Carlos Becerra, MD, recently shared the treatment considerations and decisions he makes when treating patients with metastatic colorectal cancer and hepatocellular carcinoma. Becerra, a medical oncologist at Texas Oncology, Baylor Charles A. Sammons Cancer Center, explained his treatment decisions based on 2 case scenarios during a <em>Targeted Oncology </em>live case-based peer perspectives presentation.
Carlos Becerra, MD
Carlos Becerra, MD, recently shared the treatment considerations and decisions he makes when treating patients with metastatic colorectal cancer (mCRC) and hepatocellular carcinoma (HCC). Becerra, a medical oncologist at Texas Oncology, Baylor Charles A. Sammons Cancer Center, explained his treatment decisions based on 2 case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.
A 64-year-old woman underwent a left hemicolectomy for an obstructing mass at the rectosigmoid junction. Her past medical history showed arterial hypertension, well controlled on an angiotensin-converting enzyme inhibitor, and a coronary angioplasty with stent placement 4 years ago.
Laboratory findings showed carcinoembryonic antigen levels (CEA) at 23.3 ng/mL. A pathology showed an undifferentiated adenocarcinoma, invading through the muscularis mucosa up to the pericolic fat; 10/14 nodes metastatic; peritoneal biopsy, positive.
She was later diagnosed with stage T4N2M1 mCRC. Her mutational status was expanded RAS and BRAF wild-type and she was microsatellite stable. APET showed extensive disease involving the liver, lung, and peritoneum.
TARGETED ONCOLOGY:What is your general impression of this patient?
Becerra:This is a typical case scenario for this type of cancer. One of the things we've come to realize is that in colon cancer, we are starting to subdivide the cancer into left- and right-side colon carcinoma based on the newer data looking at sidedness. We should also take a look at the mutational status of the tumor itself, whether there are mutations in extendedRASorBRAF, which would make the cancer more aggressive. WithBRAFmutations, median overall survivals decrease compared with other subtypes.
When you look at this particular case, you find that this is a woman with a left-sided lesion. The mass is obstructing, which makes it a bit higher risk for recurrence. She does have evidence of metastatic disease. There is also a mutational status in which she had an expandedRASandBRAFwild-type, which is certainly good news in that respect. The tumor was also microsatellite stable.
TARGETED ONCOLOGY:Where are the options for upfront therapy in this patient with unresectable disease?
Becerra:With this type of tumor, in the case of a patient with metastatic disease to the peritoneal cavity, one of the first things that we think about is: What kind of backbone chemotherapy should we be using? For this, we have 2 different types of chemotherapy that we would use upfront: the folinic acid, fluorouracil, oxaliplatin (FOLFOX) and the FOLFIRI regimen. The question then comes up as to whether we should be using a biologic agent and, if so, which one of the biologic agents we should be using, whether it should be bevacizumab or an epidermal growth factor receptor (EGFR) inhibitor. Given the fact that the tumor does not have a mutation inRASand thatBRAFis wild-type, perhaps there might be some consideration to use chemotherapy with an EGFR inhibitor.
TARGETED ONCOLOGY:Would you use maintenance therapy?
Becerra:After a certain period of time of patients being on chemotherapy, there are some clinicians who offer the patients some form of maintenance therapy. This could be with single-agent chemotherapy or some would even venture to continue a targeted antibody agent against vascular endothelial growth factor (VEGF) or an antibody against the EGFR inhibitor. Most clinicians would probably favor some form of maintenance with fluorouracil.
The maintenance treatment duration varies because it all depends on tolerance to treatment and the stability of the tumor on treatment. Generally speaking, one would continue the fluorouracil for as long as it is well tolerated and when there is no evidence of tumor progression.
The patient received systemic therapy with folinic acid, fluorouracil, and irinotecan hydrochloride (FOLFIRI) plus cetuximab (Erbitux). Adverse events included grade 1 rash, grade 1 thrombocytopenia were managed with dose adjustment of FOLFIRI. Follow-up imaging at 2 months and at 4 months showed significant response in the lung lesions. Patient had increasing diarrhea and fatigue and was continued on maintenance therapy with cetuximab.
