Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer.

BACKGROUND: In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival. METHODS: We randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability). RESULTS: A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI], 0.49 to 0.77; P<0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.54; P<0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio, 0.54; 95% CI, 0.43 to 0.67). CONCLUSIONS: Among patients with refractory metastatic colorectal cancer, treatment with FTD-TPI plus bevacizumab resulted in longer overall survival than FTD-TPI alone. (Funded by Servier and Taiho Oncology; SUNLIGHT ClinicalTrials.gov number, NCT04737187; EudraCT number, 2020-001976-14.).

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C.

BACKGROUND: KRAS G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest efficacy. Combining the KRAS G12C inhibitor sotorasib with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be an effective strategy. METHODS: In this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated KRAS G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator's choice of trifluridine-tipiracil or regorafenib (standard care; 54 patients). The primary end point was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary end points were overall survival and objective response. RESULTS: After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib-panitumumab and 240-mg sotorasib-panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib-panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P = 0.006), and the hazard ratio in the 240-mg sotorasib-panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P = 0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib-panitumumab. CONCLUSIONS: In this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment. Toxic effects were as expected for either agent alone and resulted in few discontinuations of treatment. (Funded by Amgen; CodeBreaK 300 ClinicalTrials.gov number, NCT05198934.).

Prognostic and predictive impact of metastatic organ involvement on maintenance therapy in advanced metastatic colorectal cancer: Subgroup analysis of patients treated within the PanaMa trial (AIO KRK 0212).

Despite molecular selection, patients (pts) with RAS wildtype mCRC represent a heterogeneous population including diversity in metastatic spread. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with 5-fluorouracil/folinic acid ± panitumumab. The study population was stratified according to (1) number of involved metastatic sites (single vs multiple organ metastasis), liver-limited disease vs (2) liver metastasis plus one additional site, and (3) vs liver metastasis plus ≥two additional sites. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints. Single organ metastasis was observed in 133 pts (53.6%) with 102 pts (41.1%) presenting with liver-limited disease, while multiple organ metastases were reported in 114 pts (46.0). Multiple compared to single organ metastases were associated with less favorable PFS (HR 1.48, 95% CI 1.13-1.93; P = .004) and OS (HR 1.37, 95% CI 0.98-1.93; P = .068) of maintenance therapy. While metastatic spread involving one additional extrahepatic site was not associated with clearly impaired survival compared to liver-limited disease, pts with liver metastasis plus ≥two additional sites demonstrated less favorable PFS (HR 1.92, 95% CI 1.30-2.83; P < .001), and OS (HR 2.38, 95% CI 1.51-3.76; P < .001) of maintenance therapy. Pmab-containing maintenance therapy appeared active in both pts with multiple (HR 0.58; 95% CI, 0.39-0.86; P = .006) as well as to a lesser numerical extent in pts with single organ metastasis (HR 0.83; 95% CI, 0.57-1.21; P = .332; Interaction P = .183). These data may support clinical decisions when EGFR-based maintenance therapy is considered.

Viscoelastic properties of colorectal liver metastases reflect tumour cell viability.

BACKGROUND: Colorectal cancer is the third most common tumour entity in the world and up to 50% of the patients develop liver metastases (CRLM) within five years. To improve and personalize therapeutic strategies, new diagnostic tools are urgently needed. For instance, biomechanical tumour properties measured by magnetic resonance elastography (MRE) could be implemented as such a diagnostic tool. We postulate that ex vivo MRE combined with histological and radiological evaluation of CRLM could provide biomechanics-based diagnostic markers for cell viability in tumours. METHODS: 34 CRLM specimens from patients who had undergone hepatic resection were studied using ex vivo MRE in a frequency range from 500 Hz to 5300 Hz with increments of 400 Hz. Single frequency evaluation of shear wave speed and wave penetration rate as proxies for stiffness and viscosity was performed, along with rheological model fitting based on the spring-pot model and powerlaw exponent α, ranging between 0 (complete solid behaviour) and 1 (complete fluid behaviour). For histological analysis, samples were stained with H&E and categorized according to the degree of regression. Quantitative histologic analysis was performed to analyse nucleus size, aspect ratio, and density. Radiological response was assessed according to RECIST-criteria. RESULTS: Five samples showed major response to chemotherapy, six samples partial response and 23 samples no response. For higher frequencies (> 2100 Hz), shear wave speed correlated significantly with the degree of regression (p ≤ 0.05) indicating stiffer properties with less viable tumour cells. Correspondingly, rheological analysis of α revealed more elastic-solid tissue properties at low cell viability and major response (α = 0.43 IQR 0.36, 0.47) than at higher cell viability and no response (α = 0.51 IQR 0.48, 0.55; p = 0.03). Quantitative histological analysis showed a decreased nuclear area and density as well as a higher nuclear aspect ratio in patients with major response to treatment compared to patients with no response (all p < 0.05). DISCUSSION: Our results suggest that MRE could be useful in the characterization of biomechanical property changes associated with cell viability in CRLM. In the future, MRE could be applied in clinical diagnosis to support individually tailored therapy plans for patients with CRLM.

