Marshall Highlights Treatment Options for Left-Sided mCRC

John Marshall, MD

John Marshall, MD

John Marshall, MD, recently discussed the treatment options and decisions he makes when treating patients with metastatic colorectal cancer. Marshall, professor of medicine and oncology, director of the Otto Reusch Center for the Cure of GI Cancer, Medstar Georgetown University Medical Center, Washington, DC, explained his treatment decisions based on 2 case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.

Case 1

February 2013

• A 53-year-old Caucasian man presented to his gastroenterologist complaining of rectal bleeding and abdominal tenderness.
• Past medical history (PMH) includes hypertension, well controlled on a beta-blocker.
• Family history: mother died from breast cancer
• He underwent colonoscopy with biopsy of a sigmoid lesion.
• Pathology results confirmed poorly differentiated adenocarcinoma.
• Genetic testing; KRAS exon 2 codon 12 mutation.
• CT of abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe.

TARGETED ONCOLOGY: What type of molecular testing should be ordered for the patient and when should testing be done?

Marshall:All patients with colon cancer in general should have microsatellite instability (MSI) testing. Certainly, in the metastatic setting, that should be done mainly to rule in or out inherited cancer syndromes and whether or not they would be a candidate at any point for checkpoint inhibitors. In patients with left-sided colon cancers, those MSIs are less likely to be seen, but they should still be checked.

Particularly, in patients with left-sided colon cancers, you must know theirRAFandBRAFstatus. There are emerging data that left-sided colon cancers that are RAFwild-type andBRAFwild-type have an improved outcome if an EGFR-targeted therapy is used in the frontline setting. At least in this patient, I would want to know that and discuss that with the patient. You already know that the patient has a KRASexon 2mutation, so you don't really need to know anything else beyond that in this patient. However, if you didn't know thatKRASmutation, you would need to know RAFandBRAF.

The last 1, which I would say should be done on almost all patients with colon cancer, is HER2. It is not really on anyone's radar, but it is important to measure this, particularly on left-sided colon cancers because it would bring up therapeutic options downstream. It would not be a choice for first-line therapy, but it would be a choice for second-line therapy.

TARGETED ONCOLOGY:What are the options for treating this patient?

Marshall:The options are going to be systemic chemotherapy, you are going to have a multidisciplinary meeting to determine whether the patient has a surgical resection option with liver and lung metastasis. Often the answer to that is no, so you are going to give initial lines of therapy, usually combination chemotherapy of fluoropyrimidine, oxaliplatin, irinotecan and, in the case of this patient, probably with bevacizumab. Liver-directed therapy is probably not [an option] in this patient, at least initially, but maybe sometime downstream in the refractory setting. 

TARGETED ONCOLOGY:What factors do you consider when determining systemic therapy for this patient?

Marshall:The factors to determine therapy in this patient are really around performance status, overall treatment goals, curative resection versus not, symptomatic or not, and toxicity. Those are the things we integrate in our decision making. Regarding left-sided, it is important, as I mentioned, to know theRAFstatus because in those patients EGFRtherapy may be superior to VEGF therapy in the frontline setting. All of this hinges on the biologics.

• The patient was started on FOLFOX (folinic acid, fluorouracil [5-FU], and oxaliplatin) and bevacizumab (Avastin); therapy was well tolerated.
• The second follow-up scan showed a marked decrease in volume of the primary tumor, 2 of the liver lesions, and the lung lesion.

March 2014

• The patient complains of intermittent shortness of breath but continues his normal activities.
• Imaging shows slow, but steady, progression in the plural lesion.

TARGETED ONCOLOGY:Do you order repeat biopsy and genetic testing?

Marshall:In almost all patients, after their initial lines of therapy and after they respond, we back off onto a maintenance kind of approach. But in this patient, after initial therapy he begins progression of disease. Right now, I would argue that we don't have firm data to repeat biopsies and genetic testing if you have already done it. However, I do think the more we are looking, the more we are seeing some changes. I would not fault anybody for doing that, particularly in later lines of therapy.

If the patient received FOLFOX and bevacizumab as frontline, and progressed and is now symptomatic with a KRASmutation, you don't have too many other choices aside from irinotecan, probably in the form of FOLFIRI and continuing on the bevacizumab in a VEGF therapy beyond progression kind of approach. I think in the second line, with these symptoms in this patient, you don't have any other choices but FOLFIRI and bevacizumab. 

• Bevacizumab therapy was continued; the patient was also started on FOLFIRI (folinic acid, fluorouracil, and irinotecan).
• Follow-up imaging shows continued regression of the lung lesion; patient continues to tolerate therapy, with management of gastrointestinal distress.

February 2017

• The patient complains of abdominal fullness, nausea, and constipation.
• He continues to work full time but feels sluggish.
• MRI indicates diffuse metastatic disease in the peritoneum, consistent with carcinomatosis.

TARGETED ONCOLOGY: What are the choices at this point and how do you manage the patient’s progression?

