Primary Tumor Resection Plus Chemo Yields No Benefit Over Chemo Alone for Stage IV CRC

Findings from the JCOG1007 clinical trial showed that in patients with colorectal cancer (CRC) and synchronous unresectable metastases, primary tumor resection followed by chemotherapy has no survival benefit over chemotherapy alone.

In an interview with Oncology Learning Network, Yukihide Kanemitsu, MD, National Cancer Center Hospital, Tokyo, Japan, discussed the background, findings, and clinical significance of the JCOG1007 study, the results of which were presented at the 2020 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (J Clin Oncol. 2020;38[suppl 4; abstr 7]).

What existing data led you and your co-investigators to conduct this research?

In theory, surgery delays the start of effective systemic therapy and bears the risk for severe complications and mortality. Surgery may, however, prevent development of complications caused by the primary tumor that may subsequently require emergency interventions that are associated with increased peri-operative mortality as well as less favorable long-term outcomes.

Given the fact that patients with metastatic disease have prolonged survival (≥2 years) with modern systemic therapy, the need for (delayed) emergency surgery may be increasing. Furthermore, removal of the primary tumor may positively affect overall survival (OS).

Although the underlying mechanisms remain unexplained at this stage, numerous recent papers have suggested a survival benefit for patients undergoing primary tumor resection compared to patients who do not have this treatment. However, these studies were all retrospective comparative survival analyses without randomization or clear explanation of the indications for resection which are at great risk for bias and misleading results.

Unfortunately, there have been no randomized controlled trials to compare upfront chemotherapy and primary tumor resection in CRC patients with asymptomatic primary tumor and synchronous unresectable metastases. 

A randomized controlled trial was required for this reason. At about the same time or after we started this trial, there was much anticipation regarding the results of several ongoing randomized controlled trials (eg, the SYNCHRONOUS trial in Germany, CAIRO4 in the Netherlands, CCRe-IV in Spain, and CLIMAT in France). Thus, elucidating clinical significance of primary tumor resection for this patient population was an important unmet need worldwide. 

Please briefly describe your study and its findings.

To the best of our knowledge, this is the first randomized controlled trial to show no survival benefit of additional primary tumor resection over chemotherapy alone in patients with incurable advanced CRC.

In summary, primary tumor resection failed to improve OS in CRC patients with asymptomatic primary tumors and synchronous unresectable metastases. There were 3 treatment-related deaths following primary tumor resection, due to postoperative complications. Primary tumor resection was associated with more frequent and more severe chemotherapy-related adverse events.

The present study has some limitations. First, the planned sample size was not achieved because early termination was recommended by the JCOG Data and Safety Monitoring Committee on the basis of the overall futile effect and ethical reasons, restricting the statistical power to support conclusions.

Second, the quality of the study was partly impaired because 5 (3%) patients were judged as ineligible and 18 (11%) did not receive planned primary tumor resection and chemotherapy, which may have affected outcomes, although the hazard ratio for death was essentially unchanged in patients assigned to primary tumor resection plus chemotherapy when calculated in a per-protocol analysis.

Third, assessment of quality of life was not done, which is a crucial consideration for patients with a limited lifespan when choosing the optimum treatment strategy. Fourth, no nutritional parameters were collected, despite their importance in CRC, especially in metastatic presentation. Finally, the results of RAS mutation tests were not collected.

This study identified the first-line of chemotherapy as a protocol treatment, using modified FOLFOX6 or CapeOX combined with bevacizumab. At the time of planning of this study, fluoropyrimidine-oxaliplatin–based chemotherapy in combination with bevacizumab was viable and frequently used—regardless of the RASstatus—as the standard of care for metastatic CRC in Japan.

Enrolled patients are appropriate candidates for primary tumor resection in accordance with enrollment criteria and detailed definitions; therefore, the results are not generally applicable to patients with poor performance statuses (PS2), minimal primary tumor burden, and high volumes of metastatic disease, because these patients were excluded from the study to minimize the risks associated with a protocol treatment.

“Asymptomatic” was defined as lack of primary tumor–related symptoms, including obstruction, active gastrointestinal bleeding requiring a transfusion, and perforation. The asymptomatic patients with tumors that cannot be endoscopically traversed or circumferential lesions were enrolled in this study as long as there was no evidence of obstruction from abnormal X-ray.

However, 13% of patients underwent palliative surgery for symptoms linked to the primary tumor in the chemotherapy alone arm. Therefore, our results should be applicable with caution to the patients with colonoscopy findings of nontraversable lesions at diagnosis, which can cause luminal obstruction attributable to progression or fibrosis from response to treatment. 

When we examined the OS hazard ratios based on a subgroup analysis, there was a prominent difference depending on the performance status, PS0 or PS1 and sidedness. Regarding the tumor location, 30% of patients had theirs on the right side and 70% on the left side in both arms.

There was a prominent difference depending on the sidedness in terms of OS. For patents with left-sided CRC, the median OS was 25 months in arm A (chemotherapy alone) and 27 in arm B (primary tumor resection plus chemotherapy). For patients with right-sided CRC, the median OS was 30 months in arm A and 17 in arm B.

Based on a subgroup analysis, right-sided tumors have a worse prognosis than left-sided cancers in the primary tumor resection followed by chemotherapy arm. Thus, for patients with a poor condition (PS1) or with right-sided CRC (which is considered biologically more aggressive), primary tumor resection may have had negative impact on survival.

What are the possible real-world applications of these findings in clinical practice?

The results of our study can change the practice of surgeons who resect asymptomatic primaries in unresectable metastatic CRC. Also, this study rigorously defined the definition of unresectable factors and the chemotherapeutic regimen used in the first-line treatment.

The only difference between the 2 arms is the difference in primary tumor resection status, so this result could be applicable to the patients even if the first-line chemotherapy regimen changes. Real-world data cannot replace such a randomized controlled trial.

It may be appropriate to conduct a study and randomly assign patients after response to initial systemic therapy (eg, after 4 cycles of chemotherapy) to undergo planned interval resection versus continued treatment to assess the potential for incremental benefit.

However, such a trial would be very difficult to conduct because our study had many intrinsic difficulties in patient accrual in view of its strict eligibility criteria, patient preferences, and biases of individual clinicians, which led to poor acceptance of random assignment.