Unresectable Colorectal Cancer Research Articles

Safety and Efficacy of Trifluridine-Tipiracil Hydrochloride Oral Combination (TAS-102) in Patients with Unresectable Colorectal Cancer.

To retrospectively examine efficacy and safety of oral combination of trifluridine and tipiracil hydrochloride (TAS-102) as the second-line therapeutic agent for unresectable colorectal cancer. Treatment outcomes of 17 patients who had received TAS-102 at our Institution from January 2015 to January 2017 were analyzed. The indications for second-line TAS-102 treatment were intolerance to other multi-drug combination (four patients) or patient refusal of the standard second-line therapy (13 patients). Among 17 patients who received TAS-102 as second-line therapy, partial response was observed in two (12%) and stable disease in two (12%). Outcomes of TAS-102 given as second-line therapy were: median overall survival of 5 months, response rate of 12% and disease control of 24%. Overall, no adverse events other than neutropenia were noted. Our findings suggest a beneficial role of TAS-102 in second-line therapy for unresectable colorectal carcinoma.

Treatment of Elderly Patients with Colorectal Cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. As society ages, the number of elderly patients with CRC will increase. The percentage of patients with right-sided colon cancer and the incidence of microsatellite instability are higher in elderly than in younger patients with CRC. Moreover, the higher incidence of comorbid diseases in elderly patients indicates the need for less invasive treatment strategies. For example, care should be taken in performing additional surgery after endoscopic submucosal dissection for elderly patients with high-risk T1 CRC. Minimally invasive surgery, such as laparoscopic colectomy, would be preferable for elderly patients with CRC. Chemotherapy for elderly patients requires careful monitoring for adverse events. The aim of this review is to summarize the clinicopathological features of CRC in elderly patients, optical surgical strategies, including endoscopic and laparoscopic resection, and chemotherapeutic strategies, including postoperative adjuvant chemotherapy and systemic chemotherapy for unresectable CRC.

Con: Liver transplantation for expanded criteria malignant diseases.

Organ shortage requires policies and guidelines to aid organ allocation along the principles of urgency or utility. Identifying patients with significant benefit and withholding liver transplantation (LT) from patients too sick for transplantation are ongoing challenges, in particular in patients with malignancies. An arbitrary threshold of >50% 5-year overall survival (OS) is broadly considered a minimum standard for LT. In patients transplanted for intrahepatic cholangiocarcinoma (iCC), this was only achieved in select cases and when the tumor had a diameter of <2 cm. In patients with extrahepatic and hilar cholangiocarcinoma (CCC), strict selection criteria and combined preoperative radiotherapy/chemotherapy according to the Mayo protocol showed that acceptable longterm results can be achieved in a single high-volume center but are difficult to repeat elsewhere. Furthermore, only rigorously selected patients with neuroendocrine tumors (NETs) meeting the NET Milan criteria adopted by United Network for Organ Sharing can also have >50% 5-year OS. A prospective study in patients with unresectable colorectal cancer metastases in the liver has shown promising OS rates, but further prospective trials are warranted. Current evidence shows that none of the proposed expanded malignant criteria justify deviation of scarce donor organs to patients with hilar CCC, iCC > 2 cm, metastatic NET beyond NET Milan criteria, or metastatic colorectal cancer (CRC) outside clinical trials. Liver Transplantation 24 104-111 2018 AASLD.

Case 1 – Successful resection after FOLFIRI plus cetuximab therapy for unresectable colorectal cancer with multiple liver metastases

This case report describes the outcome of a multidisciplinary approach which allowed successful resection in a patient diagnosed with unresectable colorectal cancer. The patient was a 66-year-old man with no important comorbidities. His main complaint was abdominal pain. The patient received a diagnosis of moderate differentiated sigmoid colon adenocarcinoma, RAS and BRAF wild type. Multiple liver metastases were detected. Conversion therapy was given and the patient received 8 therapy courses with FOLFIRI plus cetuximab. Grade 1 diarrhea and grade II skin toxicity were observed as adverse effects of the chemotherapy. The size of the tumor was reduced and the tumor was resected performing left colectomy, segment liver VI resection and performing intraoperative thermos-ablation with microwave. No recurrence was observed at 6 months after surgery.

