Hospital.[6] Isolating the physical dose as the variable and measuring local control, they reported that doses between 30 and 35 Gy produced only a 50% local control rate. Doses between 40 and 50 Gy increased local control to 70%.

These data are retrospective, however, and the analysis does not account for the chemotherapy regimen used. Moreover, the patients given the lower radiation doses were treated in the more distant past than were those given the higher doses. Biases as to why these doses were selected are neither identified nor discussed.

In the Cancer and Leukemia Group B (CALGB) trial described by Perry et al, the actuarial local control rate was 50% at 36 months. In this prospective trial of cyclophosphamide-based chemotherapy, two arms included 50 Gy of thoracic radiotherapy given concurrently either immediately with cycle one or delayed to cycle four, whereas thoracic radiotherapy was not used at all in the third arm.[7] The actuarial local failure rate at 3 years was 90% when no thoracic irradiation was employed.

A study from Yale reported a local failure rate of only 3% after 60 Gy of thoracic radiotherapy.[8] However, this set of patients had a relatively short median survival, perhaps indicating that the systemic therapy used, cyclophosphamide/etoposide/methotrexate, was not as effective as cisplatin/etoposide.

Choi et al reported on a recent prospective CALGB trial that attempted to define a dose-response relationship.[9] However, the end point chosen was acute esophagitis. The limited data compared twice-daily to once-daily treatment; however, few patients were entered for each dose cell in this phase I, dose-escalating trial.

Whether acute transient esophagitis is truly dose-limiting is not clear. Persistent, enduring acute esophagitis can be dose-limiting, however, and may be related to the length of the esophagus in the radiation field or to fractionation methodology rather than to the total dose. If acute esophageal toxicity is transient, reversible, and does not lead to permanent injury, it may be an appropriate end point for dose-escalation trials.