Primary tumor resection followed by chemotherapy failed to demonstrate a survival benefit compared with chemotherapy alone in patients with stage IV colorectal cancer who have asymptomatic primary tumors and synchronous unresectable metastases, suggesting that PTR should no longer be considered a standard of care in this patient population.
Primary tumor resection (PTR) followed by chemotherapy failed to demonstrate a survival benefit compared with chemotherapy alone in patients with stage IV colorectal cancer (CRC) who have asymptomatic primary tumors and synchronous unresectable metastases, suggesting that PTR should no longer be considered a standard of care in this patient population, according to findings from the phase 3 JCOG1007 (iPACS) trial.
With a median follow-up of 22 months, the median overall survival (OS) was 25.9 months with PTR plus chemotherapy (95% CI, 19.9-31.5) vs 26.7 months with chemotherapy alone (95% CI, 21.9-32.5; HR, 1.10; 95% CI, 0.76-1.59; P = .69).
“Elucidating the clinical significance of PTR for unresectable stage IV CRC patients without any symptoms linked to the primary tumor remained an important unmet need worldwide when our trial began, amid high anticipation of the results of ongoing randomized controlled trials in Germany, the Netherlands, Spain, France, Korea, and China,” Yukihide Kanemitsu, MD, lead study author and a medical oncologist in the Department of Colorectal Surgery at the National Cancer Center Hospital in Tokyo, Japan, said in a statement to OncLive®. “To our knowledge, our study provides the first high-quality evidence for PTR before chemotherapy in patients with CRC with asymptomatic primary tumor and synchronous unresectable metastases. For [these patients], PTR was not associated with improved survival compared with systemic chemotherapy; therefore, routine non-curative PTR is not recommended.”
Although the majority of patients with CRC are diagnosed with unresectable stage IV disease, some patients have asymptomatic primary tumors and unresectable metastatic disease. The optimal treatment of these patients is debated in the field, but some reports have shown that PTR can improve OS.
However, the significant morbidity and mortality associated with PTR, as well as the delay it causes in initiating chemotherapy, has called into question the utility of surgery before chemotherapy in this patient population. Additionally, the OS benefit reported with PTR has been demonstrated by retrospective data vs prospective data.
In order to prospectively evaluate the role of PTR followed by chemotherapy, the open-label iPACS trial randomized 165 patients from 38 cancer centers in Japan to PTR plus chemotherapy (n = 81) or chemotherapy alone (n = 84).
In the PTR plus chemotherapy arm, 3 patients were ineligible for the study because of a second primary tumor (n = 1) and deviation from specified surgical methods (n = 2). Additionally, 4 patients in this arm did not undergo PTR. After surgery (n = 77), 10 patients did not go on to receive chemotherapy because of rapid disease progression (n = 5), death (n = 3), adverse effects (AEs; n = 1), and health decline unrelated to AEs (n = 1).
In the chemotherapy-alone arm, 2 patients were not eligible to receive treatment because of a second primary tumor (n = 1) and lack of laboratory findings (n = 1). Chemotherapy was not delivered in 5 patients for health decline unrelated to AEs (n = 3) and rapid disease progression (n = 2).
In the PTR plus chemotherapy arm, 67 patients started chemotherapy, including 58 who received modified FOLFOX6 (mFOLFOX6) plus bevacizumab (Avastin) and 9 who received capecitabine plus oxaliplatin (CapeOX) and bevacizumab. Moreover, 67 patients discontinued chemotherapy because of disease progression (n = 46), AEs (n = 9), patient refusal because of AEs (n = 4), treatment-resistant depression (n = 1), and other reasons (n = 7).
In the chemotherapy-alone arm, 79 patients started chemotherapy, including 66 who received mFOLFOX6 plus bevacizumab and 13 who received CapeOX plus bevacizumab. Moreover, 79 patients discontinued chemotherapy because of disease progression (n = 43), AEs (n = 10), patient refusal because of AEs (n = 6), patient refusal unrelated to AEs (n = 1), and other reasons (n = 19).
Overall, 81 patients in the PTR plus chemotherapy arm and 84 patients in the chemotherapy-alone arm were included in the intention-to-treat analysis.
In the PTR plus chemotherapy cohort, patients underwent surgery within 21 days of enrollment under laparoscopy or laparotomy. Lymph node dissection was kept in the range of D1 to D3. After 8 to 56 days following surgery, chemotherapy was initiated per investigator’s choice of mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab. In the chemotherapy-alone cohort, chemotherapy was initiated within 14 days of enrollment.
Therapy was continued until disease progression was diagnosed clinically or by imaging, unacceptable toxicity, if treatment was delayed more than 28 days because of an AE, if an AE resulted in subsequent dose reduction after the second dose reduction, and patient or physician withdrawal.