5-FU or mitomycin C hepatic arterial infusion after failure of arterial oxaliplatin in patients with colorectal cancer unresectable liver metastases

Hepatic arterial infusion (HAI) chemotherapy with oxaliplatin is an accepted option in the management of colorectal cancer (CRC) with dominant liver metastases (LM). However, despite prolonged control, some patients experience disease progression. On the other hand, oxaliplatin leads to dose-limiting toxicity. In these cases, the use of a second-line HAI with an alternative drug has never been reported to date. We evaluated treatment outcomes in patients receiving second-line HAI with 5-FU or mitomycin C, after first-line HAI of oxaliplatin in heavily pretreated patients. Between March 2010 and June 2016, this observational study included 24 patients with unresectable CRC LM and treated with HAI of 5-FU (17 patients) or mitomycin C (7 patients), after HAI of oxaliplatin. Mean age was 61.7years. Forty-two percent of patients (10/24) had extra-hepatic metastases and 75% (18/24) at least 8 liver metastases. Including HAI of oxaliplatin, all patients had previously received at least 2lines of chemotherapy±targeted agents (100%) and 96% (23/24) received concomitant systemic therapies together with HAI of 5-FU or mitomycin C. The overall objective response rate and disease control rate were, respectively, 42% (10/24) and 71% (17/24). Median progression-free survival and overall survival (OS) were, respectively, 5.6 and 25.8months; hepatic progression-free survival was 8.5months. Thirteen percent (3/24) of the patients received further curative intent treatment after HAI 5-FU and mitomycin C. No toxic death occurred and the toxicity profile was acceptable. HAI of 5-FU or mitomycin C is an alternative option in patients with predominant CRC LM, when they experience disease progression or do not tolerate HAI of oxaliplatin.

Benefit of Surgical Resection of the Primary Tumor in Patients Undergoing Chemotherapy for Stage IV Colorectal Cancer with Unresected Metastasis

PurposeResection of the primary tumor in patients with unresected metastatic colorectal cancer is controversial, and often performed only for palliation of symptoms. Our goal was to determine if resection of the primary tumor in this patient population is associated with improved survival. MethodsThis is a retrospective cohort study of the National Cancer Data Base from 2004 to 2012. The study population included all patients with synchronous metastatic colorectal adenocarcinoma who were treated with systemic chemotherapy. The study groups were patients who underwent definitive surgery for the primary tumor and those who did not. Patients were excluded if they had surgical intervention on the sites of metastasis or pathology other than adenocarcinoma. Primary outcome was overall survival. ResultsOf the 65,543 patients with unresected stage IV colorectal adenocarcinoma undergoing chemotherapy, 55% underwent surgical resection of the primary site. Patients who underwent surgical resection of the primary tumor had improved median survival compared to patients treated with chemotherapy alone (22 vs 13 months, p < .0001). The surgical survival benefit was present for patients who were treated with either multi-agent or single-agent chemotherapy (23 vs 14 months, p < 0.001; 19 vs 9 months, p < 0.001). Surgical resection of the primary tumor was also associated with improved survival when using multivariate analysis with propensity score matching (OR = 0.863; 95% CI [0.805–.924]; HR = 0.914; 95% CI [0.888–0.942]). ConclusionsOur results show that in patients with synchronous unresected stage IV colorectal adenocarcinoma undergoing single- or multi-agent chemotherapy, after adjusting for confounding variables, definitive resection of the primary site was associated with improved overall survival. Large randomized controlled trials are needed to determine if there is a causal relationship between surgery and increased overall survival in this patient population.

Comparison of early radiological predictors of outcome in patients with colorectal cancer with unresectable hepatic metastases treated with bevacizumab

ObjectiveThe purpose was to validate the prognostic value of an early optimal morphological response on CT in patients treated with bevacizumab-containing chemotherapy for unresectable colorectal cancer liver metastases (CLM). It...

