Toxicities in RTOG Combined-Modality Trials for Inoperable Non–Small-Cell Lung Cancer

ABSTRACT: Inoperable non–small-cell lung cancer has become the domain of combined-modality treatment based on several recent, large, phase III studies. Results of Radiation Therapy Oncology Group (RTOG) phase II studies have suggested improvements in response and short-term survival, using a strategy of intensification of dosing and scheduling of cisplatin-based regimens and either standard or hyperfractionated radiation therapy. However, some trials also have shown higher rates of severe acute toxicity and more frequent severe late toxicity. There appears to be an institutional learning curve in administering these more complex, intense regimens and in effective management of the acute toxicities. As the RTOG institution accrued more cases onto the intensified regimen studies, toxicity management improved, treatment was given with fewer interruptions or dosage reductions, and survival rates improved. Quality-adjusted survival analysis, in which survival time is reduced by the amount of time spent with severe toxicity, shows that the survival gains observed with some concurrent regimens may be negated by time spent with toxicity. Future attempts to optimize combined-modality therapy must take account of toxicity issues in the study design by incorporating less toxic chemotherapy agents, normal tissue protectors, tumor-targeting sensitizing agents, normal tissue-sparing radiation therapy techniques (eg, three-dimensional conformal), and proactive, aggressive management of toxicity. [ONCOLOGY 13(Suppl 5):116-120, 1999]

Introduction

Surgery alone is the treatment of choice for stage I and II non–small-cell lung cancer (NSCLC), with long-term survival rates as high as 60% to 70%. Stage IIIA patients with limited, nonbulky N2 nodal disease may have a 10% to 15% 5-year survival rate with surgery alone. Bulky IIIA and most IIIB non–small-cell lung cancer has been the domain of radiation therapy alone, until recently with excellent palliative relief of disease-related symptoms (60% to 70%) but disappointing survival results. Reported median survival ranges from 6 to 11 months, with long-term survival rates of 3% to 10%.[1-3] Even with high doses of conventionally fractionated radiation therapy, local failure occurs in 80% of patients, and distant failure also remains frequent. Higher biologic doses of radiation therapy are possible with altered fractionation radiation therapy, but this does not address occult distant metastases; thus, even if local control improves, survival gains are modest.[2,4]

These limitations of radiation therapy alone for unresectable non–small-cell lung cancer have led to numerous clinical trials exploring adjuvant chemotherapy in various strategic associations with radiation therapy.[3-5] Meta-analyses of these trials have confirmed a long-term survival benefit for the addition of adjuvant chemotherapy to radiation therapy, in either sequential, concurrent, or alternating fashion, with median survivals in the range of 13 to 14 months and 5-year survival rates of 15% to 20%.[2,3,5] Consensus statements from several national and international cancer organizations now conclude that combined chemotherapy/radiation therapy is the new “gold standard” for the treatment of inoperable non–small-cell lung cancer.[6-8]

The survival improvement shown with combined chemotherapy/radiation therapy fostered optimism that additional survival gains might be possible by further optimizing the chemotherapy/radiation therapy combination. The possible approaches to optimization are numerous when one considers the nearly infinite ways in which the dose, scheduling, and delivery of each modality could be altered. The strategy chosen by RTOG was that of treatment intensification accomplished by one of two approaches.

The first approach was to use chemotherapy concurrently during radiation therapy as both a cytotoxic (to contribute to tumor cell kill locally and distantly) and as a radiation sensitizer (to enhance radiation tumor cell kill). Concurrent chemotherapy/radiation therapy with and without induction chemotherapy was explored. The second approach was to intensify the radiation therapy by using hyperfractionation, in which the radiation therapy dose is given twice daily to a higher total dose than standard radiation therapy, with each fraction given 6 hours apart to allow normal tissue recovery. These approaches were tested by RTOG in a series of phase II trials. Each has shown favorable results in terms of response and at least short-term survival rates that appear better than those that established induction chemotherapy and radiation therapy as an improvement over radiation therapy alone. As part of the analysis of these trials and while awaiting the results of a phase III RTOG trial (94-10) evaluating sequential vs concurrent chemotherapy and radiation therapy, the observed toxicity was analyzed in detail. The findings of these analyses are summarized.

