Surgical Options for Peritoneal Surface Metastases from Digestive Malignancies-A Comprehensive Review.

The peritoneum is a common site for the dissemination of digestive malignancies, particularly gastric, colorectal, appendix, or pancreatic cancer. Other tumors such as cholangiocarcinomas, digestive neuroendocrine tumors, or gastrointestinal stromal tumors (GIST) may also associate with peritoneal surface metastases (PSM). Peritoneal dissemination is proven to worsen the prognosis of these patients. Cytoreductive surgery (CRS), along with systemic chemotherapy, have been shown to constitute a survival benefit in selected patients with PSM. Furthermore, the association of CRS with hyperthermic intraperitoneal chemotherapy (HIPEC) seems to significantly improve the prognosis of patients with certain types of digestive malignancies associated with PSM. However, the benefit of CRS with HIPEC is still controversial, especially due to the significant morbidity associated with this procedure. According to the results of the PRODIGE 7 trial, CRS for PSM from colorectal cancer (CRC) achieved overall survival (OS) rates higher than 40 months, but the addition of oxaliplatin-based HIPEC failed to improve the long-term outcomes. Furthermore, the PROPHYLOCHIP and COLOPEC trials failed to demonstrate the effectiveness of oxaliplatin-based HIPEC for preventing peritoneal metastases development in high-risk patients operated for CRC. In this review, we discuss the limitations of these studies and the reasons why these results are not sufficient to refute this technique, until future well-designed trials evaluate the impact of different HIPEC regimens. In contrast, in pseudomyxoma peritonei, CRS plus HIPEC represents the gold standard therapy, which is able to achieve 10-year OS rates ranging between 70 and 80%. For patients with PSM from gastric carcinoma, CRS plus HIPEC achieved median OS rates higher than 40 months after complete cytoreduction in patients with a peritoneal cancer index (PCI) ≤6. However, the data have not yet been validated in randomized clinical trials. In this review, we discuss the controversies regarding the most efficient drugs that should be used for HIPEC and the duration of the procedure. We also discuss the current evidence and controversies related to the benefit of CRS (and HIPEC) in patients with PSM from other digestive malignancies. Although it is a palliative treatment, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) significantly increases OS in patients with unresectable PSM from gastric cancer and represents a promising approach for patients with PSM from other digestive cancers.

Bevacizumab Treatment for Metastatic Colorectal Cancer in Real-World Clinical Practice.

Background and Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality and morbidity worldwide. Bevacizumab was approved for the treatment of metastatic colorectal cancer (mCRC) based on favorable benefit-risk assessments from randomized controlled trials, but evidence on its use in the real-world setting is limited. The aim of the current study is to evaluate the outcomes and safety profile of bevacizumab in mCRC in a real-world setting in Romania. Patients and Methods: This was an observational, retrospective, multicentric, cohort study conducted in Romania that included patients with mCRC treated with bevacizumab as part of routine clinical practice. Study endpoints were progression-free survival, overall survival, adverse events, and patterns of bevacizumab use. Results: A total of 554 patients were included in the study between January 2008 and December 2018. A total of 392 patients (71%) received bevacizumab in the first line and 162 patients (29%) in the second line. Bevacizumab was mostly combined with a capecitabine/oxaliplatin chemotherapy regimen (31.6%). The median PFS for patients treated with bevacizumab was 8.4 months (interquartile range [IQR], 4.7-15.1 months) in the first line and 6.6 months (IQR, 3.8-12.3 months) in the second line. The median OS was 17.7 months (IQR, 9.3-30.6 months) in the first line and 13.5 months (IQR, 6.7-25.2 months) in the second line. Primary tumor resection was associated with a longer PFS and OS. The safety profile of bevacizumab combined with chemotherapy was similar to other observational studies in mCRC. Conclusions: The safety profile of bevacizumab was generally as expected. Although the PFS was generally similar to that reported in other studies, the OS was shorter, probably due to the less frequent use of bevacizumab after disease progression and the baseline patient characteristics. Patients with mCRC treated with bevacizumab who underwent resection of the primary tumor had a higher OS compared to patients with an unresected primary tumor.

Safety and Efficacy of Simultaneous Resection of Gastric Carcinoma and Synchronous Liver Metastasis-A Western Center Experience.