Patients receiving chemotherapy alone could receive palliative surgery if necessary, because of intestinal obstruction, perforation, fistulation, or hemorrhage associated with the primary tumor. Additionally, surgery to achieve R0 resection could be performed in either arm if the patients’ tumors were considered resectable based on response to chemotherapy across all prespecified non-curable factors.
OS served as the primary end point. Progression-free survival (PFS), AEs, the proportion of patients who underwent R0 resection, and the proportion of patients who underwent palliative surgery were secondary end points.
Baseline patient characteristics were well balanced between the arms, and patients were a median age of 65 years. The unresectable sites of metastatic disease were similar between the PTR plus chemotherapy and chemotherapy-alone arms, including liver (74% vs 71%, respectively), lung (27% vs 20%, respectively), distant lymph node (20% vs 27%, respectively), and peritoneum (7% vs 5%, respectively).
The majority of patients’ primary tumors were located in the colon (93%) followed by the upper rectum (7%).
Additionally, most patients had a clinical tumor stage of T3, clinical nodal stage of N0 or N1, and well or moderately differentiated tumors.
From the results of the first interim analysis, the Data and Safety Monitoring Committee recommended early termination of the study, according to the prespecified stopping criteria on the grounds of futility.
The updated analysis demonstrated that at a median follow-up of 22.1 months, the 3-year OS rate was 32.9% in the PTR plus chemotherapy cohort vs 33% in the chemotherapy-alone cohort. The median OS was 25.9 months vs 26.4 months, respectively (HR, 1.11; 95% CI, 0.78-1.58; one-sided P = .72).
Most patients in both arms––93% in the PTR plus chemotherapy arm vs 87% in the chemotherapy-alone arm––experienced disease progression.
The median PFS was 10.4 months with PTR plus chemotherapy vs 12.1 months with chemotherapy alone (HR, 1.12; 95% CI, 0.81-1.55; two-sided P = .48).
Findings from a prespecified subgroup analysis revealed a significant difference in OS based on performance status, although the number of patients with a performance status of 1 was limited.
In the PTR plus chemotherapy cohort (n = 77), 96% of patients underwent PTR with a median operative time of 189 minutes. About half (55%) of patients underwent open surgery vs laparoscopic surgery (45%). Surgical procedures included partial resection of the colon (27%), sigmoidectomy (35%), high anterior resection (18%), low anterior resection (14%), stoma (3%), laparotomy (1%), and other (1%). Most patients (96%) did not have a multivisceral resection.
Additionally, 4% of patients had postoperative mortality. Finally, grade 2, 3, or 4 early postoperative morbidity was observed in 38% of patients, whereas grade 4 early postoperative morbidity was reported in 3% of patients.
Grade 3 or higher major surgery-related complications included fever (1%), intraabdominal abscess (1%), postoperative bleeding (1%), bilirubinemia (1%), anastomotic leakage (4%), abnormal alanine aminotransferase concentration (9%), and increased aspartate transaminase (17%). One patient required reoperation for anastomotic leakage.
Three patients in the PTR plus chemotherapy cohort died during the hospital stay for PTR or death from any cause within 30 days after surgery because of hepatorrhagia or postoperative complications.
Two patients (3%) randomized to PTR plus chemotherapy and 5 patients (6%) randomized to chemotherapy alone underwent R0 resection.
In the chemotherapy-alone cohort, 13% of patients (n = 11) underwent palliative surgery for symptoms related to their primary tumors.
Patients in both arms received a median of 13 cycles of chemotherapy. Regarding chemotherapy-related AEs, grade 2 or higher and grade 3 or higher non-hematologic AEs were observed more frequently in the group who also received PTR vs those in those who received chemotherapy alone.
One treatment-related death from sudden duodenal perforation of unknown cause occurred in the PTR plus chemotherapy cohort.
Finally, no significant difference in chemotherapy regimen or the number of subsequent therapy lines was observed between the 2 cohorts.
“The results of the JCOG1007 (iPACS) study indicated that PTR is not needed in most cases of asymptomatic CRC with an unresectable metastatic tumor, and systemic chemotherapy is the main treatment for such a population,” study author Kohei Shitara, MD, chief of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, said in a statement to OncLive®.
“These results are important for physicians and patients to omit unnecessary surgery and not to miss the chance to receive effective chemotherapy. Meanwhile, this trial excluded patients with a symptomatic primary tumor, and 13% of patients with up-front chemotherapy finally received palliative surgery. Therefore, we need a multidisciplinary approach for patients with CRC during continuum treatment care,” Shitara concluded.
Kanemitsu Y, Shitara K, Mizusawa J, 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. 2021;39(10):1098-1107. doi:10.1200/JCO.20.02447