Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases:Multidisciplinary Consensus Document from the COLLISION Trial Group

The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.</p

Predicting outcome in older patients with cancer: Comprehensive geriatric assessment and clinical judgment

Objectives: Comprehensive Geriatric Assessment (CGA) has been incorporated into geriatric oncology to prevent unfavorable outcome from anticancer treatment. This study determined the value of CGA and medical oncologist's clinical judgment in predicting unfavorable outcome and explored whether treatment decisions can be based on CGA. Patients and Methods: In this prospective cohort study, a multidomain CGA was performed by a geriatric nurse and geriatrician in 110 consecutive patients aged ≥70 years, newly referred to a multidisciplinary oncology clinic. CGA domains included comorbidity, polypharmacy, mood, cognition, nutrition, functionality and physical performance. Medical oncologist's clinical judgment on expected tolerance of standard treatment was noted (N = 62). Unfavorable outcome was defined as any ≥grade three chemotherapy toxicity, dose reduction, postponement of treatment, death before start of treatment and early progression before first evaluation of treatment (N = 80). Results: CGA identified multidomain problems in 77 out of 110 patients (70.0%) and the medical oncologist had doubts about standard treatment tolerance in 30 out of 62 patients (48.4%). Unfavorable outcome occurred in 48 out of 80 patients (60%) who received anticancer treatment but could not be predicted by CGA, medical oncologists' clinical judgment or their combination. There was discrepancy between CGA and clinical judgment in 24 out of 62 patients (38.7%). Conclusion: Neither CGA, medical oncologist's clinical judgment or a combination could predict unfavorable outcome in our heterogeneous sample. CGA and clinical judgment did not align in more than one-third of patients

Loss of Muscle Mass During Chemotherapy Is Predictive for Poor Survival of Patients With Metastatic Colorectal Cancer

Low muscle mass is present in approximately 40% of patients with metastatic colorectal cancer (mCRC) and may be associated with poor outcome. We studied change in skeletal muscle during palliative chemotherapy in patients with mCRC and its association with treatment modifications and overall survival. In 67 patients with mCRC (mean age ± standard deviation, 66.4 ± 10.6 years; 63% male), muscle area (square centimeters) was assessed using computed tomography scans of the third lumbar vertebra before and during palliative chemotherapy. Treatment modifications resulting from toxicity were evaluated, including delay, dose reduction, or termination of chemotherapy. Multiple regression analyses were performed for the association between change in muscle area and treatment modification and secondly overall survival. Muscle area of patients with mCRC decreased significantly during 3 months of chemotherapy by 6.1% (95% CI, -8.4 to -3.8; P <.001). Change in muscle area was not associated with treatment modifications. However, patients with muscle loss during treatment of 9% or more (lowest tertile) had significantly lower survival rates than patients with muscle loss of less than 9% (at 6 months, 33% v 69% of patients alive; at 1 year, 17% v 49% of patients alive; log-rank P = .001). Muscle loss of 9% or more remained independently associated with survival when adjusted for sex, age, baseline lactate dehydrogenase concentration, comorbidity, mono-organ or multiorgan metastases, treatment line, and tumor progression at first evaluation by computed tomography scan (hazard ratio, 4.47; 95% CI, 2.21 to 9.05; P <.001). Muscle area decreased significantly during chemotherapy and was independently associated with survival in patients with mCRC. Further clinical evaluation is required to determine whether nutritional interventions and exercise training may preserve muscle area and thereby improve outcom

Neoadjuvant chemotherapy in older patients with gastric cancer undergoing surgery: a population-based cohort study

Background: In trials evaluating perioperative chemotherapy for gastric cancer, which serve as the basis for treatment guidelines, patients are selected. The generalizability of these trial findings to older patients is uncertain. Methods: This population-based retrospective cohort study compared the survival outcomes of patients ≥ 75 years with gastric adenocarcinoma treated with or without neoadjuvant chemotherapy between 2015 and 2019. Additionally, the percentage of patients < 75 years and ≥ 75 years who did not proceeded to surgery after receiving neoadjuvant chemotherapy were examined. Results: A total of 1995 patients, of whom 1249 aged < 75 years and 746 aged ≥ 75 years, were included. In the group of patients ≥ 75 years, 275 patients received neoadjuvant chemotherapy and 471 patients were directly scheduled for gastrectomy. Patients ≥ 75 years treated with or without neoadjuvant chemotherapy differed significantly from one and another in characteristics. Overall survival of patients ≥ 75 years treated with or without neoadjuvant chemotherapy was not significantly different (median 34.9 vs. 32.3 months; P = 0.506), also after adjusting for potential confounders (HR 0.87; P = 0.263). Of patients ≥ 75 years who received neoadjuvant chemotherapy, 43 (15.6%) did not proceed to surgery compared to 111 (8.9%) patients < 75 years (P < 0.001). Conclusion: Patients ≥ 75 years treated with or without chemotherapy were highly selected, and overall survival was not significantly different between both groups. Nonetheless, the proportion of patients who did not proceed to surgery following neoadjuvant chemotherapy was higher in patients ≥ 75 years compared to patients < 75 years. Therefore, neoadjuvant chemotherapy should be considered with more caution in patients ≥ 75 years, while identifying those who may benefit

