Currently, rates of referral of patients with peritoneal metastasis in the United States who qualify for cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) are low, in part because of the misperception of high morbidity and mortality rates. However, patients requiring major gastrointestinal surgical procedures with similar complication rates are routinely referred.
Objective
To evaluate the relative safety of CRS/HIPEC.
Design, Setting, and Participants
Retrospective cohort study of 34 114 patients who underwent CRS/HIPEC, right lobe hepatectomy, trisegmental hepatectomy, pancreaticoduodenectomy, and esophagectomy between January 1, 2005, and December 31, 2015, included in the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) database. Data analysis was performed in 2018.
Main Outcomes and Measures
Data from the NSQIP database were used to compare perioperative and 30-day postoperative morbidity and mortality rates of CRS/HIPEC (1822 patients) with other, well-accepted, high-risk surgical oncology procedures: right lobe hepatectomy (5109 patients), trisegmental hepatectomy (2449 patients), pancreaticoduodenectomy (Whipple) (16 793 patients), and esophagectomy (7941 patients).
Results
For 34 114 patients, median (interquartile range [IQR]) age was 63 (55-71) years and 42% were female. Patients undergoing CRS/HIPEC tended to be younger, with a median age of 57 years, and esophagectomy had the highest median (IQR) American Society of Anesthesiologists classification (3 [3-3]). When compared with CRS/HIPEC, higher complication rates were reported in the following categories: (1) superficial incisional infection in Whipple and esophagectomy (5.4% [95% CI, 4.4%-6.4%] vs 9.7% [95% CI, 9.3%-10.1%] and 7.2% [95% CI, 6.6%-7.8%], respectively;P < .001); (2) deep incisional infection in Whipple (1.7% [95% CI, 1.1%-2.3%] vs 2.7% [95% CI, 2.5%-2.9%];P < .01); (3) organ space infection in right lobe hepatectomy (7.2% [95% CI, 6.0%-8.4%] vs 9.0% [95% CI, 8.2%-9.8%];P = .02), trisegmental hepatectomy (12.4% [95% CI, 11.1%-13.7%];P < .001), and Whipple (12.9% [95% CI, 12.4%-13.4%];P < .001); and (4) return to the operating room for esophagectomy (6.8% [95% CI, 5.6%-8.0%] vs 14.4% [95% CI, 13.6%-15.2%];P < .001). Median (IQR) length of hospital stay was lower in CRS/HIPEC (8 [5-11] days) than Whipple (10 [7-15] days) and esophagectomy (10 [8-16] days) (P < .001). Overall 30-day mortality was lower in CRS/HIPEC (1.1%; 95% CI, 0.6%-1.6%) compared with Whipple (2.5%; 95% CI, 2.3%-2.7%), right lobe hepatectomy (2.9%; 95% CI, 2.4%-3.4%), esophagectomy (3.0%; 95% CI, 2.6%-3.4%), and trisegmental hepatectomy (3.9%; 95% CI, 3.1%-4.7%) (P < .001).
Conclusions and Relevance
Comparative analysis revealed CRS/HIPEC to be safe, often safer across the spectrum of NSQIP safety metrics when compared with similar-risk oncologic procedures. Patient selection was important in achieving observed outcomes. High complication rates are a misperception from early CRS/HIPEC experience and should no longer deter referral of patients to experienced centers or impede clinical trial development in the United States.
The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods.Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed.Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively.BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.