Plain language summary of SUNLIGHT: trifluridine/tipiracil and bevacizumab for refractory metastatic colorectal cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary describing the results from a phase 3 clinical trial called SUNLIGHT. The study looked at treatment with orally administered trifluridine/tipiracil plus intravenously administered bevacizumab in people with metastatic colorectal cancer (mCRC) that is refractory to treatment.This study included people whose cancer had grown or spread beyond its original location after no more than two previous treatments. People in the study received either the combination of trifluridine/tipiracil plus bevacizumab or they received trifluridine/tipiracil alone. The aims of the study were to see how long people lived after treatment with trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil alone and to find out how well the combination of trifluridine/tipiracil plus bevacizumab worked at slowing down the spread of the cancer. Researchers also looked at side effects from taking the medicines and at how treatment affected people's physical functioning. WHAT ARE THE KEY TAKEAWAYS?: People in the combination group lived longer (a median of 10.8 months) than people who received trifluridine/tipiracil alone (7.5 months). In addition, the time it took for the cancer to worsen was longer for those who received the combination treatment (a median of 5.6 months) compared with those who received trifluridine/tipiracil alone (2.4 months). People's physical functioning took longer to worsen with combination therapy (a median of 9.3 months) than it did with trifluridine/tipiracil alone (6.3 months), as measured by the impact of treatment on people's ability to carry out daily living activities. The most common side effects in both treatment groups were low levels of white blood cells, known as neutrophils (neutropenia), nausea, and low levels of healthy red blood cells (anemia). WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: The results from the study suggest that treatment with oral trifluridine/tipiracil plus intravenous (IV) bevacizumab could help people with refractory mCRC live longer and maintain good physical functioning, and it could slow the worsening of their cancer.Clinical Trial Registration: NCT04737187 (SUNLIGHT) (ClinicalTrials.gov).

ADJUBIL: phase II study of adjuvant immunotherapy with STRIDE regimen with/without capecitabine in biliary tract cancers.

Biliary tract cancer is a highly heterogeneous group of gastrointestinal cancers, and the only curative treatment is surgery, which is only applicable at early stages of the malignancy. ADJUBIL, a phase II trial (NCT05239169), aims to evaluate immunotherapy with durvalumab and tremelimumab with or without capecitabine in adjuvant situations for biliary tract cancers. A total of 40 prospective patients will be randomly assigned following surgery, consisting of a two-arm feasibility pilot part with a pick-the-winner design with durvalumab and tremelimumab in combination with or without capecitabine.

This article describes the design of a phase II clinical trial called ADJUBIL, which evaluates the use of immunotherapy (durvalumab and tremelimumab) with or without classic chemotherapy (capecitabine) in biliary tract cancer patients who have undergone curative surgery. This type of treatment is also called adjuvant therapy, meaning it is used after the primary treatment. Biliary tract cancer is a rare type of liver cancer, often diagnosed late. Following surgery, patients may experience an early return of the disease, called tumor relapse. To avoid or delay tumor relapse, patients need extra treatment. Pure chemotherapy (capecitabine) is the standard after curative surgery. For patients with no option for cure, chemotherapy together with new powerful immunotherapy has become standard. This study will recruit 40 adult patients with tumor removal, who will be randomly divided into two groups. Half of them will be treated with immunotherapy only (durvalumab and tremelimumab). The other half will be treated with capecitabine together with immunotherapy. This study will continue for 12 months, but the treatment can be stopped if, for example, the tumor reoccurs or any possible side effect of the therapy is detected. The most effective treatment type will be selected. This type of selection is called pick-the winner.

