Hypofractionated Radiotherapy Using
for Inoperable Non-Small Cell Lung Cancer: Preliminary Results of a
Risk-Stratified Phase I Dose Escalation Study
(p. 441-448) TCRT December 2008
No. 6 (p 415-522)
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
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
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.