Systemic chemotherapy in patients with unresectable pseudomyxoma peritonei from low-grade appendiceal mucinous neoplasms: a case series

Introduction

Appendiceal neoplasms are rare malignancies with a wide spectrum of pathologic subtypes, the least aggressive of which are low-grade appendiceal mucinous neoplasms (LAMNs). For patients diagnosed with peritoneal metastases and pseudomyxoma peritonei (PMP) secondary to LAMN primary tumors, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has become the standard of care with a median survival as high as 20 years after complete cytoreduction (1). In cases of unresectable disease, however, treatment options remain limited. In a study of 186 patients receiving modern chemotherapy regimens for unresectable appendiceal cancer, progression-free survival (PFS) was noted for up to 7.6 months; importantly, however, this study focused on a heterogeneous population including higher grade disease and adenocarcinoma patients (2). Smaller studies have also indicated a possible benefit from folinic acid, fluorouracil, and oxaliplatin (FOLFOX), mitomycin C/capecitabine, or Celecoxib/Myrtol in patients with unresectable PMP, though none have been performed specifically focusing on low grade pathology (3-6). In this case series, we describe our experience with systemic chemotherapy in a series of patients with unresectable PMP secondary to LAMNs. This article is written in accordance with the AME Case Series reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-440/rc).

Case presentation

Patient selection

A retrospective analysis was performed of all patients presenting to the University of Chicago Medical Center with PMP from LAMN between 2016–2020. Within this group, patients were included if they had biopsy-proven LAMN that was deemed to be unresectable following diagnostic laparoscopy with full evaluation of peritoneal cancer index (PCI) score to determine resectability. Patients were also only included if they received systemic chemotherapy as part of their treatment after being diagnosed with unresectable disease. Patients with prior surgeries including primary tumor resection and attempted debulking were eligible for inclusion.

Data collection

A comprehensive chart review was performed for each patient to collect information on demographic factors, disease characteristics including PCI, prior surgical treatment, and chemotherapy regimens. Based on the standard practice at The University of Chicago Medical Center, patients were typically seen every 3–6 months in clinic while undergoing chemotherapy. Routine follow-up visits included monitoring of biomarker levels, including carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). Most visits also included serial imaging with either computed tomography (CT) or magnetic resonance imaging (MRI) scans. Repeat diagnostic laparoscopy was performed in several patients to assess response to treatment. Dates of disease progression for our analyses were based on the first instance of either increasing biomarker levels, increased disease burden on CT/MRI, or observed increase in PCI on diagnostic laparoscopy. Follow-up length and PFS were measured from the date of chemotherapy initiation. Biomarker response was evaluated using a paired t-test with baseline CEA/CA 19-9 levels at the time of chemotherapy initiation as well as the lowest subsequent value after beginning systemic therapy (Version 9.1.2 for MacOS, GraphPad Software, San Diego, CA, USA). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Retrospective collection of patient data for this case series was approved by the institutional review board of the University of Chicago Medical Center (protocol # 19-0793). The requirement for informed consent was waived given the retrospective nature of the study.

Patient characteristics

Seventy-two patients were identified over the study time period who underwent treatment for PMP secondary to LAMN at The University of Chicago Medical Center. Of these, five patients were identified for inclusion based on receiving systemic chemotherapy for unresectable disease (Table 1). The five included patients had a median age of 54 (range, 42–70) years and were 60% male; 60% were non-Hispanic White, with the other 40% indicating a multiracial background. All patients had undergone surgical treatment prior to beginning systemic chemotherapy, including one patient with a recurrence following previous CRS/HIPEC. None had undergone any prior systemic chemotherapy or radiation therapy. Each patient had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 at the time of chemotherapy initiation.

Treatment characteristics

The five patients described here had extensive disease burden with a median PCI of 39 (range, 35–39). All patients had biopsy-proven low-grade disease following diagnostic laparoscopy. Patients underwent a median of 7 cycles of first-line chemotherapy (range, 6–26) with the most common regimen being FOLFOX (80%) followed by folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) (20%). Two patients received single agent chemotherapy with fluorouracil (5-FU) or capecitabine or capecitabine following first-line chemotherapy, and 60% of patients received bevacizumab as well. No anti-EGFR agents or immunologic agents were used.