Conversion to Resection in Patients Receiving Systemic Chemotherapy for Unresectable and/or Metastatic Colorectal Cancer—Predictive Factors and Prognosis

BackgroundSystemic chemotherapy increases the possibility of resection in patients with initially unresectable colorectal cancer (CRC), especially patients with hepatic metastasis. However, the predictive factors and prognosis of conversion to resection after chemotherapy in patients with various organ metastases remain largely unknown. Patients and MethodsWe reviewed the data from metastatic CRC (mCRC) patients who had received oxaliplatin- or irinotecan-based systemic chemotherapy from 2005 to 2016. The predictors for conversion to surgery were assessed by multivariate analyses. Cancer-free survival and overall survival after the initiation of treatment were compared between patients who had undergone successful conversion therapy and those who had undergone surgery first for resectable stage IV CRC. ResultsOf 99 mCRC patients receiving first-line chemotherapy, 23 underwent secondary surgical resection. Single organ metastasis, the presence of liver metastases, and the use of biologic agents were independent predictors of successful conversion therapy. The long-term survival of patients who underwent successful secondary surgery did not differ significantly from that of the 112 patients with resectable stage IV CRC who had undergone surgery first. ConclusionLiver metastases and single organ metastasis were more likely to be resected after chemotherapy than were other metastatic lesions in mCRC. The use of biologic agents contributed to the increased conversion rate. Successful conversion resulted in outcomes similar to those of resectable stage IV CRC.

Impact of the individualization of the first-line chemotherapy for advanced colorectal cancer based on collagen gel droplet-embedded drug sensitivity test.

Leucovorin (FOL) and fluorouracil (5-FU) plus oxaliplatin (l-OHP; FOLFOX) or FOL and 5-FU plus irinotecan (SN-38; FOLFIRI) are widely used as first-line chemotherapy regimens in the treatment of advanced colorectal cancer (CRC). However, second-line chemotherapy must be abandoned in certain cases due to disease progression, adverse effects or high medical cost. Therefore, the most effective regimen should be selected as first-line chemotherapy. We reported that individualization of first-line treatment (FOLFOX/FOLFIRI/Dual/Poor responder) was possible using the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) and that individualized first-line chemotherapy with CD-DST may improve the prognosis of patients with unresectable CRC. The aim of the present prospective cohort study was to evaluate the individualization of first-line chemotherapy using CD-DST, with a focus on prognosis. Between March 2008 and December 2015, tumor specimens were obtained from 120 patients with CRC who had not received preoperative chemotherapy. CD-DST was performed and the growth inhibition rate (IR) was determined by exposure for 24 h with 5-FU and l-OHP (6.0 and 3.0 µg/ml, respectively) and 5-FU and SN-38 (6.0 and 0.2 µg/ml, respectively). The cumulative distribution of IR values under each condition was evaluated on the basis that the clinical response to FOLFOX and FOLFIRI is equivalent (~50%). The prognosis of dual responder was improved compared with that of poor responders, however this difference was identified to be significant. There was no different prognosis between patients treated with an appropriate first-line regimen and patients treated with an inappropriate first-line regimen in dual responders. However, in poor responders, there were significant differences of prognosis between patients treated with an appropriate first-line regimen and patients treated with an inappropriate first-line regimen (P=0.036). In conclusion, the results from the present study suggest that administration of the recommended first-line regimen using CD-DST for patients with unresectable CRC is important for the improvement of prognosis, particularly in poor responders.

Updated survival outcomes and analysis of long-term survivors from the MORE study on safety and efficacy of radioembolization in patients with unresectable colorectal cancer liver metastases.

