It is now established that the treatment of choice for limited small-cell lung cancer (SCLC) in the United States, Canada, and Japan is thoracic radiotherapy (TRT)
ABSTRACT: It is now established that the treatment of choice for limited small-cell lung cancer (SCLC) in the United States, Canada, and Japan is thoracic radiotherapy (TRT) combined with etoposide (VePesid), either alone or in conjunction with other agents, especially a platinum agent. The specific factors related to the use of TRT in the treatment of limited SCLC are: (1) dose (total and daily), (2) volume to be irradiated, (3) fractionation, (4) timing of radiation relative to chemotherapy (concurrent, at the same time; alternating, using both within weeks; or sequential, all of one followed by all of the other without any overlap), (5) whether radiation should be given earlier or later in the treatment course, and (6) whether to use a split course (rest intervals during a course of radiotherapy) or a continuous course of radiation. This paper discusses each of these factors. [ONCOLOGY 11(Suppl 9):31-37, 1997]
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, 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.
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- or 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.
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. Nevertheless, a small but unequivocal survival advantage accrued to those who received thoracic radiotherapy.
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%. 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/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 increase toxicity and also offer no therapeutic advantage over less toxic, standard doses. 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.
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.
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. 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. 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. 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. 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.
The tissue exposed to radiation obviously needs to include the tumor. Additional tissues are commonly included in the radiation field for a variety of reasons. Before the use of CT scans, frontal chest x-rays determined the extent of tumor, but lymph nodes were difficult to appreciate. Imaging of the lymph nodes is still inaccurate: CT scans may yield both false-positives and false-negatives, failing to detect involvement of normal-sized lymph nodes. Nonetheless, CT allows clinicians to see mediastinal adenopathy and judge for themselves whether the nodes may be involved.
Moreover, CT scans provide new ways to define targets, determine volumes of "normal" lung, and record the density of all tissues traversed by beams. This, in turn, allows for an accurate record of dose deposited (so-called inhomogeneity correction) and provides a tool to redefine the tolerance of so-called normal lung for partial volumes. (Although not involved with cancer, the lungs of most small-cell lung cancer patients are not normal.)
The volume to be irradiated may have some influence on tumor control and failure pattern, but the probability of pulmonary complications also increases with larger volumes. In the past, given the uncertainty of tumor extent and the knowledge of normal lymphatic anatomy, radiotherapy portals were modeled on those used to treat Hodgkin's disease; ie, they were inclusive and treated many levels of lymph nodes. The theory in Hodgkin's disease was that dynamic blocking would provide sufficiently low doses to prevent injury to normal tissue.
Years later, however, we are seeing second lung malignancies after successful treatment of Hodgkin's disease, and thus, this wide-field concept has defects even for Hodgkin's disease. More importantly, however, lung cancer does not respond to the lower doses thought to be effective for lymphoma, and the larger volumes employed have impaired dose escalation, leading to an artificial ceiling at 60 Gy. Only recently has this ceiling been exceeded by researchers attempting to address the poor local control observed with 60 Gy.
To these extended volumes, radiation oncologists added safety margins that ensure dose coverage because of physical radiation build-up (at air-tissue interfaces) and also account for day-to-day variations in set-up by technologists/therapists, as well as inadvertent patient motion (physiologic as well as squirming). These volumes were in keeping with the prevailing methods of surgery of en bloc resections and were logical extensions of the Halsted theories concerning disease spread by contiguity. Perhaps less logically, shields to protect the spinal cord were applied even though they likely decreased the radiation dose to regions of overt central nodal disease.
Is Larger Better?-Many have suggested that treating the lymphatics, particularly the supraclavicular fossa, is wise. Even though the risk of disease is probably not very high, there is no disadvantage to including them in the treatment field. However, particularly in the era of combined-modality therapy, volumes that include the supraclavicular fossae also treat longer segments of the esophagus. Indeed, these volumes commonly include lymphatics never addressed by curative surgical dissections.