Treatment response

The first sign of progression following chemotherapy initiation was most often based on biomarker increase (40%) or clinical deterioration (40%), with one patient having initial radiographic progression (Figure 1). Median PFS following chemotherapy initiation was 10.3 (range, 3.2–21.4) months, with a median overall follow-up time of 21.5 months. Four patients had elevated CEA at baseline, with a trend toward a CEA response after receiving chemotherapy (mean 337.2 ng/mL at baseline vs. 269.4 ng/mL best response; P=0.15, paired t-test). CA 19-9 was only elevated at baseline for one patient, and no significant change was seen after beginning treatment within the cohort (mean 26.4 U/mL at baseline vs. 21.6 U/mL best response; P=0.24, paired t-test). No patients demonstrated an imaging response to chemotherapy, and none became resectable.

Figure 1 Baseline levels and best response following chemotherapy initiation for (A) CEA (mean 337.2 ng/mL at baseline vs. 269.4 ng/mL best response; P=0.15) and (B) CA 19-9 (mean 26.4 U/mL at baseline vs. 21.6 U/mL best response; P=0.24). CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; ns, non-significant.

Discussion

Unresectable PMP due to primary LAMNs is a rare diagnosis with limited treatment options.

In this report, we describe the use of oxaliplatin-based systemic chemotherapy as a potential treatment for patients who are no longer surgical candidates. To our knowledge, this is the first description of the use of chemotherapy specifically within this focused population.

Each patient in this study presented with extensive disease and a median PCI of 39 (range, 35–39), representing the most advanced subset of LAMN patients. Though this is a small sample size, our finding of a median PFS of 10.3 months compares well with previous studies that have evaluated survival in patients with unresectable PMP from various etiologies including LAMNs. In one comparable study, a PFS of 7.6 months was observed following chemotherapy initiation, though the patient population included higher grade appendiceal neoplasms (2). Our patients also demonstrated a trend toward a biomarker response in CEA, though we were unable to show a strong relationship between biomarker response and PFS. Whether this downward trend in tumor markers following chemotherapy suggests a treatment benefit cannot be discerned, though there is some evidence that in colorectal cancer, CEA levels following chemotherapy can correspond to response and are associated with prognosis (7).

The first published studies on chemotherapy for PMP suggested that chemotherapy had limited utility for PMP patients. The earliest of these was a retrospective study of 17 patients with PMP of appendiceal origin with unspecified pathology conducted by Smith et al. at between 1952 to 1989 (8). Within this cohort, of which 35% received chemotherapy, median OS was 75 months and did not differ based on receipt of systemic chemotherapy. A contemporary analysis by Gough et al. retrospectively described 29 patients with PMP of appendiceal origin of unknown histologic grade from 1957 to 1983 who underwent surgery with or without postoperative systemic chemotherapy and found that adjuvant treatment had a significantly adverse effect on OS (9). Similarly, Baratti et al. found that in 26 patients with peritoneal mucinous carcinomatosis (PMCA) and 78 patients with disseminated peritoneal adenomucinosis (DPAM), treatment with systemic chemotherapy prior to CRS/HIPEC was associated with worse OS and PFS (10). Though these studies demonstrated poor results with the early use of chemotherapy in PMP patients, their validity to guide current treatments are limited by the now outdated chemotherapy regimens they used including monotherapy with 5-FU, vincristine, cyclophosphamide, and melphalan.

A further challenge in evaluating previous studies with heterogeneous populations is selection bias in patients receiving chemotherapy. For example, Chua et al. retrospectively reviewed a multi-institutional registry of 2,298 patients who underwent CRS for PMP of appendiceal mucinous neoplasm origin, 377 of whom received preoperative systemic chemotherapy (11). On multivariate analysis, prior chemotherapy treatment was associated with worse OS and PFS, but the majority of chemotherapy recipients had PMCA rather than less aggressive DPAM. Similarly, Shaib et al. investigated 163 patients who underwent CRS/HIPEC with or without systemic chemotherapy between 1990 and 2010 for AMNs with peritoneal spread, 60 of whom had DPAMs and 88 of whom had PMCA (12). Systemic chemotherapy was associated with a worse OS, though it was also more likely to be given in patients with higher-grade histology.