Marshall:After he progresses on this, there are really only 2 choices in the approved setting. That would be either regorafenib or TAS-102 (Lonsurf). I think either is a viable option for patients such as this. You would make the decision on which 1 of those to give based on the patient's acceptance and tolerability. Interestingly, at the 2018 [Gastrointestinal Cancers Symposium], a new study ReDOS was presented which suggested some easier dosing of regorafenib, which translated into an improved outcome.¹I think we may quickly have a new standard of care for this drug, where you start at 80 mg instead of 160 mg and escalate as patients tolerate it and it may have an improved outcome. I would no longer consider starting a patient on 160 mg outside of a clinical trial.

• The patient was started on regorafenib (Stivarga) 160 mg.

Case 2

October 2016

• A 64-year-old woman underwent left hemicolectomy for an obstructing mass at the rectosigmoid junction.
• PMH includes arterial hypertension, well controlled on an ACE inhibitor; coronary angioplasty with stent placement 4 years ago.
• Carcinoembryonic antigen (CEA) elevated; 23.3 ng/mL.
• Pathology showed an undifferentiated adenocarcinoma, invading through the muscularis mucosae up to the pericolic fat; 14 nodes were biopsied, 10 of which were metastatic.
• Mutational status: RAS and BRAF wild-type.
• Microsatellite stable.
• Imaging with PET/CT showed several lung lesions, 3 measuring up to 3.0 cm in size.
• Diagnosis; high-grade colorectal adenocarcinoma, stage T4N2M1.

TARGETED ONCOLOGY:What are the options for frontline therapy in this patient with unresectable, all-RASandBRAFwild-type metastatic colorectal cancer?

Marshall:This is a patient with likely incurable metastatic disease. She has a left-sided rectal sigmoid tumor and she is RASandBRAFwild-type and microsatellite stable. You at least know the key molecular tests that are required to make this initial decision. You have also got a patient who is asymptomatic, from the lung lesions, but there is frontline subset analysis data that suggests that in left-sided metastatic colon cancer, starting with EGFRtherapy is appropriate. The negative to that is that we are all concerned about skin toxicity and what to do with maintenance therapy. I think that is a healthy debate going on in the United States whether we believe the subset analysis and survival advantage to using an EGFRtherapy in frontline in this patient or do we use it later and use a bevacizumab-based regimen frontline and save our skin toxicity for later. More and more, I have been increasingly convinced that using an EGFRtherapy in this space would be appropriate. I would confess that I have not yet done this to a patient, but I am certainly discussing this with patients as a recommendation for frontline therapy.

TARGETED ONCOLOGY:Discuss the use of maintenance therapy in this patient.

Marshall:The patient had a nice response to the initial therapy and switches over to maintenance with single-agent cetuximab. I understand this, but it is hard to give cetuximab as maintenance for a long period of time. In my patients, I often will now swap them over to a fluoropyrimidine like capecitabine with bevacizumab as maintenance. But I think maintenance cetuximab (Erbitux) is interesting and certainly a valid choice in this patient. I wouldn't fault that, but giving cetuximab or EGFRtherapy chronically can be hard on the patient's gastrointestinal tract, skin, and fatigue. So it is not as easy to give long term.

• The patient received systemic therapy with FOLFIRI plus cetuximab; she developed grade 1 rash and no other major toxicities.
• Follow-up imaging at 2 months and 4 months showed significant response in the lung lesions.
• The patient was continued on maintenance therapy with cetuximab.

August 2016

• The patient complained of weight loss, nausea, and fatigue
• CT of the chest, abdomen, and pelvis showed marked progression in 2 of the lung lesions and development of new liver lesions.

TARGETED ONCOLOGY:How do you treat the patient at this point?

Marshall:I would then switch to oxaliplatin-based therapy, you certainly need to have some form of fluoropyrimidine. In this case, capetcitabine is certainly appropriate and something we use a lot. VEGFinhibitors are also approved in this setting, so I would absolutely bring in bevacizumab in second-line therapy.

• The patient was switched to CAPEOX (capecitabine and oxaliplatin) with bevacizumab; her blood pressure was closely monitored and remained stable.
• Follow-up imaging at 2 months and 4 months showed stable disease in the lung and liver lesions and improvement of her symptoms.
• At 4 months, oxaliplatin was discontinued; maintenance therapy with capecitabine and bevacizumab was continued.

January 2017

• At 5 months, the patient reports having reappearance of her symptoms, although she continues her normal physical activity.
• CEA level rose significantly
• Follow-up CT showed further progressive disease in the lung and the appearance of several small boney lesions.
• The patient is motivated to try another therapy.

TARGETED ONCOLOGY: If the patient developed further progression, what data are available to guide selection of fourth-line therapy and beyond?

Marshall:On subsequent progression, there is a similar discussion about whether it is regorafenib or TAS-102. It is very similar when deciding how best to move things forward. There are more data that will be emerging around TAS-102 and other diseases. As we get an increased comfort level with that medicine, I think that will factor into our decision making here as well. You can consider either of those medicines in this setting. It is important for us as oncologists not to undervalue the survival benefit that is seen with these drugs. We often wait too long, until the patient is having a falling performance status, and these drugs are not very good at catching rapidly progressing disease or a falling performance status. What they are good at is catching and prolonging survival in patients with good performance status and not a rapidly progressing disease. In my opinion, earlier is better.

Reference:

Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study.J Clin Oncol. 2018;36(suppl 4S; abstr 611).