XELOX or mFOLFOX6 chemotherapy combined with resection of primary lesion versus chemotherapy alone for colon cancer with unresectable metastases: A randomized clinical trial.

3590 Background: It is still controversial for colon cancer patients with unresectable metastases whether to resect the primary tumor when there are no symptoms of primary lesion. Methods: This is an open-label, single-center, prospective, randomized, controlled phase II trial. Colon cancer patients aged 18-80 years with unresectable metastases at enrollment will be randomly allocated to either resection group (group A) or chemotherapy group (group B), and stratified by tumor response and number of organ metastases, after receiving induction chemotherapy with 4 cycles of XELOX or 6 cycles of mFOLFOX6, excluding those with disease progression, lesions radically resectable, or primary lesion unresectable. Patients in group A received resection of primary lesion and then continued chemotherapy, and patients in group B just continued chemotherapy, both up to 4 cycles of XELOX or 6 cycles of mFOLFOX6, and capecitabine maintenance afterwards. If progression occurs 3 months after discontinuation of oxaliplatin and toxicity has recovered to grade I, the original regimen can be applied again. The primary endpoint was TFS (time to failure of strategy, defined as the time from randomization to secondary progression in patients received re-introduce of the induction chemotherapy regimen, or to first progression in patients without re-introduce of the original regimen). The secondary endpoints included progression-free survival (PFS, the time from randomization to first progression), overall survival (OS, the time from enrollment to death), and adverse events (AEs). Efficacy data were analyzed on an intention-to-treat (ITT) basis. This study is registered with ClinicalTrials.gov, number NCT02291744. Results: Between April, 2015, and July, 2020, 140 patients were enrolled, and 54 patients withdrew due to colon obstruction (16), perforation (1), disease progression (22), death (1), radical resection (3), or other reasons (11). Finally, 86 patients were randomized into group A (n = 42) or group B (n = 44). The median TFS was 143 days (95%CI: 104.9-181.1) in group A, and 196 days (95%CI: 96.5-295.5) in group B (HR:0.930 95%CI:0.589-1.468, p = 0.755). The median PFS was 147 days (95%CI: 105.7-188.3) in group A, and 206 days(95%CI:180.9-231.1) in group B (HR:0.831, 95%CI:0.522-1.323, p = 0.436). The median OS was 530 days (95%CI: 308.9-751.1) in group A, and 779 days (95%CI:626.3-931.7) in group B (HR:0.948 95%CI:0.554-1.622, p = 0.845). The incidence of treatment-related AEs was similar between two groups. Conclusions: Resection of primary tumor after induction chemotherapy could not bring survival benefits. It’s not recommended for patients without symptoms of primary lesion to receive primary tumor resection, but it also requires individualized treatment as colon obstruction or perforation occurred in some patients. Clinical trial information: NCT02291744.

The Impact of Primary Tumor Resection on Survival in Asymptomatic Colorectal Cancer Patients With Unresectable Metastases

Purpose: This study was conducted to evaluate the effectiveness of primary tumor resection (PTR) in asymptomatic colorectal cancer (CRC) patients with unresectable metastases using the inverse probability of treatment weighting (IPTW) method to minimize selection bias.Methods: We selected 146 patients diagnosed with stage IV CRC with unresectable metastasis between 2001 and 2018 from our institutional database. In a multivariate logistic regression model using the patients’ baseline covariates associated with PTR, we applied the IPTW method based on a propensity score and performed a weighted Cox proportional regression analysis to estimate survival according to PTR.Results: Upfront PTR was performed in 98 patients, and no significant differences in baseline factors were detected. The upweighted median survival of the PTR group was 18 months and that of the non-PTR group was 15 months (P = 0.15). After applying the IPTW, the PTR was still insignificant in the univariate Cox regression (hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.5–1.21). However, in the multivariate weighted Cox regression with adjustment for other covariates, the PTR showed a significantly decreased risk of cancer-related death (HR, 0.61; 95% CI, 0.40–0.94).Conclusion: In this study, we showed that asymptomatic CRC patients with unresectable metastases could gain a survival benefit from upfront PTR by analysis with the IPTW method. However, randomized controlled trials are mandatory.

Primary Tumor Resection Plus Chemotherapy Versus Chemotherapy Alone for Colorectal Cancer Patients With Asymptomatic, Synchronous Unresectable Metastases (JCOG1007; iPACS): A Randomized Clinical Trial

PURPOSE It remains controversial whether primary tumor resection (PTR) before chemotherapy improves survival in patients with colorectal cancer (CRC) with asymptomatic primary tumor and synchronous unresectable metastases. PATIENTS AND METHODS This randomized phase III study investigated the superiority of PTR followed by chemotherapy versus chemotherapy alone in relation to overall survival (OS) in patients with unresectable stage IV asymptomatic CRC and three or fewer unresectable metastatic diseases confined to the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy regimens of either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab were decided before study entry. The primary end point was OS, which was analyzed by intention-to-treat. RESULTS Between June 2012 and September 2019, a total of 165 patients were randomly assigned to either chemotherapy alone (84 patients) or PTR plus chemotherapy (81 patients). When the first interim analysis was performed in September 2019 with 50% (114/227) of the expected events observed among 160 patients at the data cutoff date of June 5, 2019, the Data and Safety Monitoring Committee recommended early termination of the trial because of futility. With a median follow-up of 22.0 months, median OS was 25.9 months (95% CI, 19.9 to 31.5) in the PTR plus chemotherapy arm and 26.7 (95% CI, 21.9 to 32.5) in the chemotherapy-alone arm (hazard ratio, 1.10; 95% CI, 0.76 to 1.59; one-sided P = .69). Three postoperative deaths occurred in the PTR plus chemotherapy arm. CONCLUSION Given that PTR followed by chemotherapy showed no survival benefit over chemotherapy alone, PTR should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases.