<p>The genomic landscape of CF- and HF-resistant prostate cancer cells. <b>A,</b> Schematic of experimental design and workflow. <b>B,</b> Somatic SNV count for CF- vs. HF-resistant cells. CF-resistant cells gained twice more SNVs than HF (<i>P</i> = 0.1; Mann–Whitney <i>U</i> test). <b>C,</b> SNVs in cancer driver genes. Presented are all driver genes that are predicted to be strongly influenced by SNVs. Considered are SNVs that were identified in all three replicates for each cell type. Top, single-base substitution types. Bottom, the predicted annotation. <b>D,</b> Gained SNVs converged on partly similar cancer mutational signatures. Most signatures of known etiology, irrespective of the treatment schedule, are associated with defective DNA mismatch repair. Signature etiologies: SBS5, unknown; SBS26 and SBS15, defective DNA mismatch repair; SBS1, spontaneous deamination of 5-methylcytosine; SBS14, concurrent polymerase epsilon mutation and defective DNA mismatch repair; SBS20, concurrent <i>POLD1</i> mutations and defective DNA mismatch repair; SBS44, defective DNA mismatch repair. <b>E,</b> Somatic SV counts for CF- and HF-resistant cells. The number of somatic SVs is similar between CF- and HF-resistant cells (<i>P</i> = 1; Mann–Whitney <i>U</i> test). <b>F,</b> Distinct SVs in CF-resistant cells compared to HF across the genome. Considered are SVs that were identified in all three replicates for each cell type. Chromosome numbers are presented on the <i>x</i>-axis. The colored lines represent types of SVs: DEL, deletion; DUP, duplication; INV, inversion; TRA, translocation. <b>G,</b> Fusion transcripts that were identified in either CF- and/or HF-resistant cells. Purple, the fusion transcript was identified; white, the fusion transcript was not identified. The results are presented for three replicates for each cell line.</p>
<p>Fractionation-dependent protein profiles in radioresistant cells. <b>A,</b> The difference in relationships of consensus-module eigengenes and cellular fractions between CF- and HF-resistant cells. The colors represent the difference in correlations between consensus module eigengenes and a specific subcellular fraction of HF-resistant cells compared to CF: Blue, a higher correlation in CF-resistant cells; Red, a higher correlation in HF-resistant cells. At the top, each color represents a module, which is a detected group of positively correlated genes that are highly interconnected. <b>B,</b> Gene ontology enrichment of module genes for biological processes. The top two enrichments for each module are presented. <b>C,</b> Differences in protein abundances of driver, across different subcellular fractions and in whole cell lysates. Main, protein Cohen’s d effect sizes of significant proteins across cell fractions. Only significant changes at the level of FDR ≤ 0.025 were plotted. The dot color is the directionality: magenta and green represent upregulation and downregulation, respectively, toward CF- or HF-resistant cells. Right, the consensus modules that each gene was assigned to. For all figures, three replicates were used for CF- and HF- resistant cells. For the parental cells, at least two replicates were used.</p>
Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-dependent kinase 5 (CDK5) in neurodegenerative disorders. CDK5 has been implicated in a number of cancers, most recently as an oncogene in colorectal cancers. Our lab synthesized and characterized CP668863 - now called 20-223. In our established colorectal cancer xenograft model, 20-223 reduced tumor growth and tumor weight indicating its value as a potential anti-CRC agent. We subjected 20-223 to a series of cell-free and cell-based studies to understand the mechanism of its anti-tumor effects. In our hands, in vitro 20-223 is most potent against CDK2 and CDK5. The clinically used CDK inhibitor AT7519 and 20-223 share the aminopyrazole core and we used it to benchmark the 20-223 potency. In CDK5 and CDK2 kinase assays, 20-223 was ∼3.5-fold and ∼65.3-fold more potent than known clinically used CDK inhibitor, AT7519, respectively. Cell-based studies examining phosphorylation of downstream substrates revealed 20-223 inhibits the kinase activity of CDK5 and CDK2 in multiple CRC cell lines. Consistent with CDK5 inhibition, 20-223 inhibited migration of CRC cells in a wound-healing assay. Profiling a panel of CRC cell lines for growth inhibitory effects showed that 20-223 has nanomolar potency across multiple CRC cell lines and was on an average >2-fold more potent than AT7519. Cell cycle analyses in CRC cells revealed that 20-223 phenocopied the effects associated with AT7519. Collectively, these findings suggest that 20-223 exerts anti-tumor effects against CRC by targeting CDK 2/5 and inducing cell cycle arrest. Our studies also indicate that 20-223 is a suitable lead compound for colorectal cancer therapy.