A reason to reduce the volume irradiated is the increased toxicity likely in combined-modality regimens when healthy tissues are exposed to both chemotherapy and radiation. The theory that the gain is worth the small price has been supplanted by further experience. This experience suggests that the gain afforded by larger volumes is negligible and that the price seems to be higher than anticipated with regard to the incidence of esophagitis and lung injury and, possibly, even hematologic toxicity.
The other price is the artificial limit on tumor dose. A recent appraisal of nonprotocol small-cell lung cancer patients at the Mayo Clinic suggested that larger volumes were no better than more conservative ones. (For further discussion of this issue, readers are referred to our recent review of the benefits and liabilities of field size.)
Reassessing the need for expansive volumes makes sense because of the risk of exposing normal tissues to toxicity, especially when combined-modality programs are used. As noted, recent analysis of long-term follow-up of patients with Hodgkin's disease indicates that large-volume treatment is associated with an increased frequency of second cancers, particularly lung cancers.
Modern treatment planning allows for better target definition, as well as better identification and protection of critical structures. One can more accurately record doses to parts of organs, which permits one to assess the tolerance of such organs. The tolerance of the esophagus, heart, spinal cord, and lung may be reassessed given the ability to define more precisely the volume of these organs that have been treated and the exact radiation dose delivered.
Thus, continued use of larger volumes, with no data to support their efficacy or define their toxicity, does not seem warranted. Nevertheless, important clinical questions remain that clinical trials could answer.
The standard daily radiation dose to treat lung cancer has ranged from 1.8 to 2.0 Gy in the United States. ( It is larger elsewhere.) Until recently, the target dose in non-small-cell lung cancer (NSCLC) has been 60 Gy delivered over 6 weeks. Alternate strategies for delivering radiation to the chest are receiving a great deal of interest.
Hyperfractionation-Hyperfractionation methods use 1.0- to 1.2-Gy fractions more than once each day. With such small individual doses, less late-effect damage is done to sensitive adjacent normal tissues. However, for many solid tumors, one must question how effective these small fractions are at killing cancer cells. Although the physical doses tend to be larger and the total treatment time is roughly the same, the intervals between fractions allow repair-both in normal tissues and in the tumor. Thus, part of the antitumor effect of the increased physical dose is lost due to repair between fractions.
Accelerated Schemes-Accelerated schemes provide more intensive radiation in a shorter time frame. The fraction sizes tend to be larger (1.4 to 2.0 Gy) than those used with hyperfractionated schemes but are not greater than the standard United States fraction size. As a consequence, this strategy does not require an exquisitely sensitive tumor cell to exert its antitumor effect.
With an accelerated scheme, the overall time of treatment tends to be shorter than that needed for standard fractionation, and the total physical dose is lower, limited by the more intense acute effects to normal tissues such as the esophagus. Since the dose is applied in a short period, its biologic effect may be similar to or even greater than that of a standard dose.
This dose-intense radiotherapy gives more radiation per unit time than standard or hyperfractionated schemes. It also addresses rapidly proliferating subclones of cells, which repopulate between more lengthy time intervals. However, because of the intensity of accelerated schemes, the acute effect on tissues and tissue tolerance limit the total dose.
The Mount Vernon studies in non-small-cell lung cancer have pushed the accelerated schedule to give 54 Gy in only 12 days by using three fractions of 1.5 Gy daily, including weekends. In a comparative, randomized, prospective trial, this accelerated scheme produced a 2-year survival rate of 30%, as opposed to a rate of 20% achieved with 60 Gy in standard fractions and times.
The concept of repopulation has stimulated more interest in accelerated schemes. This theory holds that even as tumors are regressing clinically, repopulation is taking place microscopically. Strategies to surmount this effect call for shortening and intensifying the radiation.
Acute effects on normal tissues are likely to increase if this strategy is carried out. Treatment interruptions are called into question as well. For years a strategy of "split-course" radiation was used. This provided for a planned rest interval of 2 to 3 weeks during treatment to allow the tumor to regress and normal tissues to heal. If the acceler-ated repopulation theory is correct, split-course delivery unfortunately decreases the regimen's efficacy by promoting the repopulation of tumor cells. Any break, including weekends, might be viewed as accelerating repopulation.
