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O'Neil Considers Treatment Options in 2 Gastrointestinal Case Studies

Samantha Hitchcock
Published Online:3:29 PM, Thu June 28, 2018

Bert H. O'Neil, MD

Bert H. O’Neil, MD, recently shared his considerations for treatment when treating patients with gastrointestinal cancers. O’Neil, the Joseph W. and Jackie J. Cusick Professor of Oncology, Indiana University School of Medicine, and director of Phase I & GI Oncology Programs, IU Melvin and Bren Simon Cancer Center, in Indianapolis, Indiana, reviewed how he would treat patients with colon cancer and patients with hepatocellular carcinoma based on case scenarios during a Targeted Oncology live case-based peer perspectives presentation.

Case 1

February 2016

A 53-year-old Caucasian man without a previous colonoscopy presented to his primary care physician with rectal bleeding and abdominal tenderness. His past medical history showed hypertension, which was well-controlled on a beta-blocker. His mother died from breast cancer

He underwent colonoscopy with biopsy, which showed an ulcerated non-obstructive mass noted in the right colon. Pathology results confirmed poorly differentiated adenocarcinoma and molecular testing showed he was BRAF-mutated; microsatellite-stable. A CT of the abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe. The patient was diagnosed with metastatic adenocarcinoma of the right colon; stage T4N0M1.

What are your general impressions of this patient?

This patient is a gentleman with a new diagnosis of metastatic colon cancer. His tumor originates on the right side of the colon and it is poorly differentiated, which often goes along with being a right-sided tumor. His CT scan shows multiple liver lesions, so we can presume he is not going to be a good surgical candidate, in addition to at least 1 lesion in the right lower lobe of the lung.

This BRAF-mutated, microsatellite-stable colon cancer represents a particularly bad behaving variant of colon cancer. At this point, no treatment works very well. These patients have a much shorter survival than those who are BRAF wild-type. They will respond to initial chemotherapy. There is some data from the TRIBE study, out of Italy, that shows 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab (Avastin) might be a particularly good regimen to start with in a patient like this.1 It is a little bit controversial whether they should be treated with vascular endothelial growth factor receptor (VEGFR) antibodies. Generally speaking, I would not pick a VEGFR antibody for a KRAS wild-type, right-sided tumor regardless of BRAF mutation status.

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

The main factors to consider here are the side of origin, the BRAF mutation status, and the goal of treatment. For example, are we aiming for cure here or is this more palliative? If this patient did not have a BRAF mutation, that would be important in deciding whether or not we use a 2-drug chemotherapy regimen or a 3-drug chemotherapy regimen—whether or not we use a biologic. Liver disease is more limited, we may consider later surgical resection. So, I think an aggressive regimen to try to decrease the size and number of liver lesions as much as possible would be warranted. And then of course, we need to think about things like the adverse events (AEs) the patients is likely to tolerate. For example, is there diabetic neuropathy present? Can the patient tolerate neuropathy? Things of that nature.

Should the patient have additional genetic testing?

At present, I think the minimum initial testing for a patient with newly diagnosed metastatic colon cancer should include: KRAS and NRAS sequencing, an assay for BRAF mutation, as was done here, and an assessment for microsatellite status. Given what we have on this patient, that mirrors what I would have ordered initially.

What is the significance of his right-sided tumor in terms of response to biologic therapy?

If the tumor originated on the left-side, it still depends on the BRAF mutation. You can still see BRAF-mutated tumors on the left side. In which case, I think the considerations are similar. If the tumor is left-sided and wild-type for RAS and RAF, then I would become more inclined to consider an epidermal growth factor receptor (EGFR) antibody in conjunction with standard chemotherapy. That is based on data from CALGB/SWOG 80405, where there was a significant survival advantage associated with beginning with an EGFR antibody in those patients.2

The patient was started on FOLFOXIRI and bevacizumab and his therapy was well-tolerated after management of grade 2 neutropenia. Three months later, his second follow-up scan showed a 35% decrease in 2 of the liver lesions and stability in the lung lesion. He continued on folinic acid, fluorouracil, and oxaliplatin (FOLFOX) for 6 months and then switched to capecitabine and bevacizumab due to grade 1 neuropathy.

