What is the optimal treatment of medically inoperable T3N0 non-small cell lung cancer that is too large for standard SBRT?

As we see it, there is more than one way to skin the cat. RTOG 0617 has condemned protracted fractions to 70 Gy...it just might be that 70 Gy is the wrong way to treat in 35 fractions, +/- cetuximab added to weakly carbo taxol. But the study to look at thoracic dose is contaminated by those systemic additives.

@Dr. First Last has resurrected the CALGB concept of fixing the total dose and decreasing the overall study time by hypofractionating the dose as published by Bogart. He rightly points out that there was no MTD. Its upper dose of 4.11 Gy happens to be the 4 Gy used by many in 15 or 20-fraction hypofractionated regimens. I like 4.50 X 15, and all of us need to define target size, point of dose (PTV or isocenter), and constraints -- a word I dislike, because it should convey the idea of potential risk rather than absolute prohibition. We have entered an era where RTOG needed to venture a decade ago, but was more involved with adding chemotherapy and new drugs du jour, i.e., RTOG 0617...too many variables = confusion.

SBRT seems acceptable but we are scared off in the central no-fly zone. Payment dictates or at least overly influences what we choose. We may be in the Goldilocks and the three bears situation, not too long; not too short, but just right. Three weeks feels just right to me!

update on 2/26/24:

I have been asked whether I have any updates to my comments of some years ago regarding the issue of SBRT for large inoperable T3N0 lung cancers. We have not changed our practice with respect to the SBRT component of our decision-making since as I noted, we have published on the appropriateness in our experience of SBRT for T3 tumors invading the chest wall and for tumors > 5 cm. The only management update would be the more routine use of immunotherapy in the post SBRT setting instead of the more historically conventional platinum-based regimens. Likewise, although this has not been a common scenario so far that we have seen with our inoperable patients, the use of induction therapy employing immunotherapy has become routine for surgical patients, when incorporated with platinum chemotherapy. Mimicking this for the inoperable population has been less since again, platinum agents are hard to administer to fragile inoperable patients, and we have not employed immunotherapy alone for induction. 

original answer 4/2016:

I appreciate the comments of @Dr. First Last and would like to offer some further reflections on the approach to this clinical scenario. The approach to the medically inoperable T3N0 lung cancer patient will by definition reflect the status/needs of the patient as well as the particular T3 presentation of the tumor but I think it is important not to lose sight of the approach to care if the patient were in fact operable. This brings up the role of SBRT based regimens where the SBRT is acting as a surgical surrogate. I would like to bring to the attention of the readership our two institutional experiences with T3 either as a tumor invading the chest wall (Berriochoa et al., PMID 27301539) and large tumors >5 cm (Woody et al., PMID 25841625). In each of these scenarios, we have followed the model where surgical resection would be followed by adjuvant chemotherapy and "substituted" the surgical intervention with SBRT. We also felt comfortable with considering the use of SBRT in this setting based on our very extensive of this modality in the chest. In these published experiences, we want to demonstrate that the same parameters by which we can judge a "conventional" inoperable early stage lung cancer treated by SBRT to be safe and effective are readily applicable to each of these scenarios. We used the same constraint tables for these presentations and have found very good safety and efficacy in managing the primary T3 tumor with SBRT. Perhaps not unexpectedly, more challenges in administering all of the planned chemotherapy to a vulnerable population.

Please read the preceding responses first as they are excellent. I wanted to add that there are 2 prospectively evaluated dose regimens that must be noted, particularly for patients going radiation alone without SABR.

The NCIC BR.25 treated patients to 60 Gy in 15 fx dose to isocenter with local control 88% and OS 69% at 2 years. Again, a medically inoperable population. 

Much earlier, the CALGB ran a dose escalation trial 39904 (Bogart et al., PMID 19933904). Here, patients were treated to 70 Gy in cohorts of increased dose per fraction. They never reached an MTD despite reaching the highest cohort of 4.11 Gy in 17 fx. For more elegant numbers, the prior cohort was 70 Gy in 20 fractions of 350 cGy per fraction. With median f/u of 4.4 years (pretty good f/u for a medically inoperable cohort!), LC was 92%, median OS was 3.2 years. These numbers compare favorably with current SABR outcomes.

I favor the CALGB regimen since this was dosed to a volume and not to isocenter. I don't have much experience with the various institutional regimens noted above but thought that data from cooperative groups would be helpful for this discussion. I've used the VU 7.5 Gy x 8 on several occasions and have been happy with that as well.

Based on guidelines, the current standard for T3N0, IIB inoperable lung is probably chemoRT 60-66 Gy. I would not suggest going beyond 66 Gy as RTOG 0617 comparing 60 vs. 74 Gy for stage III disease showed inferior survival in the 74 Gy arm. In a fit patient, concurrent chemotherapy makes sense for stage IIB. If the patient is not fit for chemotherapy, then I would consider hypofractionation. Reasonable regimens include MD Anderson's 70 Gy in 10 fractions (if meets reasonable constraints), 60 Gy in 10 fx (that is what we/I've done at UCLA), and VUMC Netherland's 60 Gy in 8 fractions is another good option. The MD Anderson publications have published guideline constraints that one can refer to for guidance.