What treatment sequence do you follow for patients with rectal cancer who are candidates for both PROSPECT and TNT/Watch and wait?

Thanks for this question. I am not sure whether this is up to us. This is up to our patients to choose which modality they would like to omit (radiation vs surgery). I would point out that a good quality MRI rectum should be performed to r/o any T4/N2 disease or potential requirement for APR. Otherwise, it is a risk and benefit discussion with each individual patient and what their priority is in their life. Here is our editorial on this matter: Felder et al., PMID 38776515.

In addition to the above responses, which I agree with, I would also like to add that the addition of brachytherapy significantly improves the CR for patients aiming for non-operative management.

We have publications of OPERA and MORPHEUS trials that have demonstrated the benefit of brachytherapy, and these should be included in the discussion.

I mostly use TNT followed by selective surgery per OPRA. Patients with locally advanced rectal cancer (stage II and III) are eligible regardless of tumor location in the rectum.

With regards to PROSPECT, T4 and/or N2 tumors were excluded. The tumor had to be 5-12 cm from the dentate line (lower rectal tumors were excluded), and a mandatory assessment was required during induction chemotherapy to assess whether at least 20% response was achieved. About 15% of patients did not meet this requirement and were given concurrent chemoradiation. I treat per PROSPECT in patients who are not candidates for radiation (prior radiation or severe/active collagen vascular disease) or who refuse to get radiation.

There’s also the JANUS study that aims to ass...

The big difference between these approaches is the ability to do organ preservation. If organ preservation is a goal, PROSPECT is out. If the patient is clear about getting TME, then PROSPECT is very reasonable to get the potential to avoid late RT toxicities.

The ASCO guidelines for management of locally advanced rectal cancer perform a meta-analysis showing TNT improves 5-year OS compared to neoadjuvant CRT (Table 3).

If PROSPECT shows equivalent OS between neoadjuvant CRT and neoadjuvant chemo, then a reasonable conclusion to draw is that a TNT approach, per OPRA, would have improved OS over neoadjuvant CRT or neoadjuvant chemo, per PROSPECT. With the usual caveats that this is not category 1 data.

A PROSPECT approach--either neoadjuvant chemo alone or chemoRT alone--can be considered in patients who are not felt to be able to tolerate TNT, accepting that organ preservation is off the table and OS *may* be lower per the ASCO analysis. In those cases, an informed discussion can be had with the pa...