Background and objectives: Gastric cancer (GC) is often diagnosed in the metastatic stage. Palliative systemic therapy is still considered the gold standard, even for patients with resectable oligometastatic disease. The aim of the current study is to assess the potential benefit of up-front gastric and liver resection in patients with synchronous resectable liver-only metastases from GC (LMGC) in a Western population. Materials and Methods: All patients with GC and synchronous LMGC who underwent gastric resection with or without simultaneous resection of LMs between January 1997 and December 2016 were selected from the institutional records. Those with T4b primary tumors or with unresectable or more than three LMs were excluded from the analysis. All patients who underwent emergency surgery for hemorrhagic shock or gastric perforation were also excluded. Results: Out of 28 patients fulfilling the inclusion criteria, 16 underwent simultaneous gastric and liver resection (SR group), while 12 underwent palliative gastric resection (GR group). The median overall survival (OS) of the entire cohort was of 18.81 months, with 1-, 3- and 5-year OS rates of 71.4%, 17.9% and 14.3%, respectively. The 1-, 3- and 5-year OS rates in SR group (75%, 31.3% and 25%, respectively) were significantly higher than those achieved in GR group (66.7%, 0% and 0%, respectively; p = 0.004). Multivariate analysis of the entire cohort revealed that the only independent prognostic factor associated with better OS was liver resection (HR = 3.954, 95% CI: 1.542-10.139; p = 0.004). Conclusions: In a Western cohort, simultaneous resection of GC and LMGC significantly improved OS compared to patients who underwent palliative gastric resection.

Embryologic Origin of the Primary Tumor and RAS Status Predict Survival after Resection of Colorectal Liver Metastases.

Background and objectives. In colorectal cancers, the embryologic origin of the primary tumor determines important molecular dissimilarities between right-sided (RS) and left-sided (LS) carcinomas. Although important prognostic differences have been revealed between RS- and LS-patients with resected colorectal liver metastases (CLMs), it is still unclear if this observation depends on the RAS mutational status. To refine the impact of primary tumor location (PTL) on the long-term outcomes of patients with resected CLMs, the rates of overall survival (OS), relapse-free survival (RFS) and survival after recurrence (SAR) were compared between RS- vs. LS-patients, according to their RAS status. Material and Methods. All patients with known RAS status, operated until December 2019, were selected from a prospectively maintained database, including all patients who underwent hepatectomy for histologically-proven CLMs. A log-rank test was used to compare survival rates between the RS- vs. LS-group, in RAS-mut and RAS-wt patients, respectively. A multivariate analysis was performed to assess if PTL was independently associated with OS, RFS or SAR. Results. In 53 patients with RAS-mut CLMs, the OS, RFS and SAR rates were not significantly different (p = 0.753, 0.945 and 0.973, respectively) between the RS and LS group. In 89 patients with RAS-wt CLMs, the OS and SAR rates were significantly higher (p = 0.007 and 0.001, respectively) in the LS group vs. RS group, while RFS rates were similar (p = 0.438). The multivariate analysis performed in RAS-wt patients revealed that RS primary (p = 0.009), extrahepatic metastases (p = 0.001), N-positive (p = 0.014), age higher than 65 (p = 0.002) and preoperative chemotherapy (p = 0.004) were independently associated with worse OS, while RS location (p < 0.001) and N-positive (p = 0.007) were independent prognostic factors for poor SAR. Conclusions. After resection of CLMs, PTL had no impact on long-term outcomes in RAS-mut patients, while in RAS-wt patients, the RS primary was independently associated with worse OS and SAR.

The Impact of Postoperative Complications on Survival after Simultaneous Resection of Colorectal Cancer and Liver Metastases.

BACKGROUND: The aim of this study was to investigate the impact of postoperative complications on the long-term outcomes of patients who had undergone simultaneous resection (SR) of colorectal cancer and synchronous liver metastases (SCLMs). METHODS: We conducted a single-institution survival cohort study in patients with SR, collecting clinical, pathological, and postoperative complication data. The impact of these variables on overall survival (OS) and disease-free survival (DFS) was compared by log rank test. Multivariate Cox regression analysis identified independent prognostic factors. RESULTS: Out of 243 patients, 122 (50.2%) developed postoperative complications: 54 (22.2%) major complications (Clavien-Dindo grade III-V), 86 (35.3%) septic complications, 59 (24.2%) hepatic complications. Median comprehensive complication index (CCI) was 8.70. Twelve (4.9%) patients died postoperatively. The 3- and 5-year OS and DFS rates were 60.7%, 39.5% and 28%, 21.5%, respectively. Neither overall postoperative complications nor major and septic complications or CCI had a significant impact on OS or DFS. Multivariate analysis identified the N2 stage as an independent prognostic of poor OS, while N2 stage and four or more SCLMs were independent predictors for poor DFS. CONCLUSION: N2 stage and four or more SCLMs impacted OS and/or DFS, while CCI, presence, type, or grade of postoperative complications had no significant impact on long-term outcomes.

Prognostic Value of Lymph Node Ratio in Patients with Resected Synchronous Colorectal Liver Metastases and Less Than 12 Examined Lymph Nodes.

