Repeat Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Mucinous Appendiceal Adenocarcinoma: A Viable Treatment Strategy with Demonstrable Benefit.

INTRODUCTION: Many patients with mucinous appendiceal adenocarcinoma experience peritoneal recurrence despite complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Prior work has demonstrated that repeat CRS/HIPEC can prolong survival in select patients. We sought to validate these findings using outcomes from a high-volume center. PATIENTS AND METHODS: Patients with mucinous appendiceal adenocarcinoma who underwent CRS/HIPEC at MD Anderson Cancer Center between 2004 and 2021 were stratified by whether they underwent CRS/HIPEC for recurrent disease or as part of initial treatment. Only patients who underwent complete CRS/HIPEC were included. Initial and recurrent groups were compared. RESULTS: Of 437 CRS/HIPECs performed for mucinous appendiceal adenocarcinoma, 50 (11.4%) were for recurrent disease. Patients who underwent CRS/HIPEC for recurrent disease were more often treated with an oxaliplatin or cisplatin perfusion (35%/44% recurrent vs. 4%/1% initial, p < 0.001), had a longer operative time (median 629 min recurrent vs. 511 min initial, p = 0.002), and had a lower median length of stay (10 days repeat vs. 13 days initial, p < 0.001). Thirty-day complication and 90-day mortality rates did not differ between groups. Both cohorts enjoyed comparable recurrence free survival (p = 0.82). Compared with patients with recurrence treated with systemic chemotherapy alone, this select cohort of patients undergoing repeat CRS/HIPEC enjoyed better overall survival (p < 0.001). CONCLUSIONS: In appropriately selected patients with recurrent appendiceal mucinous adenocarcinoma, CRS/HIPEC can provide survival benefit equivalent to primary CRS/HIPEC and that may be superior to that conferred by systemic therapy alone in select patients. These patients should receive care at a high-volume center in the context of a multidisciplinary team.

Efficacy of Systemic Chemotherapy in Patients With Low-grade Mucinous Appendiceal Adenocarcinoma: A Randomized Crossover Trial.

Importance: Appendiceal adenocarcinoma is a rare tumor, and given the inherent difficulties in performing prospective trials in such a rare disease, there are currently minimal high-quality data to guide treatment decisions, highlighting the need for more preclinical and clinical investigation for this disease. Objective: To prospectively evaluate the effectiveness of fluoropyrimidine-based systemic chemotherapy in patients with inoperable low-grade mucinous appendiceal adenocarcinoma. Design, Setting, and Participants: This open-label randomized crossover trial recruited patients at a single tertiary care comprehensive cancer center from September 2013 to January 2021. The data collection cutoff was May 2022. Enrollment of up to 30 patients was planned. Eligible patients had histological evidence of a metastatic low-grade mucinous appendiceal adenocarcinoma, with radiographic imaging demonstrating the presence of mucinous peritoneal carcinomatosis and were not considered candidates for complete cytoreductive surgery. Key exclusion criteria were concurrent or recent investigational therapy, evidence of bowel obstruction, and use of total parenteral nutrition. Data were analyzed from November 2021 to May 2022. Interventions: Patients were randomized to either 6 months observation followed by 6 months of chemotherapy, or initial chemotherapy followed by observation. Main Outcomes and Measures: The primary end point was the percentage difference in tumor growth in treatment and observation groups. Key secondary end points included patient-reported outcomes in the chemotherapy and observation periods, objective response rate, rate of bowel complications, and differences in overall survival (OS). Results: A total of 24 patients were enrolled, with median (range) age of 63 (38 to 82) years, and equal proportion of men and women (eg, 12 men [50%]); all patients had ECOG performance status of 0 or 1. A total of 11 patients were randomized to receive chemotherapy first, and 13 patients were randomized to receive observation first. Most patients (15 patients [63%]) were treated with either fluorouracil or capecitabine as single agent; 3 patients (13%) received doublet chemotherapy (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin or folinic acid, fluorouracil, and irinotecan hydrochloride), and bevacizumab was added to cytotoxic chemotherapy for 5 patients (21%). Fifteen patients were available to evaluate the primary end point of difference in tumor growth during treatment and observation periods. Tumor growth while receiving chemotherapy increased 8.4% (95% CI, 1.5% to 15.3%) from baseline but was not significantly different than tumor growth during observation (4.0%; 95% CI, -0.1% to 8.0%; P = .26). Of 18 patients who received any chemotherapy, none had an objective response (14 patients [77.8%] had stable disease; 4 patients [22.2%] had progressive disease). Median (range) OS was 53.2 (8.1 to 95.5) months, and there was no significant difference in OS between the observation-first group (76.0 [8.6 to 95.5] months) and the treatment-first group (53.2 [8.1 to 64.1] months; hazard ratio, 0.64; 95% CI, 0.16-2.55; P = .48). Patient-reported quality-of-life metrics identified that during treatment, patients experienced significantly worse fatigue (mean [SD] score, 18.5 [18.6] vs 28.9 [21.3]; P = .02), peripheral neuropathy (mean [SD] score, 6.67 [12.28] vs 38.89 [34.88]; P = .01), and financial difficulty (mean [SD] score, 8.9 [15.2] vs 28.9 [33.0]; P = .001) compared with during observation. Conclusions and Relevance: In this prospective randomized crossover trial of systemic chemotherapy in patients with low-grade mucinous appendiceal adenocarcinoma, patients did not derive clinical benefit from fluorouracil-based chemotherapy, given there were no objective responses, no difference in OS when treatment was delayed 6 months, and no difference in the rate of tumor growth while receiving chemotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01946854.

