We have seen a big improvement in the outcome of patients with colorectal cancer [CRC], especially the group with stage IV disease. The improvement in outcome has resulted in an improvement in the survival from around the median of around 6 months to a median of around 30 months in recent studies. This improvement of survival comes from a better understanding of the biology of the disease, better treatment, and better multidisciplinary care for patients with stage IV colon cancer.

A 75-year-old male patient presented to his primary care physician with rectal bleeding, weight loss, and constipation. Workup included a colonoscopy, which revealed a mass in the ascending colon. A biopsy revealed invasive adenocarcinoma. Then staging was done using a CAT scan, which revealed multiple liver lesions including a 3-centimeter mass in the right lobe of the liver.

He subsequently had molecular testing, which showed that he was

wild-type. In addition, he was microsatellite stable. The patient underwent, from a management point of view, a diverting colostomy and then was started on FOLFOX [folinic acid, fluorouracil (5-FU), and oxaliplatin] and bevacizumab. Scans at 3, 6, and 9 months revealed a good response. He was shifted over to a maintenance regimen of capecitabine with bevacizumab. After around 12 months, the scan showed progression of these.

With stage IV colon cancer, unless the patient has resectable metastatic disease, the goal of therapy is still control of the tumor, and there&rsquo;s not a curative therapy. The cornerstone of treatment is with systemic chemotherapy combined with targeted drugs such as bevacizumab. On the average, patients with

wild-type colon cancer nowadays survive somewhat above 30 months, on the average. And we have patients who survive significantly longer than that as well.

It&rsquo;s very important, as we manage patients with stage IV colon cancer, to consider a multidisciplinary approach where a team of experts, including medical oncologists, surgical oncologists, and radiologists, confer on the management of patients. Identifying patients with limited metastatic disease could enable us to incorporate surgery as part of the treatment in addition to systemic therapy. We know from long experience with doing surgery on liver metastases from colon cancer that a proportion of patients who undergo surgery on liver metastases can be cured with surgical interventions, and that&rsquo;s why it&rsquo;s important to be aware of this and to incorporate a plan to have a multidisciplinary approach to these patients from the get-go.

With respect to our patient that we&rsquo;re discussing today, given the extent of liver metastases, he was not a good candidate for surgical resection. But for patients who have lower burden of disease in the liver, resection is still an important option to consider in the management of stage IV colon cancer.

Diagnosing and Managing Stage IV Right-Sided CRC

In my practice, I order molecular testing at diagnosis. Molecular testing in colon cancer has a huge impact on the management plan, and therefore, having the information early on in the course of the disease is key. The minimum amount of molecular testing that we need to manage a patient would be testing for microsatellite instability. That is number 1. Number 2 is an extended

mutations. This is the minimum amount of molecular testing that we need. In my practice, I tend to do next-generation sequencing because that gives me those 3 minimum things that we need in addition to a whole number of other genes that could have an impact down the line in the management of these patients.

testing is needed for all patients with colon cancer regardless of the sidedness of the tumor. Although, in right-sided tumors, the impact of

testing is not for the frontline setting. It may have an impact on management in the second-line or third-line setting. So that&rsquo;s why I believe everybody with colon cancer needs

fusions are present in a small proportion of patients with colon cancer. However, when we identify patients with

mutations, there&rsquo;s the option of doing targeted therapies that have shown to be very effective in that small subset of patients. And that&rsquo;s one of the reasons why doing a more comprehensive next-generation sequencing approach would provide the information about uncommon mutations, like

early on in the course of the management of these patients and allow us to develop a management plan that will incorporate those drugs in the first line, second line, or third line.

For a long time, we&rsquo;ve known that tumor sidedness has an impact on the outcome of patients independent of the treatment that they receive. And in that sense, it is a prognostic indicator. Patients with right-sided tumors tend to have a worse outcome than patients with left-sided tumors. In addition to its prognostic value, sidedness of the tumor has an impact on responsiveness to certain therapies, specifically EGFR inhibitors. And in that sense, it is a predictive marker. We know that patients who have right-sided tumors should be treated with chemotherapy plus bevacizumab in the up-front setting and not chemotherapy plus an EGFR inhibitor in the up-front setting, regardless of

mutational status. For right-sided tumors, we should start with bevacizumab as a targeted drug. And in that role, sidedness of the tumor is predictive.

Molecular Testing and Tumor Sidedness in CRC

The current recommendation from the NCCN [National Comprehensive Cancer Network] for patients with stage IV colon cancer who are wild-type for

is to start out with combination chemotherapy, if they are in good performance status, plus bevacizumab. Combination chemotherapy is usually a fluoropyrimidine, like 5-FU [fluorouracil] or capecitabine, in combination with either oxaliplatin or irinotecan. There are a number of trials that have shown that the combination of the fluoropyrimidine plus oxaliplatin is equivalent to a fluoropyrimidine plus irinotecan, so those options of chemotherapy could be used interchangeably in this setting.

