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Background: Patients with colon cancer may present at multiple different stages of the disease process. Many patients can be cured of colon cancer as a result of a simple surgical procedure usually performed by minimally invasive techniques. However, there are a variable number of patients, estimated at approximately 10%, who have a more advanced disease. If these patients are treated by the current conventional standard of care, the likelihood for treatment failure is extremely high. Methods: These are not patients with known disseminated disease but patients who are at high risk of recurrent disease unless special treatments are initiated preoperatively and intraoperatively. The identification of these patients is by (1) a high-quality CT scan, (2) tumor markers found preoperatively, (3) colonoscopic findings, and (4) symptoms. Results: Patients identified as being at high risk require special preoperative treatments which include neoadjuvant chemotherapy. Intraoperative chemotherapy with HIPEC should occur as part of the treatment if peritoneal metastases are documented by biopsy. In the operating room, a thorough exploration of all possible occult peritoneal spaces for metastatic disease needs to be performed. A modified cytoreductive surgical procedure along with a colon resection is performed in order to minimize sites of occult peritoneal metastases. This includes the greater omentum, ovaries, and tubes in postmenopausal women. Peritonectomy is used to create a shroud around the tumor so that all peritoneum that has been in direct contact with the tumor surface is resected and is used as a barrier against tumor cell dissemination in the process of colon cancer resection. If peritoneal metastases are visualized at any site, HIPEC should be included as part of the treatment package. Conclusions: I am convinced that patients at high risk of recurrence will have an improved outcome with proper preoperative evaluation, preoperative neoadjuvant chemotherapy, and a revised intraoperative management strategy. [ABSTRACT FROM AUTHOR]

Appendiceal mucinous neoplasms are routinely accompanied by peritoneal metastases at the time of diagnosis of the primary appendiceal tumor. In contrast, liver metastases and lymph node metastases are unusual. From an extensive database, patients with lymph node metastases identified at the time of primary appendiceal cancer resection were selected for special study. The clinical, treatment-related and histologic variables of this group of patients were statistically analyzed for their impact on overall survival. From a prospectively maintained database of 685 patients with a complete cytoreduction of a mucinous appendiceal neoplasm with peritoneal dissemination, 39 patients (5.6%) had lymph node metastases at the time of primary diagnosis. The median follow-up was 5.0 years and overall median survival was 6.0 years. Histologically, 6 of these patients (15.4%) had an appendiceal mucinous neoplasm – Intermediate type (MACA-Int). In 5 patients, the involved lymph nodes were not within the ileocolic lymph node group. The 7 patients (17.9%) who had a complete or near complete response to neoadjuvant chemotherapy prior to definite cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) showed prolonged survival (HR 4.8 (1.1, 20.5) p = 0.0323). A prior right colon resection required repeat resection in 87% of patients. Long-term survival is unusual but occasionally seen in this group of patients. Response to neoadjuvant chemotherapy is an important determinant of a favorable outcome. [ABSTRACT FROM AUTHOR]

For peritoneal metastases from a primary appendiceal mucinous neoplasm to exist, the thin wall of the appendix must perforate to allow mucus or mucus plus tumor cells to gain access to the peritoneal spaces. The proportion of specimens containing tumor cells within mucus as compared to mucus only outside the appendix may have prognostic significance. The histopathology of tumor masses was determined from the specimens resected at the cytoreductive surgery (CRS). The presence versus absence of tumor cells in mucus and the proportion of specimens with tumor cells was determined and correlated with the overall survival of these patients. In 418 patients with a complete cytoreduction for a low-grade appendiceal mucinous neoplasm (LAMN), the cellularity of all resected specimens was determined. The hazard ratio of overall survival of patients whose specimens had no cells as compared to specimens with cells in mucus by histology was 4.41 (1.61, 12.1) (p = 0.0039). If overall survival of patients with all specimens without tumor cells was compared to patients with specimens with 1–99 % tumor and compared to patients with 100 % of specimens with tumor cells, the hazard ratios were 4.3 (1.34, 13.8) (p = 0.0143) and 9.62 (2.93, 31.6) (p = 0.0002), respectively. The cellularity of mucus within the specimens removed by a complete CRS has strong prognostic implications in LAMN patients. LAMN with acellular specimens (LAMNa) as compared to LAMN with tumor cells in specimens (LAMNb) should be staged as different histologic subtypes of mucinous appendiceal neoplasms. [ABSTRACT FROM AUTHOR]