Prognostic significance of acellular mucin in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for appendiceal neoplasms.

INTRODUCTION: Appendiceal neoplasms have a propensity for peritoneal dissemination. The standard of care for select individuals is CRS/HIPEC. In the current 8th AJCC Staging system, a finding of only intraperitoneal acellular mucin (M1a) is classified as Stage IVa. There is concern that the current AJCC system may over-stage patients. METHODS: This was a single-institution retrospective review of 164 cases of mucinous appendiceal neoplasm. Patients undergoing CRS/HIPEC with M1a disease were compared to patients with peritoneal deposits containing tumor cells (well-differentiated adenocarcinoma; low-grade mucinous carcinoma peritonei-M1b,G1). Overall and recurrence-free survival were assessed. RESULTS: Median age was 51 years, 70% were female, and 75% White. Sixty-four patients had M1a disease and 100 M1b,G1 disease. M1a disease had a lower median PCI score (11 vs. 20, p = .0001) and a higher rate of complete CRS (62% vs. 50%, p = .021). Median follow-up was 7.6 years (IQR 5.6-10.5 years). For M1a disease, there were no recurrences and only one patient died during the study interval. In comparison, for M1b disease, 66/100 (66%) recurred with a 5-year RFS of 40.5% (HR 8.0, 95% CI 4.9-15.1, p < .0001), and 31/100 (31%) died with a 5-year OS of 84.8% (HR 4.5, 95% CI 2.2-9.2, p < .0001). CONCLUSIONS: Acellular mucin (M1a disease) after CRS/HIPEC for appendiceal neoplasm is associated with longer OS and RFS compared to M1b, G1 disease. Current AJCC staging does not accurately reflect the differing outcomes of these two patient populations. The presence of acellular mucin in the peritoneal cavity should not be perceived as a metastatic equivalent.

Elevated brain natriuretic peptide (BNP) is an early marker for patients at risk for complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC).

BACKGROUND: Elevated BNP is associated with adverse cardiac outcomes after noncardiac surgery. We assessed BNP values as markers of perioperative fluid status and their correlation with major/cardiopulmonary (CP) complications following CRS + HIPEC. METHODS: Fluid balance, BNP levels, and morbidity data were collected for all patients undergoing CRS + HIPEC between 6/2014 and 2/2016. RESULTS: One hundred and twenty-nine patients underwent CRS + HIPEC for appendiceal adenocarcinoma (n = 99), mesothelioma (n = 16), and colon cancer (n = 14). Less than 10% had CP comorbidities. The median PCI was 14 (range 4-39); 89% underwent CC0/1 resection (n = 115). Median blood loss (EBL) was 497 mL (50-2700). Major complications (Clavien III-V) occurred in 16 (12%), CP in 17 (13%), and major/CP in 24 (18%). Thirty-day mortality occurred in 2 (1.5%). Elevated BNP on POD1 correlated with increased risk of major/CP complications (OR 2.2, P = 0.052). This was most pronounced in the 25 patients receiving cisplatin: for each 100 unit increase in POD1 BNP the OR for major/CP complication was 7.4 versus 1.2 for the remaining patients, P = 0.083. Multivariate analysis identified increased EBL (OR 4.1 P = 0.011) and a trend toward increased BNP on POD1 (OR for each 100 unit increase 2.0, P = 0.10) as risk factors for major/CP complications. CONCLUSIONS: Postoperative BNP measurement after CRS + HIPEC may guide postoperative fluid resuscitation and facilitate identification of patients at risk for major and/or cardiopulmonary complications.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Moderately and Poorly Differentiated Appendiceal Adenocarcinoma: Survival Outcomes and Patient Selection.

