Richard Kim, MD, recently shared the treatment considerations and decisions he makes when treating patients with metastatic colorectal cancer, including the role of mutation testing and location of the tumor. Kim, associate professor of oncology, Moffitt Cancer Center, explained his treatment decisions based on 2 case scenarios during a <em>Targeted Oncology</em> live case-based peer perspectives dinner.
Richard Kim, MD
Richard Kim, MD, recently shared the treatment considerations and decisions he makes when treating patients with metastatic colorectal cancer, including the role of mutation testing and location of the tumor. Kim, associate professor of oncology, Moffitt Cancer Center, explained his treatment decisions based on 2 case scenarios during aTargeted Oncologylive case-based peer perspectives dinner.
A 51-year-old Caucasian woman presented with severe crampy right lower quadrant pain. She had a 4-month history of bloody stool and weight loss of 10 pounds in the past 8 months. Her past medical history included gastroesophageal reflux disease, and an appendectomy at age 35. Laboratory findings showed her hemoglobin level was 8.7 g/DL. An abdominal CT scan with contrast showed an obstruction at the level of the right colon and widespread lesions in both lobes of the liver. Carcinoembryonic antigen (CEA) was 4.5 ng/mL.
The patient was taken to surgery for a right hemicolectomy. Pathologic findings from biopsy of the obstructive lesion revealed an invasive, poorly differentiated adenocarcinoma with ulcer. Ten of 15 lymph nodes sampled were positive for disease. Mutation testing showedKRAS,NRAS, andBRAFwild-type. The tumor was microsatellite stable.
TARGETED ONCOLOGY:What therapy would you recommend for this patient?
Kim:At this time, mutation testing will select patients who may benefit from certain therapies. Therefore, currently, all patients with newly diagnosed stage IV colon cancer should get tested forRAS, includingBRAF, and should be tested for mismatch repair. The purpose of that mutational testing is that it will tell us who will benefit from drugs targeting EGFR and potential patients who may benefit from immunotherapy.
TARGETED ONCOLOGY:Does the location of the tumor (left versus right) play a role in patient prognosis and therapy selection?
Kim:The recent data clearly indicates that patients with right-sided tumors do worse than patients with left-sided tumors, based on multiple large phase III studies. Furthermore, it has been shown that patients with right-sided tumors do not benefit from EGFR drugs, even though they areKRASwild-type. The benefit is only seen with bevacizumab [Avastin]. On the left side, on the other hand, the benefit seems to be greater with EGFR drugs, compared to bevacizumab. The ESMO Clinical Practice Guidelines recommend that if the patient has a left-sided tumor and isRASwild-type, then they should get chemotherapy plus an EGFR drug. However, here in the United States, the NCCN guidelines give us 2 choices: either an EGFR drug, or a VEGF drug. That is mostly based on the CALGB/SWOG 80405 study that was done here in the United States.
Mutation testing is important to determine which first-line therapy to use. The location of the tumor now plays a big role in our decision making as well.
Treatment was initiated with FOLFIRI (irinotecan, fluorouracil [5-FU], and folinic acid) and bevacizumab. The patient continues to improve and reports feeling significantly better. Follow-up imaging showed reduction in the size of the liver lesions.
Follow-up CT showed progression in the liver with new lesions and new small masses in the abdomen and pelvis. The patient’s ECOG performance status was 1.
TARGETED ONCOLOGY:What would you choose as second-line therapy for this patient and why? What factors do you consider when deciding?
Kim:Once a patient fails FOLFIRI/bevacizumab, we want to change the backbone of the chemotherapy to FOLFOX. Based on multiple studies, there is data on antiangiogenic agents beyond progression, so that would be the reason to change the backbone and continue with bevacizumab. The EGFR drug may be a possibility in the second-line setting, due to the patient beingRASwild-type. Due to it being a right-sided tumor, the benefit seems to be much less in the right-sided tumor compared to left. Therefore, in this case, we would opt to change the backbone to FOLFOX and keeping on bevacizumab.
She began second-line therapy with FOLFOX (oxaliplatin, fluorouracil, and folinic acid) and bevacizumab.
The patient complained of severe fatigue and need for frequent rest during the day. A CT scan revealed progressive disease, no improvement in the size or number of abdominal lesions, and 3 pulmonary nodules in the right lung.
TARGETED ONCOLOGY:What are the goals of therapy at this point in the patient's disease course? What factors do you consider when deciding on the next line of therapy?
