Combined chemotherapy and radiation therapy have started to replace
the traditional local approach of thoracic radiotherapy alone for
unresectable stage III nonsmall-cell lung cancer. By itself,
thoracic radiotherapy provides local control and effective palliation
of symptoms, but has a minimal effect on survival.[1-3] Novel schemes
of radiation such as hyperfractionated radiation and continuous
hyperfractionated accelerated radiotherapy[5,6] have been developed
and tested. Saunders et al demonstrated the superiority of the
continuous hyperfractionated accelerated radiotherapy regimen (57.6
Gy in 36 fractions over 12 continuous days) over conventional
radiotherapy in the treatment of patients with nonsmall-cell
lung cancer, but at the expense of substantial esophagitis upon
completion of treatment.
The addition of chemotherapy to thoracic radiotherapy
sequentially[7-10] or concurrently[11-13] has shown an improvement in
survival and quality of life of unresectable nonsmall-cell lung
cancer stage III patients, especially those with a good performance
status and < 5% weight loss,[8-10] when compared to radiation
therapy alone (Table 1). The
French trial not only demonstrated an improvement in survival with
the addition of chemotherapy, but also showed an improvement in
systemic control with a reduction in distant metastasis when compared
to radiotherapy alone.
In Dillmans [8,9] study (100 mg/m² of cisplatin [Platinol]
on days 1 and 29 and 5 mg/m² of vinblastine [Velban] on days 1,
8, 15, 22, and 29, followed by radiotherapy beginning on day 50 vs
radiotherapy alone), the median survival of 13.7 months in the
combined-modality arm was significantly better than 9.6 months
observed in the radiotherapy alone arm (P = .01), and there were
twice the number of survivors at 3, 4, 5, and 7 years. This
study[8,9] was duplicated by the Radiation Therapy Oncology Group
(RTOG) and the Eastern Cooperative Oncology Group (ECOG),[10,11]
adding a third arm consisting of hyperfractionated radiation (69.6
Gy). Results showed that 1-year and median survivals in the
combined-modality arm (60% and 13.8 months, respectively) were
significantly improved compared with the hyperfractionated radiation
alone arm (51%, 12.3 months) and the standard thoracic radiotherapy
arm (46%, 11.4 months) (P = .03). The combined-modality arm continues
to show improved survival at 5-year follow-up (P = .004).
Meta-analysis of randomized studies assessing the comparative
efficacy of radiation therapy alone to combined chemotherapy and
radiation therapy in patients with locally advanced, unresectable
nonsmall-cell lung cancer showed that the relative risk for
death at 1, 2, and 3 years was reduced by 12%, 13%, and 17%,
respectively, in favor of combined-modality therapy. The benefit of
chemotherapy appeared to increase with time reaching the maximum at
31 to 36 months from the start of treatment. The mean gain in life
expectancy was approximately 2 months at the end of 3 years, with an
improvement in median survival of 1.7 months. Although chemotherapy
did not impair delivery of radiation therapy, serious toxic effects,
particularly febrile neutropenia and gastrointestinal disturbances,
were more prevalent in patients receiving cisplatin-based
chemotherapy. Thus, the addition of chemotherapy to radiotherapy
offers an advantage in patients with locally advanced, unresectable
stage III nonsmall-cell lung cancer, but the exact sequence of
combined-modality therapy, the optimal and
effective agents to be used in combination with
radiation, and the best schedule of radiation therapy, are all
subjects of continued investigation.
