Adjuvant Radiotherapy Data Play a Role in How Oncologists Choose to Treat NSCLC

Catherine Shu, MD

During a Targeted Oncology Case-Based Roundtable event, Catherine Shu, MD, an assistant professor of Medicine and clinical director of the Thoracic Medical Oncology Service at Columbia University Herbert Irving Comprehensive Cancer Center in New York, NY, moderated a discussion around the case of a 77-year-old patients with non–small cell lung cancer (NSCLC).

Targeted Oncology™: When would you consider neoadjuvant therapy in this patient?

SHU: The Lancet meta-analysis [of] preoperative chemotherapy [in NSCLC)] basically showed...an improvement in overall survival [OS].1 So at 5 years, it was about 5%, and there were no differences in survival detected across the subgroups. Also, 5% is about what we see with adjuvant chemotherapy. Preoperative chemotherapy or adjuvant chemotherapy both deliver the same improvement in OS.

A number of places will give neoadjuvant chemotherapy, sometimes followed by chemotherapy. We know that with neoadjuvant chemotherapy, patients can get more of the chemotherapy, tolerate it better, and get more time to stop smoking and eradicate the micrometastatic disease. So there are a lot of theoretical benefits.

With the onset of immunotherapy, we’re looking at other ways to improve neoadjuvant treatments. Before, it was neoadjuvant chemotherapy, but there are currently trials looking at either neoadjuvant immunotherapy or neoadjuvant immunotherapy with chemotherapy. [The LCMC3 trial (NCT02927301)] was one of the large trials that looked at single-agent neoadjuvant atezolizumab [Tecentriq], a PD-L1 inhibitor, in patients with resectable [stage IB-IIIB NSCLC]. For a patient to get into the trial, the surgeon had to say [the tumor was] resectable [before therapy]. They would then get atezolizumab for 2 cycles followed by surgical resection.²

For the end points with neoadjuvant trials, we’re looking at things like major pathologic response [MPR] or complete pathologic response [pCR]. So the end point is very soon after the patient has gone to surgery, not several years later like with adjuvant trials.

[For the LCMC3 trial], the MPR was 21% and pCR was 7%. The important thing for that trial was to see whether surgery after immunotherapy was feasible and if the surgeons were OK with it. [The conclusion was that] it was well tolerated.²

A paper published in the New England Journal of Medicine looked at neoadjuvant nivolumab [Opdivo],³ Columbia University did a neoadjuvant chemotherapy and immunotherapy trial,⁴ and another trial was done out of a group in Spain.⁵

The MPR and pCR rates were higher than with single-agent immunotherapy. Overall, we’re finding that [neoadjuvant therapy] can be done. Whether or not this will represent an improvement in disease-free survival [DFS] or OS remains to be seen.

What parameters are important when deciding whether to use adjuvant radiation therapy?

The LUNG ART trial [NCT00410683], which radiation oncologists are familiar with but maybe not all the medical oncologists are, looked at patients who had been completely resected and then had N2 disease. So it was not known that they had N2 disease beforehand, or it was known and they underwent surgery but did not get chemotherapy up front.⁶

We used to give [all these patients] PORT [postoperative radiotherapy]. But this trial looked at control versus PORT, and the primary end point was DFS. There was no significant difference [between the 2 arms (HR, 0.85; 95% CI, 0.67-1.07; P = .16)]. For the 3-year DFS, the control and PORT arms were roughly the same, and there was no survival benefit.⁶

Looking at the causes of death, the PORT arm had a much higher percentage of cardiopulmonary deaths [at 16.2% vs 2.0% for the control arm]; mediastinal relapse was much less in the PORT arm [at 25.0% vs 46.1% for the control arm].6 This really means that PORT works in terms of local control; it doesn’t necessarily provide a survival benefit, but maybe some patients do benefit.

Do the LUNG ART trial results affect your use of radiotherapy for this type of patient?

ROMESSER: Yes, I think it soured my thoughts a little bit on PORT, and one wants to be more selective in its use. I’ve seen fewer N2 patients coming along since the report, so it might even be reflected more in the referral patterns. But certainly, there [are] patients who you’d still want to treat. R1 resection would be a clear indication for treatment and maybe in patients with bulkier N2 disease.

SHU: I think that makes a lot of sense. Maybe patients with bulky disease [at] high risk for recurrence. What about the cardiopulmonary toxicity? Does that change to whom you offer it?

ROMESSER: Yes, I think you want to be cognizant of that, and certainly if someone has a vascular pathology, you’re going to add to their risk. They’ve shown clearly in the breast cancer literature that in patients with risk factors for cardiovascular disease, as you add radiation dose to the heart, the relative increase of a radiation-related cardiovascular event is higher. So I think you want to be careful in those patients.

STILES: I don’t think this closes the door. First, it’s just an abstract, so we need to see the paper. This was in a patient with complete resection, so I think that communication between surgeons and radiation oncologists or medical oncologists is important.

Sometimes we just sample the N2 nodes, and one has disease in it. If we’ve left that behind and haven’t really done a full dissection, that patient is probably still going to benefit [from radiotherapy] and disease control there. So if the radiation oncologist gives that, I’m all for it for my patients. If the surgeon has completely cleaned up and has 1 out of 20 positive nodes in the N2 stations, then maybe [the patient is] not going to benefit as much [from PORT]. I think it’s a nuanced discussion. We must talk to each other about it.

ROMESSER: Have you changed your referral pattern—even though you did talk about not overrelying on the data yet because [they haven’t] been reported, but has it changed your thoughts on referring patients?

STILES: [Before I] didn’t send too many patients with N2 disease for radiation, but I would send incidental patients or those that I know I didn’t do a good resection. I think surgeons should decide operability and radiation oncologists should decide whether or not there’s a benefit to radiation in the adjuvant setting.

SHU: I’m still sending all of my postsurgery patients with N2 disease to [radiation oncologists to] have that discussion. We discuss all these cases at our tumor board, so that’s how we decide what to do.

_REFERENCES

_{1. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for nonsmall-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet. 2014;383(9928):1561-1571. doi:10.1016/S0140-6736(13)62159-5}

_{2. Lee JM, Chaft J, Nicholas A, et al. Surgical and clinical outcomes with neoadjuvantatezolizumab in resectable stage IB-IIIB NSCLC: LCMC3 trial primary analysis. Presentedat: 2020 World Conference on Lung Cancer Singapore; January 28-31; virtual.}

_{3. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378(21):1976-1986. doi:10.1056/NEJMoa1716078}

_{4. Shu CA, Gainor JF, Awad MM, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21(6):786-795. doi:10.1016/S1470-2045(20)30140-6}

_{5. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21(11):1413-1422. doi:10.1016/S1470-2045(20)30453-8}

_{6. Le Pechoux C, Pourel N, Barlesi F, et al. An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement: primary end-point analysis of LungART (IFCT- 0503, UK NCRI, SAKK) NCT00410683. Ann Oncol. 2020;31(suppl 4):S1178. doi:10.1016/j.annonc.2020.08.2280}