Prevalence of KRAS G12C Mutation and Co-mutations and Associated Clinical Outcomes in Patients With Colorectal Cancer: A Systematic Literature Review.

PURPOSE: A systematic literature review was conducted to estimate the global prevalence of Kirsten rat sarcoma virus gene (KRAS) mutations, with an emphasis on the clinically significant KRAS G12C mutation, and to estimate the prognostic significance of these mutations in patients with colorectal cancer (CRC). DESIGN: Relevant English-language publications in the Embase, MEDLINE, and the Cochrane Library databases (from 2009 to 2021) and congress presentations (from 2016 to 2021) were reviewed. Eligible studies were those that reported the prevalence and clinical outcomes of the KRAS G12C mutation in patients with CRC. RESULTS: A total of 137 studies (interventional [n = 8], post hoc analyses of randomized clinical trials [n = 6], observational [n = 122], and longitudinal [n =1]) were reviewed. Sixty-eight studies reported the prevalence of KRAS mutations (KRASm) in 42 810 patients with CRC. The median global prevalence of KRASm was 38% (range, 13.3%-58.9%) and that of the KRAS G12C mutation (KRAS G12C) 3.1% (range, 0.7%-14%). Available evidence suggests that KRASm are possibly more common in tumors that develop on the right side of the colon. Limited evidence suggests a lower objective response rate and inferior disease-free/relapse-free survival in patients with KRAS G12C compared with patients with KRASwt or other KRASm. CONCLUSION: Our analysis reveals that KRAS G12C is prevalent in 3% of patients with CRC. Available evidence suggests a poor prognosis for patients with KRAS G12C. Right-sided tumors were more likely to harbor KRASm; however, their role in determining clinical outcomes needs to be investigated further.

Study protocol of an open-label, single arm phase II trial investigating the efficacy and safety of Trifluridine/Tipiracil combined with irinotecan as a second line therapy in patients with cholangiocarcinoma (TRITICC).

BACKGROUND: The prognosis of patients with advanced biliary tract cancer (BTC) who have progressed on gemcitabine plus cisplatin is dismal. Trifluridine/tipiracil (FTD/TPI) and irinotecan have proven efficacy in different gastrointestinal malignancies. We therefore hypothesized that this combination might improve the therapeutic outcome in patients with BTC after failure of first line treatment. METHODS: TRITICC is an interventional, prospective, open-label, non-randomised, exploratory, multicentre, single-arm phase IIA clinical trial done in 6 sites with expertise in managing biliary tract cancer across Germany. A total of 28 adult patients (aged ≥ 18 years) with histologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line gemcitabine based chemotherapy will be included to receive a combination of FTD/TPI plus irinotecan according to previously published protocols. Study treatment will be continued until disease progression according to RECIST 1.1 criteria or occurrence of unacceptable toxicity. The effect of FTD/TPI plus irinotecan on progression-free survival will be analyzed as primary endpoint. Safety (according to NCI-CTCAE), response rates and overall survival are secondary endpoints. In addition, a comprehensive translational research program is part of the study and might provide findings about predictive markers with regard to response, survival periods and resistance to treatment. DISCUSSION: The aim of TRITICC is to evaluate the safety and efficacy of FTD/TPI plus irinotecan in patients with biliary tract cancer refractory to previous Gemcitabine based treatment. TRIAL REGISTRATION: EudraCT 2018-002936-26; NCT04059562.

Standard diametric versus volumetric early tumor shrinkage as a predictor of survival in metastatic colorectal cancer: subgroup findings of the randomized, open-label phase III trial FIRE-3 / AIO KRK-0306.