January 2017

The patient did well radiologically and biochemically. Eleven months later, he developed intermittent shortness of breath, but he continued his normal activities and his ECOG performance status was 1. Imaging showed new 3-mm lung lesion with increased size of the pleural lesion and stability in the liver lesions.

What are your general impressions of this patient after disease progression?

Our patient was started on FOLFOXIRI and bevacizumab based on the TRIBE study. He tolerated it relatively well, with some neutropenia being the main issue. Three months in, he had a significant decrease in 2 of the liver lesions and stability of the lung. In this case, he had irinotecan dropped and continued FOLFOX and presumably the bevacizumab for 6 months. Eventually, he was switched to capecitabine/bevacizumab, due to the development of neuropathy, as continued maintenance.

For a patient such as this one, I think that this is pretty standard. We think of a short survival with these patients. But, they do respond to first-line therapy. Unfortunately, what you can expect beyond progression in first-line therapy is for patients not to respond to much therapy.

What are your choices for therapy at this point?

When this patient progresses on first-line therapy, I think it is important for this particular subgroup to get on some kind of clinical trial. The best data we have at present comes from the SWOG 1406 study led by Scott Kopetz, MD, PhD, where patients were randomized to get either irinotecan/cetuximab as standard therapy or irinotecan/cetuximab and the BRAF inhibitor vemurafenib (Zelboraf).3 There was a fairly significant progression-free survival (PFS) advantage associated with that triple drug combination. This is based on preclinical work suggesting that RAF inhibition alone is inadequate in colon cancer to get a response. It requires inhibition of EGFR, simultaneously.

In this particular patient population, continuing bevacizumab is less clear than it is in the more general colon cancer population. As I said before, the best treatment for a patient such as this is to find a clinical trial for him or her. My own inclination, if I use bevacizumab in the first-line therapy, would be to switch over to an EGFR antibody in the second-line setting, if I can't find a clinical trial, or to try to get off-label vemurafenib in addition to an EGFR antibody.

The patient was started on regorafenib (Stivarga).

What is the rationale for treating this patient with regorafenib?

If you use FOLFOXIRI as your first-line therapy with bevacizumab, especially in a patient with a KRAS- or NRAS-mutated tumor, where you are not going to use an EGFR antibody, then regorafenib does become a rational second-line therapy.

Whether this is a good treatment choice, particularly in a patient with BRAF mutation, is undefined at this point. But, I don't think it is unreasonable in the absence of an available clinical trial.

What dose would you start with regorafenib in a patient such as this one?

In terms of regorafenib dosing, there is a good study done by the ACCRU group and led by Tony Bekaii-Saab, MD, where patients were randomized to have standard dosing of regorafenib at 160 mg daily from the outset versus a dose-escalation strategy, which involved starting at 80 mg daily and increasing the dose by one 40 mg tablet every week if the patient tolerated it.4 if the patient began to develop AEs, he or she would drop down to the prior dose.

By doing the dose escalation, they were able to get more patients to their third cycle. It was a small study, but there was a fairly strong hint of a survival benefit by doing that. Presumably, because patients who used the dose-escalation strategy were getting more therapy. 

What are the choices for therapy when this patient develops further disease progression?

Second-line regorafenib was used in this patient and the patient progressed. The next step would depend on whether or not they have neuropathy. Has it improved to grade 1 or even less? In this case, I might go back to FOLFOXIRI. Trifluridine/tipiracil (TAS-102; Lonsurf) would also be a consideration then, or if you had not used a RAF inhibitor, then the combination of an EGFR antibody and a RAF inhibitor with or without participation in a clinical trial. 