The Metastatic colorectal cancer liver metastases Outcomes after RadioEmbolization (MORE) study was a retrospective analysis of 606 patients with unresectable colorectal liver metastases treated with radioembolization (RE) using 90Y-labeled resin microspheres. The first analysis of this study was completed with a last patient follow-up of 77.7 months. We now provide an updated survival analysis through September 15, 2016, with a last patient follow-up of 125 months. 90Y-RE was considered for patients with advanced liver-only or liver-dominant metastatic colorectal cancer which was deemed not suitable for surgery, ablation, or systemic therapy, and which had progressed or become refractory to at least one line of systemic therapy. All patients with a diagnosis of metastatic colorectal cancer who had received at least 1 RE treatment and 1 follow-up visit were included in the analysis. Patients were treated between July 2002 and December 2011 at one of 11 U.S. tertiary care centers. Data were collected at baseline, on the day of the first 90Y-RE treatment (day 0), and at all subsequent visits or until death. Patient medical charts and/or public records were accessed to obtain dates of death. Dates of death were obtained for 574 out of a total of 606 patients, and overall survival (OS) data analyzed. Updated median OS was 10.0 months (95% CI: 9.2-11.8 months) at a median follow-up of 9.5 months versus the originally reported median OS of 9.6 months (95% CI: 9.0-11.1 months) at a follow-up of 8.6 months in the first MORE analysis. Patients received a median (range) of 2 (0 to 6) lines of chemotherapy. Baseline characteristics and factors significantly associated with patient survival (P<0.01) are consistent with those reported in the first safety analysis of the MORE study. These factors include poor ECOG performance status, markers of advanced disease such as increased extent of tumor-to-target liver involvement, poor baseline liver function, pre-treatment anemia, lung shunt fraction, and number of lines of prior chemotherapy. Patient age did not significantly affect survival outcomes. Long-term follow-up confirms that 90Y-RE treatment offers favorable survival benefits for patients with unresectable metastatic colorectal cancer, even among patients who received 3 or more prior lines of chemotherapy. Our analysis also supports earlier reported prognostic factors for survival after 90Y-RE. Overall, our updated analysis confirms that 90Y-RE treatment provided a meaningful response and survival advantage for MORE patients across all ages and across diverse community and academic centers in the U.S.

Significance of E-cadherin and CD44 expression in patients with unresectable metastatic colorectal cancer.

The loss of adhesion molecules is reported to be associated with tumor invasion and metastasis in numerous types of cancer. Epithelial (E)-cadherin is an important molecule for cell-to-cell adhesion, while cluster of differentiation (CD)44 is an important molecule for cell-to-extracellular matrix adhesion. The focus of the present study was to evaluate the significance of the expression of E-cadherin and CD44 in patients with the unresectable metastatic colorectal cancer (CRC) who are undergoing palliative chemotherapy. Formalin-fixed, paraffin-embedded samples were obtained from 49 patients who underwent primary tumor resection and who were receiving palliative chemotherapy for unresectable metastatic CRC. The expression of E-cadherin and CD44 was evaluated using immunohistochemistry. The expression of E-cadherin was not significantly associated with progression-free survival (PFS; P=0.2825) or overall survival (OS; P=0.6617). The expression of CD44 was not associated with PFS (P=0.4365), but it did exhibit a certain level of association with OS (P=0.0699). However, the combined low expression of E-cadherin and CD44 demonstrated a significant association with decreased PFS (P=0.0101) and OS (P=0.0009). The combined loss of E-cadherin and CD44 expression also led to a reduction in the objective response rate and disease control rate (P=0.0076 and P=0.0294, respectively). A univariate analysis indicated that the combined low expression of E-cadherin and CD44 (P=0.0474) and sex (P=0.0330) were significantly associated with decreased PFS, and multivariate analysis confirmed combined low expression of E-cadherin and CD44 as an independent risk factor for decreased PFS [hazard ratio (HR), 8.276; 95% confidence interval (CI), 1.383-43.311; P=0.0227]. Univariate and multivariate analyses also indicated that the combined low expression of E-cadherin and CD44 expression was a significant prognostic factor for poor OS (HR, 15.118; 95% CI, 2.645-77.490; P=0.0039). Therefore the current study suggests that the combined low expression of E-cadherin and CD44 is an effective independent predictor of decreased chemotherapeutic outcome and survival in patients with unresectable metastatic CRC.

A phase II study of pembrolizumab in combination with mFOLFOX6 for patients with advanced colorectal cancer.

