Stereotactic ablative radiotherapy (SABR) yielded a shockingly low pathologic complete response (pCR) rate in a phase II trial of operable, early-stage lung cancer patients, sounding the probable death knell for use of SABR alone in this setting.
In the first study to examine neoadjuvant SABR prior to surgery in non-small cell lung cancer (NSCLC), SABR yielded a 60% pCR rate at 10 weeks post-radiation (95% CI 44%-76%), a rate far lower than hypothesized when the trial was designed, reported David Palma, MD, PhD, of the London Health Sciences Centre in London, Ontario, Canada, and colleagues, in JAMA Oncology.
“The question really is, what does a 60% pCR rate mean?” said Palma in an interview that accompanied the study. It’s hard to know for sure, he acknowledged, but it could mean that 40% of patients had disease left behind following SABR and were salvaged by subsequent surgery.
It also could simply mean that more time was needed to achieve a pCR in the trial, he said. “We can’t really distinguish between these two hypotheses.”
He cautioned that clinicians “need to keep a very close eye on patients who are fit for surgery, but who decline it and only have SABR,” as those who don’t achieve a pCR could go on to develop important recurrences.
Commenting on the findings, Dennis Wigle, MD, PhD, chair of thoracic surgery at the Mayo Clinic in Rochester, Minnesota, told MedPage Today that the “big raging debate” about SABR now is where does it fit into the overall algorithm for the treatment of stage I lung cancer.
“There is a lot of encouraging data from [early-stage] patients who are not operable, so for patients who are not able to tolerate surgery, there are some pretty promising results with SABR,” he said, but suggested that most patients with operable, early-stage disease would rather head straight to surgery and be done with it.
“I think if you polled a group of lung cancer physicians, not just radiation oncologists who deliver this treatment, but others like myself in surgery, they would have said a pCR rate of 90% or more was probably a reasonable guess as to what the pCR should have been in this trial,” Wigle said. “So to see a 60% rate from this paper is really eye-popping. I don’t think any of us would have expected a 60% pCR rate 10 weeks after SABR — and that’s just not surprising, that is in the shocking or startling category.”
The MISSILE-NSCLC study was a single-arm trial whose primary endpoint was to evaluate the pCR rate following the sequential approach along with toxicity plus oncologic outcomes.
“In many disease states, we do use more than one local therapy,” Palma explained. “We wondered whether neoadjuvant SABR would have some benefits, including sterilizing the tumor before it was resected and potentially immunological effects as well, which have been postulated to happen with SABR.”
A total of 40 patients, 36 of whom made up the per-protocol population, were assigned to SABR followed by surgery. All patients had to have adequate pulmonary reserve for resection and most (78%) had T1 tumors. “Radiotherapy dose was selected using a risk-adapted approach based on tumor size and location,” study authors explained.
T1 tumors of ≤3 cm and surrounded by lung parenchyma were treated with 54 Gy in three fractions while tumors >3 cm with chest wall contact received 55 Gy in five fractions. A dose of 60 Gy given in eight fractions was used to treat tumors within 2 cm of the mediastinum or brachial plexus. Surgery in the form of either a lobectomy or a sublobar resection was scheduled to occur 10 weeks after patients had completed the SABR protocol.
At a median follow-up of 19 months, 23% of the group had experienced a recurrent event, the investigators reported. Some 8% had a regional recurrence alone while 13% had both a regional and a distant recurrence. Another 13% experienced both a local and distant recurrence.
For those who underwent both SABR and surgery, the local control rates were 100%, with regional and distant control maintained in 53% and 76%, respectively. At 2 years, 77% of these patients were still alive.
Toxicity was comparable to that reported with surgery alone, while perioperative mortality rates were excellent with no deaths in the group overall. Based on Functional Assessment of Cancer Therapy General (FACT-G) quality of life (QOL) measures, “no significant changes in QOL score were found during follow-up, because significant decreases in physical well-being were offset by significant improvements in emotional well-being over time,” Palma and colleagues pointed out.
On the FACT for Lung QOL component, 25% of patients had a clinically meaningful improvement in QOL 9 months after surgery, as measured by Trial Outcome Index score, but 35% experienced a clinically meaningful decline.
The authors pointed out that the pCR rates, though lower than they would have expected, were actually higher than rates seen with other strategies in operable disease. For example, a recent study of neoadjuvant PD-1 blockade with nivolumab (Opdivo) given prior to surgical resection for resectable NSCLC achieved a pCR rate of only 15%.
Now that new treatments are being brought into the adjuvant setting for this patient population, “this [pCR rate] will still be the benchmark that people have to surpass,” Palma observed.
With ongoing trials examining SABR plus immune checkpoint inhibitors followed by surgery, “if we see a strong signal that the pCR rates are going up to 80%, that would be very useful to bring into the clinic and into designing phase III trials,” Palma said.
Limitations of the study included the fact that it was conducted at a high-volume tertiary care centre in Canada where favorable toxicity and QOL outcomes seen in the study may not translate into lower-volume centers.
Palma and one co-investigator hold a patent for a CT method of assessing response after radiation therapy.
Wigle had no relevant financial disclosures to declare.