Taxane-Based Chemotherapy Is Effective in Metastatic Appendiceal Adenocarcinoma

Abstract

Appendiceal cancer is a rare, orphan disease with no therapies currently approved by the FDA for its treatment. Given the limited data regarding drug efficacy, these tumors have historically been treated with chemotherapy designed for colon cancer. However, an overwhelming body of molecular data has demonstrated that appendiceal adenocarcinoma is a distinct entity with key molecular differences from colon cancer, notably rare APC mutation. Recognizing that APC loss-of-function is thought to contribute to taxane resistance and that taxanes are effective in the treatment of other gastrointestinal tumors, including gastric, esophageal, and small bowel adenocarcinoma, we completed a single-center retrospective study to assess efficacy. In a cohort of 13 patients with metastatic appendiceal adenocarcinoma, treated with taxane chemotherapy the median overall survival was 8.8 months. Of 10 evaluable patients, we observed 3 responses, 4 patients with stable disease, and 3 with progression (30% response rate, 70% disease control rate). The results of this study showing activity of taxane-based chemotherapy in appendiceal adenocarcinoma support further clinical investigation of taxane therapy in this orphan disease.

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The Oncologist, 2023, 28, e1303–e1305
https://doi.org/10.1093/oncolo/oyad263
Advance access publication 20 September 2023
Brief Communication
© The Author(s) 2023. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/
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Received: 29 June 2023; Accepted: 24 August 2023.
Taxane-Based Chemotherapy Is Effective in Metastatic
Appendiceal Adenocarcinoma
JuliaDansby1, AdityaMore1, MohammadZeineddine1, AbdelrahmanYousef1, AlishaBent1,
FarshidDayyani2, RobertWolff1,, MichaelOverman1,, John PaulShen*,1,
1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Division of Hematology/Oncology, UC Irvine Health, Irvine, CA, USA
*Corresponding author: John Paul Shen, MD, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515
Holcombe Blvd., Houston, TX 77030, USA. Email: jshen8@mdanderson.org
Abstract
Appendiceal cancer is a rare, orphan disease with no therapies currently approved by the FDA for its treatment. Given the limited data regarding
drug efficacy, these tumors have historically been treated with chemotherapy designed for colon cancer. However, an overwhelming body of
molecular data has demonstrated that appendiceal adenocarcinoma is a distinct entity with key molecular differences from colon cancer, notably
rare APC mutation. Recognizing that APC loss-of-function is thought to contribute to taxane resistance and that taxanes are effective in the
treatment of other gastrointestinal tumors, including gastric, esophageal, and small bowel adenocarcinoma, we completed a single-center ret-
rospective study to assess efficacy. In a cohort of 13 patients with metastatic appendiceal adenocarcinoma, treated with taxane chemotherapy
the median overall survival was 8.8 months. Of 10 evaluable patients, we observed 3 responses, 4 patients with stable disease, and 3 with pro-
gression (30% response rate, 70% disease control rate). The results of this study showing activity of taxane-based chemotherapy in appendiceal
adenocarcinoma support further clinical investigation of taxane therapy in this orphan disease.
Key words: appendiceal cancer; taxane chemotherapy.
Introduction
Appendiceal tumors encompass a rare and diverse group of
neoplasms, with appendiceal adenocarcinoma (AA) being
the most common histologic subtype.1 Despite a unique nat-
ural history characterized by metastatic spread limited to
the peritoneum, as well as growing evidence that appendi-
ceal tumors are molecularly distinct from colorectal cancer
(CRC),2 current National Comprehensive Cancer Network
(NCCN) guidelines suggest that appendiceal tumors should
be treated with the same chemotherapy as used for CRC.
However, recent prospective and retrospective studies have
called into question the dogma that appendiceal tumors re-
spond to chemotherapy similarly to colon cancer.3,4 In par-
ticular, a prospective, randomized, crossover design trial
showed that patients with low-grade mucinous AAs do not
derive benet from 5-FU-based chemotherapy,4 highlighting
the need to drug development efforts specic to appendix
cancer.