BACKGROUND: Moderately and poorly differentiated adenocarcinoma of the appendix represents an aggressive histological variant with a high risk of recurrence and death. METHODS: Overall, 178 patients with moderately and poorly differentiated appendiceal adenocarcinoma were identified from a prospective database. Clinical, pathologic, and treatment factors were analyzed for outcomes. RESULTS: Diagnostic laparoscopy (DL) identified radiographic occult peritoneal metastasis in 25 (42%) patients. These patients had a significantly lower peritoneal carcinomatosis index (PCI) and improved overall survival (OS) compared with those with radiographic disease. Twenty-seven (41%) patients were excluded from cytoreductive surgery (CRS) because of findings on DL, while 116 (65%) patients underwent CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), with a median disease-free survival (DFS) of 23 months. Mucinous histology (hazard ratio [HR] 0.52, p = 0.04) and PCI (HR 1.054, p = 0.02) were independent predictors of DFS. The median OS following CRS and HIPEC was 48 months. Mucinous histology (HR 0.352, p = 0.018), signet ring cells (HR 3.34, p = 0.02), positive peritoneal cytology (HR 0.081, p = 0.04), and PCI (HR 1.076, p = 0.004) were independently associated with OS. Eight-five (73.3%) patients received neoadjuvant chemotherapy, and 40 (47.1%) patients achieved a radiographic response; 36 (42.3%) had stable disease, while 9 (10.6%) had progressive disease. Stable or responsive disease was associated with improved median OS of 44 months, compared with 21 months for those with progressive disease (p = 0.011). CONCLUSIONS: In selected patients, long-term survival can be obtained. Mucinous histology, absence of signet ring cells, negative peritoneal cytology, PCI ≤ 20, and response/stable disease after neoadjuvant chemotherapy are important selection criteria for CRS and HIPEC.

Low-grade Appendiceal Mucinous Neoplasm of Uncertain Malignant Potential (LAMN-UMP): Prognostic Factors and Implications for Treatment and Follow-up.

BACKGROUND: Low-grade appendiceal mucinous neoplasm of uncertain malignant potential are poorly understood lesions characterized by extraluminal mucin or fibrosis with neoplastic cells confined to the appendiceal lumen. The purpose of this study is to investigate the clinical and pathologic parameters of these lesions to optimize our understanding and management of these tumors. METHODS: Subjects with these tumors were identified from the appendiceal tumor databases at the University of Texas MD Anderson Cancer Center. Univariate and multivariate Cox proportional hazards regression analyses assessed relationships between clinicopathologic variables [including age, gender, margin status and serum levels of the tumor markers carcinoembryonic antigen (CEA), cancer antigen (CA)-125, and CA19-9] disease-free survival, postrecurrence survival and overall survival. RESULTS: Ninety-eight subjects with this disease were identified. Most patients did not experience disease recurrence after initial appendectomy. At last follow-up, 25 (26 %) had disease recurrence or died. Of the 20 patients who had disease recurrence, 5 (25 %) died, and 15 (75 %) were alive. Disease-free survival was significantly reduced with positive margin status (p = 0.02) and elevated serum levels of CEA (p < 0.001), CA19-9 (p = 0.01), or CA-125 (p = 0.002) at the time of appendectomy. The median postrecurrence survival time was 4.7 years and the 5-year postrecurrence survival rate was 41 % (standard error = 18 %). CONCLUSIONS: Patients with Low-grade appendiceal mucinous neoplasm of uncertain malignant potential who have negative margins and normal tumor marker levels have a lower risk for recurrence. In these patients, expectant management is sufficient. Elevated tumor marker levels at the time of appendectomy marks an increased risk of recurrence or death and signals the need for closer monitoring or intervention.