BACKGROUND: Recent studies suggest that lymph node ratio (LNR) has significantly better prognostic power than N-status in patients with colorectal cancer, in particular when the number of evaluated lymph nodes (LNs) was insufficient. The aim of this study was to assess the prognostic value of LNR in patients with resected synchronous colorectal liver metastases (SCLMs) and less than 12 examined LNs. METHODS: A prospectively maintained database of patients with resected SCLMs was queried for patients with less than 12 LNs evaluated at the time of surgery. X-tile software was used to determine the LNR cutoff value able to divide the patients in two subgroups with distinct prognosis. Overall survival (OS) and disease-free survival (DFS) rates were compared by log-rank test. A multivariate Cox regression analysis identified independent prognostic factors. RESULTS: A cutoff LNR value of 0.22 divided patients into Low-LNR group (35 patients) and High-LNR group (36 patients). Both OS and DFS rates were significantly higher in Low-LNR group than those in High-LNR group. Independent predictors of poor OS were High-LNR (HR: 2.841, 95% CI: 1.480-5.453, p value = 0.002), bilobar SCLMs (HR: 2.253, 95% CI: 1.144-4.437, p value = 0.019) and lack of adjuvant chemotherapy (HR: 2.702, 95% CI: 1.448-5.043, p value = 0.002), while the only independent predictor of poor DFS was High-LNR (HR: 2.531, 95% CI: 1.259-5.090, p value = 0.009). CONCLUSIONS: LNR > 0.22 was independently associated with poor OS and DFS in patients with resected SCLMs and less than 12 evaluated LNs.

Assessment of clinical and pathological complete response after neoadjuvant chemoradiotherapy in rectal adenocarcinoma and its therapeutic implications.

Because almost one fourth of patients with rectal adenocarcinoma (RC) achieve pathological complete response (pCR) after neoadjuvant chemoradiation therapy (CRT), having significantly higher survival rates than those without pCR, the assessment of pCR represents a highly important challenge nowadays. Moreover, recent studies revealed that organ-sparing approaches could represent a reasonable alternative to radical surgery (RS) in patients with pCR, achieving similar long-term outcomes with lower morbidity rates and improved quality of life. Unfortunately, the decision of a rectum-sparing approach should be based only on clinical, endoscopic (with or without biopsy) and radiological methods, that must accurately predict the pCR after neoadjuvant CRT, in the absence of the pathological examination of the RS specimen. Thus, a surrogate parameter called clinical complete response (cCR) emerged, to assess the results of neoadjuvant CRT. The evolving accuracy of recent endoscopic and imaging methods in assessment of cCR and their predictive value for estimation of pCR achievement are presented. The usefulness of combining the results of these evaluation methods (resulting in the development of few nomograms) for a more accurate estimation of pCR, as well as the predictive factors for pCR achievement are also debated. Moreover, the changing landscape of therapeutic approaches based on cCR assessment is discussed, emphasizing the advantages and pitfalls of rectum-sparing approaches, compared to RS. Because there are no reliable methods to estimate with 100% accuracy the pCR, the only way to decrease as much as possible the risk of misleading treatment choices is the multidisciplinary team-based decision.

Influence of the Primary Tumor Location on the Pattern of Synchronous Metastatic Spread in Patients with Stage IV Colorectal Carcinoma, According to the 8 th Edition of the AJCC Staging System.

BACKGROUND AND AIMS: The correlations between primary tumor location (right colon cancer - RCC, left colon cancer - LCC and rectal cancer - RC) and the incidence of metastatic sites are scarce and divergent. The current study is the first which compares the pattern of metastatic distribution (M1a: metastasis to one organ/site, excluding peritoneum; M1b: two or more metastatic sites; M1c: peritoneal metastases) between RCC, LCC and RC, respectively. METHODS: All patients operated for colorectal cancer (CRC) between January 2006 and December 2015 were analyzed to assess the primary tumor location, the presence and site of synchronous metastases. Univariate analysis determined the statistical significance of association between each CRC location and the metastatic pattern. Multinomial logistical regression model compared the prevalence of each metastatic pattern for each CRC location. RESULTS: Out of 5,107 patients, 1,318 (25.80%) had metastases on the moment of CRC diagnosis. There were no statistically significant association between the metastatic pattern and the patients' gender (M1a, p=0.321; M1b, p=0.539; M1c, p=0.417, Chi-square) or patients' age (p=0.616 Mann-Whitney U-test). RC had a significant higher relative risk for M1a (RR of 1.437, p=0.014) and a lower relative risk for M1c (RR of 0.564, p=0.001), compared to LCC. On the contrary, compared with LCC, the RCC showed a significant lower relative risk for M1a (RR of 0.673, p=0.006) and a higher relative risk for M1c (RR of 1.834, p=0.0001). CONCLUSION: There is a strong correlation between the primary location of CRC and the pattern of the metastatic spread, with potential prognostic implications.