3541 Background: Pembrolizumab (PEM) has activity in patients with deficient mismatch repair (dMMR) colorectal cancer (CRC). Oxaliplatin (OX) and 5FU lead to immunogenic cell death and increased antigen presentation. We hypothesized that combining mFOLFOX6 and PEM may enhance immunogenic cell death and improve outcome in patients with CRC irrespective of MMR status. Methods: Subjects ≥18 years old with untreated, unresectable CRC were assigned to a single arm study. The study had a safety run in cohort of six patients (OX 85 mg/m2, leucovorin 400 mg/m2, 5FU 400 mg/m2, 5FU infusion 2400 mg/m2over 46 hours) and PEM 200 mg Q 3 weeks, followed by a phase II cohort. The primary objective was median progression free survival (mPFS), with secondary objectives: safety and toxicity per CTCAE V4.03, median overall survival, response rate, immune related response, disease control rate, and molecular correlates. Results: Between 4/2015 and 9/2016, 30 subjects were enrolled with following characteristics: 11 female, 26 Caucasian, median age: 45 years (25-75), 3 with dMMR, 22 MMR-proficient, and 5 with no available data. During the safety run in, 2 patients had G3 febrile neutropenia (FN) and 1 G4 neutropenia. The data safety monitoring committee recommended dose reduction of mFOLFOX6 to OX 68 mg/m2, leucovorin 400 mg/m2, 5FU of 320 mg/m2, 5FU infusion of 1920 mg/m2over 46 hours and PEM 200 mg Q 3 weeks. At the data cut off (12/29/16), median follow up was 24 weeks (10-66) and 27 patients remained on study. Rate of G3/4 toxicity associated with FOLFOX/PEM and PEM alone was 36.7% and 13.2%, respectively. No further FN was observed. No grade 5 toxicity was seen on study. Best response was recorded as: 1 complete response, 15 partial response (CR +PR = 53%), and 14 stable disease, with 100% DCR at 8 weeks. One patient with dMMR had resection after 2 months of therapy with complete pathologic response. MPFS has not been reached (95% CI: 5.5 months, NR). Conclusions: Based on these preliminary results, PEM/mFOLFOX6 has acceptable toxicity though demonstrated a suggestion of increased neutropenia in the initial cohort. Clinical activity was seen in patients with untreated advanced CRC including those with proficient MMR. Clinical trial information: NCT02375672.

REsect: Blinded assessment of amenability to potentially curative treatment of previously unresectable colorectal cancer liver metastases (CRC LM) after chemotherapy ± RadioEmbolization (SIRT) in the randomized SIRFLOX trial.

3532 Background: Secondary resection and radiofrequency ablation (RFA) of primarily unresectable LM from CRC can prolong survival and cure some patients (pts). Effective downsizing treatments are needed but their impact on secondary amenability to surgery/RFA is difficult to evaluate objectively. The added value of SIRT is not well established. Methods: Baseline (BL) and follow-up (FU) imaging at best response for CRC pts treated with FOLFOX chemotherapy±bevacizumab (bev) (CT) vs. CT+SIRT in the phase III SIRFLOX RCT were reviewed by 3−5 expert HPB surgeons (from a panel of 15) for resectability of LM. Reviewers were blinded to each other and to all clinical information incl. time of imaging (BL/FU). Resectability was defined as ≥60% of reviewers assessing a pt as resectable. For non-resectable cases, surgeons indicated whether a combination of surgery and RFA could completely remove all LM. Lesions deemed suitable for RFA by a surgeon needed to be confirmed by an interventional radiologist. Pts were defined as “clearable” if ≥60% of reviewers assessed them as amenable to complete removal of LM by surgery alone or surgery+RFA. Results: 472 pts were evaluable (CT, n = 228; CT+SIRT, n = 244). There was no significant difference in LM resectability at BL (CT, n = 25, 10.96%; CT+SIRT, n = 29, 11.89%; p = 0.77). At FU, significantly more pts in the SIRT arm had resectable LM (CT, n = 66, 28.95%; CT+SIRT, n = 93, 38.11%; p &lt; 0.0001). Of 203 pts in the CT arm and 215 pts in the CT+SIRT arm deemed unresectable at BL, 46 (22.66%) and 67 (31.16%), respectively, were converted to resectability (p &lt; 0.0001). Assessing “clearability” using surgery and RFA, again no difference was noted at BL (CT, n = 31, 13.60%; CT+SIRT, n = 42, 17.21%; p = 0.309). At FU, a trend in favor of CT+SIRT was seen (CT, n = 79, 34.65%; CT+SIRT, n = 102, 41.80%; p = 0.1296). Conclusions: The addition of SIRT to FOLFOX(±bev) based CT significantly increased the gain in resectability of primarily unresectable CRC LM compared with CT alone. For amenability to the combination of surgery+RFA, this effect was still seen, albeit attenuated. Subgroup analyses are ongoing. Clinical trial information: NCT00724503.

