Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma Guideline

ASCO Guidelines

Dr. Van Morris presents the new evidence-based guideline on systemic therapy for localized anal squamous cell carcinoma. Dr. Morris discusses the key recommendations from the Expert Panel, including recommended radiosensitizing chemotherapy agents, dosing and schedule recommendations, the role of induction chemotherapy and ongoing adjuvant chemotherapy, and considerations for special populations. He emphasizes the importance of this first guideline from ASCO on anal squamous cell carcinoma for both clinicians and patients with stage I-III anal cancer, and ongoing research the panel is looking to for the future.

Read the full guideline, “Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline” at www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

This guideline, clinical tools, and resources are available at http://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-24-02120

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. Van Morris from MD Anderson Cancer Center, co-chair on “Systemic Therapy for Stage I-III Anal Squamous Cell Carcinoma: ASCO Guideline.”

Thank you for being here today, Dr. Morris.

Dr. Van Morris: Thank you for having me. On behalf of our committee who put together the guidelines, I'm really excited to be here and talk with you today.

Brittany Harvey: Great. 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. Morris, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, to jump into the content of this guideline, Dr. Morris, can you provide an overview of both the purpose and the scope of this guideline on stage I to III anal squamous cell carcinoma?

Dr. Van Morris: So anal cancer is considered a rare malignancy for patients in the United States and across the world as well. Even though it's not something we see as commonly, for example, as the adjacent colorectal cancer, this still is a cancer that is rising in incidence every year in the United States. And really, despite the presence of the preventative HPV vaccines, which we hope will ultimately prevent and eradicate this cancer, we still expect the incidence to continue to rise in the coming decades before we really start seeing numbers begin to decrease as a result of the vaccine. So this is an alarming trend for which oncologists will continue to see likely more and more cases and new diagnoses every year. So we wanted to review the most recent literature and provide oncologists up to date recommendations for how they can best take care of patients with a new diagnosis of localized anal cancer.

Brittany Harvey: Absolutely. I appreciate that background and context to set the stage for this guideline.

So then next I'd like to review the key recommendations of this guideline. So starting from the first clinical question, what are the recommended radiosensitizing, doublet or single chemotherapy agents for patients with stage I to III anal cancer?

Dr. Van Morris: It's true that really the standard treatment for patients with localized anal cancer has not changed over the last literally half century. When the Nigro regimen was first reported back in 1974, 50 years ago, the standard of care for patients with a new diagnosis of localized anal cancer centers around concurrent chemotherapy and radiotherapy. And we looked at the various randomized control trials and the highest level of evidence which has been reported over the past decades, and really for most patients, the standard of care continues to remain doublet cytotoxic chemotherapy in combination with radiation. We reported that the most commonly, and I think most accepted, regimen here is a combination regimen of 5-FU, intravenous 5-fluorouracil with mitomycin C. And this most commonly is given on a week 1 to 5 regimen. The 5-FU, we recommended a dose of 1000 milligrams per meter squared per day on days 1 to 4 and then on days 29 to 32 of the radiation treatment. And then the mitomycin C, looking at various trials, has been given at a dose of 10 milligrams per meter squared on day 1 and day 29, or alternatively a single dose of mitomycin C at 12 milligrams per meter squared on day 1.

I think that the thing that's important for clinicians and patients alike to remember is that this chemotherapy can be very toxic in patients who are undergoing a curative-intent therapy for this diagnosis of localized anal cancer. I think it's just important for oncologists to be watching closely the blood counts for the patients to make sure that the myelosuppression doesn't get too bad. And then in select cases, if that is the case, when the oncologist opts to go for the day 1 and day 29 dosing, it may be prudent, if the myelosuppression is too excessive, to consider withholding that day 29 dose.

Brittany Harvey: Great. Thank you for providing those recommendations along with some of those dosing and the schedule recommendations from the expert panel.

So are there any other alternate dose or schedule recommendations from the expert panel?

