Dr. Sepideh Gholami and Dr. Aaron Scott join us to discuss the latest evidence-based guideline from ASCO on the management of locally advanced rectal cancer. They review the recommendation highlights on topics including assessment, total neoadjuvant therapy, timing of chemotherapy, nonoperative management, and immunotherapy. Additionally, we discuss the importance of this guideline for both clinicians and patients, and the outstanding research questions in the management of locally advanced rectal cancer.

Read the full guideline, "Management of Locally Advanced Rectail Cancer: ASCO Guideline" at www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.01160

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at ASCO.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Aaron Scott from the University of Arizona Cancer Center and Dr. Sepideh Gholami from Northwell Health, co-chairs on, "Management of Locally Advanced Rectal Cancer: ASCO Guideline." Thank you for being here, Dr. Scott and Dr. Gholami.

Dr. Sepideh Gholami: Thank you for having us.

Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Scott and Dr. Gholami, who have joined us here today, are available online with a publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to kick us off on the content of this episode, Dr. Gholami, first, what is the purpose and scope of this guideline on locally advanced rectal cancer?

Dr. Sepideh Gholami: Well, I think, historically, this is the group of patients with locally advanced rectal cancer for which we've used multiple therapies to address their management. And with the advent of the total neoadjuvant approach, we really have seen tremendous changes. So the purpose really of these guidelines was to consolidate the various approaches that we've had in several clinical trials and to provide the oncology community a general management recommendation guideline to really optimize the outcomes for these patients. And I would further notice that with the specifics to like which patients are included for these, so we define patients with locally advanced rectal cancer as any of those patients with T3 or T4 tumors and/or lymph node positive disease.

Brittany Harvey: Great. I appreciate you providing that background and context of this guideline.

So then, next, I'd like to review the key recommendations of this guideline. So, Dr. Scott, starting with the first section of the guideline, what are the recommendations for assessment of locally advanced rectal cancer?

Dr. Aaron Scott: Yeah, thank you. So really, we were charged with trying to answer, I think, several very important questions as it comes to the treatment of locally advanced rectal cancer. And the first step in doing so is to define the patient group. So, as far as the first section goes in the assessment, we were really charged with defining what locally advanced rectal cancer means. We think that this is best done with a high resolution pelvic MRI, dedicated rectal sequence prior to any treatment for risk assessment and proper staging, and the use of standardized synaptic MRI is recommended that includes relation of the primary tumor to the anal verge, sphincter complex, pelvic lymph nodes, the mesorectal fascia, otherwise known as the MRF, and includes assessment of the EMVI tumor deposits and lymph nodes.

Brittany Harvey: I appreciate you reviewing those highlights for assessment of locally advanced rectal cancer.

So following that, Dr. Gholami, what does the panel recommend regarding total neoadjuvant therapy and standard neoadjuvant chemotherapy for patients with proficient mismatch repair or microsatellite stable tumors?

Dr. Sepideh Gholami: Yeah, thanks so much for that question, Brittany. I would say that the guidelines really provide a lot more details, but in general, the consensus was that TNT should be offered as really initial treatment for patients with low rectal locally advanced rectal cancers or those who have higher risk for local and distant metastases. Those risk factors included anyone with either T4 disease, extramural vascular invasion and/or tumor deposits identified on the MRI for any threatening of the mesorectal fascia or the intersphincteric plane.

Brittany Harvey: Excellent. So then, Dr. Gholami just discussed who should be offered TNT. But Dr. Scott, what are the recommendations regarding timing of TNT?

Dr. Aaron Scott: So the way I take this question, think about this question, is a lot of the work that we put toward defining whether chemoradiation plus consolidation versus induction chemotherapy is the right choice, and there are a lot of implications to consider in this situation. The panel recognizes that the decision to proceed with chemoradiation followed by chemo versus chemotherapy followed by chemoradiation often depends on logistics regarding the time to treatment start, concern for distant metastases, and desire for local control that may impact surgical decision making.

When we look at the subgroup analysis for overall survival of patients treated with TNT, it doesn't seem to matter which approach you take. Either induction or consolidation doesn't seem to have an impact on overall survival. However, there are other outcomes that may be of importance. Based on the CAO/ARO/AIO-12 randomized phase II trial, both pathologic complete response rates and sphincter sparing surgery were numerically higher with consolidation chemo. That said, there was no difference in disease free survival. So if you have a patient that really wants to consider some sort of sphincter sparing surgery, or a patient has a highly symptomatic disease burden, etc., these are patients that we would recommend starting with chemoradiation followed by consolidation chemotherapy.