Taxanes have been shown to be ineffective in colorectal
cancer but are active in small bowel adenocarcinoma (SBA).5
It has been reported that APC loss-of-function is a mecha-
nism of taxane resistance.6 Unlike CRC, where APC is mu-
tated in >70% of tumors, APC mutation is uncommon in
subtypes of appendiceal cancer (9.0%).2 We, therefore, hy-
pothesized that taxane chemotherapy would have activity in
AA.
Materials and Methods
The MD Anderson adapted version of the Palantir-Foundry
software system was used to perform an automated query of
the MD Anderson GI Medical Oncology database to identify
patients with AA treated with paclitaxel-based regimens be-
tween 2003 and 2022. Manual chart review was performed to
conrm patients met eligibility criteria and to extract outcome
variables. Eligible patients had pathologic diagnosis of AA,
mucinous adenocarcinoma, signet ring cell adenocarcinoma,
or goblet cell adenocarcinoma, and more than one dose of
taxane-based therapy and were not enrolled in a clinical tri-
al. Radiographic response was assessed retrospectively based
upon the treating physician’s assessment and categorized as
response, stable disease, progression; response could not be
evaluated (NA) if the patient did not have imaging performed
after starting taxane therapy. Biochemical response was eval-
uated based on the percent change in tumor marker before
and after treatment. Patients with a greater than 20% decrease
were categorized as response, less than 20% change as stable,
and greater than 20% increase as progression. Those whose
respective tumor markers were not elevated were indicated as
such, and those whose tumor markers were not measured were
classied as NA. In cases where biochemical response differed
from radiographic response, radiographic response was used
for nal response determination. Median overall survival (OS)
was determined using the Kaplan-Meier method.
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e1304 The Oncologist, 2023, Vol. 28, No. 12
Results
Thirteen patients with AA treated with paclitaxel-based
therapy were identied and met inclusion criteria. Median
age was 64 years (range 29-77) with roughly equal splits
between male and female as well as well, moderate, and
poorly differentiated tumors (Supplementary Table S1).
All 13 patients had inoperable peritoneal disease at time
of treatment, and 4 (30.1%) had prior surgical resection.
The cohort was heavily pretreated with median of 3 prior
lines of therapy (range 1-5), 10 of the 13 had prior treat-
ment with either FOLFOX or CapeOx. Ten patients received
taxane-based combinations (gemcitabine combination in 7,
platinum combination in 2, and uoropyrimidine combina-
tion in 1), 3 received paclitaxel monotherapy. Four of the
combination-treated patients received nab-paclitaxel, the
rest paclitaxel.
The median OS from the start of taxane therapy was 8.77
months (range 0.7-31.0 months, Fig. 1A) with 3 of 13 pa-
tients still alive at time of analysis. Four patients stopped
therapy after 3 or fewer taxane treatments due to either
small bowel obstruction (SBO) or deteriorating perfor-
mance status, median progression-free survival (PFS) for
the remaining 9 patients was 7.4 months (range 0.8-15.5
months, Supplementary Table S1). Median time on treat-
ment was 2.5 months (range 0.2-13.1 months, Fig. 1B)
with 3 patients remaining on treatment at time of analysis.
Of the 10 patients that could be assessed for radiographic
response, 3 showed response, 4 with stable disease, and 3
with progression for a response rate of 30% and a disease
control rate of 70% (Fig. 1C). Of the 9 patients with elevat-
ed CEA, biochemical response was seen in 3 (33%), stable
disease in 3 (33%), and progression in 3 (33%). Of the 6
patients with elevated CA 19-9, biochemical response was
seen in 2 (33%), stable disease in 2 (33%), and progres-
sion in 2 (33%). Two patients received rst-line carbopla-
tin and paclitaxel, both had response; the third responding
patient was treated with gemcitabine and nab-paclitaxel.
