ONCAlert | 2018 Gastrointestinal Cancers Symposium
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Morse Details Treatment Considerations in 2 Colorectal Cancer Case Scenarios

Shannon Connelly
Published Online:4:04 PM, Mon October 9, 2017

Michael A. Morse, MD
Michael A. Morse, MD, recently discussed treatment decisions centered around the care of patients with metastatic colorectal cancer. Morse, professor of Medicine, Duke Cancer Institute, explained his treatment decisions in 2 case scenarios during a Targeted Oncology live case-based peer perspectives dinner.

Case 1

December 2014

A 51-year-old Caucasian female presented with severe crampy right lower quadrant pain. She had a 4-month history of occult bleeding and weight loss of 10 pounds in the last 8 months. She sought medical treatment after experiencing bloody diarrhea. Her past medical history included gastroesophageal reflux disease, and an appendectomy at age 35. Laboratory findings were remarkable for Hb, 8.7 g/dL; CEA 4.5 ng/mL.

A colonoscopy revealed a large mass in her ascending colon, measuring approximately 15 cm. A biopsy showed an invasive, poorly differentiated adenocarcinoma. A CT scan revealed widespread lesions in both lobes of the liver. It was deemed unresectable. Additional pathologic testing showed the tumor was KRAS, NRAS, and BRAF wild-type and microsatellite stable. Her performance status was 0. She had no major comorbidities, had mild anemia, and normal liver function tests. Her CEA was 267.

TARGETED ONCOLOGY:  What role does mutation testing play in your initial therapy selection?

Morse: It is important to know all of the potential therapeutic options for a particular patient in order to maximize the number of lines of therapy (the so called continuum of care) available to them. The initial chemotherapy choice (FOLFOX, FOLFIRI, FOLFOXIRI, CapeOx) is based on a patient-physician discussion about toxicities of the different therapies and is not dependent on mutational status; however the choice of biologic to add to the chemotherapy way be impacted by the results of mutational analysis.

Although this is a right sided colon cancer where anti-EGFR-antibodies would not be offered first line due to inferior outcome, anti-EGFR antibodies may be a consideration for later lines of therapy if the malignancy is KRAS and NRAS wild-type. Further BRAF mutations are associated with very poor prognosis which may be helpful to identify early. Although anti-PD-1 therapy is not approved for first line therapy, it would be an option after prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan if the tumor is microsatellite instability high or mismatch repair deficient.  

Treatment was initiated with FOLFIRI and bevacizumab. The patient experienced neutropenia, mucositis, and severe diarrhea with the first cycle (suspected to have DPD deficiency rather than UGT1A1*28 polymorphism). She subsequently tolerated therapy well with significant dose reductions. Follow-up imaging showed reduction in the size of the liver lesions. She was given maintenance therapy with capecitabine (Xeloda) plus bevacizumab.

November 2015

A follow-up CT scan showed progression in the liver with new lesions and new small masses in peritoneum of the abdomen and pelvis. Her performance status was 1.

TARGETED ONCOLOGY: What would you choose as a second-line treatment for this patient? 

Morse: We typically switch the chemotherapy to the combination not used in the first-line. In the case of someone who received FOLFIRI plus bevacizumab, we would typically pick FOLFOX or CAPEOX plus bevacizumab; however, there is also data supporting irinotecan plus cetuximab (or panitumumab).

TARGETED ONCOLOGY: What factors do you considering when deciding therapy?

Morse: Patient choice and performance status remain important considerations. Again, trying to maximize the lines of therapy available would argue to use FOLFOX plus bevacizumab and reserve anti-EGFR therapy for third line. would
The patient began therapy with FOLFOX and bevacizumab. Her CEA levels stabilized.

March 2016

The patient complained of severe fatigue and need for frequent rest during the day. A CT scan revealed progressive liver metastases, no improvement in the size of number of the abdominal lesions, and 3 pulmonary nodules in the right lung.

TARGETED ONCOLOGY: What would you choose as a third-line treatment for this patient and why?

Morse: Here you have a person who has already had chemotherapy with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab, but they're RAS wild-type and BRAF wild-type, so they still have available to them anti-EGFR antibody therapy, either cetuximab (Erbitux) or panitumumab (Vectibix), which you could deliver as single agents. They have both been compared with each other in the ACCENT trial, and that showed that they were equivalent in efficacy, so you could use either one as a single agent. We also know that if you combine anti-EGFR therapy plus irinotecan that the efficacy is greater than with single-agent anti-EGFR therapy. Therefore, my choice would be irinotecan plus either cetuximab or panitumumab. The choice of EGFR antibodies doesn't really matter unless you are in a part of the country where there is a high rate of anaphylactic reactions to cetuximab, such as the part of the country where I practice. In which case, we prefer to use panitumumab because of the lower rate of severe allergic reactions. 

