Integrating Thoracic Radiotherapy in the Treatment of Limited Small-Cell Lung Cancer

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,[1] 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.[4]

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,[5] 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[6] 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.[2] 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.

Dose

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.[7] 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.[4]

As mentioned above, Papac et al used 60 Gy thoracic radiotherapy, which seemed to produce excellent control with only 3% local failure.[6] 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.[8] 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.

Volume

The volume of thoracic radiotherapy treatment has been analogized to non-small-cell lung cancer, and the more successful strategies applied in Hodgkin’s disease, and the century-old paradigm of Halsted-including en bloc lymph node stations considered at risk. Failure after thoracic radiotherapy appears to be in sites of prior bulk disease, not at the margins of the ports or in neighboring lymph node stations, such as the supraclavicular or contralateral hilar regions, areas that, when treated, cause exposure to a longer length of esophagus or more lung alveoli.

Standing defenses of this strategy were that inclusion of uninvolved nodes caused no added toxicity or risk. Precise data on these points are hard to find. Definition of failure in subsets or regions (primary site, in regional nodes [hilum mediastinum], in nodal sites adjacent to these, or in lung parenchyma away from the original primary site [ipsilateral or contralateral] or pleura [bulky disease or fluid]) may clarify volume strategies and help resolve some confusing issues. It is important to consider whether failure can be prevented by using expanded radiotherapy portals or adhering to the original target volume and size, or whether failure largely represents inadequate systemic control.

Use of larger portals, either after chemotherapy reduction or at the outset, exposes tissues to both radiation and chemotherapy, and may compound toxicity that limits acceptability of combined-modality therapy.

Until relatively recently, the volume of thoracic radiotherapy included sites of initial bulk and uninvolved nodes. If radiotherapy is used concurrently at cycle 1, the presenting volume of disease is the only logical choice, with or without inclusion of clinically uninvolved nodal regions. If one delays to subsequent cycles or defers thoracic radiotherapy for use after completion of chemotherapy (sequential treatment), a postchemotherapy volume could treat residual disease, but reduce exposure of radiation to normal tissues formerly included to treat the prechemotherapy volume and uninvolved lymph nodes. This subject has been reviewed;[9] however, no compelling data for either strategy exist, and modern PE-based chemotherapy studies have not addressed this issue.

Fractionation

Fractionation issues involve delivery of thoracic radiotherapy and total time of treatment. As with delivery of chemotherapy as continuous infusion, daily times five, weekly, or once every 3 to 4 weeks, schedules are favored based on attractive scientific theory, but the convenience of schedules often dictates what is used.

Thoracic radiotherapy fractionation, by time-honored tradition, has been once a day, 5 days a week. We have learned that fractions larger than 2 to 2.5 Gy risk normal tissue damage that is commonly expressed well after therapy is completed. Decreasing the fraction size below standard necessitates longer treatment times and higher total doses achieved to obtain an equivalent effect against the tumor. The benefit is that lower doses are associated with fewer late-effect injuries, such as esophageal stricture and pulmonary fibrosis. (note: This does not apply to acute injury like esophagitis or pneumonitis.) We also know that small-cell lung cancer grows rapidly clinically, and that in vitro sensitivity is such that smaller doses per exposure exponentially kill small-cells and do not produce as much injury to normal tissue.[10]

A series of pilot studies verified these observations [11-13] and used newer variations of the PE combination initially described by the Memorial group [14] as initial treatment. Others had used PE with once-daily schedules of thoracic radiotherapy.[15,16] We reported initial results of a trial of over 400 patients comparing these two strategies, and the results surpassed all expectations, in terms of 2-year survival, for both arms. The only significant observation has been significantly more esophagitis for the twice-daily arms.[2]

Recent, and as yet unpublished, analysis has demonstrated a signifi-cant survival advantage for the twice-daily regimen, showing 46% 2-year survival and nearly 30% 5-year actuarial survival. The results in both arms are superior to any previously conducted large trial. Although the thoracic radiotherapy regimen used was an accelerated, hyperfractionated schema delivering 45 Gy in 3 weeks (vs 45 Gy in 5 weeks), it is fair to hypothesize that a larger dose (55 to 65 Gy) administered in standard fractions, or a comparable dose delivered in 3 weeks (2.6 to 3.5 Gy/day), might produce similar survival. With fractionation, the issues of dose, time, and toxicity confound unequivocal isolation of one variable in any trial.