The Role of Primary Tumor Resection in Colorectal Cancer Patients with Asymptomatic, Synchronous, Unresectable Metastasis: A Multicenter Randomized Controlled Trial

We aimed to assess the survival benefits of primary tumor resection (PTR) followed by chemotherapy in patients with asymptomatic stage IV colorectal cancer with asymptomatic, synchronous, unresectable metastases compared to those of upfront chemotherapy alone. This was an open-label, prospective, randomized controlled trial (ClnicalTrials.gov Identifier: NCT01978249). From May 2013 to April 2016, 48 patients (PTR, n = 26; upfront chemotherapy, n = 22) diagnosed with asymptomatic colorectal cancer with unresectable metastases in 12 tertiary hospitals were randomized (1:1). The primary endpoint was two-year overall survival. The secondary endpoints were primary tumor-related complications, PTR-related complications, and rate of conversion to resectable status. The two-year cancer-specific survival was significantly higher in the PTR group than in the upfront chemotherapy group (72.3% vs. 47.1%; p = 0.049). However, the two-year overall survival rate was not significantly different between the PTR and upfront chemotherapy groups (69.5% vs. 44.8%, p = 0.058). The primary tumor-related complication rate was 22.7%. The PTR-related complication rate was 19.2%, with a major complication rate of 3.8%. The rates of conversion to resectable status were 15.3% and 18.2% in the PTR and upfront chemotherapy groups. While PTR followed by chemotherapy resulted in better two-year cancer-specific survival than upfront chemotherapy, the improvement in the two-year overall survival was not significant.

A randomized phase III trial comparing primary tumor resection plus chemotherapy with chemotherapy alone in incurable stage IV colorectal cancer: JCOG1007 study (iPACS).

7 Background: It is still controversial whether primary tumor resection (PTR) before chemotherapy (CTX) improves overall survival (OS) of colorectal cancer (CRC) patients (pts) with synchronous unresectable metastases. There are several retrospective analyses suggesting better outcomes in pts who underwent PTR compared to pts without it, but no prospective studies confirming these results. We conducted a randomized controlled trial to confirm the superiority of PTR plus CTX to CTX alone in asymptomatic unresectable stage IV CRC patients. Methods: Eligibility criteria included histologically proven colon and upper rectal adenocarcinoma, cT1-4 without involvement of other organs, presence of three or less unresectable factors confined to either liver, lungs, distant lymph nodes, or peritoneum, aged 20-74, no symptoms due to primary tumor and PS 0-1. Eligible patients were randomized to either PTR followed by CTX or CTX alone. CTX regimens were declared before study entry; options included mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab. The primary endpoint was the OS. The planned sample size was 140 pts per arm, with one-sided alpha of 5%, and 70% power detecting a median OS difference of 8 months (24 months vs. 32 months). Results: Between Jun 2012 and Apr 2019, 160 patients were randomized. 78 pts were allocated to PTR plus CTX, and 82 pts to CTX alone. When the first interim analysis was performed in Sep 2019, with 50% (114/227) of the expected events observed, the DSMC recommended the early termination of the trial based on its futility. With a median follow-up period of 22.0 months for 160 patients, median OS was25.9 months (95% CI 19.9 – 31.5) with PTR plus CTX and 26.7(21.9 – 32.5) with CTX alone (hazard ratio 1.10 [0.76 – 1.59], one-sided p = 0.69). Median PFS was 10.4 (8.6-13.4) with PTR plus CTX and 12.1 (9.4 – 13.2) with CTX alone (hazard ratio 1.08 [0.77 – 1.50]). There were three treatment related deaths following PTR due to postoperative complications. Conclusions: PTR followed by CTX has no survival benefit over CTX alone. PTR is not recommended for CRC patients with asymptomatic primary tumor and synchronous unresectable metastases. Clinical trial information: UMIN000008147.

How Do Synchronous Lung Metastases Influence the Surgical Management of Children with Hepatoblastoma? An Update and Systematic Review of the Literature

Approximately 20% of children with hepatoblastoma (HB) have metastatic disease at diagnosis, most frequently in the lungs. In children with HB, lung metastatic disease is associated with poorer prognosis. Its treatment has been approached with a variety of methods that integrate chemotherapy and surgical resection. The timing and feasibility of complete extirpation of lung metastases, by chemotherapy and/or metastasectomy, is crucial for the surgical treatment of the primary liver tumor, which can vary from major hepatic resections to liver transplantation (LT). In children with unresectable HB, which can be surgically treated only by LT, the persistence of unresectable metastases after neoadjuvant chemotherapy excludes the possibility of recurring to LT with consequent negative impact on patients’ outcomes. Due to limited evidence and experience, there is no consensus amongst oncologists and surgeons across institutions regarding the surgical treatment for HB with synchronous metastatic lung disease. This narrative review aimed to update the current management of pulmonary metastasis in children with HB and to define its role in the decision-making strategy for the surgical approach to primary liver tumours.