Patients with colorectal cancer die as a result of metastases to liver, lymph nodes or the peritoneal surfaces. The primary is almost always controlled by colon or rectal cancer resection. Consecutive patients with isolated metastases to peritoneal surfaces (no lymph node, liver or systemic metastases) were referred to the Washington Cancer Institute from all over the United States and abroad. The study of this particular group of patients was to determine the impact of clinical and histologic features on overall survival. These variables were collected from the primary colorectal cancer resection performed at the referring institute and from the cytoreductive surgery (CRS) performed at the Washington Hospital Center. The data was prospectively accumulated and retrospectively analyzed. Thirty-one consecutive patients had a complete cytoreduction. This restricted cohort of patients was studied in an attempt to eliminate confounding variables. The median age was 47 years (range 19–80). There were 14 (45%) males. The median overall survival following CRS was 67.9 months with a 5-year and 10-year survival of 51.9% and 43.6%, respectively. None of the clinical or histologic features, including peritoneal cancer index (PCI) and presence of signet ring cells, significantly predicted survival except for carbohydrate antigen 19-9 (CA19-9) (p = 0.0033). None of the involved abdominopelvic regions predicted a guarded outcome. In this restricted group of lymph node negative colorectal PM patients with a complete cytoreduction, a high PCI or the presence of signet ring cells should not exclude patients from CRS and perioperative chemotherapy. [ABSTRACT FROM AUTHOR]

Peritoneal metastases is the second most common colorectal cancer dissemination. The anatomic sites at which colorectal peritoneal metastases are located within the abdomen and pelvis has not been previously determined. A prospective database has been maintained on patients treated by cytoreductive surgery (CRS) plus perioperative chemotherapy. The patients in this current study all had peritoneal metastases histologically confirmed, and a complete cytoreduction. The patterns of dissemination of the peritoneal metastases recorded after a prior left colon resection or right colon resection at the time of the CRS were analyzed. The major goal was to identify the location of colorectal cancer peritoneal metastases at abdominopelvic anatomic sites. In these 77 patients, by the abdominopelvic regions, the highest incidence of histologically documented cancer was the pelvis (85.7%), central region (75.3%), right upper quadrant (50.6%) and right lower (53.2%). Specific anatomic sites free of disease at the time of primary resection at which cancer was documented at the time of CRS was the abdominal incision or laparoscopy port sites at 57.1% and the anatomic site for the primary cancer resection at 76.6%. Right colon cancer had a statistically significant increase in the right flank region 8 (p = 0.0350) and borderline significant increase of left colon cancer in the left lower region 5 (p = 0.0699). When data is pooled from many patients, physiology of the peritoneal spaces and tumor cell entrapment contribute to the distribution of disease within the abdomen and pelvis. [ABSTRACT FROM AUTHOR]

The PRODIGE 7-trial investigated the additional value of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) to cytoreductive surgery (CRS) for patients with colorectal peritoneal metastases (CPM). The results of PRODIGE 7 were presented at the 2018 ASCO meeting showing that 30 min oxaliplatin-based HIPEC did not improve overall survival. The current study investigated the impact of PRODIGE 7 on the worldwide practice of CRS and HIPEC. CRS-HIPEC experts from 19 countries were invited through the Peritoneal Surface Oncology Group International (PSOGI) to complete an online survey concerning the current CRS-HIPEC practice in their hospital and country, and were asked to appraise the effect of PRODIGE 7. The survey was completed by 18/19 experts. Although their personal opinions of CRS-HIPEC were barely influenced by PRODIGE 7, they reported a substantial impact on daily practice. This included a switch towards Mitomycin-C based HIPEC-regimens and prolongation of HIPEC perfusion time, a reduction in the number of referrals from non-HIPEC centers, a reduction in national consensus, the removal of HIPEC from national guidelines, and a reduced reimbursement rate. The PRODIGE 7 has had a major impact on the practice of CRS-HIPEC for CPM worldwide. HIPEC remains an attractive option with potential for control and eradication of disease and further studies into the optimal HIPEC-regimen are urgently needed. Meanwhile, given the complexity of the treatment of patients with CPM, and the proven benefits of optimal CRS, referral of patients with potentially resectable CPM to expert centers is recommended whilst the precise role of HIPEC is further evaluated. [ABSTRACT FROM AUTHOR]