Brittany Harvey: Understood. And so you have both mentioned radiation included in treatment regimens. So Dr. Gholami, what is recommended in the neoadjuvant setting? Short course radiation or long course chemoradiation?

Dr. Sepideh Gholami: Yeah, we actually had a really long discussion about this, but I think in general the consensus was that if radiation is included in any patient's treatment plan, neoadjuvant long course chemoradiation is preferred over short course RT for patients with locally advanced rectal cancer. And really the recommendation was based on the long term results that we've seen from the RAPIDO phase 3 clinical trial, which showed a significant higher rate of five year local regional failure with a total neoadjuvant approach with short course of 10% compared to the standard chemo RT with only 6% of the local recurrence rate. So that's why they opted for the long course, if the patients can actually tolerate it.

Brittany Harvey: Excellent. I appreciate reviewing the recommendation and the supporting evidence that the panel reviewed to come to those recommendations.

Then following that, Dr. Scott, for those patients who have a complete clinical response after initial therapy, what is recommended regarding nonoperative management?

Dr. Aaron Scott: First, I would like to just say that this is really an area that still remains somewhat controversial and needs more investigation to best select patients for this approach. This topic was not systematically reviewed for the ASCO guideline. However, the expert panel was surveyed and most agreed with the time interval used in the OPRA phase 2 trial, which assessed patients for clinical complete response within eight weeks plus or minus four weeks after completion of TNT. Expert panel members and reviewers noted that if the radiation therapy component of TNT is delivered first, then an eight week interval following subsequent chemotherapy may result in a prolonged period of no treatment and therefore a first assessment of this response in this scenario would occur on the earlier side of the recommended interval. If a near clinical complete response is noted, then reevaluation within eight weeks is recommended to assess for developing a clinical complete response.

Brittany Harvey: Absolutely. That information is helpful to understand what is recommended regarding nonoperative management and clinical complete responses.

Then the final clinical question, Dr. Gholami, for patients with tumors that are microsatellite instability high or mismatch repair deficient, which treatment strategy is recommended?

Dr. Sepideh Gholami: Yeah, I think we really came up to summarize that in general, when there is no contraindication to immunotherapy, then patients with MSI high tumors should be really offered immunotherapy. The evidence for this recommendation was relatively low, though, just due to the small sample size of the data that's currently available. But we did want to highlight that the data is very promising, but a definitive recommendation by the committee should be validated in future larger clinical trials.

Brittany Harvey: Absolutely. Well, thank you both for reviewing the highlights of these recommendations for each clinical question.

Moving on, Dr. Scott, in your view, what is the importance of this guideline and how will it impact both clinicians and patients with locally advanced rectal cancer?

Dr. Aaron Scott: This would be the first guideline through ASCO to spell out management options for locally advanced rectal cancer. This has largely been needed due to the increased number of phase II and III trials investigating the specific patient population that have investigated a variety of different TNT approaches and treatment combinations utilizing systemic therapy, radiation, and surgical treatment. So, in this guideline, we really set out to define what locally advanced rectal cancer is, have organized and analyzed impactful large randomized studies to address multimodality therapy, and have consolidated this information into what we consider a concise and generalizable approach to help clinicians and patients individualize their management based on specific clinical pathologic features of their cancer.

Brittany Harvey: Yes, this has been a mountain of work to review all the evidence, consolidate it into a concise review of that evidence, and develop recommendations for best clinical practice for management of locally advanced rectal cancer.

So then, finally, to wrap us up, Dr. Gholami, what are the outstanding questions regarding management of locally advanced rectal cancer?

Dr. Sepideh Gholami: Yeah, I think I just want to reiterate, Brittany, what you mentioned, this was a tremendous amount of body work, and we really would like to thank the committee and everyone from ASCO to help us with creating these general guidelines. I think one of the outstanding questions really still remains is the use of circulating tumor DNA as a management tool for patients with rectal, locally advanced rectal cancer. And also, I think outside of what we can think of the straightforward populations to deduce from PROSPECT, be really interested to see what other patient populations, for example, could also potentially maybe avoid radiation therapy. And lastly, I think we really wanted to highlight that this guideline really focuses on the locally advanced, and it would be great to see future guidelines for early stage rectal cancer which will be forthcoming.

Brittany Harvey: Definitely. We'll look forward to answering those outstanding questions and for upcoming guidelines on earlier stage rectal cancer. So, I want to thank you both so much for, as you said, the tremendous amount of work that went into these guidelines and thank you for taking the time to speak with me today, Dr. Scott and Dr. Gholami.

Dr. Aaron Scott: Thank you.

Dr. Sepideh Gholami: Thank you so much for having us. Appreciate it.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please read and review the podcast and be sure to subscribe so you never miss an episode.

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