TARGETED ONCOLOGY: What factors do you consider when deciding treatment?

Morse: The factors are that they are RAS wild-type, they've progressed on the other prior therapies, and they aren't a candidate yet for regorafenib (Stivarga) or TAS-102 (Lonsurf), because they haven't had EGFR therapy yet. Eventually, they were able to tolerate FOLFIRI in the first-line, so we know there is a dose of irinotecan they can tolerate. I would give irinotecan plus anti-EGFR antibody therapy. 

Case 2

A 69-year-old Caucasian male presented with severe left lower quadrant pain. He sought medical treatment after experiencing bloody diarrhea. PMH was remarkable for hypertension, managed with telmisartan (Micardis). He was active and could perform daily activities without restrictions. Laboratory findings showed CEA was 6.5 ng/mL. A colonoscopy showed a fungating mass in the sigmoid colon, which was biopsied. Pathological findings showed invasive poorly differentiated adenocarcinoma.
A chest, abdominal, and pelvic CT scan showed a 3-cm mass in the right lobe of the liver, 2 masses (2.5 and 6 cm in the left lobe adjacent to the left hepatic vein) and a 10-cm mass in the sigmoid colon. Metastatic disease was deemed borderline resectable. Additional molecular testing on the primary tumor was requested. Testing revealed the tumor was NRAS mutated, KRAS, and BRAF wild-type, and  microsatellite stable.

TARGETED ONCOLOGY: What treatment would you select for this patient?

Morse: You have to consider that the goal is to try to achieve regression of liver metastases by trying to give the therapy with the highest response rate, which is actually FOLFOXIRI plus bevacizumab. However, that is a fairly toxic regimen and many patients won't feel that they can tolerate that. Furthermore, it uses both oxaliplatin and irinotecan, so if you don't get the resectability, you essentially have 1 line less therapy.
Treatment was initiated with FOLFIRI and bevacizumab. Imaging at 3 and 6 months showed decreased size of the liver nodules, but was not deemed resectable.

August 2015

The patient complained of increased fatigue, requiring the need for frequent rest. A CT scan showed increasing size of the liver nodule (4 cm) and the appearance of 4 new small liver lesions (<2 cm).

He began therapy with FOLFOX and bevacizumab.

March 2016

The patient reported weight loss, increasing fatigue, and shortness of breath. A CT scan revealed progressive disease with no improvement in the primary and metastatic lesion size and/or number. A new pulmonary nodule was seen in the right lung.

He was switched to trifluridine /tipiracil (Lonsurf). A PET/CT at 3 months showed stable disease. At 6 months, he reported moderate improvement in fatigue.

TARGETED ONCOLOGY:  What benefit would you quote to this patient for using the TAS-102 at this point in his disease course?

Morse: The median overall survival is 7.1 months with TAS-102 versus 5.3 months with placebo. The hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 and 0.48 for OS and PFS, respectively; both P< 0.0001. In addition to survival benefit, there is also a progression-free survival benefit. PFS was 2.0 months in the TAS-102 group and 1.7 months in the placebo group. (HR = 0.47; 95 % CI: 0.30–0.74; P = 0.001).

TARGETED ONCOLOGY: What strategies do you use to manage neutropenia?

Morse: ANC should be checked at day 15, and particularly at the beginning of the next cycle on day 28. If the ANC at day 28 is not 1500 or greater, then you should withhold therapy and check again a week later. If the ANC is greater than 1500 and the platelets are greater than 75,000, then treat the patient at the same dose they received in the previous cycle. In other words, you delay their therapy, but you do not need to dose reduce them. Obviously, if they have febrile neutropenia or another grade 3/4 toxicity, or are delayed an additional week or more because of continued low ANC, then you have to dose reduce for the next cycle, but the emphasis should be more on dose delays than on dose reductions. 

TARGETED ONCOLOGY:  If you had chosen regorafenib instead, what strategies would you use to manage adverse events?

Morse: On the assumption people start with full dose, you have to warn people about diarrhea and hand-foot reaction, fatigue and then making sure the person is taking it correctly with a low-fat meal. Depending on the toxicities, dose reduction if needed in the next cycle. 

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