DUBLINTwo metaanalyses have pointed to small but clear-cut survival gains for patients with inoperable locally advanced non-small-cell lung cancer (NSCLC) who receive chemotherapy and radiotherapy. Now, a randomized phase III Japanese study indicates that response rates are higher and survival longer when the two therapeutic modalities are given concurrently rather than sequentially.
Dr. Y. Takada of Hyogo Medical Center reported the results at the 8th World Conference on Lung Cancer on behalf of the West Japan Lung Cancer Group.
He and his colleagues treated 314 patients with unresectable stage IIIA or IIIB NSCLC with two cycles of the MVP regimen (mitomycin, 8 mg/m2, on days 1 and 29, plus vindesine(Drug information on vindesine), 3 mg/m2, on days 1, 8, 29, and 36, plus cisplatin(Drug information on cisplatin), 80 mg/m2, on days 1 and 29) spaced four weeks apart.
The concurrent treatment arm started radiotherapy on the second day of chemotherapy, with patients receiving 14 fractions of 2-Gy each over a period of three weeks, followed by a 10-day rest period and then another three-week course of radiation.
In contrast, in the sequential treatment group, radiotherapy was delayed until the completion of chemotherapy, at which point patients received the same total dose in 28 fractions of 2-Gy each.
Preliminary analysis of the results spotlighted a highly significant difference in response to the two regimens: 84% of patients responded to concurrent therapy, compared with 66% of patients treated sequentially.
The difference in timing also translated into significant differences in survival. Median survival was 16.4 months with early treatment versus 13.3 months with delayed treatment, Dr. Takada said.
He stressed that, among concurrently treated patients, two-year survival was 35% and three-year survival was 23.1%, whereas in the sequential group, two- and three-year survival rates were 27.1% and 13.7%, respectively.
On the other hand, the timing of radiotherapy appeared to have no impact on the site of initial progression.
Although myelosuppression and neutropenic fever were more of a problem with concurrent therapy, there was no increased risk of such nonhematologic complications as radiation pneumonitis.
Calling concurrent therapy a small but definite advantage over the current gold standard, Dr. David Ball, head of the Lung Unit, Division of Radiation Oncology, at the Peter McCallum Cancer Institute, Melbourne, Australia, suggested that this outcome might have been anticipated on theoretical grounds.
Possible explanations, he speculated, could be that concurrent chemotherapy takes advantage of both the lack of cross-resistance between the two treatment modalities and the radiosensitizing properties of cisplatin.
Dr. Ball also pointed out that sequential therapy prolonged the overall treatment duration by at least three weeks, which might have permitted accelerated repopulation of tumor clones before radiotherapy was even started.
Confirmation of the Japanese results could be forthcoming from the Radiation Therapy Oncology Groups (RTOG) study 94-01, which is still underway.
The RTOG investigators are randomizing patients to three groups: cisplatin-vinblastine followed by 63 Gy of radiation; cisplatin-vinblastine concurrently with 63 Gy; or cisplatin-etoposide together with 69.6 Gy in hyperfractionated doses.