The role of neoadjuvant chemotherapy in repeat local treatment of recurrent colorectal liver metastases: A systematic review and meta‐analysis

The additive value of neoadjuvant chemotherapy (NAC) prior to repeat local treatment of patients with recurrent colorectal liver metastases (CRLM) is unclear. A systematic search was performed in PubMed, Embase, Web of Science, and an additional search in Google Scholar to find articles comparing repeat local treatment by partial hepatectomy and/or thermal ablation with versus without NAC. The search included randomized trials and comparative observational studies with univariate/multivariate analysis and/or matching as well as (inter)national guidelines assessed using the AGREE II instrument. The search identified 21,832 records; 172 were selected for full‐text review; 20 were included: 20 comparative observational studies were evaluated. Literature to evaluate the additive value of NAC prior to repeat local treatment was limited. Outcomes of NAC were often reported as subgroup analyses and reporting of results was frequently unclear. Assessment of the seven studies that qualified for inclusion in the meta‐analysis showed conflicting results. Only one study reported a significant difference in overall survival (OS) favoring NAC prior to repeat local treatment. However, further analysis revealed a high risk for residual bias, because only a selected group of chemo‐responders qualified for repeat local treatment, disregarding the non‐responders who did not qualify. All guidelines that specifically mention recurrent disease (3/3) recommend repeat local treatment; none provide recommendations about the role of NAC. The inconclusive findings of this meta‐analysis do not support recommendations to routinely favor NAC prior to repeat local treatment. This emphasizes the need to investigate the additive value of NAC prior to repeat local treatment of patients with recurrent CRLM in a future phase 3 randomized controlled trial (RCT)

Health-Related Quality of Life in Patients With Metastatic Colorectal Cancer Undergoing Systemic Therapy With or Without Maximal Tumor Debulking

Background: Maintaining a sufficient health-related quality of life (HRQoL) is important in the palliative treatment of patients with metastatic colorectal cancer (mCRC). The ORCHESTRA trial (Clinical-Trials.gov identifier: NCT01792934) is designed to prospectively evaluate overall survival benefit and impact on HRQoL of tumor debulking when added to first-line palliative systemic therapy in patients with multiorgan mCRC. In the present study, we report the HRQoL associated with this combination treatment compared with standard systemic therapy. Methods: Patients included in the ORCHESTRA trial with clinical benefit after 3 or 4 cycles of first-line palliative systemic therapy with fluoropyrimidines and oxaliplatin with or without bevacizumab were randomly assigned to maximal tumor debulking followed by systemic therapy versus systemic therapy alone. Patients completed the EORTC Quality of Life Questionnaire-Core 30 and the Multidimensional Fatigue Inventory questionnaire at prespecified time points during treatment. Between-group differences in HRQoL over time were evaluated with linear mixed model analyses. A pattern mixture approach was applied to correct for missing questionnaires due to progressive disease. Results: A total of 300 patients were randomized to the intervention arm (n5148) or the standard arm (n5152). No statistically significant or clinically relevant differences in HRQoL and fatigue were observed when tumor debulking was added to systemic therapy. In patients of both study arms, HRQoL after 1 year of treatment was not significantly different from HRQoL at the time of randomization. Patients in the intervention arm experienced serious adverse events (SAEs) twice as often as patients in the standard arm (P#.001). Conclusions: Maximal tumor debulking in combination with palliative systemic therapy in patients with multiorgan mCRC was significantly associated with more SAEs resulting from local therapy but no difference in HRQoL compared with palliative systemic therapy alone. There is a remarkable lack of association between the occurrence of SAEs and impact on HRQoL.</p

Repeat local treatment of recurrent colorectal liver metastases, the role of neoadjuvant chemotherapy: An amsterdam colorectal liver met registry (amcore) based study