GOOD TO KNOW: The ALPPS Procedure - Embracing a New Technique.

BACKGROUND: Hepatic resection is the only potentially curative treatment for primary liver tumors and hepatic metastases. The most frightening postoperative complication of extensive hepatectomies is liver failure due to insufficient future liver remnant (FLR). The ALPPS technique (Associating Liver Partition and Portal vein Ligation for Staged hepatectomy) effectively increased the resectability of otherwise inoperable liver tumors (primary or secondary malignant liver tumor) by achieving a rapid and an effective hypertrophy of the FLR, which lowers postoperative liver failure risk. AIM: To present the ALPPS classic right trisectionectomy and its technical variants which were invented to decrease the high rate of post-operative morbidity and mortality, reported in early case series. TECHNIQUE: ALPPS involves two stages. The first surgical procedure consists in the ligation of the right portal branch and the partition of the liver at the site of the falciform ligament (insitu splitting). In contrast to a classical hepatectomy, the tumoral hemiliver is left in situ and remains vascularized by the right hepatic artery only. The biliary and systemic venous drainages represented by the right biliary duct and respectively the hepatic veins, are preserved. The second step of the procedure is usually performed within 7 to 15 days after the firststage. The tumoral hemiliver is removed by sectioning the right hepatic artery, the biliary duct and the systemic venous pedicle. Conclusions: The ALPPS technique is a therapeutic method for inoperable liver tumors by standard methods of hepatectomy ± portal vein ligation (PVL). By careful patient selection and technical adjustment to the particular conditions of each case, better outcomes have been achieved, leading toan increasing number of surgeons who perform ALPPS.

A role for hepatic surgery in patients with liver metastatic breast cancer: review of literature.

Traditionally, patients with metastatic breast cancer were seen as carrying a grim prognosis and therapy was based mainly on palliative chemotherapy and hormonal therapy, with surgery being considered as ineffective. However, in the last 20 years different centers worldwide published series of metastatic breast cancer patients who underwent resection for different metastatic sites (liver, brain, lung), reporting favorable results. Most of these papers addressed to the role of liver surgery in patients with breast cancer liver metastases, mainly due to the favorable results achieved by liver resection in patients with metastatic colorectal cancer. In this review are presented the results achieved by liver surgery in patients with breast cancer liver metastases.

Surgical options for initially unresectable colorectal liver metastases.

Although the frontiers of liver resection for colorectal liver metastases have broadened in recent decades, approximately 75% of these patients present with unresectable metastases at the time of their diagnosis. In the past, these patients underwent only palliative treatment, without the chance of a cure. In the previous two decades, several therapeutic strategies have been developed that render resectable those metastases that were initially unresectable, thus offering the chance of long-term survival and even a cure to these patients. The oncosurgical modalities that are available include liver resection following portal vein ligation/embolization, "two-stage" liver resection, one-stage ultrasonically guided liver resection, hepatectomy following conversion chemotherapy, and liver resection combined with thermal ablation. Moreover, in recent years, certain authors have recommended the revisiting of the concept of liver transplantation in highly selected patients with unresectable colorectal liver metastases and favorable prognostic factors. By employing such therapies, the number of patients with colorectal liver metastases who undergo a potentially curative treatment could increase to 40%. The safety profile of these approaches is acceptable (morbidity rates as high as 45%, mortality rates of less than 5%). Furthermore, the 5-year survival rates (approximately 30%) are significantly increased over those that were achieved with palliative treatment.

Metastatic colorectal cancer--what about the primary?

BACKGROUND: Approximately 25% of patients with colorectal cancer present synchronous metastases, most frequently located in the liver. AIMS: The assessment of optimal therapeutic strategies for the primary tumor in such patients. METHODS: We analyzed the outcomes of 209 patients who underwent simultaneous or delayed resection of the primary tumor and liver metastases, the survival rates of patients with initially unresectable liver metastases that were rendered resectable, and the prognostic factors related to the primary tumor. RESULTS: The outcomes of simultaneous resections were similar to those of delayed resection. In patients with initially unresectable liver metastases that were rendered resectable, the survival rates were similar to those of patients with initially resectable metastases. The survival rate of N2 patients was significantly lower than those of N1 and N0 patients. CONCLUSIONS: Simultaneous resection provides a safety profile and survival rate similar to that of delayed resection. The N category allows for prognostic estimation in metastatic colorectal patients.