Presumably, the addition of a second cytotoxic agent con-
tributed to response, however, the activity of carboplatin
and gemcitabine in appendiceal cancer is unknown. One pa-
tient was initially diagnosed with a primary ovarian tumor
and changed to 5-FU and bevacizumab after 3 cycles once
expert pathology review made diagnosis of AA. The second
patient had concurrent diagnoses of stage III squamous cell
carcinoma of the lung and goblet cell adenocarcinoma of
the appendix and was treated initially with weekly carbo-
platin and paclitaxel with concurrent radiation and then
carboplatin and paclitaxel plus pembrolizumab per NSCLC
guidelines. Treatment with carboplatin and paclitaxel is on-
going, with marked radiographic improvement in peritone-
al carcinomatosis and complete response of NSCLC based
on imaging and endobronchial biopsies. There was not an
associated between grade and radiographic response. Three
of four GNAS mutant tumors did not respond, consistent
with prior reports suggesting intrinsic resistance to therapy
in the case of mutant GNAS.3
Discussion
Complete cytoreductive surgery (CRS) with heated intra-
peritoneal chemotherapy (HIPEC) remains the treatment
of choice for patients with metastatic AA;7 however, for
many patients the extent of peritoneal metastatic disease
precludes this treatment option. There is unfortunately
very little prospective data to guide chemotherapy choice
for these nonoperative patients. To our knowledge, this
is the largest cohort of patients with appendiceal cancer
treated with taxane-based therapy reported in the liter-
ature. Although we recognize the inherent limitations of
this small, retrospective study design, the favorable disease
control rate in a heavily pretreated cohort indicates that
taxane-based chemotherapy is active in AA and should be
further studied in a prospective fashion. These ndings are
consistent with the activity of taxanes in SBA5,8 and are
also consistent with the activity of intraperitoneal injec-
tion of paclitaxel in orthotopic PDX models of appendiceal
cancer.9,10
Funding
This work was supported by the Col. Daniel Connelly
Memorial Fund, the National Cancer Institute
(K22 CA234406) to J.P.S., and the Cancer Center Support
Grant (P30 CA016672), the Cancer Prevention & Research
Institute of Texas (RR180035 to J.P.S., a CPRIT Scholar in
Cancer Research), and a Conquer Cancer Career Development
Award (CDA-7604125121 to J.P.S). to J.P.S. Any opinions,
ndings, and conclusions expressed in this material are those
Figure 1. Outcomes for patients with AA treated with taxane-based therapy. (A) Overall survival from the start of treatment. (B) Time on treatment. (C)
Radiographic response.
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e1305The Oncologist, 2023, Vol. 28, No. 12
of the author(s) and do not necessarily reect those of the
American Society of Clinical Oncology or Conquer Cancer.
Conflict of Interests
Farshid Dayyani reported consulting/advisory relationships
Eisai, Exelixis, Ipsen, and AstraZeneca; honoraria from
Sirtex, Ipsen, and Servier; and research funding to institution
from Amgen, AstraZeneca, BMS, Eisai, Exelixis, Roche, Ipsen,
Natera, and Taiho. Robert Wolff reported royalty payments
from McGraw-Hill, Coeditor of MD Anderson Manual of
Medical Oncology. Michael Overman serves on the scien-
tic advisory board for ACPMP. John Paul Shen reported
consulting/advisory relationships with Engine Biosciences
and NaDeNo Nanoscience; research funding from the NIH,
ASCO, and CPRIT; medical advisory board for ACPMP. The
other authors indicated no nancial relationships.
Author Contributions
Conception/design: M.O., J.P.S. Provision of study material
or patients: A.B., M.O., F.D., R.W., J.P.S Collection and/or as-
sembly of data: J.D., A.M., M.Z., A.Y., J.P.S. Data analysis
and interpretation: J.D., J.P.S. Manuscript writing: J.D., J.P.S.
Final approval of manuscript: All authors.
Data Availability
The data underlying this article are available in the article and
in its online supplementary material.
Supplementary Material
Supplementary material is available at The Oncologist online.
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