In this study we did a comparative effectiveness analysis comparing concurrent chemoradiotherapy for locally advanced cancers, many different disease sites, delivered with photon radiotherapy, which is the common standard approach, versus proton radiotherapy. There is limited data comparing these two treatments, very, very limited data prospectively, and we wanted to see if proton therapy, which theoretically might be able to reduce side effects by reducing the amount of normal tissue that’s radiated, whether that would, in fact, translate to clinically meaningful reductions in toxicity without sacrificing cancer outcomes. So our primary endpoint was acute 90-day from start of treatment grade 3 or higher CTC toxicities. These are the severe adverse events that typically lead to hospitalisations. We also had secondary endpoints – the CTC grade 2 and higher toxicities, decline in ECOG performance status during treatment and then disease free survival and overall survival. Our hypothesis was that proton therapy would reduce these acute severe side effects without reduction in cancer control outcomes.
To do this we did a comparative effectiveness study where we included almost 1,500 patients treated at the University of Pennsylvania with curative intent treatment for non-metastatic disease from 2011 to 2016. Most of these patients had head and neck cancer, lung cancer, primary brain cancer or GI cancers but there were also gynaecologic cancers represented as well. Importantly we gathered the toxicity data prospectively so each toxicity that the patients experienced was scored weekly on treatment visit using standardised forms. We also gathered the oncologic follow-up data for recurrence prospectively as well. We also gathered a large and very complete database consisting of clinical demographic, pathologic and treatment variables including detailed radiation specific variables like the planning target volume size, the dose, the number of fractions given etc.
We enlisted the services of Nandita Mitra who is an excellent biostatistician and she led a machine-learning ensemble propensity analysis. Based on that analysis we found that there was a more than two-thirds reduction in rates of grade 3 and higher toxicities in favour of the proton arm. There was a similarly statistically significant reduction in grade 2 toxicities and a decline in ECOG performance status. There was no difference in disease free overall survival which we did not anticipate since these patients were treated by the same doctors using the same dose and chemotherapy agents and the same dose of radiotherapy.
This research points towards some very fruitful potential avenues of research. One of them is it shows that we may be able to further intensify chemoradiotherapy treatments with either higher doses of radiation or more aggressive systemic therapies. It also points to a role for, in the future, broadening inclusion criteria for concurrent chemoradiotherapy trials to include older, sicker patients who may be able to benefit but who currently are not being offered concurrent chemoradiotherapy.
The take home message is that now we have data from a very large patient cohort, the largest that has been reported, that is showing a significant improvement in reducing toxicity without reducing oncologic outcomes because it’s always possible to reduce toxicity but in the process worsen oncologic outcomes. So to oncologists I would say that we should really go out of our way now to try to open and enrol patients on clinical trials comparing proton versus photon to try to get even better and even more data to help make decisions. To me, this data is very compelling and based on it if I were a patient I would want to receive concurrent chemoradiotherapy with protons instead of photons. But, again, it really should be up to the radiation oncologist and the treating doctor to make those determinations and unfortunately proton therapy is just not widely available so it’s not something that many patients would have access to and that’s unfortunate. I hope that will change as protons become less expensive and more widely available. But we need data like this to show that protons have value to try to spur development and interest and funds towards making it more economically comparable to photon radiation.