Intrathoracic Chemoperfusion Decreases Recurrences in Patients with Full-Thickness Diaphragm Involvement with Mucinous Appendiceal Adenocarcinoma.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is the preferred treatment for selected patients with mucinous appendiceal adenocarcinoma. Frequently, the hemidiaphragms are infiltrated with tumor, requiring partial diaphragm resection (DR) in order to obtain complete cytoreduction (CC-0). The clinical significance of diaphragmatic invasion and the optimum management to prevent transmission of disease from abdomen to chest is largely unknown. METHODS: This was a retrospective review of 78 patients with mucinous appendiceal adenocarcinoma undergoing cytoreduction and partial DR at a single institution between 2010 and 2014. RESULTS: Partial DR was necessary in 31 (39.7 %) patients in order to obtain CC-0. DR was not associated with increased morbidity or poor survival. Of the 31 patients who had a DR, 26 (83.9 %) were treated with thoracoabdominal chemoperfusion. The remaining five (16.1 %) patients had the diaphragm closed prior to HIPEC. Thoracoabdominal chemoperfusion was not associated with increased 30-day grade III/IV morbidity or respiratory complications. Overall, five (20 %) patients with a DR developed thoracic recurrence. There were two (8 %) thoracic recurrences in the 26 patients treated with thoracic chemoperfusion compared with three (60 %) in the five patients who had their diaphragm closed prior to HIPEC (p = 0.002). In univariate analysis histology, CC-0 and thoracoabdominal chemoperfusion were associated with thoracic disease-free survival; however, none of these were significant on multivariate analysis. CONCLUSION: DR is not associated with increased morbidity and should be performed, if needed, to obtain a CC-0. Following DR, patients remain at significant risk of developing thoracic recurrence. Thoracoabdominal chemoperfusion reduces this risk without increasing morbidity.

Feeding tube placement during cytoreductive surgery and heated intraperitoneal chemotherapy does not improve postoperative nutrition and is associated with longer length of stay and higher readmission rates.

BACKGROUND: Patients with colorectal cancer and peritoneal carcinomatosis (CRC/PC) may benefit from cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC). Nutritional support is frequently required for patients after CRS/HIPEC. It remains unclear if placement of feeding access is of benefit in regard to improving postoperative nutrition in this patient population. MATERIALS AND METHODS: Patients with CRC/PC who underwent complete cytoreduction were evaluated. Preoperative and postoperative nutritional data and discharge outcomes were retrospectively recorded. The presence of a feeding tube and PCI scores were recorded by review of operative notes. Readmission rates were calculated for patients at 30 d and 60 d after discharge from hospital. RESULTS: Forty-one patients underwent CRS/HIPEC, 25 had feeding tube placement at the time of surgery. Weight loss was common after HIPEC as 38 of 41 patients demonstrated weight loss. The mean weight loss was 7.6%. total parenteral nutrition was required at discharge in four patients (7.9%); three of these patients had feeding access placed. There was no difference in the degree of weight loss between groups (7.1 ± 3.7% no tube versus 7.9 ± 5.8% patients with tube; P = 0.608). The mean decrease in albumin was 12.7% but was not significantly different in patients with feeding access and those without (10.0% versus 14.75%; P = 0.773). Sixty-day readmission rates were higher in patients with feeding tubes (36% compared with 0%, P < 0.01). CONCLUSIONS: Significant nutritional loss is common after CRS/HIPEC for patients with CRC/PC. Feeding tube placement does not prevent this and appears to be related to higher readmission rates and longer length of stay.

Preoperative vitamin D replacement therapy in primary hyperparathyroidism: safe and beneficial?

BACKGROUND: The significance of vitamin D deficiency with primary hyperparathyroidism (PHPT) remains unclear. The safety and value of preoperative vitamin D (Vit D) replacement is unknown. METHODS: A prospective surgical database of PHPT patients was queried to identify those who were vitamin D sufficient, deficient, and deficient but repleted. Biochemical parameters were measured preoperatively, after vitamin D replacement, at 1-month follow-up, and at 6-months follow-up. RESULTS: Of 301 patients, 118 (39%) had a vitamin D level of 30 ng/mL or more; 71 patients (24%) were deficient, and 112 patients (37%) were vitamin D deficient but underwent repletion. The median duration of replacement was 28 days, and the dose of ergocalciferol was 400,000 U. Among the 112 patients who underwent repletion, the mean serum calcium remained relatively unchanged or decreased in 91 patients (81%). The gland size was smallest in patients with a preoperative sufficiency and largest in those deficient and not repleted. Postoperative PTH values at 1 month and at 6 months in the baseline-normal group were significantly less than in the other 2 groups (P = .05 and = .009, respectively), with no differences observed between the deficient and the deficient-repleted groups. CONCLUSION: Preoperative Vit D replacement therapy was safe in PHPT patients and did not increase serum calcium levels. Vit D status affects gland size and postoperative PTH elevation. Repletion in this population is not durable.