This cohort study aimed to evaluate efficacy, safety, and survival outcomes of neoadjuvant chemotherapy (NAC) followed by repeat local treatment compared to upfront repeat local treatment of recurrent colorectal liver metastases (CRLM). A total of 152 patients with 267 tumors from the prospective Amsterdam Colorectal Liver Met Registry (AmCORE) met the inclusion criteria. Two cohorts of patients with recurrent CRLM were compared: patients who received chemotherapy prior to repeat local treatment (32 patients) versus upfront repeat local treatment (120 patients). Data from May 2002 to December 2020 were collected. Results on the primary endpoint overall survival (OS) and secondary endpoints local tumor progression‐free survival (LTPFS) and distant progression‐free survival (DPFS) were reviewed using the Kaplan– Meier method. Subsequently, uni‐ and multivariable Cox proportional hazard regression models, accounting for potential confounders, were estimated. Additionally, subgroup analyses, according to patient, initial and repeat local treatment characteristics, were conducted. Procedure‐related complications and length of hospital stay were compared using chi‐square test and Fisher’s exact test. The 1‐, 3‐, and 5‐year OS from date of diagnosis of recurrent disease was 98.6%, 72.5%, and 47.7% for both cohorts combined. The crude survival analysis did not reveal a significant difference in OS between the two cohorts (p = 0.834), with 1‐, 3‐, and 5‐year OS of 100.0%, 73.2%, and 57.5% for the NAC group and 98.2%, 72.3%, and 45.3% for the upfront repeat local treatment group, respectively. After adjusting for two confounders, comorbidities (p = 0.010) and primary tumor location (p = 0.023), the corrected HR in multivariable analysis was 0.839 (95% CI, 0.416–1.691; p = 0.624). No differences between the two cohorts were found with regards to LTPFS (HR = 0.662; 95% CI, 0.249–1.756; p = 0.407) and DPFS (HR = 0.798; 95% CI, 0.483–1.318; p = 0.378). No heterogeneous treatment effects were detected in subgroup analyses according to patient, disease, and treatment characteristics. No significant difference was found in periprocedural complications (p = 0.843) and median length of hospital stay (p = 0.600) between the two cohorts. Chemotherapy‐related toxicity was reported in 46.7% of patients. Adding NAC prior to repeat local treatment did not improve OS, LTPFS, or DPFS, nor did it affect periprocedural morbidity or length of hospital stay. The results of this comparative assessment do not substantiate the routine use of NAC prior to repeat local treatment of CRLM. Because the exact role of NAC (in different subgroups) remains inconclusive, we are currently designing a phase III randomized controlled trial (RCT), COLLISION RELAPSE trial, directly comparing upfront repeat local treatment (control) to neoadjuvant systemic therapy followed by repeat local treatment (intervention)

Primary tumor sidedness, ras and braf mutations and msi status as prognostic factors in patients with colorectal liver metastases treated with surgery and thermal ablation: Results from the amsterdam colorectal liver met registry (amcore)

The aim of this study was to assess primary tumor sidedness of colorectal cancer (CRC), rat sarcoma viral oncogene homolog (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations and microsatellite instability (MSI) status as prognostic factors predicting complications, survival outcomes, and local tumor progression (LTP) following surgery and thermal ablation in patients with colorectal liver metastases (CRLM). This Amsterdam Colorectal Liver Met Registry (AmCORE) based study included 520 patients, 774 procedures, and 2101 tumors undergoing local treatment (resection and/or thermal ablation) from 2000 to 2021. Outcomes following local treatment were analyzed for primary tumor sidedness of CRC, RAS, and BRAF mutations and MSI status. The Kaplan–Meier method was used to estimate local tumor progression-free survival (LTPFS), local control (LC), distant progression-free survival (DPFS), and overall survival (OS). Uni-and multivariable analyses were performed based on Cox proportional hazards model. The chi-square test was used to analyze complications. Complications (p = 0.485), OS (p = 0.252), LTPFS (p = 0.939), and LC (p = 0.423) was not associated with tumor-sidedness. Compared to right-sided colon cancer (CC) (reference HR 1.000), DPFS was superior for left-sided CC and rectal cancer (p = 0.018) with an HR for left-sided CC of 0.742 (95% CI, 0.596–0.923) and for RC of 0.760 (95% CI, 0.597–0.966). Regarding RAS mutations, no significant difference was found in OS (p = 0.116). DPFS (p = 0.001), LTPFS (p = 0.039), and LC (p = 0.025) were significantly lower in the RAS mutation group. Though no difference in LTPFS was found between RAS wildtype and RAS mutated CRLM following resection (p = 0.532), LTPFS was worse for RAS mutated tumors compared to RAS wildtype following thermal ablation (p = 0.037). OS was significantly lower in the BRAF mutation group (p < 0.001) and in the MSI group (p < 0.001) following local treatment, while both did not affect DPFS, LTPFS, and LC. This AmCORE based study suggests the necessity of wider margins to reduce LTP rates in patients with RAS mutated CRLM, especially for thermal ablation. Upfront knowledge regarding molecular biomarkers may contribute to improved oncological outcomes