Liam Davenport

July 10, 2017

BARCELONA, Spain — For patients with metastatic colorectal cancer whose tumors originated on the right side of the colon, adding liver-directed radiation therapy to chemotherapy significantly improves overall survival.

This finding, which comes from an analysis of more than 1000 patients participating in three studies, was presented here at the 19th World Congress on Gastrointestinal Cancer (WCGC).

When the analysis included all patients, there was no overall survival benefit.

However, restricting the analysis to patients with right-sided primary tumors revealed a significant improvement in median overall survival with the combined approach of chemotherapy plus selective internal radiation therapy (SIRT) using yttrium-90–loaded resin microspheres.

"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 lead researcher Guy van Hazel, MD, School of Medicine and Pharmacology, University of Western Australia, in Perth.

"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," he commented in a conference press release.

However, an expert discussing the new results at the meeting suggested that this finding should be considered "hypothesis generating" and that the results need to be replicated in a randomized clinical trial.

But the finding was welcomed by other experts at the meeting. These new results are relevant to recent debates on the biological heterogeneity of colon cancers and tumor localization, commented Dirk Arnold, MD, PhD, from the Instituto CUF de Oncologia in Lisbon, Portugal, and Eric Van Cutsem, MD, PhD, Congress co-chair and professor of internal medicine at the University of Leuven, Belgium.

"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 said in a statement.

"Additionally, the well-known worse prognosis of right-sided tumors increases the relative importance of a nonsystemic treatment option. More data on the molecular factors determining these results are warranted," they added.

Analysis of Data From Three Studies

In the first presentation, Harpreet S. Wasan, MD, Hammersmith Hospital, Imperial College London, the United Kingdom, explained that the findings come from a combined analysis of data from three studies:

  • SIRFLOX, which recruited 530 patients in Australia between 2006 and 2013;

  • FOXFIRE, which recruited 364 patients in the United Kingdom from 2009 to 2014;

  • and FOXFIRE Global, which added sites in Asia and the United States to those in SIRFLOX study and recruited 209 patients between 2013 and 2014.

Patients were required to have adenocarcinoma of the colon or rectum and unresectable/unablatable liver metastases and be eligible for systemic chemotherapy as a first-line treatment for metastatic colorectal cancer.

They received four cycles of FOLFOX chemotherapy (folinic acid, fluorouracil and oxaliplatin), with or without bevacizumab (Avastin, Genentech) or cetuximab (Erbitux, Imclone), at the investigators’ discretion. For those patients who also received SIRT, a single treatment was given with chemotherapy in cycle one or two.

After 122 ineligible patients were excluded from the analysis, the team examined a total of 1103 patients, of whom 549 were treated with chemotherapy and 554 with chemotherapy plus SIRT.

The two groups were well balanced in terms of patient characteristics at baseline. There were few differences in treatment, although more patients in the chemotherapy-only group received bevacizumab compared to those who received both chemotherapy and SIRT (46.6% vs 35.6%).

Dr Wasan pointed out that 8.5% of patients in the SIRT group did not receive the additional treatment.

In the overall analysis, there was no significant difference in overall survival between patients given chemotherapy alone and those also treated with SIRT (P = .609), a finding that was repeated in subgroup analyses, including patients with liver-only or liver-dominant metastatic disease.

There were also no significant differences in progression-free survival (P = .108) between the two treatment groups.

There was a significant difference in liver-specific progression-free survival between the chemotherapy and the chemotherapy plus SIRT groups, at a hazard ratio of 0.51 in favor of SIRT (P < .001). The inverse was seen for nonliver progression as a first event.

Analysis of the best radiologic response also favored chemotherapy plus SIRT, at an odds ratio of 1.52, compared with chemotherapy alone (P = .001). Similar findings were seen for the best hepatic response, which was significantly higher with chemotherapy plus SIRT (P < .001).

There was, however, no significant difference in the resection rate between chemotherapy and chemotherapy plus SIRT arms, and there was no difference in health-related quality of life.

Dr Wasan noted that the proportion of patients with grade ≥3 adverse events was higher with chemotherapy plus SIRT compared with chemotherapy, at 74.0% and 66.5%, respectively.

This was attributable to a higher rate of hematologic adverse events and a greater incidence of fatigue, abdominal pain, and peripheral neuropathy with the combination therapy.