Malignant peritoneal mesothelioma is an aggressive local-regional disease with dissemination to all parts of the abdomen and pelvis at the time of diagnosis. Recently, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been used and improved survival was documented with this local-regional treatment strategy. Concerning CT features were described that were specific for malignant peritoneal mesothelioma. The incidence of concerning radiologic features and their impact on survival was determined. The prognostic assessment of concerning CT features was compared to the peritoneal cancer index (PCI) and the completeness of cytoreduction score (CC score). One hundred patients with a preoperative CT were evaluated by 11 concerning CT features. The incidence of these CT features varied between 5% and 41%. Nine of the 11 CT features statistically significantly predicted a reduced survival in these patients treated in a uniform manner. When concerning radiologic features were grouped as none, a single feature or two or more features, a significant composite analysis was achieved with p < 0.001. The prognostic information from concerning CT features compared favorably with the prognostic implications of PCI and CC score. The availability of the concerning CT features to predict prognosis at the initiation of treatments for malignant peritoneal mesothelioma shows that this radiologic assessment may be of great value to the clinician in planning a treatment strategy for an individual patient. Synopsis: Preoperative CT findings, quantitatively evaluated, showed a statistically significant impact on outcome of treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. This objective prognostic information was available to the multidisciplinary team at the time of the patient's evaluation for an aggressive surgical intervention. [ABSTRACT FROM AUTHOR]

A rare appendiceal malignancy is characterized by both glandular and neuroendocrine histology. It often presents with dissemination of the perforated tumor to peritoneal surfaces. Current treatments involve systemic chemotherapy, cytoreductive surgery and perioperative intraperitoneal chemotherapy. The impact of clinical, histological and treatment-related characteristics on survival were evaluated and subjected to univariate statistical analyses. All patients had stage IV disease and were treated by a uniform treatment strategy. Survival was determined from onset of disease until death or most recent follow-up. There were 47 patients available for study of whom 17 were male. Median age was 48 with a range of 27–65. None or a single symptom vs. 2 or more symptoms had a significant effect on survival. Median survival of the entire cohort was 45 months and 34.88% and 8.72% of patients survived 5 and 10 years, respectively. The use of neoadjuvant chemotherapy showed no impact on survival. Patients with a peritoneal cancer index (PCI) of 0–20 as compared to PCI > 20 survived longer (p = 0.012). The survival of patients able to have a complete resection as compared to an incomplete resection of disease was significant (p = 0.0087). The type of perioperative chemotherapy did not alter survival. These data show that patients with a lesser extent of disease with a complete cytoreduction had an improved prognosis. No benefit from systemic or perioperative regional chemotherapy was apparent. With long-term follow-up, patients with the combined glandular and neuroendocrine histology exhibiting peritoneal metastases have a guarded prognosis. [ABSTRACT FROM AUTHOR]

Numerous studies have suggested benefit for heated intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal metastases from colon cancer. However, the PRODIGE 7 trial that randomized 265 colon cancer patients to surgery plus HIPEC vs. surgery alone after neoadjuvant chemotherapy (NACT) did not confirm benefit. These data were published as an abstract and not as a peer-reviewed manuscript. One concern is that prior drug exposure may select for drug resistance and blunt HIPEC efficacy. A database query identified colon cancer specimens evaluated for chemotherapy sensitivity by ex-vivo analysis of programmed cell death (EVA/PCD), a primary culture platform that examines drug-induced cell death (apoptotic & non-apoptotic) by morphologic, metabolic and histologic endpoints. Of 87 fresh colon cancer specimens, 54 (62%) were untreated and 33 (38%) had received prior folinic acid, 5-fluorouracil, oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX). In an apoptosis assay, the lethal concentration of 50% (LC50) in untreated patients was significantly lower than in patients treated by FOLFOX (p = 0.002). Then to approximate PRODIGE 7, treated patients were separated by having received oxaliplatin treatment less than or greater than 2 months before EVA/PCD analysis. The degree of resistance increasing significantly for patients who received treatment less than 2 months prior to EVA/PCD (p < 0.002). Activity for mitomycin and irinotecan was not significantly different for untreated vs. treated patients, but 5-FU was more resistant (P = 0.048). The failure of PRODIGE 7 to improve survival with surgery plus HIPEC following NACT may reflect diminished oxaliplatin cytotoxicity in patients whose residual disease has been selected for oxaliplatin and 5-FU resistance. [ABSTRACT FROM AUTHOR]