OBJECTIVES: Early tumor shrinkage (ETS) quantifies the objective response at the first assessment during systemic treatment. In metastatic colorectal cancer (mCRC), ETS gains relevance as an early available surrogate for patient survival. The aim of this study was to increase the predictive accuracy of ETS by using semi-automated volumetry instead of standard diametric measurements. METHODS: Diametric and volumetric ETS were retrospectively calculated in 253 mCRC patients who received 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) combined with either cetuximab or bevacizumab. The association of diametric and volumetric ETS with overall survival (OS) and progression-free survival (PFS) was compared. RESULTS: Continuous diametric and volumetric ETS predicted survival similarly regarding concordance indices (p > .05). In receiver operating characteristics, a volumetric threshold of 45% optimally identified short-term survivors. For patients with volumetric ETS ≥ 45% (vs < 45%), median OS was longer (32.5 vs 19.0 months, p < .001) and the risk of death reduced for the first and second year (hazard ratio [HR] = 0.25, p < .001, and HR = 0.39, p < .001). Patients with ETS ≥ 45% had a reduced risk of progressive disease only for the first 6 months (HR = 0.26, p < .001). These survival times and risks were comparable to those of diametric ETS ≥ 20% (vs < 20%). CONCLUSIONS: The accuracy of ETS in predicting survival was not increased by volumetric instead of diametric measurements. Continuous diametric and volumetric ETS similarly predicted survival, regardless of whether patients received cetuximab or bevacizumab. A volumetric ETS threshold of 45% and a diametric ETS threshold of 20% equally identified short-term survivors. KEY POINTS: • ETS based on volumetric measurements did not predict survival more accurately than ETS based on standard diametric measurements. • Continuous diametric and volumetric ETS predicted survival similarly in patients receiving FOLFIRI with cetuximab or bevacizumab. • A volumetric ETS threshold of 45% and a diametric ETS threshold of 20% equally identified short-term survivors.

Early weight loss is an independent risk factor for shorter survival and increased side effects in patients with metastatic colorectal cancer undergoing first-line treatment within the randomized Phase III trial FIRE-3 (AIO KRK-0306).

Body weight loss is frequently regarded as negatively related to outcomes in patients with malignancies. This retrospective analysis of the FIRE-3 study evaluated the evolution of body weight in patients with metastatic colorectal cancer (mCRC). FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab or bevacizumab in mCRC patients with RAS-WT tumors (ie, wild-type in KRAS and NRAS exons 2-4). The prognostic and predictive relevance of early weight loss (EWL) regarding patient outcomes and treatment side effects were evaluated. Retrospective data on body weight during first 6 months of treatment were evaluated (N = 326). To correlate with efficacy endpoints and treatment side effects, patients were grouped according to clinically significant EWL ≥5% and <5% at Month 3. Age constituted the only significant predictor of EWL following a linear relationship with the corresponding log odds ratio (P = .016). EWL was significantly associated with the incident frequencies of diarrhea, edema, fatigue, nausea and vomiting. Further, a multivariate analysis revealed EWL to be an independent negative prognostic factor for overall survival (32.4 vs 21.1 months; hazard ratio [HR]: 1.64; 95% confidence interval [CI] = 1.13-2.38; P = .0098) and progression-free survival (11.8 vs 9.0 months; HR: 1.72; 95% CI = 1.18-2.5; P = .0048). In conclusion, EWL during systemic treatment against mCRC is significantly associated with patient age. Patients exhibiting EWL had worse survival and higher frequencies of adverse events. Early preventative measures targeted at weight maintenance should be evaluated, especially in elderly patients being at highest risk of EWL.

Efficacy of FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in 1st-line treatment of older patients with RAS wild-type metastatic colorectal cancer: an analysis of the randomised trial FIRE-3.

BACKGROUND: The evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients' age and sidedness of primary tumour. METHODS: The study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan-Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS. RESULTS: Overall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31). CONCLUSIONS: In FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC. CLINICAL TRIAL: FIRE-3 (NCT00433927).

Sodium Thiosulfate Reduces Acute Kidney Injury in Patients Undergoing Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy with Cisplatin: A Single-Center Observational Study.

BACKGROUND: Cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) represents a multimodal treatment concept for patients with peritoneal surface malignancies. The use of intraperitoneal cisplatin (CDDP) is associated with a risk of acute kidney injury (AKI). The aim of this study is to evaluate the protective effect of perioperative sodium thiosulfate (STS) administration on kidney function in patients undergoing CRS and CDDP-based HIPEC. PATIENTS AND METHODS: We retrospectively analyzed clinical data of all patients who underwent CRS and CDDP-based HIPEC at our hospital between March 2017 and August 2020. Patients were stratified according to the use of sodium thiosulfate (STS vs. no STS). We compared kidney function and clinical outcome parameters between both groups and determined risk factors for postoperative AKI on univariate and multivariate analysis. AKI was classified according to acute kidney injury network (AKIN) criteria. RESULTS: Of 238 patients who underwent CRS and CDDP-based HIPEC, 46 patients received STS and 192 patients did not. There were no significant differences in baseline characteristics. In patients who received STS, a lower incidence (6.5% vs. 30.7%; p = 0.001) and severity of AKI (p = 0.009) were observed. On multivariate analysis, the use of STS (OR 0.089, p = 0.001) remained an independent kidney-protective factor, while arterial hypertension (OR 5.283, p < 0.001) and elevated preoperative urea serum level (OR 5.278, p = 0.032) were predictors for postoperative AKI. CONCLUSIONS: The present data suggest that STS protects patients from AKI caused by CRS and CDDP-based HIPEC. Further prospective studies are needed to validate the benefit of STS among kidney-protective strategies.

