Debating the Standard of Care for Resectable Colorectal Cancer Liver Mets

Surgical resection is the only treatment currently available that ensures long-term survival for patients with resectable colorectal cancer liver metastases (CRLMs), a common result of colorectal cancer progression, yet more than 75% of patients still experience relapse.¹Emerging data suggest that the combination of chemotherapy and surgery may reduce the risk of relapse and improve surgical outcomes for select patients.

Whether neoadjuvant chemotherapy should be combined with the standard of care was the subject of a heated debate at the 2018 Debates and Didactics in Hematology and Oncology meeting in July in Sea Island, Georgia.

Two oncologists from the Winship Cancer Institute of Emory University reviewed data for and against the use of chemotherapy for patients with resectable CRLMs. Mehmet Akce, MD, spoke in favor of chemotherapy, while Shishir K. Maithel, MD, argued against it.

Findings For and Against

Akce, an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, emphasized that neoadjuvant chemotherapy in combination with surgery should be considered the standard of care for patients with resectable CRLMs.

In the randomized, phase III EORTC 40983 trial, for example, patients who were treated with perioperative chemotherapy experienced improved progression-free survival (PFS) compared with surgery alone after a follow-up of 3.9 years (18.7 vs 11.7 months; HR, 0.79; 95.66% CI, 0.62-1.02;P= .058) in all randomly assigned patients; the PFS benefit was statistically significant in all eligible and resected patients.²

“This clinical trial looked at the role of perioperative chemotherapy with FOLFOX4,” Akce said in a follow-up interview withTargeted Therapies in Oncology(TTO). “Patients were treated with 3 months of preoperative and 3 months [of] postoperative chemotherapy. It was well tolerated and met its primary endpoint.”

Although the design of the trial was not powered to examine overall survival (OS), the phase III CHARISMA trial is enrolling patients to accurately evaluate the effect that neoadjuvant chemotherapy has on OS. Patients with resectable, high risk CRLMs will be randomized to either surgery alone or 6 cycles of neoadjuvant oxaliplatin-based chemotherapy in combination with surgery.

From the long-term results of EORTC 40983 trial, there were 6 deaths per arm from toxicity of protocol treatment on the trial involving complications of protocols surgery, or toxicity of further cancer treatment.³This finding, Akce argued, suggests that neoadjuvant chemotherapy before surgery does not result in increased treatment-related mortality compared with surgery alone.

At a median follow-up of 8.5 years, 107 (59%) of patients in the perioperative chemotherapy arm had died compared with 114 (63%) in the surgery alone arm (HR, 0.88; 95% CI, 0.68-1.14;P= .34).

Regarding toxicity, Akce said that overtreatment with chemotherapy is a valid concern and a patient should not be treated for over 3 months in the neoadjuvant setting. “Limit systemic therapy to 2 to 3 months,” he suggested. “If they progress on chemotherapy, we know that the patient most likely had bad biology of their disease and would have recurred sooner anyway.”

Akce cited a meta-analysis of prospective studies comparing neoadjuvant and adjuvant chemotherapy versus surgery alone. Investigators demonstrated a PFS trend advantage for combined treatment versus surgery alone (pooled HR, 0.75; 95% CI, 0.62-0.91; P= .088),¹but were unable to demonstrate an improved OS benefit.

For select patients who receive (neo)adjuvant chemotherapy combined with surgery, Akce strongly encouraged timely reassessment of the disease. “You need to know if the disease is progressing,” he said. “If it is, that is a bad prognostic sign, because [the disease] is getting worse on chemotherapy.” During his presentation, he suggested scanning the patient every 8 weeks.

On the other side of the debate, Maithel, a professor of surgery in the Division of Surgical Oncology at Emory University School of Medicine, argued that neoadjuvant chemotherapy should not be considered the standard of care.