The combination of systemic chemotherapy and local treatment may improve the survival of patients with unresectable metastatic colorectal cancer.

With the development of systemic chemotherapy, the survival time of patients with advanced colorectal cancer (CRC) has increased. In addition, local treatments, such as microwave ablation and radioactive seed implantation, have been shown to be effective. However, the number of studies reporting on the effect of systemic chemotherapy combined with local treatments is limited. The present study was conducted to determine the effect of local treatment combined with systemic chemotherapy in patients with initial unresectable metastatic CRC (mCRC). Clinicopathological and follow-up data from 273 patients with initial unresectable mCRC between April, 2007 and October, 2013 were retrospectively analyzed. A total of 51 patients received minimally invasive treatments combined with systemic chemotherapy and 39 patients achieved tumor-free survival (TFS). The median TFS time was 9 months (range, 2–45 months); the median overall survival (OS) time was 40 months (range, 12–108 months). In patients who did not achieve TFS, the OS was 37 months. Thus, patients who achieved TFS exhibited a significantly longer OS compared with those who did not achieve TFS (P=0.049). The results of the univariate analysis demonstrated that certain characteristics, such as the number of lesions and maximum tumor diameter, were associated with the achievement of TFS. The patients assessed herein achieved TFS in response to local treatments combined with systemic chemotherapy. Furthermore, the achieved TFS provided an OS benefit.

Hepatic intra-arterial therapies for unresectable and chemo-refractory colorectal cancer liver metastases: systematic review and pooled analysis

Objective: Most patients with colorectal cancer liver metastases (CRCLM) become unresectable during the course of their disease requiring palliative treatments. This meta-analysis aims to compare the survival benefit of three hepatic intra-arterial therapies in unresectable and chemo-refractory CRCLM: conventional trans-arterial chemoembolization (cTACE), drug-eluting bead trans-arterial chemoembolization (DEB-TACE) and Yttrium-90 radioembolization (Y-90). Methods: A systematic literature search was conducted and prospective studies were selected according to predetermined criteria. Study data was extracted from studies that reported on survival outcomes. Median survivals and tumor responses according to RECIST were pooled and compared indirectly. Studies were qualitatively appraised using Downs and Black's tool. Results: Twenty of the 3498 studies identified were included and analyzed: 5 cTACE (n=746), 4 DEB-TACE (n=202) and 11 Y-90 (n=569) studies. Most patients had failed at least one therapy in addition to systemic chemotherapy. Extrahepatic disease was rare in the cTACE patients (2%) but present in approximately one third of patients in the DEB-TACE and Y-90 studies. The pooled median survival was superior in the cTACE and DEB-TACE studies (15.7 and 17.6 months) compared to Y-90 (10.4 months). Radiological responses following index intervention based on RECIST criteria were strongest in the DEB-TACE studies (40.6%) as compared to the cTACE (23.1%) or the Y90 (23.5%) studies. Conclusion: While limited by methodological and statistical heterogeneity, it appears that DEB-TACE and cTACE provide superior survival benefits compared to Y-90 radioembolization. Given the common use of radioembolization in this setting and the significant cost differences between the various treatments, a more robust prospective comparative trial is warranted.

Recent improvement of survival prognosis after pulmonary metastasectomy and advanced chemotherapy for patients with colorectal cancer.