FIRE-9 - PORT / AIO-KRK-0418: a prospective, randomized, open, multicenter Phase III trial to investigate the efficacy of adjuvant/additive chemotherapy in patients with definitely-treated metastatic colorectal cancer.

BACKGROUND: Additive/adjuvant chemotherapy as concept after local treatment of colorectal metastases has not been proven to be successful by phase III trials. Accordingly, a standard of care to improve relapse rates and long-term survival is not established and adjuvant chemotherapy cannot be recommended as a standard therapy due to limited evidence in literature. The PORT trial aims to generate evidence that post-resection/ablation/radiation chemotherapy improves the survival in patients with metastatic colorectal cancer. METHODS: Patients to be included into this trial must have synchronous or metachronous metastases of colorectal cancer-either resected (R0 or R1) and/or effectively treated by ablation or radiation within 3-10 weeks before randomization-and have the primary tumor resected, without radiographic evidence of active metastatic disease at study entry. The primary endpoint of the trial is progression-free survival after 24 months, secondary endpoints include overall survival, safety, quality of life, treatments (including efficacy) beyond study participation, translational endpoints, and others. One arm of the study comprising 2/3 of the population will be treated for 6 months with modified FOLFOXIRI or modified FOLFOX6 (investigator´s choice, depending on the performance status of the patients but determined before randomization), while the other arm (1/3 of the population) will be observed and undergo scheduled follow-up computed tomography scans according to the interventional arm. DISCUSSION: Optimal oncological management after removal of colorectal metastases is unclear. The PORT trial aims to generate evidence that additive/adjuvant chemotherapy after definitive treatment of colorectal metastases improves progression free and overall survival in patients with colorectal cancer. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov ( NCT05008809 ) and EudraCT (2020-006,144-18).

A Reduction of Calcineurin Inhibitors May Improve Survival in Patients with De Novo Colorectal Cancer after Liver Transplantation.

Background and Objectives: After liver transplantation (LT), long-term immunosuppression (IS) is essential. IS is associated with de novo malignancies, and the incidence of colorectal cancer (CRC) is increased in LT patients. We assessed course of disease in patients with de novo CRC after LT with focus of IS and impact on survival in a retrospective, single-center study. Materials and Methods: All patients diagnosed with CRC after LT between 1988 and 2019 were included. The management of IS regimen following diagnosis and the oncological treatment approach were analyzed: Kaplan−Meier analysis as well as univariate and multivariate analysis were performed. Results: A total of 33 out of 2744 patients were diagnosed with CRC after LT. Two groups were identified: patients with restrictive IS management undergoing dose reduction (RIM group, n = 20) and those with unaltered regimen (maintenance group, n = 13). The groups did not differ in clinical and oncological characteristics. Statistically significant improved survival was found in Kaplan−Meier analysis for patients in the RIM group with 83.46 (8.4−193.1) months in RIM and 24.8 (0.5−298.9) months in the maintenance group (log rank = 0.02) and showed a trend in multivariate cox regression (p = 0.054, HR = 14.3, CI = 0.96−213.67). Conclusions: Immunosuppressive therapy should be reduced further in patients suffering from CRC after LT in an individualized manner to enable optimal oncological therapy and enable improved survival.

Mutational profiles of metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab before and after secondary resection (AIO KRK 0306; FIRE-3).

Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after conversion treatment are limited. Next generation sequencing was performed in formalin-fixed mCRC samples from patients of the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post-hoc analysis. Median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild-type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 [95% CI 0.14-1.12], P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab-based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti-VEGF or anti-EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti-EGFR antibodies were observed in only one-third of patients.

FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial.