For both hyperfractionation and accelerated schemes, the interval between doses has ranged from 4 to 8 hours to allow for repair of healthy tissues. For both of these multiple daily schemes, acute tissue reactions remain dose-limiting. In the era of the SCLC meta-analysis, doses and fractionation schemes generally were limited to 30 to 50 Gy in 2 to 5 weeks.
Fractionation Schemes Compared-Perhaps not surprisingly, because of the apparent exquisite sensitivity and responsiveness to chemo- and radiotherapy of small-cell lung cancer, the practice in the United States for the last 2 decades has been to deliver 40 to 50 Gy in 3 to 5 weeks, even though 60 Gy has been the standard dose for non-small-cell lung cancer. The total dose and fractionation scheme for thoracic radiotherapy in small-cell lung cancer, which is not firmly established, will be discussed below.
Table 1 shows the relative scales of two acute- and two late-effect parameters using the nominal standard dose equations, which include a time variable, and the a/b models, which omit time but rely heavily on individual fraction size. The biologic effective dose depends on a/b ratios, which are estimates that have been assigned as 10 for acute reactions and 3 for late reactions since direct measurements are not possible in clinical tumors.
Table 1 demonstrates the relative differences between 45 Gy given once daily and twice daily, and compares them to reference non-small-cell lung cancer schemes using 60 Gy, 69.6 Gy given in a hyperfractionated schedule, and 54 Gy given in an accelerated schedule. Despite the disparity in the physical doses in the displayed schemes, the biologic effects are different, and the yardsticks used demonstrate the differences in acute and late effects.
Many treatment fractionation schemes have titrated doses by the acute effects, but the late effects may vary considerably. Simply stated, the smaller the fraction size and the longer the duration of treatment, the lower is the likelihood of late effects. However, protracted schemes risk the emergence of repopulating resistant clones. This must be balanced against the demand to destroy acutely proliferating tumors and the relative risks to acute tissues.
These are complex issues that can be resolved only through clinical trials. The displayed models aremathematic attempts to predict these effects.
Timing of Modalities
Because normal tissues and tumors are exposed to both chemotherapy and radiotherapy, the results of clinical trials must be assessed by their relative toxicity and relative efficacy. In small-cell lung cancer, with its propensity for systemic metastasis, chemotherapy remains the cornerstone of therapy. Nevertheless, radiation may kill chemotherapy-resistant cells. Furthermore, these chemotherapy-resistant cells may be eliminated by certain sequences of radiotherapy with chemotherapy but not by others, and judicious timing may eliminate such cells before they have the opportunity or ability to metastasize. Once chemotherapy-resistant clones leave the local site, local therapy is likely to be in vain, and patients succumb unless strategies address the distant, resistant disease.
The choice of chemotherapeutic agent and its timing relative to thoracic radiotherapy may also influence toxicity. Tumor and normal tissue effects have been modeled in laboratory systems.
Lelieveld and colleagues reported on the use of a variety of different chemotherapy schedules in rodent tumor and normal tissue models. Although these models did not include all of the drugs currently used against small-cell lung cancer, the report underscores the importance of timing and specific chemotherapy properties that may influence the therapeutic index. It points out that adding doxorubicin to some schedules produces, overall, more toxicity than increased tumor cell kill. On the other hand, cisplatin-based schedules were more likely to produce a net therapeutic gain by destroying more tumor compared with damage to normal tissue.
Clearly, some drugs have intrinsic organ toxicity. If an organ is to be irradiated, using a drug that also causes toxicity to that organ may decrease the organ's tolerance. Drugs with intrinsic pulmonary toxicity are likely to pose a hazard if substantial volumes of normal lung must be irradiated. Doxorubicin may pose problems because of the augmented normal tissue effects it causes when used in close temporal proximity to thoracic radiotherapy.