Other studies have had more promising results in unresectable PMP, even with the use of alternative regimens. Raimondi et al. studied capecitabine and cyclophosphamide in 23 patients with unresectable or relapsed low-grade PMP of presumed appendiceal origin, while Pietrantonio et al. studied capecitabine and bevacizumab in 15 patients with low-grade (n=10) or high-grade (n=5) PMP of appendiceal origin who developed progressive disease despite CRS/HIPEC (13,14). Raimondi et al. found a median PFS of 9.5 months and disease control rate of 74% though no partial or complete response in any patients, while Pietrantonio et al. found a median PFS of 8.2 months and a partial response rate of 20%. A 2008 study conducted by Farquharson et al. assigned 40 patients with unresectable PMP, 27 of which had DPAM, to receive systemic mitomycin and capecitabine (5). Of 39 assessable patients, 15 patients saw reductions in mucinous deposits or stabilization of disease with 2 able to undergo eventual curative-intent CRS/HIPEC despite being deemed unresectable at first. Within this group, 11 patients saw reductions in CEA by more than 50% and there was a statistically significant reduction in both CEA (P=0.001) and carbohydrate antigen 125 (CA 125) (P=0.002) following treatment, though the authors noted that there was no relationship between treatment response and change in tumor marker level. This is consistent with findings from other studies, which have shown that while various tumor makers such as CEA, CA 19-9, and CA 125 are elevated in metastatic peritoneal disease and decline following either surgical or chemotherapeutic treatment, the prognostic value of these changes, and whether they signify adequate response to treatment, is relatively unclear (15-18). In our study, four patients demonstrated a trend toward biomarker response in CEA levels, though given our small sample size and relatively short time horizon, we cannot conclude that this trend alone necessarily signified disease control.

While these studies demonstrated encouraging results with alternative regimens, regimens based on oxaliplatin, 5-fluorouracil, and irinotecan are the most often used in patients with appendiceal cancer, often based on data from similarly staged colorectal cancer patients (19-25). Accordingly, these were the regimens used in each of the patients in the current study.

Data from Shapiro et al. in a 2010 review of 186 patients diagnosed with appendiceal neoplasms between 2000 and 2005, which included patients with high-grade disease, low-grade disease, and adenocarcinomas, represented the first large dataset in this population with modern chemotherapy regimens (2). Of these, 54 were suboptimal surgical candidates and received systemic chemotherapy, of which 16 also received HIPEC. The authors found a PFS of 7.6 months and an OS of 56 months with 30 patients (55.6%) achieving disease control. The PFS of 10.3 months observed in our cohort is in line with these findings, particularly considering the inclusion of patients with higher grade disease in the Shapiro paper. Importantly, this was the earliest description of a population receiving modern regimens for unresectable PMP, as well as one of the first touse vascular endothelial growth factor (VEGF) inhibitors as an adjunct. In a later analysis from the same institution, Choe et al. retrospectively reviewed the MD Anderson Cancer Center tumor registry for patients with appendiceal cancers not amenable to surgical resection treated with systemic chemotherapy with or without biologic agents (26). The use of bevacizumab improved both OS and PFS compared to those who received systemic chemotherapy alone across all histologic subtypes, though it appears that the majority of the appendiceal cancers were adenocarcinomas. A separate study by Jimenez et al. in 59 patients with peritoneal carcinomatosis from appendiceal cancer who had previously undergone CRS/HIPEC (15 with DPAM, 44 with PMCA) found that receipt of bevacizumab was not associated with survival (27).