Intensification of Chemoradiation

Speculating that intensification of the local-regional and systemic treatment components could further augment local and distant control, and, thereby, survival, RTOG conducted five phase II trials evaluating three radiation therapy/chemotherapy strategies:

induction chemotherapy followed by standard radiation therapy (ChT ® SRT),

induction ChT followed by concurrent ChT and standard RT (ChT ® ChT/SRT), and

concurrent ChT and hyperfractionated RT (ChT/HfxRT).

To compare the toxicity and survival results for the three strategies, it was decided to pool the data from the five trials according to strategy. Since the objectives of the five phase II trials did not include combining their data, the studies did differ somewhat in eligibility and patient characteristics. Therefore, the studies were analyzed to evaluate the validity of combining and comparing the data. Patient characteristics are shown in Table 1.

All five trials required a Karnofsky performance status of ³ 70%; three trials (N = 147) set no weight loss requirement, and two trials (N = 336) required < 5% weight loss. All five trials used cisplatin-based chemotherapy combined with either vinblastine (Velban) or etoposide (VePesid). Patients staged as IIIA had radiographically evident bulky N2 disease. There were minor differences in chemotherapy type, chemotherapy dose, and radiation therapy dose. Despite the differences noted above, it was concluded that the five studies were similar enough that differences in toxicity, response, failure patterns, and survival according to treatment strategy might still be evident.[9] It should be understood, however, that inferences from pooled data might be weakened by inclusion of patients in some of the trials with less favorable performance and tumor characteristics.

Toxicity Differences by Strategy

Acute toxicity was defined as that occurring within 90 days from the start of radiation therapy; late toxicities included those occurring > 90 days after the start of radiation therapy.

Acute Toxicity

All three treatment strategies had a similar incidence of grade 4/5 acute toxicity. Significantly more patients treated with ChT/RT had acute nonhematologic toxicity ³ grade 3 (55%) than patients treated with either ChT ® SRT (27%; P < .0001) or ChT ® ChT/SRT (34%; P = .0005). This was due to a significantly higher (P < .0001) incidence of esophagitis ³ grade 3 (34%) for ChT/HfxRT compared to ChT ® SRT (1.3%) or ChT ® ChT/SRT (6%; Figure 1).[9]

Late Toxicity

Overall grade 4/5 late toxicities also did not differ by strategy. Late nonhematologic toxicities ³ grade 3 were significantly more frequent with ChT ® ChT/SRT (26%; P = .046) and ChT/HfxRT (28%; P = .003), compared to ChT ® SRT (14%; Figure 2). Although there was a trend toward more frequent late esophageal toxicity ³ grade 3 with the two concurrent strategies, late lung toxicity ³ grade 3 was significantly more frequent (P = .033) for ChT ® ChT/SRT (21%) and ChT/HfxRT (20%), compared to ChT ® SRT (10%; Figure 2).

Response, Failure Patterns, and Survival

The three strategies were compared in terms of response, in-field failure, 3-year progression-free survival, 3-year in-field progression-free survival, and 3-year overall survival (Table 2). The overall response rate was significantly higher for patients who received either ChT ® ChT/SRT (77%; P = .03) or ChT/HfxRT (79%; P = .003), compared to those who received ChT ® SRT (63%). Although in-field failures were significantly different between the strategies, differences in 3-year progression-free survival, in-field progression-free survival, and overall survival were not. Outcomes did not differ for patients with < 5% weight loss or stage IIIA disease, compared to the overall group.

Institutional Experience May Affect Toxicity and Outcome

The data from two of the trials included in the above analysis, RTOG 91-06 (ChT/HfxRT) and RTOG 92-04 (ChT/HfxRT and ChT ® ChT/SRT), were recently reanalyzed.[10] The aim of the reanalysis was to evaluate a possible relationship between clinical experience with more complex and intense combined-modality regimens and both toxicity and outcome. There was concern that institutions in RTOG, some of which had probably never attempted chemotherapy/radiation therapy regimens with the potential acute toxicity of 91-06 or 92-04, might have some initial difficulty managing the resultant toxicity. While some institutions might deal effectively with such new problems, some might use dose reduction of chemotherapy or radiation therapy, be reluctant to accrue additional patients, or display a management learning curve resulting in better premedication to prevent toxicity and/or more aggressive and effective management of toxicities. Any truncation of the treatment could result in poorer outcomes.