Kim:This is a third-line therapy, and at this time, there are 2 active drugs currently approved in the refractory setting: TAS-102 [Lonsurf] and regorafenib [Stivarga]. There is no head-to-head study of TAS-102 versus regorafenib, so it is tough to say one is better than the other. However, the toxicity profile is different. TAS-102 has more hematologic toxicity compared to regorafenib where you have more of a hand-foot skin reaction, rash, and possibly fatigue as well.
In terms of factors that make the decision, it depends on the toxicity profile. For example, if the patient had a lot of hematologic toxicity with prior chemotherapy, I may go with regorafenib. On the other hand, if the patient had a lot of skin problems and hand-foot reaction, I would go with TAS-102. Despite what you start on, most likely once they progress on one oral agent, they'll go to the other agent upon progression.
TARGETED ONCOLOGY:How do you suggest managing these toxicities in patients?
Kim:The important thing is proactive monitoring, especially with drugs like regorafenib where you need to see the patient once a week or every 2 weeks to monitor the toxicity effect, including hand-foot skin reaction, rash, and fatigue, in order to dose reduce appropriately.
The appropriate dose of regorafenib is unclear. My personal experience is I start at a high dose, 160 mg, and titrate down with very proactive monitoring. TAS-102, on the other hand, is a drug that causes hematologic toxicity, so therefore it is recommended that the patients come back in 2 weeks to check the central venous catheter and manage the hematologic toxicity accordingly.
A 55-year-old Caucasian man was admitted to the hospital with severe right lower quadrant pain. He had a 2-month history of constipation, general abdominal discomfort, and fatigue. His past medical history was remarkable for hyperlipidemia managed with diet and statin therapy. Laboratory findings were remarkable for hemoglobin level, 9.0 g/dL. A chest, abdominal, and pelvic CT showed a probable mass in the sigmoid colon and no metastases. His CEA was 6.7 ng/mL.
A biopsy performed during colonoscopy showed poorly differentiated adenocarcinoma. He underwent sigmoid colectomy, which showed tumor infiltrates the full thickness of the bowel wall into subserosal adipose tissue; neither perineural invasion (PNI) or lymphovascular invasion (LVI). R0 resection with clear margins. Zero of 13 lymph nodes were positive. He was microsatellite stable.
TARGETED ONCOLOGY:What factors should be considered when determining the need for adjuvant therapy for this patient?
Kim:In this case, the patient has stage IIa colon cancer with a right-sided tumor. Based on the final pathology report, there are no poor prognostic features and, importantly, the patient is microsatellite stable. In this case, generally speaking, for stage IIa patients who have no high-risk features, we generally do not recommend any adjuvant chemotherapy, because the benefit of chemotherapy, if there was one, would be probably less than 2%. Sometimes there is a test called Oncotype DX, which is available to use, however, the testing is prognostic, but not predictive of the benefit of chemotherapy, therefore, typically, I do not order it in my practice. On the other hand, if the patient had PNI or LBI, then this patient would be considered to have high-risk features, so we would offer the patient adjuvant chemotherapy.
In stage IIa colon cancer with high-risk features, as long as the patient is mismatch repair proficient, I would offer fluorouracil, as the benefit of traditional oxaliplatin in stage II patients with high-risk features is unclear. If the patient has 4 positive lymph nodes, that would make it a stage III patient. At the recent 2017 ASCO Annual Meeting, there was an IDEA trial presentation, which now mentions that if you have a low-risk, stage III patient, those patients may get similar benefit of receiving adjuvant FOLFOX for 3 months, compared to 6 months.
The IDEA study was a prospective, pre-planned analysis of pulled data from 6 phase III trials, and this was basically to compare 3 months of chemotherapy versus 6 months in patients with stage III disease. What it shows was that in the patients with stage III low-risk colon cancer, which was defined as T3 or N1, the 3-year disease-free survival was almost close to identical in patients who received 3 months versus 6 months of chemotherapy. However, the neuropathy was much less if they received chemotherapy for 3 months. On the other hand, in patients with high-risk features, such as T4 or possibly N2 disease, there seems to still be a benefit of chemotherapy where 6 months seems to be a little bit better than 3 months.
Therefore, in this case, since the patient has N2 disease, based on the IDEA study I would still recommend giving 6 months of adjuvant chemotherapy.
Shi Q, Sobrero AF, Shields AF, et al. Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration.J Clin Oncol.2017;35(suppl; abstr LBA1).