In my practice, I tend to use FOLFOX [folinic acid, fluorouracil, and oxaliplatin] plus bevacizumab as a first-line choice in stage IV colon cancer patients, especially if they have right-sided tumors or have mutations in the

pathway. The reason for choice of bevacizumab is based on the sidedness and the mutational panel. The reason for oxaliplatin rather than irinotecan is a preference related to the side effect profile of the drugs. But that being said, using bevacizumab and FOLFIRI [folinic acid, fluorouracil, and irinotecan] in the frontline setting is a very acceptable standard of care as well.

So for younger patients who are very well fit, there is an option for using a triplet regimen, which includes 5-FU, oxaliplatin, and irinotecan up front in combination with bevacizumab. An approach like that would carry a higher chance of response, but it does carry a higher chance, also, for side effects. And, therefore, you have to be very judicious in who you select for the triplet regimen versus the doublet regimen. On the other end of the spectrum, for older patients, like patients in their 80s and above, or patients who have borderline performance status, there is also option of using a single chemotherapy regimen with bevacizumab, and the regimen that&rsquo;s most commonly used is capecitabine plus bevacizumab in that setting.

If this patient had left-sided colon cancer, the options for therapy in the frontline setting would be more complex. Patients with left-sided colon cancer who are

wild-type could either start with a combination chemotherapy plus bevacizumab, or combination chemotherapy plus an EGFR inhibitor. Both options would be viable options in that population. Physician&rsquo;s choice between bevacizumab versus an EGFR inhibitor depends on differences in side effects and patient preference. But efficacy-wise, the 2 regimens appear to be acceptable options in left-sided colon cancer.

My personal preference in practice is to use bevacizumab up front because I feel that the side effects of the bevacizumab are less intrusive as compared to the side effects of EGFR inhibitors. And specifically, I&rsquo;m talking about issues related to skin toxicities, which can be very intrusive in a patient&rsquo;s quality of life.

Frontline Therapy for Stage IV Right-Sided CRC

Nowadays, the majority of patients who receive up-front therapy with combination chemotherapy plus a targeted drug do have either response or stable disease. Very, very few patients have primary refractory disease and progression on frontline therapy. This is very good news for our patients. They can expect a good outcome from frontline therapy.

Unfortunately, as we keep patients on combination chemotherapy for a prolonged period of time, side effects become more prevalent. Therefore, around 4 to 6 months into treatment, the side effects become more prevalent and the disease control becomes less of an issue. It is an accepted strategy to try and decrease the chemotherapy to enhance the balance between benefit and toxicity. Usually the drug that you would remove at that point in the program would be oxaliplatin or irinotecan. Especially with oxaliplatin, because of the cumulative neuropathy, it is advisable not to continue the oxaliplatin until progression and rather to stop after 4 to 6 months and then start maintenance.

Maintenance regimens could include capecitabine alone or capecitabine plus bevacizumab or a 5-FU [fluorouracil] regimen plus bevacizumab. Any of those options would be reasonable. In my practice, I tend to use capecitabine plus bevacizumab because I feel the data that support prolonged disease control with that regimen are slightly better. In addition, I feel the capecitabine offers patients an oral option, which also has an impact on their quality of life.

As we see in this patient, many patients unfortunately do progress while on frontline therapy. On the average, the time to progression is around 9 to 11 months. And at the time of progression, there are several options that could be entertained. Those options would depend on the sidedness of the tumor and the mutational panel. In our specific patient, given this patient has disease in the ascending colon, I would prefer to continue with the bevacizumab into the second-line setting, continuing the 5-FU into the second-line setting, and then exchange the oxaliplatin to irinotecan so the patient would be on FOLFIRI [folinic acid, fluorouracil, and irinotecan]/bevacizumab in the second-line setting, reserving the EGFR inhibitor for later lines of therapy.

In my practice, I reserve EGFR inhibitors for later lines of therapy, like the third line and beyond. In patients who have

wild-type and tumors on the right side of the colon, I usually would prefer using bevacizumab in the first line and second line and keep the EGFR option for later on.

The future for colorectal cancer [CRC] is going to be us looking at a more personalized approach for patients. Personalizing the approach will depend on molecular profiling as well as better imaging and better staging. With better imaging and better staging, we will be able to select the patients who benefit from metastasectomy. With molecular profiling, we will be able to select subgroups of patients that benefit from specific therapies.

We are already entering this age, because now we select an EGFR inhibitor based on a

mutation and sidedness. We have specific therapy for

-mutated colon cancer, which is evolving. And we have specific therapy for patients who have MSI [microsatellite instability]high tumors, and specific therapy for patients who have

mutations. This list is going to expand and grow. I think next will be specific therapy for patients who have overexpression of

. And as this list expands and grows, we&rsquo;re going to be able to tailor therapy more to the patient&rsquo;s needs and select therapy that has a bigger impact, although it&rsquo;s applicable for smaller subgroups of patient but has a bigger impact on those small subgroups.

A 75-Year-Old Man With Right-Sided mCRC | Case Based Peer Perspectives

EP 1: Diagnosing and Managing Stage IV Right-Sided CRC

EP 2: Molecular Testing and Tumor Sidedness in CRC

EP 3: Frontline Therapy for Stage IV Right-Sided CRC

EP 4: Treating Stage IV Right-Sided CRC Beyond Progression