BACKGROUND: Cetuximab plus FOLFIRI improved overall survival compared with bevacizumab plus FOLFIRI in KRAS wild-type metastatic colorectal cancer (mCRC) in FIRE-3, but no corresponding benefit was found for progression-free survival. This analysis aimed to determine whether cetuximab improves response and survival versus bevacizumab among response-evaluable patients receiving first-line FOLFIRI for RAS wild-type mCRC and the effect of primary tumour side on outcomes. METHODS: The intent-to-treat population included 593 patients with KRAS exon 2 wild-type mCRC. Further testing identified 400 patients with extended RAS wild-type disease; of these, 352 (88%) who received ≥3 cycles of therapy and had ≥1 post-baseline scan were evaluable for response and constituted the per-protocol population (169 cetuximab and 183 bevacizumab). Patients received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) with either weekly cetuximab or biweekly bevacizumab given on day 1 of each 14-day cycle until response, progression or toxicity occurred. The primary endpoint was the objective response rate (ORR) in the per-protocol population. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). The effect of primary tumour location was evaluated. RESULTS: Median OS in the RAS wild-type population was 31 vs 26 months in the cetuximab and bevacizumab groups, respectively (HR 0.76, P = 0.012). In the per-protocol population, outcomes favoured cetuximab for ORR (77% vs 65%, P = 0.014) and median OS (33 vs 26 months, HR 0.75, P = 0.011), while PFS was comparable between groups. The advantage of cetuximab over bevacizumab occurred only in patients with left-sided primary tumours. CONCLUSIONS: FOLFIRI plus cetuximab resulted in a significantly higher ORR and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumours. The superior response associated with cetuximab may particularly benefit patients with symptomatic tumours or borderline-resectable metastases. CLINICALTRIALS. GOV IDENTIFIER: NCT00433927.

Factors That Influence Conversion to Resectability and Survival After Resection of Metastases in RAS WT Metastatic Colorectal Cancer (mCRC): Analysis of FIRE-3- AIOKRK0306.

BACKGROUND: Tumor assessments after first-line therapy of RAS wild-type mCRC with cetuximab (cet) versus bevacizumab (bev) in combination with FOLFIRI were evaluated for factors influencing resectability, conversion to resectability, and survival after best response. METHODS: Conversion to resectability was defined as conversion of initially unresectable to resectable disease at best response as determined by retrospective assessment. Univariate and multivariate logistic models were fitted with resectability at best response as response variable. A Cox model comparing the survival from best response was used to measure the influence of treatment, resectability at best response, and resection. Interaction of resection and treatment arm on survival was tested by likelihood ratio test. RESULTS: Overall, 270 patients were evaluable (127 cet-arm, 143 bev-arm). Lung metastases (odds ratio [OR] 0.35, 95% confidence response [CI] 0.19-0.63), BRAF mutation (OR 0.33, 95% CI 0.12-0.82), and elevated alkaline phosphatase (OR 0.42, 95% CI 0.18-0.9) before randomization were associated with less chance of successful conversion and were integrated into a nomogram. Early tumor shrinkage (OR 1.86, 95% CI 1.06-3.3; p 0.034) and depth of response (OR 1.02, 95% CI 1.01-1.03; p < 0.001) were associated with successful conversion therapy. Resection of metastases improved post-best-response survival (hazard ratio 0.53, 95% CI 0.29-0.97; p = 0.039), predominantely in cet-treated patients (interaction test, p = 0.02). CONCLUSIONS: Conversion to resectability is significantly associated with baseline characteristics that can be used in a nomogram to predict conversion. Moreover, early efficacy parameters (ETS and DpR) are associated with successful conversion therapy. In FIRE-3, resection of metastases was associated with improved post-best response survival, this effect originated predominantly from the cetuximab-based study arm.

Predictive and prognostic value of magnesium serum level in FOLFIRI plus cetuximab or bevacizumab treated patients with stage IV colorectal cancer: results from the FIRE-3 (AIO KRK-0306) study.