Patients accrued by institutions enrolling ³ 5 and < 5 patients in each trial were grouped separately. Although the ³ 5-patient institutions enrolled fewer women to RTOG 91-06 (P = .05) and had a larger number of patients with a Karnofsky performance status of 90% to 100% for RTOG 92-04 (P = .09), there were no significant differences in pretreatment characteristics for the combined group. The ³ 5-patient institutions tended to have fewer severe acute toxicities (P = NS); however, they had a significantly greater number of late toxicities of all types (P = .02) and late nonhematologic toxicities (P = .007) than the < 5-patient institutions. The cases accrued at ³ 5-patient institutions had a longer median survival time than those accrued at < 5-patient institutions in both trials and in the combined analysis (Table 3). Institutional accrual ³ 5 or < 5 patients was a significant prognostic factor by multivariate analysis for RTOG 91-06 (P = .05), RTOG 92-04 (P = .004), and the combined group (P = .001). Institutional accrual remained a significant factor even when chemotherapy delivery was included in the analysis (P = .001).

These findings have important implications for cooperative group clinical research involving potentially toxic new chemotherapy/radiation therapy regimens. It appears that as experience dealing with new or more severe acute toxicities grows, the ability to effectively manage the acute toxicities improves, permitting delivery of the full treatment as prescribed by the protocol. Further, the more likely that prescribed treatment can be given without interruption or modification, the more likely it is that the patient will benefit from any improvement in outcome attributable to the new treatment. However, even if the acute toxicity phase can be effectively managed, increased late toxicity consequences may still accompany the improved outcome.

The higher incidence of severe late toxicities for the ³ 5-patient institutions probably reflects the fact that the full protocol regimen was received. It has been postulated that despite possible increases in acute toxicity with more intense altered fractionation radiation therapy, resolution of these effects is still possible with proper management, and severe acute toxicity may not necessarily translate into severe late toxicity. However, this may not always be the case when altered fractionation radiation therapy is combined with chemotherapy. The chemotherapy may further impair cellular subsystems responsible for repair of acute sublethal radiation therapy injury and this may promote development of late toxicity.

Also of note, both RTOG 92-04 and 91-06 were conducted in the early 1990s, when experience with full-dose cisplatin-based regimens combined concurrently with full-dose standard radiation therapy or hyperfractionated radiation therapy was limited. As more institutions become familiar with premedication, nutritional support, and acute toxicity management regimens for these schedules and increase their own tolerance level for dealing with severe acute toxicity, one would expect fewer toxicity-induced modifications to the chemotherapy/radiation therapy regimens. Patients, too, have become better educated about the trade-offs between toxicity and outcome, especially those with access to treatment-related information on the internet. The newer generation chemotherapy agents now being incorporated into combined-modality regimens may also yield less severe acute toxicity, although this still remains to be proven.

Quality-Adjusted Survival

How best to measure the trade-off between the survival gains of intensified chemotherapy/radiation therapy regimens and the cost of their increased acute and/or late toxicity? One approach is the Quality-Adjusted Survival (QAS) analysis. In essence, this statistical technique involves subtracting from the measured survival time the amount of time the patient spends with ³ grade 3 (severe) acute toxicity or symptoms related to uncontrolled tumor. The rationale is that any survival spent with either severe toxicity or uncontrolled tumor is not quality time and is a measure of the relative inadequacy of the treatment to do the intended job. Namely, the treatment should effectively control tumor with acceptable and recoverable toxicity. A new treatment that is highly effective, but very toxic, could have an equivalent QAS to a nontoxic, but moderately effective, treatment.