The patient complained of weight loss, nausea, and fatigue. A 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 would you treat the patient at this point?
Becerra:The patient received FOLFIRI and cetuximab in the frontline setting, and there was evidence of stability of disease for a period of time. Then she went on to maintenance therapy with cetuximab. There was a repeat scan that revealed evidence of progression in 2 lesions and new lesions in the liver. Usually, we consider changing the backbone therapy. In this case, the patient who was receiving FOLFIRI would now receive FOLFOX in addition to the consideration of using a VEGF-targeted agent.
TARGETED ONCOLOGY:Should the patient be evaluated for localized treatment of her lung and liver lesions?
Becerra:Sending a patient for some form of localized therapy when the tumor is progressing is not advisable. You need good tumor control to consider any form of localized therapy for these patients. It has been tried in the past, unsuccessfully, to salvage a patient with this particular scenario, where there is progression of the tumor on chemotherapy, and then try to go on to some form of localized therapy, such as liver-directed plus lung-directed therapy. You first need to control the disease, before considering any localized therapy.
The patient was then switched to capecitabine and oxaliplatin (CAPEOX) with bevacizumab (Avastin). Follow-up imaging at 2 months and at 4 months showed stable disease in the lung and liver lesions and improvement of her symptoms. At 4 months, she discontinued oxaliplatin Maintenance therapy with capecitabine and bevacizumab was continued.
Five months later, the patient reported reappearance of her symptoms, although she continued her normal physical activity. Laboratory findings showed CEA levels at 8.6 ng/mL. A follow-up CT showed further progressive disease in the lung and appearance of several small bone lesions.
TARGETED ONCOLOGY:What are the options for this patient?
Becerra:We are going beyond second-line therapy. For this type of situation, there are additional treatment options, including regorafenib (Stivarga) and trifluridine/tipiracil (TAS-102). The decision about using one or the other is fairly individualized by the clinician because there are no randomized studies that have compared one to the other head-to-head. There is a small sequencing study that was done recently that might favor the use of regorafenib followed by trifluridine, but that has not been published in peer-review journals yet and the data are very scarce. It is preliminary, but that is what we have [with regards to sequencing]. Most clinicians determine whether or not to use regorafenib or trifluridine based on their own experiences with their patients and how patients have tolerated treatment.
The one critical aspect regarding the use of oral agents is the fact that we need to stay in close communication with the patient to try to detect toxicities early on and, if need be, modify the doses of the drugs that are being used. In general, toxicities with regorafenib include hand-foot syndrome, which you do not see in trifluridine. Additionally, there is more fatigue associated with regorafenib, but in my own experience, I have seen it with both. On the other hand, there is more marrow toxicity associated with trifluridine.
A 63-year-old Asian man with chronic hepatitis B infection was referred for further imaging studies after suspicious findings on routine ultrasound surveillance for HCC. Laboratory findings showed alpha-fetoprotein levels at 5400 IU/mL. His Child-Pugh class was A. His platelets were 230,000 cells/mcL; bilirubin was 1.0 mg/dL; albumin was 3.5 g/dL. He did not have hepatic encephalopathy and ascites were not present.
A CT scan revealed 2 lesions in the right hepatic lobe measuring 2 cm and 5 cm, no extrahepatic disease.Biopsy findings showed grade 2 HCC with moderate fibrosis and both lesions were resected with R0 margin.
TARGETED ONCOLOGY:What are your general impressions of this patient?
Becerra:With these types of patients, usually the prognosis is not as good as you might think. There is a prognostic index that you can look into in order to more accurately determine the percentage of recurrence. However, when you look at the data, the majority of patients will recur from their HCC.
TARGETED ONCOLOGY:Is there any evidence for the use of adjuvant therapy in patients with HCC?
