Neoadjuvant immunotherapy utilizing novel combinations has the potential to transform the standard of care for locally/regionally advanced melanoma. We hypothesized that neoadjuvant ipilimumab in ...combination with high dose IFNα2b (HDI) is safe and associated with durable pathologic complete responses (pCR).
Patients with locally/regionally advanced melanoma were randomized to ipilimumab 3 or 10 mg/kg × 4 doses bracketing definitive surgery, then every 12 weeks × 4. HDI was given concurrently. We evaluated the safety and efficacy of the combination with ipilimumab 3 or 10 mg/kg. The impact on T-cell fraction and clonality were investigated in tumor and blood.
Thirty patients (age 37-76), 15 each at 3 and 10 mg/kg, 18 male and 12 female were treated. Considering immune related adverse events (irAEs) of interest, more grade 3/4 irAEs were seen with ipilimumab 10 mg/kg versus 3 mg/kg (p = 0.042). Among 28 evaluable patients, 11 relapsed, of whom 5 died. Median follow-up for 17 patients who have not relapsed was 32 months. The radiologic preoperative response rate was 36% (95% CI, 21-54); 4 patients at ipilimumab 3 mg/kg and 6 at 10 mg/kg and 2 (at 10 mg/kg) later relapsed. The pCR was 32% (95% CI, 18-51); 5 patients at ipilimumab 3 mg/kg and 4 at 10 mg/kg and one (at 3 mg/kg) had a late relapse. In patients with pCR, T-cell fraction was significantly higher when measured in primary melanoma tumors (p = 0.033). Higher tumor T-cell clonality in primary tumor and more so following neoadjuvant therapy was significantly associated with improved relapse free survival.
Neoadjuvant ipilimumab-HDI was relatively safe and exhibited promising tumor response rates with an associated measurable impact on T-cell fraction and clonality. Most pCRs were durable supporting the value of pCR as a primary endpoint in neoadjuvant immunotherapy trials.
ClinicalTrials.gov, NCT01608594 . Registered 31 May 2012.
Introduction
Early recurrence (ER) is a significant challenge for patients with colorectal peritoneal metastases (CRPM) following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy ...(CRS HIPEC). Preoperative risk stratification for ER would improve preoperative decision making.
Methods
We conducted a retrospective study examining patients who underwent CRS HIPEC for CRPM from 2000 to 2018. Optimal definition of ER was determined via minimum p-value approach based on differentiation of post-recurrence survival. Risk factors for ER were assessed in a derivation cohort by uni- and multivariate logistic regression. A predictive score for ER was generated using preoperative variables and validated in an independent cohort.
Results
384 patients were analyzed, 316 (82%) had documented recurrence. Optimal length of post-operative RFS to distinguish ER (
n
= 144, 46%) vs. late recurrence (LR) (
n
= 172, 63%) was 8 mos (
p
<0.01). ER patients had shorter median OS post-CRS-HIPEC (13.6 vs. 39.4 mos,
p
<0.01). Preoperative BMI (OR 1.88), liver lesions (OR 1.89), progression on chemotherapy (OR 2.14), positive lymph nodes (OR 2.47) and PCI score (16-20: OR 1.7; >20: OR 4.37) were significant predictors of ER (all
p
<0.05). Using this model, patients were assigned risk scores from 0 to 9. Intermediate (scores 4-6) and high-risk patients (score 7-9) had observed rates of ER of 56% and 79% and overall 2-year survival rates of 27% and 0% respectively. The model showed fair discrimination (AUC 0.72) and good calibration (Hosmer-Lemeshow GOF
p
= 0.68).
Conclusions
ER predicts markedly worse OS following surgery. Preoperative factors can accurately stratify risk for ER and identify patients in whom CRS-HIPEC for CPRM is futile.
The current study examined prospective relationships between preoperative depressive symptoms and short-term (30-day morbidity and readmission) and long-term (overall survival) outcomes after ...hyperthermic intraperitoneal chemotherapy with cytoreductive surgery (HIPEC + CS).
Ninety-eight patients scheduled for HIPEC + CS completed the Center for Epidemiologic Studies-Depression (CES-D) scale before surgery. Demographic and disease-specific factors and information about morbidity and readmission within 30 days after discharge were gathered from medical records. Survival was measured from date of surgery to death.
