Dose Escalated, Hypofractionated Radiotherapy Using Helical Tomotherapy for Inoperable Non-Small Cell Lung Cancer: Preliminary Results of a Risk-Stratified Phase I Dose Escalation Study

(p. 441-448) TCRT December 2008
Volume 7
No. 6 (p 415-522)
December 2008
ISSN 1533-03

To improve local control for inoperable non-small cell lung cancer (NSCLC), a phase I dose escalation study for locally advanced and medically inoperable patients was devised to escalate tumor dose while limiting the dose to organs at risk including the esophagus, spinal cord, and residual lung. Helical tomotherapy provided image-guided IMRT, delivered in a 5-week hypofractionated schedule to minimize the effect of accelerated repopulation.

Forty-six patients judged not to be surgical candidates with Stage I-IV NSCLC were treated. Concurrent chemotherapy was not allowed. Radiotherapy was delivered via helical tomotherapy and limited to the primary site and clinically proven or suspicious nodal regions without elective nodal irradiation. Patients were placed in 1 of 5 dose bins, all treated for 25 fractions, with dose per fraction ranging from 2.28 to 3.22 Gy. The bin doses of 57 to 80.5 Gy result in 2 Gy/fraction normalized tissue dose (NTD) equivalents of 60 to 100 Gy. In each bin, the starting dose was determined by the relative normalized tissue mean dose modeled to cause < 20% Grade 2 pneumonitis. Dose constraints included spinal cord maximum NTD of 50 Gy, esophageal maximum NTD < 64 Gy to ≤ 0.5 cc volume, and esophageal effective volume of 30%.

No grade 3 RTOG acute pneumonitis (NCI-CTC v.3) or esophageal toxicities (CTCAE v.3.0 and RTOG) were observed at median follow-up of 8.1 months. Pneumonitis rates were 70% grade 1 and 13% grade 2. Multivariate analysis identified lung NTDmean (p=0.012) and administration of adjuvant chemotherapy following radiotherapy (p=0.015) to be independent risk factors for grade 2 pneumonitis. Only seven patients (15%) required narcotic analgesics (RTOG grade 2 toxicity) for esophagitis, with only 2.3% average weight loss during treatment. Best in-field gross response rates were 17% complete response, 43% partial response, 26% stable disease, and 6.5% in-field thoracic progression. The out-of-field thoracic failure rate was 13%, and distal failure rate was 28%. The median survival was 18 months with 2-year overall survival of 46.8% 9.7% for this cohort, 50% of whom were stage IIIB and 30% stage IIIA.

Dose escalation can be safely achieved in NSCLC with lower than expected rates of pneumonitis and esophagitis using hypofractionated image-guided IMRT. The maximum tolerated dose has yet to be reached.

Tomotherapy safely delivers higher doses in shorter time
Preliminary results from an ongoing clinical trial reveal that helical tomotherapy may enable higher biologically-effective radiation doses to be delivered to non-small cell lung-cancer patients, with lower than expected toxicities. In contrast to most dose escalation studies, the researchers - from the University of Wisconsin School of Medicine and Public Health (Madison, WI) - did not increase the total number of fractions (which could result in tumour regrowth). Instead, all patients received 25 treatment fractions over five weeks, with the dose-per-fraction and total dose set according to each individual's likelihood of lung toxicity (TCRT 6 441).

For the 46 patients in the study, the overall two-year survival rate was 46.8%, a large increase over historical rates of 21.5% for the same stage-range of disease. The study showed that higher doses of radiation (typically around 60 Gy in 2-Gy fractions) could be delivered safely using this hypofractionated tomotherapy schedule. Lung and oesophageal toxicities were lower than expected from dose escalation using conventional radiotherapy, with no patients experiencing grade-3 or higher pneumonitis or oesophagitis. "The early results of this study suggest that a hypofractionated schedule with dose-escalation can safely be achieved and, although preliminary, the survival data look promising," said senior author Minesh Mehta.