A number of risk factors have been identified that are associated with early recurrence of PSM in CRC. Positive peritoneal cytology, visible evidence of peritoneal carcinomatosis at time of initial operation, perforated primary tumor, and synchronous ovarian metastasis are among these risk factors. In addition, emergently treated bleeding or obstructed primary tumors or mucinous T3 stage or T4 stage tumors with adjacent organ involvement, as well as margin positive resection are high risk factors, which may be responsible for early recurrence of PSM of CRC origin 12
Careful patient selection is an important component in the decision making process for second look laparotomy. Medical co-morbidities (heart, lung, kidney, low performance status), poor nutritional status, 3 or more liver metastases are relative contraindications for second look laparotomy. A recent study, however, suggested that morbidity is not significantly increased when performing hepatobiliary surgery during CRS and HIPEC 38
. Potential contraindications depending on severity of presentation include obesity, and acute abdomen with ileus 3
. Bucci et al. stated in 1994 that the serum tumor marker CEA (carcinoembryonic antigen) -directed second-look surgery is not a reliable or cost-effective approach 22
. An elevated serum CEA today prompts cross sectional and functional diagnostic imaging, which as discussed previously, is typically unrevealing for PSM of CRC origin. The above studies provide an evidence basis to forego imaging and proceed straight to second look surgery inpatients at high risk for PSM due to CRC.
Other factors that should be considered in selecting patients for second look laparotomy include tumor differentiation, and subtype (e.g. signet ring cell histology), synchronous versus metachronous PSM. It is well established that signet ring cell adenocarcinoma is a virulent form of gastrointestinal malignancy that is associated with a dismal prognosis; second look operation in patients with this tumor subtype is unlikely to be of significant benefit. Therefore, it is useful to determine the histopathological subtype of tumor in high risk patients by use of a precise immunohistochemical (IHC) approach 39
. A locally advanced primary tumor stage category reflects depth of tumor invasion with high likelihood of lymphatic dissemination, and it has been shown previously that more advanced T-stage primary tumors such as Stage II and III T-4 tumors have 25% incidence of peritoneal spread as the only metastatic site of disease 40
. The Tumor-Node-Metastasis (TNM) staging classification is an evolving document based on advances in evidence-based medicine. In the future other disease-specific aspects may be taken into account as well; for example, recent morphometric analysis revealed that the peritoneal elastic lamina was a useful marker of level of tumor invasion, and powerful indicator of prognosis in CRC 41
. Interestingly it has been demonstrated that the angiogenic phenotype may differ between intestinal and diffuse type gastric cancer 42-44
. Translating these data to CRC signet ring cell adenocarcinoma, mucinous adenocarcinoma and perhaps metastatic phenotype may also be of value in risk stratification for PSM.
Lymphatic as well as vascular invasion and peri-neural infiltration are clinically relevant parameters amongst the various types of gastrointestinal cancers in terms of tumor biology and prognosis. The risk benefit ratio for second look operation in a patient with extensive lymphovascular invasion histopathologically would not favor this approach based on the low likelihood of benefit. Tumor heterogeneity remains a complex phenomenon that pertains to the primary tumor as well as the individual patient with advanced disease given the observed genotypic heterogeneity evident between the primary tumor and different metastatic sites 45
Malignant ascites as a manifestation of peritoneal carcinomatosis is an adverse prognostic indicator. Sangisetty et al. recently showed that although patients with PSM and ascites may not be cured by a multi-modality approach, these patients may derive palliative benefit from laparoscopic heated intra-peritoneal chemotherapy 46
; randomized trials are not available and are needed 47
. The role of laparoscopic second look operation is unclear.
Multi-modality treatment approaches in both the neoadjuvant and adjuvant setting is an important part of the clinical pathway in gastrointestinal malignancy. Defining the value of adding systemic therapy after CRS + HIPEC, particularly after performing a second look laparotomy is an oncological challenge. Another goal of the future will be the assessment of treatment response, specifically selecting patients for multi-modality therapy based on reliable indicators of tumor biology 48
. However, careful consideration ought to be given to the fact that 35 years after the (only) experiment, which lead to the World Health Organization classification of tumor response to treatment, no additional studies have been conducted or proposed 49
Targeted therapy directed by tumor specific testing at either the gene or protein expression is another basis for 'next generation' or precision cancer therapy. Despite rapid advances in our understanding of targeted therapy for GI cancers, the durable impact on cancer survival has been marginal overall. Targeted anti-angiogenic therapy, for instance, can also have unpredictable results and be a 'double-edged sword' for while vascular endothelial growth factor (VEGF) inhibitors reduce primary tumor growth, they may simultaneously promote tumor growth and metastatic spread through other mechanisms 50-52
Intra-abdominal surgery leads to post-operative adhesions. The nature, extent, and functional impact of adhesions are highly variable. Minimal residual disease may reside within these adhesions; therefore, complete adhesiolysis is imperative during any kind of second look cancer operation and CRS + HIPEC with curative intent. The fact that tumor cells become sequestered in avascular intra-peritoneal adhesions explains partly the resistance to, and ineffectiveness of systemic chemotherapy alone for peritoneal carcinomatosis.
The presence of an anatomic barrier, the peritoneal-plasma partition, has enabled administration of high local concentrations of chemotherapy at the peritoneal surface, far in excess of systemically administered agents when drug delivery is intra-peritoneal as opposed to intravenous. High molecular weight agents such as Mitomycin C (334 Da), and Oxaliplatin (397 Da), for example, have favorable pharmacokinetic profiles (AUC, peritoneal fluid relative to plasma: Mitomycin C, 75:1; Oxaliplatin, 25:1) permitting dose-dense intra-peritoneal therapy over prolonged periods with rapid tissue concentration (in residual tumor deposits and peritoneum), but limited systemic absorption or toxicity. This particular therapeutic approach addresses the problem of systemic chemotherapy resistance and, with its reduced systemic toxicity, provides distinct pharmacological advantage over systemic drug delivery. This makes completeness of cytoreduction imperative, which is conducted with the intent to eradicate macroscopic deposits of tumor and optimize the efficacy of hyperthermic chemotherapy in obliterating minimal residual disease. Optimal therapeutic synergy is achieved when intra-peritoneal heated chemotherapy is administered immediately following maximal cytoreduction, thereby minimizing trapping of viable peritoneal tumors cells in fibrin and post-operative adhesions, and maximizing kill of tumor cells shed during resection. Adhesions are lysed during cytoreduction to facilitate uniform distribution of heated chemotherapeutic perfusate, maximize direct contact of drug with residual peritoneal tumor cells, and harness the advantage of “thermo-chemotherapeutic” anti-tumor synergism.
Bristow et al. showed that using a hyaluronate-carboxymethylcellulose (HA-CMC) barrier for prevention of pelvic adhesion formation in women undergoing primary cytoreductive surgery with radical oophorectomy for locally advanced epithelial cancer is associated with a significant reduction in the extent and density of pelvic adhesion 53
. It might also be possible that, in the future, a patient who undergoes primary resection of a colon cancer and is found to have high-risk features, such as local PSM, that the operation is completed, HA-CMC applied to the viscera prior to abdominal closure, and the patient subsequently referred to a center of excellence in PSM for subsequent second look operation and cytoreductive surgery + HIPEC.