One step FORWARC.

Top Line: Why do we give chemoradiation or chemotherapy for locally advanced rectal cancer?
The Study: A major conundrum with neoadjuvant therapy for rectal cancer is that the response to therapy and “yp” stage are consistently strong predictors of disease and survival outcomes. At the same time, regimens that clearly produce higher rates of pathologic complete response and downstaging don’t consistently improve survival. As a result, the data for both neoadjuvant chemoradiation and adjuvant chemo is all over the place, with neither showing consistent improvements in disease-free (DFS) or overall (OS) survival. The proposed solution? First of all, we gotta get rid of radiation because, well, just because. Second, we gotta find a back-door way of showing chemo alone is just as good as chemoradiation. Boom, let’s compare regimens that don’t consistently improve DFS to see which one improves DFS. The FOWARC trial randomized patients with T3/4 or N+ rectal cancer to receive one of three neoadjuvant regimens: [1] standard fluorouracil/leucovorin (FU) with 46-50.4 Gy radiation, [2] FOLFOX with the same radiation, or [3] mFOLFOX6 alone. Each group then received the same chemo adjuvantly. The initial FOWARC results demonstrated doublings of pathologic complete response rate (pCR) from mFOLFOX6 (7%) to FU/RT (14%) to FOLFOX/RT (28%). FOLFOX/RT also increased the downstaging (to stage 0/1) rate from ~36% to 56%. In the final results, though, there was no significant improvement in the primary outcome of 3-year DFS. In fact, the DFS rate in all arms (72-77%) actually matched the estimated improvement (60 → 75%) used for the study power calculation. The rates of 3-year local recurrence after R0/1 resection were all <10%, and there was no difference in overall survival. 
TBL: FOLFOX, either with or without radiation prior to surgery for locally advanced rectal cancer does not improve local recurrence or disease-free survival compared to the standard of 5-FU and radiation. | Deng, J Clin Oncol 2019


  1. No difference in 3y DFS, but this trial was not non-inferiority! So, equivalence of mFOLFOX6 cannot be concluded.
    Issue: RT coverage of external iliacs not specifically mentioned, which is a significant issue considering ~33% were T4. Additionally, the mFOLFOX6 arm had "addition of RT before or after surgery at the physician's discretion".

    This is like the ESPAC-1 of rectal cancer.

    Do y’all think it’s much of an issue that they don’t mention external iliac coverage? For me, the main issue is the background therapy on the chemo alone arm.

    1. Lastly, ypT0N0 is clearly associated with superior DFS (at least) across a number of disease sites. As a result, It kind of grinds my gears to hear folks say that pCR doesn’t matter. #TNT


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