Twenty-eight percent of patients had CES-D scores indicative of clinically significant depressive symptoms. Thirty-day morbidity occurred in 31.9% of patients and readmission in 22.2%. At the time of analysis (median follow-up of 49 months), 71.6% of patients were deceased, with median survival time of 11 months for those who died. After adjusting for relevant preoperative demographic and disease-specific factors, depressive symptoms were associated with greater odds of 30-day morbidity (n = 68; odds ratio, 5.50; 95% CI, 1.23 to 24.73; P = .03) and greater likelihood of 30-day readmission (n = 72; odds ratio, 5.92; 95% CI, 1.27 to 27.64; P = .02). Depressive symptoms were associated with shorter survival after adjustment for preoperative demographic and disease-specific factors (n = 87; hazard ratio, 1.88; 95% CI, 1.07 to 3.31; P = .03). This association was no longer significant when intraoperative/postoperative prognostic variables were added to the statistical model (n = 87; hazard ratio, 1.31; 95% CI, 0.72 to 2.37; P = .37).
Patients with clinically significant levels of preoperative depressive symptoms are at risk for poor clinical outcomes after HIPEC + CS, including greater risk of 30-day morbidity and readmission. Further research is warranted to determine biobehavioral mechanisms and examine whether effective interventions targeting preoperative depressive symptoms can reduce postoperative risk in this patient population.
Background
Failure to thrive (FTT) is a complex syndrome of nutritional failure and functional decline. Readmission for FTT following cytoreductive surgery and hyperthermic intraperitoneal ...chemotherapy (CRS HIPEC) is common but underexamined. This study aims to determine features, risk factors, and prognostic significance of FTT following CRS HIPEC.
Patients and Methods
We reviewed patients who underwent CRS HIPEC from 2010 to 2018 at our institution. Patients were categorized into no readmission, FTT readmission, and other readmission. FTT was determined by coding and chart review. We compared baseline characteristics, oncologic data, perioperative outcomes, and survival among the three cohorts.
Results
Of 1068 discharges examined, 379 patients (36%) were readmitted within 90 days, of which 134 (12.5%) were labeled as FTT. Patients with FTT readmission had worse preoperative functional status, higher rates of malnutrition, more complex resections, longer hospital stays, and more postoperative complications (all
p
< 0.001). Ostomy creation relative risk ratio (RRR) 4.06, in-hospital venous thromboembolism (VTE), discharge to nursing home (RRR 2.48), pre-CRS HIPEC chemotherapy (RRR 1.98), older age (RRR 1.84), and female gender (RRR 1.69) were all independent predictors for FTT readmission on multinomial regression (all
p
< 0.01). FTT readmission was associated with worse median overall survival on multivariate analysis hazard ratio (HR) 1.60,
p
< 0.001 after controlling for oncologic, perioperative, and baseline factors.
Conclusions
FTT is common following CRS HIPEC and appears to be associated with baseline patient characteristics, operative burden, and postoperative complications. Perioperative strategies for improving nutrition and activity, along with early recognition and intervention in FTT may improve patient outcomes.
Background
Ninety-day hospital readmission rates following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) range from 20 to 40%.
Objective
The aim of this study was to ...develop and validate a simple score to predict readmissions following CRS/HIPEC.
Study Design
Using a prospectively maintained database, we retrospectively reviewed clinicopathologic, perioperative, and day-of-discharge data for patients undergoing CRS/HIPEC for peritoneal surface malignancies between 2010 and 2018. In-hospital mortalities and discharges to hospice were excluded. Multivariate logistic regression was utilized to identify predictors of unplanned readmission, with three-quarters of the sample randomly selected as the derivation cohort and one-quarter as the validation cohort. Using regression coefficient-based scoring methods, we developed a weighted 7-factor, 10-point predictive score for risk of readmission.
Results
Overall, 1068 eligible discharges were analyzed; 379 patients were readmitted within 90 days (35.5%). Seven factors were associated with readmission: stoma creation, Peritoneal Cancer Index score ≥ 15, hyponatremia, in-hospital major complication, preoperative chemotherapy, anemia, and discharge to nursing home. In the validation cohort, 25 patients (9.2%) were categorized as high risk for readmission, with a predicted rate of readmission of 69.3% and an observed rate of 76.0%. The score had fair discrimination (area under the curve 0.70) and good calibration (Hosmer–Lemeshow goodness-of-fit
p
-value of 0.77).
Conclusion
Our proposed risk score, easily obtainable on day of discharge, distinguishes patients at high risk for readmission over 90 days following CRS/HIPEC. This score has the potential to target high-risk individuals for intensive follow-up and other interventions.
