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

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]


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:

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

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

  3. 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

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

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
). 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).


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