Granulosa cell tumors of the ovary (GCT) are the most common type of sex cord stromal tumors. Although most of patients are diagnosed at early stage and has favorable 5‐year overall survival rate, 16–23% of GCT ultimately develop recurrent disease. Recurrences are characterized by disseminated peritoneal metastasis. The treatment options include systemic chemotherapy, secondary CRS or palliative localized radiation therapy have not yet standardized due to the rarity of disease. Aggressive CRS followed up by hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to provide benefit in other peritoneal disease but limited data available for recurrent GCT. We have a case of recurrent Adult‐type GCT (AGCT) who was treated with CRS followed by HIPEC with mitomycin C and doxorubicin. The patient has no evidence of recurrence for approximately 11 years. An electronic search of the PubMed database with the following search terms: GCT, HIPEC showed that there were total 21 patients with recurrent GCT treated in seven different studies and 13 of 21 (61.9%) patients had no evidence of disease during follow‐up ranging from 6 to 100 months. Three patients (14.2%) died of the disease. Six studies used cisplatin for HIPEC. At least 76.2% (16 of 21, data not available for five patients) had complete cytoreduction with total 16 cases of perioperative complications but no perioperative mortality was observed. Although further investigation is needed, we propose that CRS and HIPEC can be an effective therapeutic option for recurrent GCT at experienced institutions. [ABSTRACT FROM AUTHOR]

Peritoneal surfaces are a common site for the dissemination of gastrointestinal and gynecologic malignancy. Often, the surgeon can achieve a complete response. Unfortunately, current perioperative chemotherapy regimens fail to maintain control of cancer nodules within the abdomen and pelvis. More effective perioperative chemotherapy is needed. The nanoparticle pegylated liposomal doxorubicin (PLD) was instilled directly into the peritoneal space in peritoneal metastases patients following maximal efforts of cytoreductive surgery to resect abdominal and pelvic disease. Pharmacokinetics were determined intraoperatively during hyperthermic intraperitoneal chemotherapy (HIPEC) conditions and postoperatively during early postoperative intraperitoneal chemotherapy (EPIC) at normothermic conditions. The retention of PLD within the peritoneal tissues over a 90-min HIPEC was only approximately 20% and 180 min of HIPEC 40%. The median area under the curve ratio of peritoneal fluid concentration times time as compared to plasma concentration times was over 1000 and increased with dose escalation from 50 to 100 mg/m2. When PLD was instilled for EPIC, the area under the curve ratios were very similar to the HIPEC but retention of drug within the peritoneal tissues with access to cancer nodules was maintained for 24 h with approximately 80% drug utilization. Adverse events were tabulated and found to be absent. No evidence of peritoneal dysfunction from sclerosis was evident with a 1 year of follow-up. The nanoparticle PLD is slowly absorbed into the intraperitoneal tissues and not appropriate for HIPEC. EPIC is the preferred methodology for administration. [ABSTRACT FROM AUTHOR]