Background
Appendiceal mucinous neoplasms (AMNs) with disseminated disease (pseudomyxoma peritonei) are heterogeneous tumors with variable clinicopathologic behavior. Despite the development of ...prognostic systems, objective biomarkers are needed to stratify patients. With the advent of next-generation sequencing (NGS), it remains unclear if molecular testing can improve the evaluation of disseminated AMN patients.
Methods
Targeted NGS was performed for 183 patients and correlated with clinicopathologic features to include American Joint Committee on Cancer/World Health Organization (AJCC/WHO) histologic grade, peritoneal cancer index (PCI), completeness of cytoreduction (CC) score, and overall survival (OS).
Results
Genomic alterations were identified for 179 (98%) disseminated AMNs. Excluding mitogen-activated protein kinase genes and
GNAS
due to their ubiquitous nature, collective genomic alterations in
TP53
,
SMAD4
,
CDKN2A
, and the mTOR genes were associated with older mean age, higher AJCC/WHO histologic grade, lymphovascular invasion, perineural invasion, regional lymph node metastasis, and lower mean PCI (
p
< 0.040). Patients harboring
TP53
,
SMAD4
,
ATM
,
CDKN2A
, and/or mTOR gene alterations were found to have lower OS rates of 55% at 5 years and 14% at 10 years, compared with 88% at 5 years and 88% at 10 years for patients without the aforementioned alterations (
p
< 0.001). Based on univariate and multivariate analyses, genomic alterations in
TP53
,
SMAD4
,
ATM
,
CDKN2A
, and/or the mTOR genes in disseminated AMNs were a negative prognostic factor for OS and independent of AJCC/WHO histologic grade, PCI, CC score, and hyperthermic intraperitoneal chemotherapy treatment (
p
= 0.006).
Conclusions
Targeted NGS improves the prognostic assessment of patients with disseminated AMNs and identifies patients who may require increased surveillance and/or aggressive management.
Background and Objectives
Ocular melanoma has a predilection for liver metastases. Systemic treatment is ineffective and the optimal regional therapy approach is poorly defined. Isolated hepatic ...perfusion (IHP) with melphalan has emerged as a viable treatment option, however a subset of patients are not candidates for this treatment. We therefore sought to determine if melphalan could be safely administered via the hepatic artery for these patients.
Methods
A retrospective review of patients treated with hepatic artery infusion (HAI) of melphalan was undertaken. All patients had contraindications to IHP and were without other therapy options. Melphalan infusion was repeated every four weeks with consideration for dose escalation in the absence of toxicity or significant disease progression.
Results
Fourteen patients were treated with HAI of melphalan from 2010 to 2015. All patients had hepatic dysfunction or prohibitive tumor volume precluding IHP. There were no procedure‐related complications. Three patients (21%) died within 30 days and the median survival was 2.9 months. Elevated baseline bilirubin > 2.5 mg/dL was associated with worse overall survival (0.93 vs 6.3 months, P < 0.05).
Conclusion
HAI of melphalan is safe and feasible for patients with metastatic ocular melanoma. Further study to determine the optimal utilization of this treatment approach is warranted.
Background
Diagnostic terminology and grading of primary appendiceal mucinous neoplasms lacks uniformity. We sought to identify discordance in pathologic reporting by reviewing pathology slides for ...cases referred to our institution.
Methods
Using guidelines from Peritoneal Surface Oncology Group International (PSOGI) and American Joint Committee on Cancer 8th edition (AJCC8), we compared diagnostic terminology/grading of primary appendiceal mucinous neoplasms (
n
= 115) between pathology reports from referring institutions and review of slides by pathologists at our high-volume institution.
Results
There was discordance in pathologic terminology and grading of primary appendiceal mucinous neoplasms between referring institutions and our institution in 28% and 50% of patients, respectively. In particular, 24% of patients referred with mucinous adenocarcinoma (MACA) had LAMN on our review, and a higher grade MACA was found in 48% of patients referred with low-grade (G1) MACA and 16% of patients referred with high-grade (G2) MACA following our review. Discordance in tumor grade between primary and metastatic disease was seen in 19% of cases based on referred primary tumor grading compared with only 4% following our review. Systemic chemotherapy was unnecessarily administered to four cases of LAMN (6%) and inappropriately not administered to four cases of MACA (6%) before referral due to inaccurate diagnosis/grading by referring institutions.
Conclusions
We found significant discordance in diagnostic terminology/grading of primary appendiceal mucinous neoplasms following review of referred cases. Inaccurate pathologic assessment was associated with overtreatment or undertreatment with chemotherapy. These data highlight the need for pathologic review of such rare cases at high-volume centers.
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