Building on these early findings, recent studies in unresectable PMP represent the most comparable studies to our cohort. Pietrantonio et al. retrospectively evaluated 20 patients with unresectable or recurrent PMP from low- and high-grade AMNs who were treated with FOLFOX-4 between 2011 and 2013 (3). They report a 20% partial response rate and a 65% disease control rate with a median PFS of 8 months and OS of 26 months using FOLFOX, similar to previously reported data by Shapiro et al. While this study used a single, modern chemotherapy regimen comparable to our cohort and specifically targeted patients with unresectable disease, the authors did not differentiate outcomes based on histologic grade. As a result, it is difficult to compare these findings to our own. Hiraide et al. performed a similar retrospective review of 6 patients with unresectable PMP who were treated with mFOLFOX6 (4). The authors found a disease control rate of 87.5%, a median PFS and OS of 13 and 28 months, respectively, and a decline in CEA and CA 19-9 levels in 5 patients. This cohort of patients included mostly high grade appendiceal adenocarcinoma, however, as well as a patient with ovarian cancer and one with a urachal primary. Finally, Shen et al. recently published a prospective study in which 24 patients with inoperable low-grade mucinous appendiceal adenocarcinoma with mucinous peritoneal carcinomatosis were randomized to either 6 months of observation followed by chemotherapy, or 6 months of initial chemotherapy followed by observation (28). Chemotherapy regimens consisted mostly of single agent fluorouracil or capecitabine, but some patients also received doublet chemotherapy and 5 received bevacizumab. The authors found no significant difference in tumor growth during observation versus during treatment, nor any difference in OS, with a median OS of 76.0 (range, 8.6–95.5) months in the observation-first group versus 53.2 (range, 8.1–64.1) months in the treatment-first group. While these recent studies, used modern chemotherapeutic regimens in patients with unresectable peritoneal disease from appendiceal primaries, there are no previous studies to our knowledge that specifically address the role of systemic chemotherapy in unresectable peritoneal disease secondary to LAMNs. All aforementioned studies are described in Table 2.

There are multiple limitations to interpreting the results from our cohort of patients. The chief limitation is of course our small sample size and retrospective design, which is attributable to both the rarity of this disease and the infrequent use of systemic chemotherapy in this low-grade population. Multicenter trials are likely needed in the future to build a larger population to assess the effect of chemotherapy in unresectable LAMN. This would require either significant cross-collaboration and data-sharing amongst institutions or the creation of a large multiinstitutional registry with standardized data inputs. It would also require a broad consensus on how to classify and describe LAMNs, as one of the largest obstacles to a multiinstitutional registry is the heterogeneity with which people currently thinkg about this disease. A further challenge to our study and the other studies described is the difficulty in accurately evaluating disease progression or recurrence. As shown by Sugarbaker et al. in adenocarcinoma patients, radiographic and biomarker progression are less sensitive than histopathologic and intra-operative evaluation, raising the possibility that actual PFS is shorter in this cohort (29).

Conclusions

Despite the limitations with our study, it is the first to specifically assess the use of oxaliplatin-based systemic chemotherapy in patients with metastatic peritoneal disease from LAMNs when surgery is not feasible. Larger, prospective studies will be needed to define the exact benefit of chemotherapy in unresectable LAMNs.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the AME Case Series reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-440/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-440/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-440/coif). A.S. reports the following potential conflicts of interest: Advisory Board: Merus, Guardant, Pfizer, Regeneron/Sanofi and Catalyst Pharmaceuticals; Speaking/Presentation of Poster: Great debates in GI oncology, Takeda, OncLive, OSCO/ASCO Direct, ACPMP, Cholangiocarcinoma Summit, Cholangiocarcinoma Foundation, ASCO Advantage; Research support (to institution): Hutchison MediPharma, Takeda, Merck, Verastem Oncology, Turning Point Therapeutics, Gritstone, Bolt Therapeutics, BMS, Pfizer, Astellas, Oncologie, Macogenics, Seattle Genetics, Amgen, Daiichi, Lilly, Jacobio, Astrazeneca, Jazz pharma, Agenus; Consultant: KLJ associates; Participant of the Cure CRC Summit 12/2023. K.K.T. reports that he consulted for Merck over 3 years ago but no longer has an existing relationship. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Retrospective collection of patient data for this case series was approved by the institutional review board of the University of Chicago Medical Center (protocol # 19-0793). The requirement for informed consent was waived given the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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