Objective: To determine the
applicability and safety of an ifosfamide, cisplatin, and etoposide
(VIP) regimen as a neoadjuvant chemotherapy to a concomitant thoracic
radiotherapy and cisplatin continuous infusion in locally advanced
non-small cell lung cancer (NSCLC).
methods: Forty-four patients (stage IIIb in 43 and stage IIIa in
1) entered a study of VIP, followed by concomitant thoracic
radiotherapy and cisplatin continuous infusion. Chemotherapy consisted
of three courses of cisplatin 25 mg/m2, ifosfamide 1.5
g/m2 (with uroprotection), and etoposide 100
mg/m2 given on days 1 to 4 of a 21-day cycle with
hematopoietic support using recombinant human methionyl granulocyte
colony stimulating factor. Patients who achieved a response or a
stabilization were planned to receive a split-course normofractionated
thoracic radiotherapy (first course: 30 Gy/10; 4-week rest period;
second course: 25 Gy/10). A continuous cisplatin infusion of 6
mg/m2 daily was administered using an autonomous
chemotherapy delivery device. Total plasma platinum titration was
performed daily during the two courses in five of the patients.
Analyses were done on an intent-to-treat basis.
Results: Thirty-nine of the 44 patients received the
three-cycle chemotherapy program. Received dose intensity was 82%.
Thirty-eight patients received the radiotherapy and, among them, 35
received the complete concomitant continuous cisplatin infusion.
Objective (complete) response rates were 48% (7%) at the end of
chemotherapy and increased up to 61% (16%) by the end of
radiotherapy. At the end of the first radiotherapy cycle, the mean
total plasma platinum concentration was twice as high as that of the
residual postinduction chemotherapy concentration. During induction
chemotherapy, myelosuppression was the limiting toxicity requiring
hospital readmission in 23 patients. During radiotherapy, the main
toxicity was acute esophagitis. A relatively high rate of pulmonary
fibrosis was observed using the subjective objective management
analytic—late effects of normal tissue score without life-threatening
pulmonary function impairment. None of the patients died from toxic
reactions. Probability of survival at 1, 2, and 3 years was 49%, 19%,
and 5%, respectively. Primary cause of failure was a local relapse in
63% of the patients, brain metastases in 24%, and hematogeneous
metastases to other sites in 13%.
Neoadjuvant VIP followed by concomitant radiotherapy-chemotherapy is
feasible, but the split-course radiotherapy did not prevent a high rate
of local recurrences. The high rate of toxic reactions requiring
hospital readmission limits further development of such an aggressive
regimen in NSCLC.
Abbreviations: CAP = cisplatin, doxorubicin
(Adriamycin), cyclophosphamide; CI = confidence interval;
MVP = mitomycin C, vinblastine or vindesine, cisplatin;
NSCLC = non-small cell lung cancer; r-metHuG-CSF = recombinant
human methionyl granulocyte colony stimulating factor;
SOMA-LENT = subjective objective management analytic—late effects of
normal tissues; VIP = cisplatin, etoposide, ifosfamide combination;
WHO = World Health Organization