New chemotherapeutic regimens (i.e. FOLFOX or FOLFIRI with molecular targeted drugs) have improved the prognosis of patients with unresectable or recurrent colorectal cancer. To estimate the prognostic impact of these chemotherapies, we examined the chronological change in survival rates of patients who underwent pulmonary metastasectomy for colorectal cancer metastasis. Using a large database, we conducted a retrospective, multi-institutional study to collect data of 1223 eligible patients from 26 institutions who had undergone pulmonary metastasectomy with curative intent. We divided those patients who underwent metastasectomy in different time periods according to the major trend of chemotherapy regimens for recurrent colorectal cancer: those who underwent metastasectomy between 1990 and 1999 ( N = 451, Group A), between 2000 and 2004 ( N = 433, Group B) or between 2005 and 2007 ( N = 339, Group C). Five-year overall survival rates after metastasectomy were 45% in Group A, 56% in Group B and 66% in Group C ( P < 0.0001) whereas rates after metastasectomy plus chemotherapy were 32% in Group A, 47% in Group B and 70% in Group C ( P = 0.0059). The prognosis of patients who underwent both metastasectomy and chemotherapy in Group C was significantly better than that of the other two groups. Overall survival of patients who did not receive chemotherapy was not significantly different between the groups. Survival rates of patients after pulmonary metastasectomy for colorectal cancer metastasis who underwent chemotherapy have increased over the years. It implies that newer chemotherapy regimens might have had a positive impact on these patients.

Prognostic value of pretreatment diffusion-weighted magnetic resonance imaging for outcome prediction of colorectal cancer liver metastases undergoing 90Y-microsphere radioembolization

To investigate the clinical potential of pretreatment apparent diffusion coefficient (ADC) on diffusion-weighted magnetic resonance imaging (DWI) for therapy response and outcome prediction in patients with liver-predominant metastatic colorectal cancer (CRC) undergoing radioembolization with 90Yttrium-microspheres (90Y-RE). Forty-six consecutive patients with unresectable CRC liver metastases underwent standardized clinical DWI on a 1.5T MR scanner prior to and 4-6 weeks after 90Y-RE. Pretreatment clinical parameters, ADC values derived from region-of-interest analysis, and the corresponding tumor sizes of three treated liver metastases per subject were recorded. Long-term tumor response to radioembolization was categorized into response (partial remission) and nonresponse (stable disease, progressive disease) according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST) 3 months after treatment. Associations between long-term tumor response and the clinical and imaging parameters were evaluated. The impact of pretreatment clinical and imaging parameters on progression-free survival (PFS) and overall survival (OS) was further assessed by Kaplan-Meier and multivariate Cox-regression analyses. Nonresponders had higher hepatic tumor burden (p = 0.021) and lower ADC values than patients responding to 90Y-RE, both pretreatment (986 ± 215 vs. 1162 ± 178; p = 0.036) and posttreatment (1180 ± 350 vs. 1598 ± 225; p = 0.002). ADC values higher than 935 × 10-6 mm2 (5 vs. 3 months; p = 0.022) and hepatic tumor burden ≤25% (6 vs. 3 months; p = 0.014) were associated with longer median PFS, whereas ADC >935 × 10-6 mm2 (14 vs. 6 months; p = 0.02), hepatic tumor burden ≤25% (14 vs. 6 months; p = 0.048), size of the largest metastasis <4.7cm (18 vs. 7 months; p = 0.024), and Eastern Cooperative Oncology Group (ECOG) score <1 (8 vs. 5 months; p = 0.045) were associated with longer median OS. On multivariate analysis, ADC >935 × 10-6 mm2 and hepatic tumor burden ≤25% remained prognostic factors for PFS, and ADC >935 × 10-6 mm2 and size of the largest metastasis <4.7cm were independent predictors of OS. Pretreatment ADC on DWI represents a valuable prognostic biomarker for predicting both the therapeutic efficacy and survival prognosis in CRC liver metastases treated by 90Y-RE, allowing risk stratification and potentially optimizing further treatment strategies.

Predictors and prognosticators for survival with Yttrium-90 radioembolization therapy for unresectable colorectal cancer liver metastasis.

