Impact of perioperative chemotherapy on survival outcomes among patients with metastatic colorectal cancer to the liver

To our knowledge, this is the largest real-world study that looked at the chemotherapy effect in metastatic CRC with only liver metastases who were treated with metastasectomy and compared the OS between patients who received perioperative chemotherapy versus patients treated with surgery only in addition to comparing the OS between adjuvant chemotherapy and neoadjuvant chemotherapy and comparing the OS between single-agent and multiagent chemotherapy.

Our study showed that patients with metastatic CRC with liver metastases who were treated with chemotherapy in addition to surgery had statistically significant better OS compared with patients who didn't receive chemotherapy. Also, in the multivariable analysis, we found that chemotherapy was independently associated with better OS.

There is limited data about the role of perioperative chemotherapy in patients with liver metastases from CRC. Most of the studies had a small number of patients and were designed to evaluate the effect of chemotherapy on recurrence- and PFS rather than overall survival. And the majority of the studies that evaluated the effect of chemotherapy on OS didn't report a significant difference in the OS between patients who received perioperative chemotherapy and patients who did not.

Nordlinger et al., in a European Organization for Research and Treatment of Cancer trial based on 364 patients with metastatic CRC and up to four liver metastases, who were recruited from 78 hospitals from different European countries, compared the outcomes of 182 patients who received perioperative FOLFOX-4 chemotherapy to those of 182 patients who had surgery only. Initial results showed chemotherapy was associated with better 3-year PFS compared with surgical resection alone. After a median follow-up of 8·5 years, it was found that patients who received perioperative chemotherapy had a better median OS and 5-year OS, but it wasn't statistically significant. There are multiple factors in that study that could contribute to the lack of difference in the OS between the two groups. In addition to the small number of included patients, the study was designed with PFS being the primary end point whereas OS was a secondary end point. Also, the perioperative group had a higher number of non-cancer deaths compared with the surgery-only group [12,15]. Similarly, Portier et al., in the FFCD trial compared the outcomes between patients who had surgery only versus patients who had adjuvant chemotherapy with fluorouracil and folinic acid in 173 patients with liver metastases from CRC. They found that patients who received adjuvant chemotherapy had better 5-year OS, but it wasn't statistically significant. Several factors could be behind this result, the study wasn't designed with overall survival as an end point, also recurrences in both groups were treated by second-line chemotherapy, or by repeat liver resections, which influenced the natural history of the disease [16]. Hasegawa et al., in a randomized controlled trial, assigned 180 patients with CRC liver metastasis into two groups; patients who received adjuvant chemotherapy with uracil-tegafur and leucovorin and patients who had had surgery only. They found that patients who received adjuvant chemotherapy had significantly reduced recurrence compared with the patients who had surgery only, but there was no difference in the OS (66.1% vs 66.8%; p = 0.409). Multiple limitations also may have contributed to this result; the short period of follow-up (median follow-up was less than 5 years), a small number of included patients, and the way the study was designed with recurrence-free survival as the primary end point whereas the OS was a secondary end point [17]. Kemeny et al., did a randomized trial of 75 patients with one to three hepatic metastases of CRC where patients were randomized to hepatic resection alone or resection followed by hepatic arterial infusion of floxuridine and systemic 5-FU. The results showed that patients who received chemotherapy had a better 4-year OS and median OS, but the difference wasn't statistically significant (p = 0.6) [18].

While the previously mentioned studies failed to show a significant effect of chemotherapy on OS, another study reported a positive effect of chemotherapy on OS. A pooled analysis of two trials done by Mitry et al., that included 278 patients with metastatic CRC (171 patients with liver metastases from the FFCD trial and 107 patients with liver or lung metastases from the ENG trial) and found that compared with patients who had surgery alone, patients who had adjuvant chemotherapy had better median PFS and median OS, but the differences were not statistically significant. Whereas, in multivariable analysis, they found that adjuvant chemotherapy was associated with better PFS and OS [19] which aligns with our findings.

On the other hand, Kanemitsu et al., in a randomized trial of 300 patients with metastatic CRC with an unlimited number of liver metastases, found that patients who had adjuvant modified FOLFOX6 regimen had better disease-free survival, but a numerically worse 3-year OS and worse 5-year OS compared with patients who had hepatectomy alone, but the differences were not statistically significant [20].

Among patients who received chemotherapy, we found that patients were treated with neoadjuvant chemotherapy had better OS compared with patients were treated with adjuvant chemotherapy. Also, we found patients who received multiagent chemotherapy had better OS compared with patients who received single-agent chemotherapy.