Concurrent vs Sequential vs Alternating Therapy-Thoracic radiotherapy may be combined with systemic therapy in three basic ways: the sequential approach, which provides all of one modality followed by the other; the alternating approach, which gives either modality during week 1, followed by the other during week 2 or 3, followed by or interdigitated with rest periods to allow normal tissue to recover; and the concurrent approach, which gives both modalities at the same time. There are variations that combine the basic features of these approaches. Some studies use one to four cycles of chemotherapy first, followed by concurrent therapy. These sequences may be important in either the efficacy or the toxicity of the regimens.
In the United States, concurrent therapy has been considered the standard for clinical trials when cisplatin/etoposide is used. On the other hand, in clinical practice, many American physicians have taken the agents and doses from concurrent schemes and applied them instead to a sequential strategy, presuming the outcomes will be similar. The meta-analysis described above included no up-front cisplatin-based trials; moreover, despite testing for an effect of sequence, the investigators found no difference when comparing alternating with sequential methodologies.
Recently, Takada and his colleagues from Japan showed that the concurrent administration of radiotherapy with cycle one of four cycles of cisplatin/etoposide produces superior survival when compared with the same chemotherapy regimen followed sequentially by the same radiotherapy treatment. Thus, concurrent therapy was isolated as the variable that improved survival over the sequential strategy. The 2-year survival rates of patients in both arms exceeded 40%.
Early vs Delayed Concurrent Therapy-Two trials looked at the timing of concurrent thoracic radiotherapy with chemotherapy.[7,18] The CALGB reported a randomized trial of thoracic radiotherapy comparing three arms: cyclophosphamide-based chemotherapy alone (no thoracic radiotherapy), concurrent thoracic radiotherapy with cycle one, or concurrent thoracic radiotherapy with cycle four. The early administration of thoracic radiotherapy with chemotherapy attenuated subsequent chemotherapy doses, whereas delaying thoracic radiotherapy until cycle four allowed chemotherapy in fuller doses.
The delayed-thoracic radiotherapy treatment arm seemed to produce, or at least was associated with, better survival. Both thoracic radiotherapy arms produced better local control than chemotherapy alone, but all arms had less than 50% local control. No cisplatin/etoposide therapy was used in this study, although patients may have received it after failure of the primary regimen.
A Canadian trial alternated cyclophosphamide/doxorubicin/vincristine with cisplatin/etoposide. Thoracic radiotherapy was randomized to be early; concurrent with cycle two, which was a cisplatin/etoposide cycle; or delayed, concurrent with cycle six, the last cisplatin/etoposide cycle. Both arms received cyclophosphamide/doxorubicin/vinblastine as the first cycle and as interdigitating cycles (cycles three and five) between the three cisplatin/etoposide cycles (cycles two, four, and six).
The early concurrent therapy significantly improved survival. The authors theorized that early therapy eliminated a chemotherapy-resistant clone that was prone to metastasis, and that once a resistant cell escapes the primary, the patient is doomed. Eliminating this clone in a proportion of patients reduced that phenomenon and improved survival to a small but significant degree.
Pilot studies conducted in the 1980s suggested better outcomes in patients with limited small-cell lung cancer when cisplatin/etoposide is used with thoracic radiotherapy. The Southwest Oncology Group (SWOG) ultimately reported on a pilot study that started at Wilford Hall Air Force Base, and the Eastern Cooperative Oncology Group (ECOG) published follow-up of a University of Pennsylvania study. Both studies employed early concurrent therapy with cycle one cisplatin/etoposide treatment and thoracic radiotherapy. The results of both pilot studies suggested a 2-year survival rate of about 40%.
An Intergroup study was designed to test the effects of concurrent cisplatin/etoposide and thoracic radiotherapy. The ECOG, joined by the Radiation Therapy Oncology Group and, later, SWOG, conducted and recently completed a trial randomizing patients to one of two arms: (1) 45 Gy in 5 weeks delivered as one 1.8-Gy fraction per day, as was done in the SWOG study; or (2) 45 Gy in 3 weeks delivered as two 1.5-Gy fractions daily, as was done in the ECOG study. Patients in both arms were treated with concurrent cisplatin (60 mg/m2 intravenously on day 1) and etoposide (120 mg/m2 daily intravenously for 3 days). Only four cycles of chemotherapy were used-no maintenance treatment-and full doses were mandated for cycles one and two, irrespective of cycle one toxicity.