Peritoneal carcinomatosis may be diagnosed by cytology or CT-guided biopsy, but routine radiologic and endoscopic workup not reveal a primary site. The clinical condition is referred to as peritoneal carcinomatosis of unknown primary site. Over a 30-year time interval all patients treated with an initial diagnosis of carcinomatosis of unknown primary site were managed on a special clinical pathway. Upper gastrointestinal endoscopy, colonoscopy, and abdominal and pelvic CT were performed. Immunostains suggested a gastrointestinal origin of the carcinomatosis. After these tests, exploratory laparotomy was performed. Twenty-five patients fulfilled the criteria for peritoneal carcinomatosis of unknown primary site and all 25 of these patients underwent an exploratory laparotomy. Special attention to the anatomic site of the appendix occurred during the exploratory laparotomy. No site within the gastrointestinal tract including a non-cancerous appendix was observed in 9 patients (36%). In 7 patients (28%), the carcinomatosis was so extensive that an adequate exploration to determine a primary site was not possible. In a third group of 9 patients (36%), exploratory laparotomy revealed an occult appendiceal malignancy. Peritoneal carcinomatosis of unknown primary site was caused by an occult appendiceal adenocarcinoma in 36% of our patients. This error in diagnosis may lead to suboptimal treatment. Surgical exploration to visualize the anatomic site of the appendix should occur prior to making a definitive diagnosis of peritoneal carcinomatosis of unknown primary site. [ABSTRACT FROM AUTHOR]

• Peritoneal metastases from colorectal cancer are lethal. • Cytoreductive surgery plus perioperative chemotherapy is a treatment option. • A perioperative FOLFOX regimen with intraperitoneal oxaliplatin was described. • The pharmacokinetic studies suggested efficacy. Colorectal cancer can disseminate malignant cells to the peritoneal surfaces which over time progress to peritoneal metastases. Management of this type of metastatic disease has been approached using a combined treatment that consists of cytoreductive surgery and perioperative chemotherapy. To optimize these treatments a more effective chemotherapy that is used as planned part of the surgical procedure is required. Pharmacologic studies to initiate a new perioperative chemotherapy treatment were modeled after the successful systemic treatments of metastatic colorectal cancer referred to as FOLFOX. A management plan that included all of the essential features of successful systemic chemotherapy was formulated. Pharmacokinetic studies of 5-fluorouracil given both intravenously and intraperitoneally and oxaliplatin given intraperitoneally were investigated. The compatibility of 5-fluorouracil and oxaliplatin was documented showing no degradation of either drug when they were mixed in-vitro over 24 h. The pharmacokinetic analysis of hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin showed cytotoxic concentrations for 120 min. In order to maximize oxaliplatin's effect, both intravenous bolus and continuous infusion 5-fluorouracil was combined with early postoperative intraperitoneal chemotherapy (EPIC). In total, 200 mg/m2 of oxaliplatin was combined with a minimum of 1600 mg of 5-fluorouracil over the 24 -h treatment plan. This perioperative FOLFOX treatment was completed in 2 patients and the clinical effectiveness as a result of this in-depth case reports was presented. Formal phase II studies, as a result of these pharmacokinetic and clinical investigations, have been initiated. [ABSTRACT FROM AUTHOR]

• Determine metastases as hematogenous, lymphatic or transcoelomic. • In the past splenic metastases was assumed to be hematogenous. • Splenic metastases may occur in the absence of hematogenous dissemination. • Gastrointestinal or gynecologic splenic metastases are likely implants. Metastases from gastrointestinal and gynecologic malignancy may occur through lymphatic channels, through venules of the cancer or into the peritoneal space. The metastatic process involves lymphatic, hematogenous or transcoelomic dissemination. Two patients with splenic metastases are presented. Their clinical course is presented in an attempt to identify the route of cancer dissemination to the spleen. Lymphatic, hematogenous, or transcoelomic patterns of cancer dissemination are possible. Transcoelomic cancer dissemination into the peritoneal space results in peritoneal metastases. In a woman with ovarian cancer peritoneal metastases, a large lesion within the parenchyma of the spleen was described. This disease was present at multiple other sites as peritoneal metastases but no hematogenous or lymphatic metastases. A second patient with mucinous appendiceal neoplasm with peritoneal metastases was studied. Hematogenous metastases from this malignancy is extremely rare and lymphatic metastases were not present at the time of right colon resection. After studying these two patients, our hypothesis is that splenic metastases result from transcoelomic dissemination to the splenic hilum or splenic notches with progression of disease into the parenchyma of the spleen. When oncologists are considering aggressive local-regional treatments for peritoneal metastases important patient management decisions are influenced by the presence versus absence of hematogenous metastases. We suggest that the presence of splenic metastases does not indicate systemic (hematogenous) or lymphatic metastatic process but an extension of peritoneal metastases at the hilum of the spleen or within splenic notches deep into the parenchyma of the spleen. [ABSTRACT FROM AUTHOR]

