April’s Paper of the Month looks into the combined findings from two pivotal randomised controlled trials (RCTs): SYNCHRONOUS and CCRe-IV.

These trials focused on patients with colon cancer with synchronous unresectable metastasis, trying to address a critical question: whether primary tumour resection (PTR) or up-front chemotherapy yields better overall survival in such cases due to low patient accrual, data from the two trials were pooled.

Primary Tumor Resection Before Systemic Therapy in Patients With Colon Cancer and Unresectable Metastases: Combined Results of the SYNCHRONOUS and CCRe-IV Trials
Nuh N. Rahbari, MD; Sebastiano Biondo, MD; Ricardo Frago, MD; Manuel Feißt, PhD; Esther Kreisler, MD; Inga Rossion, MD; Monica Serrano, MD; Dirk Jäger, MD; Monika Lehmann, PhD; Florian Sommer, MD; Axel Dignass, MD; Claus Bolling, MD; Ilka Vogel, MD; Ulrich Bork, MD; Markus W. Büchler, MD; Gunnar Folprecht, MD; Meinhard Kieser, PhD; Florian Lordick, MD; and Jürgen Weitz, MD, MSc; on behalf of the SYNCHRONOUS and CCRe-IV Trial Groups

J Clin Oncol, February 2024

What is known about the subject?

Management of newly diagnosed stage IV colorectal cancer (CRC) poses challenges, balancing risks of primary tumour-related complications against perioperative complications that may hinder systemic chemotherapy initiation. Controversy persists regarding resection necessity in colon cancer patients with asymptomatic or mildly symptomatic primaries and synchronous unresectable metastases.

Several randomised trials have been initiated including the Japanese iPACS trial, the Dutch CAIRO IV trial, and a Chinese trial (ClinicalTrials.gov: NCT04416854). Preliminary findings from CAIRO IV revealed higher 60-day mortality in patients randomized to primary tumour resection (PTR) compared to systemic treatment, while the Japanese iPACS trial was stopped early due to futility, failing to show a survival benefit for PTR.

What the study adds?

This study, conducted at 100 centres in Austria, Germany, and Spain, randomised 393 treatment-naïve patients with metastatic colon cancer diagnosed between November 2011 and March 2017. Excluding patients with tumor-related symptoms or surgical indications, the study's primary outcome was overall survival (OS).

The results indicate that PTR does not extend OS compared to chemotherapy alone. In addition, PTR is associated with a lower likelihood of receiving chemotherapy (24% of PTR patients did not undergo chemotherapy), likely due to a notable postoperative morbidity rate (22.5%). However, serious adverse events (SAEs) were significantly more common in the chemotherapy alone group (18% v 10.2%), mainly due to gastrointestinal SAEs. The number of SAEs because due to bowel obstruction was lower in the PTR group, but the absolute frequency of SAEs remained low in both groups.

Implications for colorectal practice

This study further underscores the lack of survival benefit associated with PTR at diagnosis in patients with metastatic colon cancer who have no symptoms related to the primary site. The relatively low number of SAEs in patients with an intact primary tumour, together with a considerable number of patients who did not receive chemotherapy in the PTR group, supports the use of systemic therapy over PTR in this clinical context.


  1. RahbariNN, LordickF, FinkC, et al: Resection of the primary tumour versus no resection prior to systemic therapy in patients with colon cancer and synchronous unresectable metastases (UICC stage IV): SYNCHRONOUS—A randomised controlled multicentre trial (ISRCTN30964555). BMC Cancer 12:142, 2012
  2. BiondoS, FragoR, KreislerE, et al: Impact of resection versus no resection of the primary tumor on survival in patients with colorectal cancer and synchronous unresectable metastases: Protocol for a randomized multicenter study (CR4). Int J Colorectal Dis 32:1085-1090, 2017
  3. KanemitsuY, ShitaraK, MizusawaJ, et al: Primary tumor resection plus chemotherapy versus chemotherapy alone for colorectal cancer patients with asymptomatic, synchronous unresectable metastases (JCOG1007; iPACS): A randomized clinical trial. J Clin Oncol 39:1098-1107, 2021
  4. van der Kruijssen DEW, Elias SG, Vink GR, et al: Sixty-day mortality of patients with metastatic colorectal cancer randomized to systemic treatment vs primary tumor resection followed by systemic treatment: The CAIRO4 phase 3 randomized clinical trial. JAMA Surg 156:1093-1101, 2021
  5. Chinese trial (ClinicalTrials.gov: NCT04416854).