Case 2

February 2014

A 63-year-old Asian man with chronic hepatitis B virus (HBV) was referred for further imaging studies after a suspicious finding on routine ultrasound surveillance for hepatocellular carcinoma (HCC).

His alpha-fetoprotein (AFP) level was 5400 IU/mL. Laboratory findings showed: platelets, 230,000 cells/mcL; bilirubin, 1.0 mg/dL; albumin, 3.5 g/dL; hepatic encephalopathy, none; ascites, not present. The patient was deemed Child-Pugh class A.

A CT scan revealed 2 lesions in the right hepatic lobe measuring 2 cm and 5 cm, with no extrahepatic disease. Biopsy findings showed grade 2 HCC with moderate fibrosis. Both lesions were resected with R0 margin.

What are your general impressions of this patient?

This is a 63-year-old Asian male with chronic HBV infection who was found on ultrasound surveillance to have a suspicious lesion. He underwent further testing and was found to have an AFP of 5400, which would essentially field a diagnosis of HCC. In terms of liver function, he had intact liver function and was Child-Pugh class A with a normal bilirubin. Additionally, he had a fairly good albumin and no evidence of hepatic encephalopathy or ascites. He had 2 lesions in the right hepatic lobe at 2 cm and 5 cm. The 5-cm lesion would put him out of range for transplant. He had no extra hepatic disease. In spite of the high APF, this patient got a biopsy. Depending on what the imaging was like, it may or may not be necessary to do that. The patient then underwent resection with an R0 margin. 

Is there any evidence for use of adjuvant therapy in patients with HCC?

This is a patient who we would not offer systemic therapy to at this point, although we understand that the patient’s risk of recurrence is quite high, perhaps as high as 70%. Several studies have been conducted in terms of adjuvant therapy, but we have never seen a positive adjuvant therapy study in HCC. I would not say that there is any use for adjuvant therapy at this time.

August 2016

Routine follow-up imaging showed a new lesion in the liver measuring 2.3 cm. A chest CT showed 3 small lesions (<1 cm) in the left upper lobe of the lung.

The patient was started on sorafenib (Nexavar) 400 mg twice daily and tolerated therapy well after management of grade 1 diarrhea.

What are your general impressions of this patient after progression?

Our patient is followed up after surgery and then, unfortunately but not surprisingly, he develops some recurrence. In this case that means 3 lesions in the left upper-lobe of the lung. So, we are now left with someone with extra hepatic metastasis of HCC. This would be an indication for use of a systemic therapy. First choice in this case would generally be sorafenib.
This patient was started on sorafenib at 400 mg twice a day. He tolerated therapy well after management of some low-grade diarrhea.

What factors do you consider when deciding when to initiate therapy with sorafenib? 

Sorafenib is still the initial standard of care for someone with advanced HCC. When we say advanced, we mean someone who is not a candidate for surgical resection or transplant, someone who has extrahepatic disease or major portal vein thrombosis, or someone who has been treated for local regional therapy and had a recurrence, especially if there is recurrence in multiple lesions. This patient, having extra hepatic metastases, is considered an excellent candidate for a systemic therapy like sorafenib.

How will this change with the availability of lenvatinib (Lenvima)?

This is an interesting question. Lenvatinib was compared head-to-head with sorafenib. Statistically speaking, there was no overall survival (OS) advantage between lenvatinib and sorafenib. Lenvatinib did do better than sorafenib in a couple of secondary endpoints, including radiographic response and PFS. Whether these are meaningful for this patient population is a little hard to say.

Both drugs have fairly challenging AE profiles. So, it will be interesting to see whether physicians prefer one or the other. For sorafenib, your main issues are things that we have seen for a long time now. These include: hand/foot/skin reaction, which can be prevented by recommending patients not wear shoes that are going to cause a lot of rubbing on their feet, avoiding repetitive activities with their hands, using gloves, using creams, and of course we can manage this with dose reduction. Other AEs, such as diarrhea, are relatively easy to manage.