Dr. Van Morris: Yeah, but I think that we saw with the ACT II data that was a randomized trial that was done out of the UK that compared 5-FU mitomycin with 5-FU cisplatin as two different doublet cytotoxic regimens, that overall outcomes were very similar between the two regimens in terms of curative outcomes for patients treated whether 5-FU mitomycin or 5-FU cisplatin. So certainly there is evidence supporting the use of cisplatin as a second cytotoxic agent with 5-fluorouracil. In the ACT II study that was given at a dose of 60 milligrams per meter squared on days 1 and 29 along with the 5-FU at the regimen I talked about previously. There is other lower level of evidence data suggesting that even the 5-FU and cisplatin can be given on a weekly schedule and that that can be safe. Actually, at my institution at MD Anderson, that is our standard practice pattern as well.

There's also the option when we're thinking about giving pelvic radiation for patients with lower GI cancers, many oncologists in the treatment of localized rectal adenocarcinoma are accustomed to using capecitabine as a chemosensitizer in patients with localized rectal cancer. If I'm giving chemoradiation for a patient with localized anal cancer, can I substitute the intravenous 5-FU with oral capecitabine? And although the evidence is not as strong in terms of available data with regards to randomized controlled trials, there certainly is data that suggests that capecitabine may be an acceptable alternative in lieu of intravenous 5-fluorouracil that would be given at a dose of 825 milligrams per meter squared on days of radiation. But certainly, I think that that's a feasible approach as well and maybe even associated with less hematologic toxicity than intravenous 5-FU would be.

Brittany Harvey: Great. It's important to understand all the options that are out there for patients with early-stage anal squamous cell carcinoma.

So in addition to those chemoradiation recommendations, what is recommended from the expert panel regarding induction chemotherapy or ongoing adjuvant chemotherapy for this patient population?

Dr. Van Morris: When we think about treating patients with lower GI cancers with curative intent therapies, when we think about the more common rectal adenocarcinoma, oncologists may be used to giving chemoradiation followed by subsequent cytotoxic chemotherapy. But actually when you look at the data for anal cancer, really there's not any data that strongly supports the use of either induction chemotherapy prior to chemoradiation or adjuvant post-chemoradiation chemotherapy. The RTOG 98-11 study was a trial which evaluated the role of induction 5-fluorouracil prior to chemoradiation and did not show any survival benefit or improved outcomes with the use of induction chemotherapy in a randomized control trial setting.

The ACT II trial, which I referenced earlier, was a 2 x 2 design where patients were either randomized to concurrent chemoradiation with 5-FU mitomycin C or concurrent chemoradiation with 5-FU cisplatin. But then there was a second randomization after chemoradiation where half of the study participants received adjuvant cisplatin 5-fluorouracil after completion of their chemo radiation, or the other half were randomized to the standard of care, which of course would be observation. And what that trial showed was that there was no added benefit with the addition of post-chemoradiation cytotoxic chemotherapy. So we look at these data and say that in general, for the general population of patients with localized stages I to III anal cancer, there really is no supporting data suggesting benefit of either induction chemotherapy or adjuvant chemotherapy. And to that end, really it's concurrent chemoradiation remains the standard of care at this time for patients with a new diagnosis of localized anal cancer.

Brittany Harvey: Absolutely. It's just as important to know what is not recommended as it is to know what is recommended for these patients. And so I thank you for explaining the evidence behind that decision from the panel as well.

So then, are there any other considerations for special populations that oncologists should consider?

