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For patients with colorectal cancer that has metastasized to the liver, having a primary tumor on the left side, as opposed to the right side of the colon, is known to be a significant advantage in terms of treatment response.

But now a new study, presented during the 19th World Congress on Gastrointestinal Cancer of the European Society of Medical Oncology (ESMO), held June 28 – July 1, 2017 in Barcelona, Spain, suggests this imbalance may be at least partially redressed.[1]

Colorectal cancer is the fourth most frequently diagnosed cancer worldwide, and the third leading cause
of cancer deaths, taking almost 700,000 lives annually. [2] More than half of all patients with colorectal
cancer will be diagnosed with metastases, most commonly in the liver. [3][4]

While the impact of primary tumor side on outcomes after selective internal radiation therapy or SIRT of patients with metastatic colorectal cancer or mCRC liver metastases has not previously been examined,? a survival benefit in patients with right-sided primary tumors (RSP) was reported in an exploratory analysis of the FOXFIRE studies. [1]

Reversing the usual pattern, patients whose liver metastases had spread from right-sided primary tumors (RSP) had a 36% better survival rate after treatment with a combination of first-line chemotherapy and selective internal radiation therapy (SIRT) using Y-90 resin microspheres, compared to chemotherapy alone, according to the study.

The study results showed that the same treatment combination was no better than chemotherapy only in patients with left-sided primary tumors (LSP).

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It remains to be confirmed whether these results mean that right-sided tumors are more sensitive to this kind of radiotherapy…

?These findings are good news for patients with right-sided primary tumors, who have a much worse prognosis and fewer treatment options than patients with left-sided tumors,? said study investigator Guy van Hazel, MD, from the University of Western Australia in Perth, Australia.

?We are excited because hitherto no treatment apart from the addition of bevacizumab to chemotherapy has improved the dismal outcome of liver metastases coming from right-sided primary tumors.?

The analysis included 739 patients from two completed studies called SIRFLOX (SF) and FOXFIRE-Global (FFG).

Both SIRFLOX and FOXFIRE-Global are international multi-center randomized controlled clinical studies investigating the use of Selective Internal Radiation Therapy (SIRT) using SIR-Spheres Y-90 resin microspheres for the treatment of liver metastases from primary colorectal cancer.

Study design
All patients participating in the study had liver-only or liver-dominant metastatic colorectal cancer (mCRC), and had been randomized to receive either standard chemotherapy alone, or combined with SIRT. The chemotherapy regimen was mFOLFOX6, and most patients received bevacizumab as well.*

Information on the patients? primary tumor location was recorded at the start, with 24% having right-sided and 73% left-sided disease (the remaining 3% had primary tumors on both sides of the colon, or the primary tumor site was unknown).

Overall, outcomes were not different between the chemotherapy alone and chemotherapy plus SIRT groups, with median overall survival (OS) and progression-free survival (PFS) around 24 months and 11 months, respectively.

However, when the investigators examined patients with RSP and LSP separately they saw a clear difference.

Patients with liver metastases from RSP had significantly better OS when SIRT was added to their chemotherapy compared to those who had chemotherapy alone (22.0 vs. 17.1 months, respectively; p=0.007; Hazard Ratio [HR]: 0.64 [95% CI: 0.46-0.89]), but this was not the case for patients with LSP (24.6 vs. 25.6 months; p=0.279; HR: 1.12 [0.92-1.36]).

?That means that RSP patients treated with chemotherapy plus SIRT have a 36% reduced risk of dying at any time point,? said van Hazel.

There was also a 27% improvement in PFS, although this was not statistically significant.

?This is the first time that location of primary tumor has been linked to radiation therapy,? said van Hazel, and although it?s possible that it may only apply to patients receiving first-line therapy, he said it opens a new treatment option for these patients.

There were no differences in side effects between patients with RSP and LSP tumors, and although patients who had both chemotherapy and SIRT did experience more side-effects than those who had chemotherapy alone, these were ?predictable and manageable,? said van Hazel.

Biological heterogeneity
Commenting on the study, ESMO spokespersons Dirk Arnold, from Instituto CUF de Oncologia in Lisbon, Portugal and Eric Van Cutsem, University Hospitals Leuven, Belgium, noted that these findings contribute to the recent debates on both the biological heterogeneity of colon cancers and tumor localization.

?It remains to be confirmed whether these results mean that right-sided tumors are more sensitive to this kind of radiotherapy ? or whether this is simply related to the fact that the molecular characteristics of right-sided tumors allow less treatment options, because they have more mutations,? they explained.

?Additionally the well-known worse prognosis of right-sided tumors increases the relative importance of a non-systemic treatment option. More data on the molecular factors determining these results are warranted.?

* mFOLFOX6 or modified FOLFOX-6 is a combination chemotherapy regimen that is used to treat colorectal cancer. It includes? leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin. There are several different FOLFOX regimens that differ in the doses and ways in which the three drugs are given.

Last editorial review: July 1, 2017

Featured Image: Barcelona, Spain. National museum with fountain at summer day Courtesy: ? 2017 Fotolia. Used with permission.

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