Lenvatinib has a little bit of a different toxicity profile. There is not as much hand/foot/skin syndrome, but there is a quite a bit more hypertension. As we are used to with other agents that target the VEGF access, we are going to need to be vigilant with treating significant hypertension in these patients. For both drugs, the most difficult to manage AE is fatigue and this is still a vexing problem with some of these tyrosine kinase inhibitors (TKIs) that we don't have good answers for. My impression is that there should not be a whole switch over from sorafenib to lenvatinib based on the available data. 

April 2017

The patient complained of increasing fatigue and a follow up CT scans showed new lesions in the lung nodules. His ECOG performance status of 1.

What are the options for therapy after the patient progresses on sorafenib?

This patient is now progressing. He is complaining of fatigue and undergoes CT scans that show new lesions in the lungs, consistent with progression on first-line therapy. His ECOG performance status of 1 is still good.

Regarding second-line therapy, a couple of years ago the answer would be slim. The answer now is that we have several potential options. The 2 that are already approved are regorafenib, which was approved based on randomized trial data against best supportive care, and nivolumab (Opdivo), which was approved care based on a phase I/II study, which was mostly based on responses and durability of some of those responses.

This is now a difficult choice between these 2, and there are no head-to-head data. In my opinion, either of them is a reasonable option. Nivolumab has the potential to create long-term responses, which is exciting for us when it happens for our patients. But the chance of this happening is relatively small. Regorafenib, when you compare survival curves, at least across studies, which is always a little bit dangerous to do, it seems to help more people but it does not create these long-term responses in very many of them. It is interesting that regorafenib, when studied against placebo in the second-line, performed just as well as sorafenib in the first-line. I think it is a very viable option.

Lastly, there is data with cabozantinib (Cabometyx) in this population. It hasn't been approved yet, but it looks a bit like regorafenib in that it seems like a fair number of patients benefit from the drug, but we don't see the long-term responses that we can occasionally see with the checkpoint inhibiting antibodies.

The patient was started on regorafenib 160 mg, but later complained of intermittent diarrhea.

What are your general impressions of this patient after he progresses?

Our patient was started on regorafenib at 160 mg. The ReDOS trial data, with the dose-escalating dosing strategy, don't exist for HCC. Although, I don't think it is unfair to say that they might apply in this situation. Our patient has intermittent diarrhea, which often can be managed with medications such as Imodium or Lomotil, without requirement for dose reduction, if that's the only issue. If the patient has multiple issues, I think that I would generally be quick to reduce the dose to avoid escalation of AEs and a longer than necessary break from treatment. Management of regorafenib is a little bit similar to that of sorafenib. Again, we are dealing with things such as the hand/foot syndrome, rash, fatigue, and some gastrointestinal AEs.

What are the options for this patient when further disease progression develops?

If our patient progresses on second-line therapy, we are in an area where there aren't really data at this point. I think that with progression on 2 different TKIs, I would most likely put the patient on immunotherapy at that point. For example, nivolumab or a clinical trial. Cabozantinib does have a different mechanism than regorafenib or sorafenib. So, that is a potential consideration. Between those 2 options, I think my preferred option would be a trial of nivolumab.

  1. Cremolini A, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015;16(13):1306-1315. doi: 10.1016/S1470-2045(15)00122-9.
  2. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1o) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016;34(suppl; abstr 3504). meetinglibrary.asco.org/record/123617/abstract.
  3. Kopetz S, McDonough S, Morris V, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). Presented at: 2017 Gastrointestinal Cancers Symposium; January 19-21, 2017; San Francisco, CA. Abstract 520. meetinglibrary.asco.org/record/139642/abstract.
  4. 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). meetinglibrary.asco.org/record/155600/abstract.

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