Dr. Van Morris: I think so. I think that anal cancer is a disease where we don't see that many patients being diagnosed earlier at a younger age, especially in relation to the alarming trend of early onset colorectal cancer that we're currently seeing right now. So there may be patients who come with a new diagnosis of localized anal cancer who are an octogenarian at an advanced age or may have other significant medical comorbidities. And if that is the case, we get called about this quite frequently from outside institutions. I have an 85 year old who is coming to my clinic with this diagnosis. I don't feel comfortable giving this patient doublet cytotoxics, what options do I have? Especially given other organ dysfunction that may precede this diagnosis. And I think that in that case, there are times when it's okay safely to drop the mitomycin C and opt for single agent 5-fluorouracil as a single cytotoxic agent. So I think that that would be something that we've certainly incorporated into our practice at our institution. There's also an association between various autoimmune disorders, patients on immunosuppression, even persons living with HIV being at higher risk for this virally associated cancer. So I think that, again, if the patient is coming with baseline immunosuppression for these reasons prior to treatment, certainly kind of being in tune to the potential for hematologic toxicity. And watching these patients very closely as they're getting chemoradiation remains really important.

Brittany Harvey: Definitely. So, you've just discussed some of those comorbidities and patient characteristics that are important for clinicians to consider when deciding which regimens to offer. So in addition to those, in your view, what is the importance of this guideline and how will it impact clinical practice for clinicians who are reading this guideline.

Dr. Van Morris: Chemoradiation remains a very effective option and most patients will be cured with this diagnosis and with this treatment. So it's important to make sure that these patients are able to safely get through their treatment, minimizing treatment delays due to toxicities which may come about because of the treatment, and really help to carry them over the finish line so that they have the best likelihood for achieving cure. So we really hope that these data will provide oncologists with a readily available summary of the existing data that they can refer to and continue to help as many patients as possible achieve and experience a cure.

Brittany Harvey: Absolutely. So then to build on that, it's great to have this first guideline from ASCO on anal squamous cell carcinoma. But how will these new recommendations affect patients with stage I to III anal cancer?

Dr. Van Morris: I certainly hope it will allow patients and oncologists to know what their options are. It certainly is not a one size fits all treatment approach with regards to the options which are available. Depending on the patient, depending on the various medical conditions that may accompany them, these treatments may need to be tailored to most safely get them through their treatment.

Brittany Harvey: I appreciate you describing the importance of this guideline for both clinicians and patients.

So what other outstanding questions and future research do you anticipate seeing in this field?

Dr. Van Morris: It's a really good question and I think that there is a lot coming on the horizon. Even though the standard treatment has really not changed over the last half century, I think it still remains true that not all patients will achieve cure with a chemoradiation treatment. So a recent trial has completed enrollment in the United States, this is the EA2165 trial led by one of our committee members, Dr. Rajdev and Dr. Eng as well, that's looking at the use of nivolumab anti PD-1 immunotherapy after completion of concurrent chemo adiation. So in that trial, patients were randomized to concurrent chemoradiation followed by either observation or six months of adjuvant anti PD-1 therapy. We're really awaiting the results of that. Hopefully if we see an improvement with the addition of nivolumab following concurrent chemoradiation, our hope would be that more patients would be able to achieve a cure. So we're certainly looking forward to the outcomes of that EA2165 study.

And then I think one question that we often get from our patients in the clinics is, “What is the role of circulating tumor DNA in the management of my disease?” And really, to date there have been some series which have shown that we can assess patients or circulating tumor DNA after completion of their concurrent chemo radiation that may need to start about three months after to give time for the radiation to wear off and most accurately prognosticate that. But I think that this will be a powerful tool moving forward, hopefully, not only in the surveillance to identify patients who may be at high risk for recurrence, but ultimately to translate that into next generation clinical trials which would treat patients at higher risk for recurrence by virtue of a detectable circulating tumor DNA result. In doing so, hopefully cure even more patients with this diagnosis.

Brittany Harvey: Yes, we'll look forward to these developments and hope to add more options for potential treatment and surveillance for patients with anal cancer.

So, I want to thank you so much for your work to develop these guidelines and share these recommendations with us and everything that the expert panel did to put this guideline together. Thank you for your time today, Dr. Morris.

Dr. Van Morris: Thank you. And thank you to ASCO for helping to keep this information out there and ready for oncologists for this rare cancer.

Brittany Harvey: Absolutely.

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