• 0.5 % of appendectomy specimens show neuroendocrine and 0.5 % show epithelial malignancy. • In 2 patients these two malignancies were in the same appendectomy specimen. • Patients peritoneal metastases occurred from the mucinous epithelial malignancy only. • Rather than routine right hemicolectomy, radical appendectomy is suggested. Although uncommon, neoplasms of the appendix do exist. The two most common types are neuroendocrine tumors and mucinous appendiceal neoplasms. In two patients unusual gross and microscopic findings in an appendectomy specimen were recorded. Special immunocytochemistry studies were used to determine the histologic type of the tumors in the appendix. The clinical features and histopathology of two patients who had both a neuroendocrine tumor and a low grade appendiceal mucinous neoplasm in the same appendectomy specimen were described. Possibilities for the causation and treatment of this unusual condition were discussed. The incidence of this double malignancy was estimated at 2.5 in 1000 appendectomy specimens. Although extremely unusual, a neuroendocrine tumor and a mucinous appendiceal neoplasm can exist in the same appendix. This condition is reported in two young patients. [ABSTRACT FROM AUTHOR]

• Pelvic exenteration is an unusual procedure in patients with peritoneal metastases from appendiceal cancer. • Pelvic exenteration may be considered in a fit patient who is made visibly disease-free by surgery. • More intensive local-regional chemotherapy may be considered in patients who fail cytoreductive surgery plus HIPEC and EPIC. • Surgical features noted intraoperatively provide important information regarding a decision to proceed. Surgery which includes peritonectomy, visceral resections, and perioperative chemotherapy has been used extensively to treat peritoneal metastases from appendiceal mucinous adenocarcinoma. The results of treatment vary with the grade of the neoplasm, the extent of abdominal and pelvic disease and the completeness of tumor removal. The clinical features, surgical procedures and outcome of two patients with mucinous appendiceal neoplasms were reviewed. The decision to move to total pelvic exenterative surgery after prior treatment failure was critically evaluated. Patient 1 had three extensive surgical procedures prior to total pelvic exenteration and one surgical procedure after. Patient 2 had one 16-h surgical procedure prior to total pelvic exenteration. Patient 1 had 8 years and 1 month survival from onset of disease until death. Patient 2 is free of disease at 27 years from onset of pseudomyxoma peritonei. After recovery of the patients from the extensive surgery, their quality of life was acceptable. Total pelvic exenteration surgery is seldom used in patients with peritoneal metastases from appendiceal neoplasms. These two patients were studied in an attempt to determine the indications for this procedure with this disease. [ABSTRACT FROM AUTHOR]

• For long-term benefit to result from cytoreductive surgery, all visible disease must be removed. • Peritoneal metastases obscured from visible detection by the surgeon will not be resected. • Peritoneal tunnels in the inguinal and porta hepatis regions were identified. • For optimal cytoreduction, peritoneal tunnels must be opened and tumor resected. Peritoneal metastases from gastrointestinal cancer can be treated by a combination of surgery to remove visible evidence of disease and perioperative intraperitoneal chemotherapy to eradicate microscopic disease. Complete cytoreduction is necessary for long-term benefit. Two sites for incomplete cytoreduction because tumor is hidden from visual inspection were identified. Patients who developed recurrence at these anatomic sites were studied. A peritoneal tunnel along a patent processus vaginalis allowed tumor to be sequestered along the inguinal canal in a female patient. A peritoneal tunnel beneath a hepatic bridge over the round ligament obscured mucinous tumor in a male patient. Peritoneal tunnels in the inguinal region or at the porta hepatis should be opened by surgical dissection so that all foci of peritoneal metastases are removed at a complete cytoreductive surgery and these sites treated with chemotherapy. [ABSTRACT FROM AUTHOR]