Maithel also presented data from the EORTC 40983 trial, but he found the details of the study to be less promising. For example, there was a 6% difference in the unresectability rate between the chemotherapy/surgery arm versus those treated with surgery alone (10% vs 4%).²Of the 364 patients randomized equally to each group, 159 patients (87.4%) in the chemotherapy/surgery arm and 171 patients (94.0%) in the surgery arm underwent surgical resection. Further, there were more postoperative complications in the chemotherapy arm (25% vs 16%; P= .04), although all complications were reversible.

“The curves separated right at the time of surgery because they found that patients were not resectable, and then the curves stay completely parallel. The effect of chemotherapy does nothing down the road,” argued Maithel during aTTOfollow-up interview.

Additionally, he stated that the OS data were minimally different at the cost of higher toxicity. For patients who received chemotherapy/surgery, at a median follow-up of 8.5 years, the median OS was 61.3 versus 54.3 months for patients treated with surgery alone (HR, 0.88; 95% CI, 0.66-1.14;P= .34).³Thirty-six of the patients in the chemotherapy arm did not go on to receive postoperative chemotherapy because of toxicity from the preoperative chemotherapy and perioperative complications.

“This comes down to minimal, if any, improvement in outcome [with] increased morbidity,” he said.

Maithel also cited several retrospective studies in his presentation to further highlight the toxicity profile of patients treated with chemotherapy/surgery. For example, preoperative chemotherapy was associated with increased rates of morbidity compared with surgery alone in an analysis of 67 patients who underwent major liver resection (38% vs 13.5%;P= .03).⁴

“What often happens is that patients are treated with chemotherapy for way too long, and then they have toxicities to the point where the patients are not even amenable to resection. That is a huge disservice for patients,” Maithel said.

During his argument, Maithel specified toxicities associated with the different chemotherapy backbones used for the treatment of resectable CRLMs. In one retrospective study, oxaliplatin-based chemotherapy was associated with sinusoidal dilation compared with no chemotherapy (18.9% vs 1.9%;P<.001).⁵With irinotecan-based chemotherapy, on the other hand, treatment was associated with steatohepatitis compared with no chemotherapy (20.2% vs 4.4%;&nbsp;P<.001).

Although chemotherapy is often combined with surgery in practice, Maithel encouraged all medical oncologists to perform a multidisciplinary evaluation for their patients to determine if it is truly necessary and how much they should receive before surgery.

&ldquo;In my talk you can see that there is plenty to suggest that [chemotherapy] is not necessary in many instances, and there are a few randomized trials that [demonstrate] chemotherapy doesn&rsquo;t even change the survival in patients with resectable CRLMs,&rdquo; Maithel concluded.

References:

1. Ciliberto D, Prati U, Roveda L, et al. Role of systemic chemotherapy in the management of resected or resectable colorectal liver metastases: a systemic review and meta-analysis of randomized controlled trials.Oncol Rep.2012;27(6):1849-1856. doi: 10.3892/or.2012.1740.
2. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemother- apy with FOLFOX4 and surgery versus surgery alone for resectable liv- er metastases from colorectal cancer (EORTC intergroup trial 40983): a randomized controlled trial.Lancet. 2008;371(9617):1007-1016. doi: 10.1016/S0140-6736(08)60455-9.
3. Nordlinger B, Sorbye H, Glimelius B, et al; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetas- tasen und—tumoren in der Chirurgischen Arbeitsgemeinschaft Onkol- ogie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); F&eacute;d&eacute;ration Francophone de Canc&eacute;rologie Digestive (FFCD). Periop- erative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial.Lancet Oncol.2013;14(12):1208-1215. doi: 10.1016/S1470-2045(13)70447-9.
4. Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoper- ative chemotherapy on the risk of major hepatectomy for colorec- tal liver metastases.Ann Surg. 2006;243(1):1-7. doi: 10.1097/01. sla.0000193603.26265.c3.
5. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen pre- dicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases.J Clin Oncol.2006;24(13):2065- 2072. doi: 10.1200/JCO.2005/05/3074.