The study accrued over 400 patients in 3 years. Treatment was well tolerated, with few deaths, and there was good compliance with the study guidelines.
The trial now has 2 years' minimum follow-up. Both arms produced at least a 40% 2-year survival. Significantly more esophagitis, particularly grade 3 esophagitis, occurred in the twice-daily arm; however, the incidence of grade 4 complications did not differ between the two arms. Neither regimen caused long-term strictures.
Local control appears to be significantly improved in the twice-daily thoracic radiotherapy arm. A number of end points-median survival, 2-year survival, duration of response-tend to favor twice-daily thoracic radiotherapy; however, given the sample size, the differences are not significant.
The important result of this trial is that cisplatin/etoposide therapy and concurrent thoracic radiotherapy produce 40% survival at 2 years with only four cycles of chemotherapy. Any differences with the hyperfractionated accelerated treatment are more modest than the study was designed to detect, namely, a 15% survival difference at 2 years.
The current world standard would seem to be cisplatin/etoposide plus concurrent thoracic radiotherapy. The Europeans continue to include doxorubicin in their treatment schedules. As a consequence, they persistently report excess toxicity and poorer results than Canadian, Japanese, and United States' trials but steadfastly reject the concept that concurrent or alternating therapy is better than sequential therapy because of doxorubicin's ensconced position. Economic reasons related to the cost of the drugs, the need for more treatment days, and hospital costs with the platinum-based regimen underlie this practice.
Because of the high clinical relapse rate in the brain and the inability of most drugs to penetrate the blood-brain barrier, brain irradiation to prevent central nervous system relapse was adopted in the early 1970s. The downside of prophylactic cranial irradiation (PCI) was the risk of late effects, dementia, and imaging abnormalities. These late effects have been attributed to the fraction size, the timing of PCI relative to chemotherapy, or the use of PCI during the first, second, or third cycle of chemotherapy. Prophylactic cranial irradiation may damage or impair the blood-brain barrier and allow chemotherapy to seep into the central nervous system during subsequent cycles.
The results of early PCI trials have been reviewed extensively, but most estimated failure rates are derived from crude relapse figures rather than the use of actuarial methods. This seri-
ously underestimates the magnitude of brain failure in surviving patients. Also, the frequency of brain toxicity has been overestimated. Prior randomized trials commonly showed a reduction in the brain failure rate, but this did not lead to a survival advantage.
Prophylactic cranial irradiation remains controversial. The latest information comes from a prospective randomized trial conducted in France. This trial randomly assigned over 300 patients who had achieved a complete response (most of whom had limited disease initially) to either 24 Gy in eight fractions (3 Gy per fraction) or to observation with only neurocognitive assessment and imaging follow-up.
The actuarial rate of total brain relapse exceeded 60%. The untreated observation group had a threefold increase in first-site brain metastasis. There was a 7% difference in survival, which was insignificant given the numbers in the trial.
A trial from the United Kingdom and the European Organization for the Research and Treatment of Cancer has largely verified these results. This study demonstrated that 24 Gy in 2-Gy fractions was largely ineffective, indicating that lower biologic doses do not work. The frequency of late
effects in these studies was less than 10%.
The remaining issues in the combined-modality treatment of small-cell lung cancer include the problem of systemic failure and the need for better systemic agents. Thoracic failure rates also remain unacceptable, and methods to optimize thoracic radiotherapy are quite important. As systemic control improves, local control will become even more important. Dose escalation, volume reduction, and altered fractionation schemes all have the potential to improve the results of thoracic radiotherapy and need further study.
Although concurrent treatment is used in much of the world, the experience of our European colleagues suggests that it is too toxic. Cisplatin/etoposide regimens reduce this toxicity, while doxorubicin regimens increase it. Using reduced postchemotherapy volumes and delaying radiotherapy to cycles two, three, or four may help reduce toxicity, particularly if doxorubicin is omitted from the treatment regimen.
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