Episode 029: Lung Cancer Series, Pt. 7: Treatment of early stage NSCLC (continued)

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we round out our discussion of early stage lung cancer treatment!

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When deciding if a patient can get surgery upfront or not, remember the three “Fellow on Call” criteria for early stage lung cancer:  

• Mass invading other structures or mediastinum

• Central lymph nodes (single digit station)

• Tumor >7 cm

If surgery is NOT an option at this time, where do we go from here?

1. Treat with definitive concurrent chemoradiation

2. Treat with “induction” chemotherapy, chemoimmunotherapy, or induction concurrent chemoradiation followed by definitive surgery

If surgery is/may be possible 

What are the goals of “induction” treatments? 

1. Eradicate microscopic disease (most important)

2. Improved local control, possibly shrinkage

3. Adding radiation may allow you to downstage tumor or lymph nodes to have a possible improvement in surgical outcomes

What sorts of discussions are being had a thoracic tumor board in patients with newly diagnosed early stage NSCLC? 

• Is the patient a surgical candidate?

• If the patient is not a surgical candidate, then what are the options:

  • Definitive concurrent chemoradiation (usually) followed by immunotherapy

    • Pearl 1: Always choose this if surgeon thinks the patient is unresectable up front (don’t assume that induction therapy will shrink and downstage tumors!)

    • Pearl 2: Always choose this if 2 out of 3 criteria fellow on call criteria we discussed above are met

    • Pearl 3: Always choose this if N3 disease (supraclavicular or contralateral lymph node)

  • “Induction” regimen with either chemotherapy alone or concurrent chemoradiation followed by surgery
    

What’s the idea behind “induction” chemo or chemoradiation? 

• There is a good chance that patients with these high risk features already have micrometastatic disease, so treatment upfront can help address that

• There is a chance that after surgery, patient may suffer deconditioning, which may preclude the use of adjuvant chemo +/- radiation (up to 90% of patients complete neoadjuvant treatment; this drops to ~60% in the adjuvant setting)

• Local disease control to achieve the best possible surgical outcome (R0 resection) and also prevent any microscopic residual disease from then having the opportunity to spread systemically, especially in areas where the mass may be adjacent to many blood vessels or lymph nodes

• Pearl: notably always use up front induction chemoradiation for pan coast tumors because local and systemic disease control is critical in this situation due to tumor close to important surrounding structures

What to treat with in the neoadjuvant setting?

• Platinum containing regimens (“platinum doublets”):

  • Carboplatin + paclitaxel (not preferred with chemo alone)

  • Cisplatin + etoposide

  • Cisplatin + gemcitable

  • Cisplain + pemetrexed (use for adenocarcinoma)

• Can combine this with radiation

How does the data about chemotherapy+IO in the neoadjuvant setting fit in here (CHECKMATE 816)?

• In patients with Stage IIB to IIIA (8th edition) WITHOUT EGFR or ALK mutation, treatment with NEOADJUVANT chemotherapy q3w x3 cycles (most got cisplatin based therapy) + nivolumab 360mg q3w x3 cycles resulted in improved event free survival (31.6 months vs. 20.8 months) AND pathological complete response was 24.0% vs. 2.2%

• Current NCCN guidelines state that if nivolumab is used in neoadjuvant setting, it should not be used in adjuvant setting

• There is still uncertainty about how this fits into treatment compared to “traditional” neoadjuvant approaches with chemo+/-radiation though many centers may prefer the neoadjuvant chemo+IO approach for higher risk patients

So after neoadjuvant treatment, does everyone go to surgery?

• Always re-assess the status of the disease; if there is progression of disease, then will go to definitive chemoradiation

• Discuss with surgeons to confirm if the patient is still a surgery candidate

If patient undergoes surgery, then what?

• If patient got neoadjuvant therapy and an R0, then they are done with treatment

• If R0 resection was not able to achieved, then either radiation “boost” to the area (if they previously got radiation), a course of radiation (if they just got induction chemo) or re-resection

• We discuss the adjuvant setting in more detail in Episode 026 (https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s)

If surgery is not possible 

If patient cannot go through to surgery, then definitive chemoradiation:

• Same chemotherapy agents as above, but treatment course is longer.

• For instance, for NSCLC, total 60Gy in 2Gy divided fractions (5 days/week, 6 weeks of treatment) with chemotherapy

Additional immunotherapy after chemoradiation (PACIFIC Trial) 

• Randomized patients who underwent definitive concurrent chemoradiation and had stable disease or better to durvalumab q2week x 12 months vs. placebo

• Ideally start durvalumab as soon as possible after concurrent chemoradiation due to theory that there is up regulation of PD-L1 and expression of tumor antigens after chemoradiation

• Found that “consolidation” durvalumab had 18 month PFS of 44% vs 20% and 5-year survival benefit 40% vs. ~30% without treatment

References:

https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450 - NCCN Lung Cancer guidelines

https://www.nejm.org/doi/full/10.1056/nejmoa1709937 - PACIFIC Trial (NEJM 2017)

https://www.nejm.org/doi/10.1056/NEJMoa2202170 - CHECKMATE 816 (NEJM 2022)

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