This critical review aims to explore predictive and prognostic biomarkers of Yttrium-90 (Y90) radioembolization therapy of colorectal liver metastases. A brief overview of established predictive and prognostic molecular and genetic biomarkers in colorectal cancer therapies will be discussed. A review of the literature on imaging modalities, genetic, metabolic and other molecular markers and the subsequent outcomes in post-Y90 treatment will be presented. How these biomarkers and future biomarker research can inform locoregional treatment decisions in the clinical setting of metastatic colorectal cancer lesions of the liver will be explored. There are opportunities for personalized cancer treatment in the setting of Y90 radioembolization. The ability to predict tumor response after Ytrium-90 radioembolization therapy can greatly impact clinical decision making and enhance treatment outcomes, therefore further research into the field is needed.

Prognostic Significance of C-reactive Protein/Albumin Ratio in Patients with Locally Advanced Unresectable Colorectal Cancer

Despite the poor prognosis of unresectable colorectal cancer (CRC), some patients survive after intensive chemotherapy followed by complete resection of the primary and metastatic tumors. The pretreatment C-reactive protein/albumin ratio (CAR) is a significant prognostic indicator in various carcinomas. Therefore, in this retrospective study, we evaluated the prognostic significance of pretreatment CAR in patients with unresectable CRC. The 61 patients were diagnosed as having initially unresectable disease between January 2004 and December 2013. We analyzed the clinical courses of these patients. Blood samples were taken routinely at their first visit to our hospital. C-reactive protein (CRP), albumin (ALB), and carcinoembryonic antigen (CEA) were analyzed. The median survival time (MST) and 2-year overall survival (OS) of the patients was 9months (range, 1-96months) and 23%, respectively. The median CRP, ALB, CAR, and CEA levels of the patients were 2.2mg/dL, 3.5g/dL, 0.65, and 20.6ng/mL, respectively. There was no correlation between CEA levels and the CAR. Patients were divided into two sub-groups using the median CAR level as the cut-off: high CAR (>0.65) and low CAR (≤0.65). Both MST and 2-year OS were significantly lower in the 30 high-CAR patients (4months, 6.7%) than in the 31 low-CAR patients (13months, 38.7%, p<0.001). The primary tumors of three low-CAR patients could be removed after intensive chemotherapy. Thus, low-CAR patients with locally advanced CRC with or without distant metastasis may survive following intensive treatment, even if their tumors were previously deemed to be unresectable.

Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer.

SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1–20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed. Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations, and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system. Using The Cancer Genome Atlas data on CRC, the characteristics of SMAD4 and transforming growth factor-β pathway mutations were evaluated according to different consensus molecular subtypes of CRC. Among 734 patients with CRC, 90 (12%) had SMAD4 mutations according to hotspot testing. SMAD4 mutation was associated with colon cancer more so than with rectal cancer (odds ratio 2.85; p<0.001), female sex (odds ratio 1.71; p = 0.02), and shorter overall survival than in wild-type SMAD4 cases (median, 29 months versus 56 months; hazard ratio 2.08; p<0.001 [log-rank test]). SMAD4 mutation was not associated with age, stage at presentation, colonic location, distant metastasis, or tumor grade. A subset of patients with metastatic CRC (n = 44) wild-type for KRAS, NRAS, and BRAF who received anti-epidermal growth factor receptor therapy with mutated SMAD4 (n = 13) had shorter progression-free survival duration than did patients wild-type for SMAD4 (n = 31) (median, 111 days versus 180 days; p = 0.003 [log-rank test]). Full-length sequencing confirmed that missense mutations at R361 and P356 in the MH2 domain were the most common SMAD4 alterations. In The Cancer Genome Atlas data, SMAD4 mutation frequently occurred with KRAS, NRAS, and BRAF mutations and was more common in patients with the consensus molecular subtype 3 of CRC than in those with the other 3 subtypes. This is one of the largest retrospective studies to date characterizing SMAD4 mutations in CRC patients and demonstrates the prognostic role and lack of response of CRC to anti-epidermal growth factor receptor therapy. Further studies are required to validate these findings and the role of SMAD4 mutation in CRC.