Sequence

Despite general agreement that a combined-modality approach to treatment is necessary, there is considerable controversy and discussion about timing and sequence. Concurrent, sequential, and alternating chemotherapy with radiotherapy are the three options for combining both modalities. One could also use any of these early in the treatment course, and I will arbitrarily label treatment within the first three cycles as early, and treatment at or after the fourth cycle as late.

The use of concurrent therapy has been adopted in North America [2,17] and Japan.[3] Results of trials conducted in Europe suggest that the use of concurrent therapy produces more toxicity than alternating therapy, and that sequential therapy is the safest.[18,19] None of the strategies leads to better survival. Sequence, however, is not the only factor. Europeans use PE chemotherapy less frequently and more commonly use doxorubicin, even in strategies that employ concurrent use with thoracic radiotherapy. Experience in the United States has revealed that significant toxicity occurs when doxorubicin is employed in proximity to thoracic radiotherapy.[20,21] Even cyclophosphamide-based regimens[22] are associated with excess toxicity. An important point is that sequence, toxicity, and possibly synergy are also dependent on choice of chemotherapy. European studies strongly indicate that the use of doxorubicin and concurrent or alternating strategies leads to an unfavorable ratio of toxicity to potential benefit. From these data, it is reasonable to conclude that doxorubicin may be more responsible for the problems than the timing.

Timing

Since systemic risk has primacy, and the use of thoracic radiotherapy may necessitate reducing the doses or intensity of the chemotherapy, many oncologists favor giving the bulk of chemotherapy before thoracic radiotherapy. The Perry study from CALGB bolstered this opinion.[4] In this study, patients received either no thoracic radiotherapy, or thoracic radiotherapy concurrent with either cycle 1 or cycle 4. The study reported that the cycle 4 timing produced the best results. Those randomized to cycle 1 therapy indeed were less likely to get full doses for subsequent cycles of chemotherapy.

Murray et al[17] in a trans-Canada trial showed that early concurrent thoracic radiotherapy (cycle 2) produced superior survival to delayed concurrent therapy (cycle 6). A difference between these two studies was the chemotherapy regimens. The Perry trial used concurrent cyclophosphamide, etoposide, and vincristine (Oncovin) and later substituted doxorubicin for the etoposide. The Canadian trial used six alternating cycles-cyclophosphamide, doxorubicin, and vincristine for cycles 1,3, and 5 and cisplatin/etoposide for cycles 2, 4, and 6.

Recently, Takada et al[3] reported the trial of concurrent thoracic radiotherapy (45 Gy) and PE chemotherapy in cycle 1 vs sequential therapy with thoracic radiotherapy (45 Gy) following four cycles of PE. The concurrent therapy was significantly superior. The Japanese trial[3] and the US fractionation trial[2] both used only four cycles of PE chemotherapy, and these shorter-course therapies have produced excellent survival.

Future Directions

The most pressing issue in combined-modality therapy is the development of strategies for incorporating new drugs like gemcitabine (Gemzar), the taxanes (paclitaxel [Taxol] and docetaxel [Taxotere]), tirapazamine, the topoisomerase I inhibitors (irinotecan [Camptosar], topotecan [Hycamtin]), and vinorelbine (Navelbine). Establishing response rates for these agents and assessing the feasibility of combining one or two of them with PE (or substituting carboplatin) is a high priority.

Combining two active new drugs like gemcitabine and topotecan, or paclitaxel and tirapazamine, may hold promise. Once a new regimen has been determined to be active, one could contemplate using two cycles before definitive therapy, thus avoiding the uncertainties of combining these drugs with radiotherapy. It is clear that there will be additive toxicity with the use of gemcitabine and the taxanes. Less likelihood of interaction exists with tirapazamine or vinorelbine. But the data are really too premature to know what drugs to use, how many cycles to try, or whether we should merely add a new drug to PE.

The Radiotherapy Treatment Oncology Group has an ongoing pilot directed by Abrams and Ettinger of Johns Hopkins, Baltimore, Maryland, USA. It also incorporates twice-daily radiotherapy. New strategies for prophylactic cranial irradiation are also warranted.

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