A QAS analysis was performed on multiple combined-modality RTOG trials using the same range of strategies noted above.[11] There was a reported 2-month median survival advantage for ChT/HfxRT regimens (15.8 months) compared to regimens employing ChT ® SRT (13.8 months). When QAS was performed on the ChT/HfxRT group, the median survival was reduced to 13.7 months, since 2.1 months were spent with severe acute toxicity from the regimen. QAS done on the ChT ® RT group only reduced the median survival to 13.2 months, making the two regimens nearly equal in terms of QAS. Thus, the survival benefit of the concurrent regimen displayed a toxicity cost that virtually negated the gain.

For some patients, the cost of the survival gain with concurrent chemotherapy/hyperfractionated radiation therapy would probably induce them to opt out of such treatment, assuming the toxicity risks were lucidly explained prior to treatment. Some patients might still opt for the more toxic regimen, if they are from the “do anything no matter the cost” school of thought. Nevertheless, these findings are a clear indicator of the direction of future combined-modality clinical research. The options could include, but are not limited to:

(1) reducing chemotherapy toxicity and/or increasing effectiveness by

using less toxic, newer agents,

altering dose or scheduling,

adding chemoprotectors (eg, amifostine (Ethyol), etc.), or

deintensifying chemotherapy and adding chemosensitizers (eg, tiripazamine, etc.); and

(2) reducing radiation therapy toxicity and/or increasing radiation therapy effectiveness by

altering fractionation,

reducing field size (eg, three-dimensional conformal radiation therapy, etc.),

adding radioprotectors (eg, amifostine, etc.), or

deintensifying radiation therapy and adding radiosensitizers (eg, tiripazamine, etc.).

These approaches and others are currently the focus of developing clinical trials in various cooperative groups.

Conclusions

In RTOG studies, both strategies using a form of concurrent chemotherapy/radiation therapy were associated with a better tumor response compared to sequential chemotherapy/standard radiation therapy, but this did not translate into a difference in ultimate failure patterns. The median survivals (14 to 19 months) observed for each of the four concurrent chemotherapy/radiation therapy strategies appeared better than historical benchmarks for radiation therapy alone (9 to 12 months); however, the absence of a long-term survival benefit may reflect only partial clearance of occult micrometastases and a delay in, but not prevention of, their growth into overt metastases. Further, the two concurrent chemotherapy/radiation therapy strategies were associated with a significantly higher risk of acute esophageal and late lung toxicity ³ grade 3. This suggests an imperfect therapeutic ratio for the intensified regimens, unless means can be found to reduce toxicity through the use of protectors or alterations of radiation therapy or chemotherapy scheduling or delivery.

It is interesting that the high incidence of severe acute esophagitis seen with the concurrent strategies also trended toward yielding a significantly higher incidence of severe late esophagitis. It may be that the repair of late normal tissue damage permitted by hyperfractionated radiation therapy can be overwhelmed if intense chemotherapy is given concurrently. The chemotherapy may delay or prevent the recovery of normal tissue following sublethal radiation therapy damage in the daily 6- to 8-hour interfraction interval. Another possibility is that the added chemotherapy may prolong recovery from acute toxicity beyond the acute period so that it extends into the late toxicity interval (ie, “consequential” toxicity).

It is clear that as attempts at treatment intensification push the envelope of normal tissue recovery, toxicity recovery limitations will be found that may require a different strategy than a “smart bomb” approach. Closer attention to radiation biology and chemotherapy agent pharmacodynamics in formulating new chemotherapy/radiation therapy cocktails may be necessary if more is to be obtained from the current generation of radiation therapy delivery systems and chemotherapy agents. Investigator experience managing the consequences of these intense regimens is critical to maintaining their effectiveness.

As patients, providers, and insurers become increasingly attuned to both the risks and benefits of new treatments, more attention must be paid to developing treatments that maintain quality of life, not just quantity of life. Doses of radiation therapy up to 50% higher than standard are possible with newer radiation therapy technology (eg, three-dimensional conformal, intensity-modulated radiation therapy, etc.), with exposure of much smaller volumes of normal tissue to the full dose of radiation therapy. As these radiation therapy techniques are refined and combined with newer generation chemotherapy agents with targeted tumor cell cytotoxicity and with the ability to selectively sensitize tumor cells to radiation therapy, the goals of treatment intensification may come closer to realization.

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