Case Studies in Stage III NSCLC: A Summary of the Presentation by Dr. Nancy Nixon

At the 2018 Canadian Lung Cancer Conference (CLCCO), Dr. Nancy Nixon, a medical oncologist at the Tom Baker Cancer Centre in Calgary, discussed two cases of patients with stage III non-small cell lung cancer (NSCLC). Her presentation, summarized in this article, highlighted traditional treatments as well as new options available to each patient given their presenting symptoms.

Dr. Nixon presented the following two cases during her talk:

Case #1 – Mr. A

History and presentation:

  • 52-year-old man;
  • Smoked half a pack per day from the age of 18 until about two years ago;
  • Has been having left-sided chest pain radiating to the back for the past six months;
  • Experiences shortness of breath while doing stairs;
  • Chest x-ray showed a left hilar mass;
  • Computed tomography (CT) scan of the chest showed a 3.2 cm by 5.4 cm mass in the left lower lobe associated with collapse; and
  • A bronchoscopy showed that in station 4L, seven lymph nodes were positive.

Based on these results, Mr. A presented with a station 4L, N2, T3 tumour, and was diagnosed with stage IIIb NSCLC. According to these criteria, his expected probability of survival is 44% at two years and 26% at five years.

A member of the audience stated that stage III NSCLC is an interesting cancer, given that there are several ways to go about treating it: trimodality treatment, chemoradiation therapy (concurrent or sequential), surgery followed by radiotherapy, and chemoradiation followed by durvalumab. Dr. Nixon agreed that these stage III NSCLC cases require multidisciplinary discussion as they can be managed through multiple modalities, with various combinations of surgery, radiation therapy, and chemotherapy showing modest improvements, but none standing out over the others.

Given that outcomes are poor with radiation alone, chemoradiotherapy has emerged as a good option. The rationale for using this approach is that it may act on different cell populations, may reduce or eliminate micrometastases, allows for maximization of each treatment due to non-cross reacting toxicities, and may radiosensitize the tumour cells. The major disadvantage of chemoradiotherapy is its related toxicity. Early studies from the 1990s demonstrated only modest improvements in overall survival (OS) with sequential chemoradiotherapy when compared with radiotherapy alone.1–3 Furthermore, several metanalyses that looked at chemoradiation, both sequential and concurrent, also demonstrated modest improvements in median OS.4–6 Notably, concurrent chemoradiation therapy is thought to be more beneficial than sequential chemoradiation therapy. This is based on a study published in 1999 which demonstrated a statistically significant improvement in response rate (84% vs. 66%; p <0.001) and median OS (16.5 months vs. 13.3 months; p = 0.04) with concurrent chemoradiation therapy over the sequential approach.7 Similar results were seen in the RTOG 94-10, which looked at different chemotherapy approaches.8 The median OS was once again statistically improved with concurrent chemoradiation therapy versus sequential (17.0 months vs. 14.6 months; p = 0.046). A Cochrane review, published in 2010, also demonstrated similar results.9 However, one must question whether the three-month improvements that were seen in these studies really are significant for patients and whether the increase in efficacy is worth the increased toxicity.

Case #2 – Mrs. B

History and presentation:

  • 47-year-old woman;
  • Current smoker of a pack a day since age of 20;
  • Recently involved in a motor vehicle accident and complained of rib pain;
  • Chest x-ray showed a left hilar mass;
  • CT scan of the chest showed a 2.8 cm by 1.5 cm mass; and
  • A bronchoscopy showed one level 4L node enlarged.

Based on her history and presentation, Mrs. B was diagnosed with stage IIIa NSCLC. Her case went to tumour board discussion for trimodality therapy. The board decided that she should be treated with concurrent chemoradiation and then move on to surgery. This approach is supported by a phase III trial that compared chemoradiation therapy with surgical resection to chemoradiation alone.10 The study found a significant improvement in progression-free survival (PFS) in patients undergoing chemoradiation plus surgery (HR = 0.77; p = 0.017), but no improvement in OS. (Figure 1) The authors postulated that one reason why a PFS advantage did not translate to an OS benefit could be that patients who went on to receive surgery may not have received as much chemotherapy afterwards. The treatment-related mortality was also higher in patients undergoing surgery.

Considering these two cases, patients wonder if there are any other options for them. The latest results of the PACIFIC trial, presented in 2017, demonstrated that there are indeed more options for these patients. PACIFIC is a phase III, randomized, international trial investigating the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab as consolidation therapy in patients with stage III (both a and b), locally advanced, unresectable NSCLC, following platinum-based concurrent chemoradiation therapy.11 Dr. Nixon noted that it is important to consider what type of patients the study included when applying it to her own cases. The patients in PACIFIC had already undergone two cycles of chemoradiation therapy and had not progressed, had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and were not allowed to go on the study if they had residual grade 2 toxicities from their treatment.

The PACIFIC trial had two primary endpoints, PFS and OS. So far only the PFS results have been published, which were quite impressive. The median PFS was significantly longer with durvalumab (16.8 months) versus placebo (5.6 months; HR = 0.52; p <0.0001). (Figure 2) Notably, almost all subgroups benefited from durvalumab and PD-L1 expression was not a factor for PFS. The one group that did not benefit were the epidermal growth factor receptor mutation-positive patients, which is consistent with other immunotherapy studies. Initially, there was a concern about the risk of increased radiation pneumonitis with these patients, given that they had already received high doses of radiation and then followed that with immunotherapy. However, grade 3/4 rates of radiation pneumonitis were quite low and similar between the two groups.

In summary, the addition of chemotherapy improves outcomes of patients with locally advanced NSCLC. Concurrent chemoradiation therapy is more beneficial than sequential, although at the cost of higher toxicity. The results of the PACIFIC trial are practice changing in favour of durvalumab, but how physicians get access to the drug is the next question. Furthermore, the results of PACIFIC have uncertain implications for extrapolation of results to other stages of disease or populations, for example for patients with worse ECOG PS. Lastly, PACIFIC also poses uncertain implications for the future of trimodality therapy, and oncologists will need to consider where surgery fits into the current picture.

Figure 1. Progression-free survival of intention-to-treat population

Figure 2. PFS by BICR (ITT population)

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