Magnesium wasting is a frequent side effect of epidermal growth factor receptor (EGFR)-antibody treatment as magnesium-absorption mechanisms are dependent on EGFR signaling. EGFR-inhibition results in decreased renal reabsorption. There is evidence that hypomagnesemia during cetuximab treatment correlates with response. The prognostic role of hypomagnesemia during bevacizumab treatment has not been studied yet. Here, we evaluate the prognostic value of hypomagnesemia in patients with metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab as first-line therapy. A total of 391 of 752 patients of the firstline irinotecan study population had magnesium levels measured at baseline and for the first three cycles (6 weeks) of treatment. Of those, 240 had Rat Sarkoma wildtype tumors. Overall hypomagnesemia was more common in the cetuximab compared to the bevacizumab arm (80 vs. 43%, P < 0.005). During therapy, magnesium showed a time-dependent decrease to 80% of baseline in the cetuximab and to 89% in the bevacizumab arm. Whereas magnesium continued to decrease over time in the cetuximab-treated patients, it remained stable in the bevacizumab-treated. Overall response rate (ORR) was associated with higher magnesium at week 6 (20.9 vs. 79.1%, P = 0.041). Bevacizumab-treated patients with magnesium levels below the median value at week 6 had a significantly longer progression-free survival (PFS; 11.7 vs. 9.9 months, P = 0.034; hazard ratio 0.73) and a trend towards longer overall survival (OS) (29.6 vs. 23.2 months, P = 0.089; hazard ratio 0.77). Hypomagnesemia at predefined time points and magnesium nadir had no significant effect on ORR, OS and PFS in the cetuximab arm. Our data show different magnesium kinetics in patients with metastatic colorectal cancer treated with cetuximab or bevacizumab. For patients treated with cetuximab, hypomagnesemia did not have an impact on response and survival. Hypomagnesemia might have a prognostic value in bevacizumab treatment.

[Prerequisites of magnetic resonance imaging for treatment planning in locally advanced rectal cancer - Interdisciplinary recommendations]. / Stellenwert und qualitative Voraussetzungen der Magnetresonanztomografie für die Therapieplanung beim lokal fortgeschrittenen Rektumkarzinom ­ Interdisziplinäre Empfehlungen.

For the purpose of indication and patient stratification of perioperative treatment of locally advanced rectal cancer, magnetic resonance imaging (MRI) has become indispensable. In this report, we describe the importance of MRI diagnostics and the qualitative conditions.

Panitumumab-based maintenance after oxaliplatin discontinuation in metastatic colorectal cancer: A retrospective analysis of two randomised trials.

Panitumumab is approved for RAS wild-type metastatic colorectal cancer and was evaluated in Phase III (PRIME, NCT00364013) and Phase II (PEAK, NCT00819780) first-line randomised studies. This retrospective analysis of these trials investigated efficacy and toxicity of panitumumab-based maintenance after oxaliplatin discontinuation in RAS wild-type patients. First-line regimens were FOLFOX4 ± panitumumab in PRIME and mFOLFOX6 plus panitumumab or mFOLFOX6 plus bevacizumab in PEAK. Outcomes included median progression-free survival (PFS) and overall survival (OS), from randomisation and oxaliplatin discontinuation, and toxicity. Overall, median duration of panitumumab plus 5-fluorouracil/leucovorin (5-FU/LV) maintenance was 21 (interquartile range: 11-41) weeks; that of 5-FU/LV ± bevacizumab maintenance was 16 (6-31) weeks. Median OS from randomisation was 40.2 (95% confidence interval: 30.3-50.4) and 39.1 (34.2-63.0) months for panitumumab plus 5-FU/LV maintenance and 24.1 (17.7-33.0) and 28.9 (21.0-32.0) months for 5-FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. Median PFS from randomisation was 16.6 (11.3-23.6) and 15.4 (11.6-18.4) months for panitumumab plus 5-FU/LV maintenance and 12.6 (9.4-16.2) and 13.1 (9.5-16.6) months for 5-FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. From oxaliplatin discontinuation, median OS was 33.9 (24.7-42.8) and 33.5 (24.5-54.9) months for panitumumab plus 5-FU/LV maintenance and 16.4 (12.4-24.1) and 23.3 (15.7-26.3) months for 5-FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively; PFS was 11.7 (7.8-19.2) and 9.7 (5.8-14.8) months and 7.1 (5.6-10.2) and 7.0 (3.9-10.6) months, respectively. The most frequently reported adverse events were rash, fatigue and diarrhoea. Maintenance of panitumumab plus 5-FU/LV after oxaliplatin discontinuation was well tolerated and may be an acceptable treatment paradigm for patients demonstrating a good response to first-line treatment. Prospective studies are warranted.