Recent research explored the role of chemotherapy in the multimodality treatment of appendix adenocarcinomas, which are rare and aggressive tumors. Study results suggest that patients with positive node status may derive the most benefit from systemic chemotherapy. These findings were recently presented by study author Madeleine C. Strach, MBBS, BMedSc, MPH, from The Christie NHS Foundation Trust, Manchester, U.K., during the 2023 ESMO Sarcoma and Rare Cancers Congress (Abstract 80).
"Appendix adenocarcinomas are rare with an incidence of 1-2 per million and frequently present with peritoneal metastases. Prognosis is poor with 5-year survival less than 50 percent in most cohorts," Strach noted while discussing the rationale and goals of their study. "Data has been challenging to interpret due to heterogenous nomenclature and inclusion of low-grade appendiceal mucinous neoplasms in these cohorts."
The most recent pathology classification is the WHO 2019 classification, according to Strach, who outlined the following definitions:
* Mucinous adenocarcinoma: more than 50 percent mucin and less than 50 percent signet ring cells
* Adenocarcinoma not otherwise specified: less than 50 percent mucin
* Signet ring cell adenocarcinoma: more than 50 percent signet ring cells.
"Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) is the mainstay of treatment," Strach stated. "The role of systemic chemotherapy remains unclear with mixed results from small cohorts. The aim of our study is to evaluate the outcomes of patients with appendix adenocarcinoma as classified by WHO 2019 and look at the role of systemic chemotherapy."
Research Details
The study authors collected data from a prospective database (2005-2021) and included patients with appendix adenocarcinoma undergoing cytoreductive surgery and heated intraperitoneal chemotherapy.
"The peritoneal cancer index is scored by the surgeon and reflects the burden of peritoneal disease," Strach explained. "The cytoreductive score, or CC score, is also calculated by the surgeon at the end of the cytoreductive procedure and is scored from 0 to 3, reflecting a range of no residual disease to high burden residual disease (CC0 [no residual disease, RD], CC1 [<0.25cm RD], CC2 [0.25-2.5cm RD], or CC3 [>2.5cm RD])."
Strach and colleagues categorized patients in receipt of chemotherapy groups: no chemotherapy (none); prior chemotherapy more than 6 months before CRS (prior); chemotherapy within 6 months before CRS or less than 6 months after CC0-1 CRS ([neo]adjuvant); or after CC2-3 CRS or unresectable, recurrent disease (palliative). The primary endpoint of the study was overall survival. Secondary endpoints included progression-free survival, objective response rate, and pathological response. Statistical analysis included Kaplan-Meier survival analysis and Cox multivariate regression.
Study authors identified 1,077 patients with appendix adenocarcinomas between 2005 and 2021. Of those, patients with appendiceal mucinous neoplasms (n=733), goblet cell adenocarcinoma (n=117), colorectal primary (n=8), and other diagnosis (n=3) were excluded. As a result, the total cohort included 216 patients: 141 mucinous adenocarcinoma, 71 adenocarcinoma not otherwise specified, and four signet ring cell adenocarcinoma. A total of 141 patients had peritoneal-only metastasis.
Strach and colleagues performed multivariate analysis for overall survival on 208 patients and for progression-free survival on 209 patients. The median age of included patients was 59 years and 58 percent were female. In this cohort, 147 patients presented with metastatic disease. Of 216 patients, 182 (84%) had CRS/HIPEC (76% mitomycin C), with CC0-1 achieved in 172 (95%). Systemic chemotherapy was given to 97 patients (45%) with the following timing breakdown: 10 percent prior, 6 percent neoadjuvant, 7 percent adjuvant, and 24 percent palliative. The most common chemotherapy regimen used was oxaliplatin/fluoropyrimidine (29%).
After median follow-up of 56 months, the study authors reported a median overall survival of 122 months. The 5-year and 10-year overall survival was 63 percent and 51 percent, respectively. Median progression-free survival was 41 months with 5-year and 10-year rates of 43 percent and 40 percent, respectively. Among patients who received systemic chemotherapy, the objective response rate was 12 percent.
For node-positive patients, median overall survival was not reached for those who had neoadjuvant or adjuvant chemotherapy. The median overall survival was 81 months for those with prior chemotherapy and 28 months for palliative chemotherapy.
Multivariate analysis showed that chemotherapy was associated with a reduced risk of death for patients with positive nodes compared to no chemotherapy, according to Strach, who noted that "we can see that patients who receive neoadjuvant and adjuvant chemotherapy and those who have prior chemotherapy clearly have improved outcomes compared to those who have no chemotherapy in patients with node-positive disease."
Conclusions, Next Steps
This study represents the single largest series of pure appendix adenocarcinomas with long-term follow-up data that evaluates the role of systemic chemotherapy in different disease settings, noted Strach.
"Patients with high burden of residual disease, signet ring cells, and positive lymph nodes had the poorest outcomes," she said. "These groups should be the focus for clinical trials and development of novel therapies.
"This study confirms that positive lymph node status identifies a subgroup of patients with appendix adenocarcinomas who derive the most benefit from systemic chemotherapy," Strach concluded, while acknowledging the limitations of their research. "Despite the large initial cohort, the subgroups are small in numbers [and] retrospective data is impacted by selection bias. We propose a prospective study of chemotherapy in this group."
Catlin Nalley is a contributing writer.