Reply to M.C. Strach et al

We greatly appreciate the letter by Strach et al,¹ which raises very interesting discussion points for our study to define the impact of genomic alterations on the molecular features and clinical behavior of appendiceal adenocarcinomas (ACs).² We agree with the authors that there is a notable paucity of AC studies given the extreme disease rarity, leading to management uncertainty.

Many patients with AC may exhibit long disease-free intervals after a complete cytoreductive surgery (CRS).^3-6 The completeness of cytoreductive (CC) surgery score evaluates overall resection success on a scale from CC0 (no visible residual disease), CC1 (<0.25 cm residual disease), CC2 (0.25-2.5 cm residual disease), and CC3 (residual disease in excess of 2.5 cm).^5,7 CC scores are associated with CRS outcomes in a similar fashion to the intraoperative peritoneal cancer index (PCI), a related metric that we reported in our study to quantify disease burden in nine different abdominal quadrants that is associated with resectability and recurrence risk.^5,7,8 We also reported the number of CRSs per patient as a continuous variable to partially account for the increased disease control benefit seen in patients who undergo multiple surgeries.

Our initial survival analysis examined 149 patients with stage IV metastatic mucinous appendiceal adenocarcinoma (mMAAP), the main predominant subtype of AC. Of 149 patients in this analysis, 126 patients underwent at least one CRS and 107 of these patients (85%) were assessed for overall CC (Table 1). In this mMAAP cohort, 72% of patients (77 of 107) had a CC score of 0 (Table 1). There were no significant differences in CC scores per molecular subtype using the Kruskal-Wallis rank sum test (P = .56). There were also no significant differences in the proportion of patients who exhibited a complete cytoreduction (CC score of 0) versus incomplete cytoreduction (CC score of 1 or more) across molecular subtypes using the chi-square statistical test (P = .29).

TABLE 1.

Completeness of Cytoreduction for Patients With mMAAP

We repeated this analysis in the broader cohort of patients with any type of stage IV metastatic AC, including patients with colonic-type and goblet cell ACs. In the larger cohort, 192 patients received at least one CRS and 162 (84%) were evaluated for overall CC (Table 2). Using the same respective statistical tests as the MAAP cohort, there were no significant differences in the proportion of patients with CC scores per molecular subtype (P = .53) or the proportion of patients in each subtype with a complete (CCO) versus incomplete (CC1 or more) cytoreduction (P = .38).

TABLE 2.

Completeness of Cytoreduction for Patients With Any Metastatic AC

Overall, we believe that completeness of cytoreduction does not represent a major confounder of our findings. Importantly, however, akin to PCI, surgical resectability is dependent on the extent of disease and associated underlying tumor biology. Our previous study provides evidence that certain molecular subtypes show significantly higher intraperitoneal disease burden (GNAS-mutation [mut] predominant) and a lesser (RAS-mut predominant) or greater (TP53-mut predominant) propensity to exhibit destructive stromal penetration of peritoneal tissues. Although surgical completeness was possible to a similar extent among molecular subtypes, numerical trends toward lower CC0 rates in patients with GNAS-mut predominant tumors may be plausibly derived from the underlying molecular characteristics. Randomized clinical trials for subgroups of patients with rare cancers are challenging to accrue, but we agree that investigation of molecular features in prospective translational studies with dedicated AC cohorts, such as the Intraperitoneal Chemotherapy After cytoReductive Surgery (ICARuS: ClinicalTrials.gov identifier: NCT01815359) study, will be crucial to both evaluate the deterministic role of molecular features in disease behavior and engineer improved management algorithms for this unique disease.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Reply to M.C. Strach et al

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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