Concurrent Chemotherapy and Radiation
In an attempt to decrease the toxicity of cisplatin-based
chemoradiation, we conducted a pilot study using weekly carboplatin
(Paraplatin), the less toxic analog of cisplatin, and concurrent
thoracic radiotherapy in patients with locally advanced
nonsmall-cell lung cancer. In this study, 35 previously
untreated patients with stage III nonsmall-cell lung cancer
were given 100 mg/m² of carboplatin weekly, with concurrent
thoracic radiotherapy (total dose, 60 Gy). The response rate was 34%,
and median survival was 13 months. The treatment was well tolerated,
with only three patients requiring treatment prolongations of > 1
week. This regimen demonstrated efficacy and feasibility with a mild
toxicity profile, and appeared suitable for combination with other
chemotherapeutic agents. In a subsequent study, we added paclitaxel
(45 mg/m² given over 3 hours), followed by carboplatin (100
mg/m² over 30 minutes) with concurrent thoracic radiotherapy
(60-65 Gy over 6 or 7 weeks)[14,15] (Table
Paclitaxel Plus Carboplatin
The rationale for including paclitaxel was based on its known
clinical activity and its radiosensitizing potential in preclinical
and clinical studies.[16-18] In advanced and metastatic
nonsmall-cell lung cancer, it has shown impressive activity
both as a single agent[19-20] and in combination with
carboplatin.[21-24] When used in combination with thoracic radiation
therapy as a single agent, the recommended dose of paclitaxel is 60
mg/m² administered as a short infusion (1 or 3 h). In our
study, we used a lower paclitaxel dose of 45 mg/m² to account
for the toxicity related to the addition of carboplatin in this combined-modality
regimen. Only nine of the 38 patients treated who had one or more
weekly doses of chemotherapy interrupted treatment for more than 1
week due to grade 3 neutropenia; the incidence of severe esophagitis
was 6%. The survival of patients treated with our regimen for locally
advanced nonsmall-cell lung cancer at 1, 2, and 3 years was
61%, 39%, and 39%, respectively.
Choy and colleagues have also reported the results of their combined
chemoradiotherapy utilizing paclitaxel and carboplatin.[26,27] Their
regimen consisted of paclitaxel (50 mg/m² 1-hour infusion
weekly), carboplatin weekly (with a dose targeted to achieve an area
under the concentration-time curve of 2 [AUC in mg/mL · min]),
and concurrent thoracic radiation therapy (total dose, 66 Gy) (Table
3). Patients then went on to receive two additional cycles of
full-dose chemotherapy with the same combination of paclitaxel and carboplatin.
Among the 37 evaluable patients, the overall response rate was 75%
and the 1- and 2-year survival rates were 54% and 40%, respectively.
The incidence of esophagitis (National Cancer Institute Common
Toxicity Criteria grades 3 and 4) observed was 49%, but was of short
duration. Other rare toxicities included nausea, vomiting,
neuropathy, weight loss, and pulmonary complications.
Choy et al recently presented the results of another phase II
study of 43 patients with locally advanced nonsmall-cell lung
cancer who received concurrent weekly low-dose paclitaxel (50
mg/m²) and carboplatin (AUC of 2) with hyperfractionated
radiation (69.6 Gy administered twice daily) instead of standard
fractionation utilized in the previous trial, followed by two cycles
of full-dose chemotherapy with the same agents. The incidence of
grades 3 and 4 esophagitis, as measured by the RTOG scale, was 26%;
16.5% of patients had grades 3 and 4 pulmonary toxicity. One-year
survival was 63%, and the median survival has not been reached. If
this trial utilizing hyperfractionated radiation is put into
perspective with the data previously reported by Belani et al,[14,15]
and combined with data from Choys group utilizing the same
chemotherapeutic agents with standard daily radiotherapy, there
appears to be no advantage to giving concurrent twice-daily
Hyperfractionated Accelerated Radiation
Hyperfractionated accelerated radiation therapy with no treatment on
weekends has also been combined with chemotherapy in a sequential
fashion. Two cycles of carboplatin (AUC of 6) and paclitaxel (175 to
225 mg/m²), followed by hyperfractionated accelerated radiation
therapy to the postchemotherapy tumor volume (given in three divided
daily fractions to a dose of 57.6 Gy in 12 treatment days), was used
by Wagner et al at the H. Lee Moffitt Cancer Center in patients with
stage III nonsmall-cell lung cancer. Induction chemotherapy
was well tolerated and all 21 patients completed hyperfractionated
accelerated radiation therapy as scheduled. Two weeks after
hyperfractionated accelerated radiation therapy, grade 3 or 4
esophagitis occurred in 11 patients, and 10 of these required
hospitalization for toxicity. The median survival for all patients
was 12 months; survival at 18 months was 30%. This same schedule is
now being tested in a randomized setting by the ECOG (with study
chairs Chandra P. Belani and Henry Wagner) to determine the effect of
hyperfractionated accelerated radiation therapy compared with
standard daily radiotherapy after induction with carboplatin and
paclitaxel for patients with locally advanced, unresectable
nonsmall-cell lung cancer (Figure
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survival in carcinoma of the lung treated with irradiation [published
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