Dr Wasan concluded: "The addition of SIRT to FOLFOX first-line chemotherapy in patients with liver-only or liver-dominant metastatic colorectal cancer did not improve overall survival or progression-free survival."

Although he noted that there was a significant benefit in terms of liver-specific progression-free survival and radiologic response with SIRT, he said: "The toxicity was higher in the FOLFOX plus SIRT group, particularly hematological toxicities."

Location Makes All the Difference

In the second presentation, Dr van Hazel explained that the location of the primary tumor in metastatic colorectal cancer is becoming a "major prognostic factor and predictor of response to treatment" and that treatment response is worse for patients with right-sided disease than for those with left-sided tumors. Patients with right-sided disease also have a worse prognosis.

He presented the results of analyzing the data from the studies described above by taking into account the location of the original tumor. For that analysis, the patients were divided into two group, one comprising 179 patients with right-sided tumors, and one comprising 540 patients with left-sided tumors.

He emphasized that the mean tumor burden at baseline was comparable between the two groups.

Dr van Hazel and colleagues found that among patients with right-sided primary tumors, median overall survival was significantly better with chemotherapy plus SIRT than with chemotherapy alone, at 22.0 months vs 17.1 months, at a hazard ratio of 0.64 (P = .007).

There was no significant difference among patients with left-sided tumors.

There was also a trend toward a significant improvement in progression-free survival with chemotherapy plus SIRT vs chemotherapy alone in patients with tumors of right-sided origin, at 10.8 months vs 8.7 months (P = .053). Again, no difference was seen in for patients with left-sided tumors.

No significant differences in the incidence of adverse events were reported between the two groups.

"The observed improvement in overall survival represents a potentially significant clinical outcome for a subgroup of metastatic colorectal patients relatively resistant to standard-of-care systemic chemotherapy regimens and may support a side-based approach to first-line selection for SIRT," Dr van Hazel commented.

"The drivers of these observed side-based differences in treatment impact remain to be elucidated."

Discussing the two presentations, John Zalcberg, MD, Monash University, Melbourne, Australia, highlighted the assumptions that were implicit in the trials that were conducted ― that greater control of liver metastases by a localized therapy might prolong overall survival in patients with primary tumors in situ ― and that this greater local control of liver metastases would prolong overall survival in patients with extrahepatic metastases.

He pointed out, however, that neither the assumption of a benefit in patients with primary tumors in situ, which was seen in approximately 50% of patients, and in those with extrahepatic metastases, which was seen in approximately 33% of patients, is borne out by results from the literature.

He then set out a series of other potential points of debate arising from the studies, including the fact that for patients given SIRT, there was an increase in the number of liver lesions after treatment.

Focusing on the second presentation, Dr Zalcberg said that there is evidence to suggest that the improvements seen in patients with right-sided tumors could be explained by a greater resistance to chemotherapy, which in turn leads to a greater benefit from SIRT.

He concluded that the studies "represent a very impressive effort to demonstrate the benefit or otherwise of SIRT in first-line metastatic colorectal cancer."

However, because an overall survival benefit, which was the primary endpoint of the study, was not achieved with the technique, it "should not be used first line until a subgroup known to benefit can be identified."

Dr Zalcberg then described the results in right-sided tumors as "hypothesis generating" and said that they should be repeated in a randomized study.

He finished by addressing the question of which metastatic colorectal cancer patients should receive SIRT as a first-line therapy, given the current data. In his opinion: "In the first-line setting, I think SIRT can be considered as a single agent in patients with symptomatic, extensive, and unresectable liver-dominant metastatic disease who are not otherwise fit for triplet or doublet chemotherapy."

The studies were funded by Sirtex Medical. Dr Wasan is a member of advisory boards and has received speaker fees, research grants, and travel expenses from Sirtex Medical, Merck KGA, and Roche, as well as grants from Cancer Research UK. Dr van Hazel has received grants, research support, and consultant and speaker fees from Sirtex Medical. Dr Zalcberg has received research and travel support, honoraria, and pharmaceutical stocks from numerous sources, although he has disclosed no financial relationships with Sirtex Medical.

19th World Congress on Gastrointestinal Cancer (WCGC). Abstracts O027 and LBA-006, presented July 1, 2017.

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