The vast majority of trials, that were done on metastatic CRC, assessed the effect of perioperative chemotherapy compared with surgical resection only, and while the comparison between adjuvant and neoadjuvant chemotherapy in non-metastatic CRC has been investigated, there are very few prospective studies done in metastatic cases. While some studies suggest neoadjuvant chemotherapy is beneficial in unresectable disease and helps in improving the complete resection success rate [21], other studies showed that neoadjuvant chemotherapy was associated with increased liver toxicity and suggest adjuvant chemotherapy was more beneficial in managing micro-metastases with less liver toxicity-related complications [22–25].

Despite its use it is not very common, using neoadjuvant chemotherapy in the sitting of unresectable colorectal liver metastases, which is referred to as conversion chemotherapy, seems to have a survival benefit in these cases. This area of interest is still under extensive study and evaluation. The ideal chemotherapy regimen has not been established yet and different matters regarding to the chemotherapy timing, dosage and live toxicity should be taken into consideration [26,27]. Adam et al., evaluated the impact of conversion chemotherapy on the outcome of 1104 patients with unresectable colorectal liver metastases. They found that conversion chemotherapy allowed 12.5% of patients with unresectable colorectal liver metastases to be rescued by liver surgery [28].

In the setting of not having a head-to-head comparison between adjuvant and neoadjuvant chemotherapy in metastatic disease [29,30], the National Comprehensive Cancer Network guidelines still recommends using peri-operative chemotherapy for a total of 6 months without a preference for adjuvant or neoadjuvant chemotherapy [31].

When it comes to the comparison between the single-agent and multiagent chemotherapy, few studies looked at that in the setting of metastatic disease. Seymour et al., evaluated 2135 patients with inoperable metastatic or locoregional CRC and compared the OS in three different chemotherapy strategies; the first group received single-agent as a first line and single-agent as a second line, the second group received single-agent as a first line and combination chemotherapy as a second line, the third group received combination chemotherapy as a first line. The study showed that the group treated with combination chemotherapy as a first line had better OS compared with the group that received single-agent chemotherapy in both first and second line. Interestingly, there was no statistically significant difference in the OS between the group that received single-agent chemotherapy as a first and second line and the group that received single-agent chemotherapy as a first line and combination chemotherapy as a second line. These results are similar to our result in one way that patients who received multiagent chemotherapy as a first line had better OS than patients who received single-agent as a first line. Unfortunately, the NCDB doesn't provide details about the second line chemotherapy to be able to compare patients according to second line chemotherapy like the mentioned study [32]. The biggest limiting factor in this study is that recruited patients were selected as a poor-prognosis group who were definitely incurable and patients with operable metastases were excluded.

Koopman et al., in phase III randomized controlled trial (CAIRO study), reported no statistically significant difference in the OS between patients with advanced CRC who received combination chemotherapy as a first line and patients who received the same chemotherapy agents but were given sequentially [33]. Similar to what we mentioned before, the chemotherapy details in NCDB are limited to first line chemotherapy.

It is worth mentioning that the two mentioned studies [32,33] enrolled metastatic CRC cases are not amenable for curative surgery, while patients in our study received surgery for the primary tumor and the metastatic liver metastases.

Our study has some limiting factors that need to be discussed; first, the type of chemotherapy that patients received was not available. This could have impacted the outcomes of some patients receiving adjuvant chemotherapy. Second, the differentiation between single-agent and multiagent chemotherapy is limited to the first line of chemotherapy not total chemotherapy the patient may have received. Third, the distribution and completeness of surgical resection of liver metastases were not specified in the database. Fourth, data about liver metastases like number, dimension, site or resectability and molecular profile (RAS/BRAF) are not available in NCDB. This is an important element that could have affected patients' outcomes if there is an imbalanced between both groups. Fifth, NCDB also doesn't have details about other oncologic end points like disease-free survival and cancer-specific survival (both represent important end points to evaluate the effect of chemotherapy). Sixth, the retrospective nature of data collection within the NCDB might have affected the veracity of the analyses as well.

It is worth mentioning as well that in our study, patients who had surgery only were older compared with patients who received perioperative chemotherapy (mean age in years 70 vs 58) which could be a significant factor that affects the difference in the OS between the two groups as older patients tend to have more comorbidities and as a result more likely not to receive chemotherapy. To account for this potential bias, we did a propensity score matching for age and Charlson comorbidity score as well as multivariable Cox regression analysis incorporating other relevant baseline factors.

In conclusion, our study shows that the addition of chemotherapy to surgery improves the OS in metastatic CRC with liver metastases treated with metastasectomy. Also, neoadjuvant and multiagent chemotherapy seem to improve the OS compared with adjuvant and single-agent chemotherapy, respectively. Further large-scale studies are needed to evaluate the effect of chemotherapy role and timing not only on recurrence and PFS but also on OS.

F Baidoun: data analysis, data interpretation, manuscript writing. Z Merjaneh: manuscript writing. R Nanah: manuscript writing. AM Saad: manuscript editing, critical revision. O Abdel-Rahman: study concept, manuscript editing, critical revision.

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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