Becerra:There was an attempt to use sorafenib from the metastatic to the adjuvant setting, and the study [results] showed that sorafenib did not improve the overall survival in this patient population. The study I’m referring to is the phase III double-blind placebo-controlled STORM trial, which was published inLancet Oncologyin October 2015.1The bottom-line of this study was that sorafenib was not an effective intervention in the adjuvant setting for [patients with] HCC following resection or ablation.
A routine follow-up imaging showed a new lesion in the liver measuring 2.3 cm and 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 a day and tolerated therapy well after management of grade 1 diarrhea.
TARGETED ONCOLOGY:What factors do you consider when deciding when to initiate therapy with sorafenib?
Becerra:As expected, routine follow-up imaging revealed a new lesion in the liver measuring 2.3 cm, and his chest CT showed 3 small lesions less than 1 cm in the left upper lobe of the lung. The patient was started on sorafenib and tolerated therapy well after managing grade 1 diarrhea.
For this patient, you would need to consider the clinical factors. This means the patient’s performance status. You would also need to consider the remaining liver dysfunction and the record of its Child-Pugh score. Of course, you will also need to consider the toxicities associated with the treatment to determine whether the patient can and should receive sorafenib or not.
This patient is an overall good candidate for sorafenib. The patient had a good performance status, and I am assuming that his liver function tests were within reasonable parameters. His Child-Pugh score was an A, so he went on to receive sorafenib.
TARGETED ONCOLOGY:How will this change with the availability of lenvatinib (Lenvima)?
Becerra:The REFLECT trial, which is a randomized studying looking at lenvatinib versus sorafenib, was a noninferiority trial.2In this case, you can pick your poison. Lenvatinib has toxicities that sorafenib does not have and vice versa. Generally speaking, the median duration on treatment with lenvatinib is a little bit higher than sorafenib. Discontinuation with lenvatinib was also a little bit higher with sorafenib. However, it was shown that lenvatinib was noninferior. So, it is an option, or an alternative, to the use of sorafenib.
TARGETED ONCOLOGY:What are practical strategies to manage toxicities?
Becerra:Depending on the toxicities the patient is experiencing, sometimes you have to dose reduce the agent for the patient to be able to tolerate the treatment. The management of toxicities depends on the symptoms. For example, with diarrhea you would use antidiarrhea agents, and with hypertension you would modify blood pressure. It depends on the toxicities associated with the regimen. You may need to modify the dose or use other medications to control the toxicities.
The patient complained of increasing fatigue and CT scans showed widely scattered lung nodules. He had an ECOG performance status of 1. He was then started on regorafenib 160 mg daily and later complained of intermittent diarrhea.
TARGETED ONCOLOGY:What are the options for therapy in the second-line setting?
Becerra:The patient complained of increasing fatigue. A CT scan showed widely scattered lung nodules, and the patient had an ECOG performance status of 1. Regorafenib and nivolumab (Opdivo) are options that were not available several years ago. We already know about the toxicities associated with regorafenib. Nivolumab, the new kid on the block, is an immune checkpoint inhibitor that has shown promising activity in the second line, including response rates and what appears to be prolonged tumor control in a smaller population of patients, even after stopping the agent. These are 2 options for this patient. Regorafenib is based on 1 placebo-controlled trial, and nivolumab is based on an expansion cohort of patients with HCC that had either underlying hepatitis B, hepatitis C, nonhepatitis cirrhosis, or HCC.
Regarding the regorafenib dose, you might want to consider using a lower dose, such as 80 mg, because there are a lot of toxicities associated the higher dose of 160 mg. And then you would increase the doses tolerated based on the ReDOS trial.3
TARGETED ONCOLOGY:How would you manage disease progression at this point?
Becerra:If the patient has disease progression on sorafenib, I would probably move on to one of these 2 agents in the second-line. If there is further disease progression, I would consider the addition of an agent beyond [the] second line if the patient still has good functional status and has adequate laboratory parameters.