Patients with peritoneal surface malignancies (PSM) represent a heterogenous group ranging from primary peritoneal cancer to peritoneal metastases secondary to various primaries. Since its introduction in the 1980s, Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS-HIPEC) has revolutionized the management of peritoneal malignancies (1, 2). When once associated with a dismal prognosis, selected patients receiving optimal treatment now boost a 10 year survival, with rates of up to 63% reported in patients with pseudomyxoma peritonei (1, 3–6). CRS-HIPEC is now widely regarded as central to the management of PSM in selected patients (6–8).

However, PSM are frequently clinically occult with patients presenting insidiously and with nonspecific symptoms thereby posing significant diagnostic challenges (9–16). Establishing a histological diagnosis often proves challenging, and even at the tertiary level, interpretation of potentially indeterminate imaging characteristics and difficulties in determining histological characteristics result in further delay towards timely diagnosis and treatment of such malignancies (9, 17). In addition, general awareness, and knowledge amongst the physician population towards PSM is poor. In a locally conducted survey, up to 50% of survey participants acknowledged that they were unfamiliar with the disease entity and were unaware of the presence of local PSM specialist units for referrals (18), representing a potential source contributing to delayed specialist review.

Several studies suggest a significant correlation between delays incurred in diagnostic evaluation and poorer oncologic outcomes in various tumor histologies (19–25). While the current evidence in literature concurs that delivery of curative surgery in an expedient manner is crucial to the optimal management of PSM (19, 26), the causative factors and overall impact of delays incurred from patient and healthcare-related factors on oncologic outcomes has not been well-studied.

Therefore, we aim to evaluate the incidence and causes of delayed presentation and surgery and examine its impact on oncological outcomes in patients with PSM.

Our study demonstrates insight into the factors contributing to treatment delays in PSM, which consist of several potentially actionable causes predominantly attributable to provider-related delays incurred in work processes involved in transfer of care between healthcare institutions (43.1%). These findings represent, to our knowledge, the first attempt in current literature at describing actionable factors contributing to treatment delays in peritoneal malignancies. Our findings also suggest that delayed presentation may result in poorer overall survival and disease-free survival among patients with PSM. Interestingly, however, a delayed time to treatment of >90 days did not result in any significant difference in overall survival or disease-free survival in our study cohort. While the literature consistently supports the early diagnosis and treatment of peritoneal malignancies (27–29) the quantitative effect of diagnostic and treatment delays on oncologic outcomes in such patients has not been sufficiently studied. Furthermore, given the highly litigated nature of oncologic practice in general, delayed evaluation and treatment of such conditions may prove also to be a significant source of financial and legal burden to healthcare systems worldwide (30). Therefore, quantifying the causative factors of treatment delays and identifying the impact of such treatment delays on oncologic outcomes is crucial to addressing public health concerns pertaining to the evaluation and treatment of peritoneal malignancies.

A large proportion of study patients suffered delays attributable to provider-related delays incurred by processes involved in transfer of care between institutions (43.1%) and delayed presentation (31.0%) predominantly contributed by a lack of patient awareness regarding signs and symptoms of peritoneal disease. These findings suggest that treatment delays are predominantly influenced by factors within the healthcare system that can be further mitigated with improved professional education and streamlining of administrative processes. Considering the well-documented challenges involved in evaluation of peritoneal malignancies given their significant heterogeneity, varying nature of initial presentation and overall rare occurrence (14, 15, 17, 31–34), healthcare professionals at large would benefit from better awareness on the initial presentations, appropriate evaluation strategies and treatment options for peritoneal malignancies. Additionally, treatment delays incurred here are also contributed at least in part by patients’ failure to recognize symptoms that suggest underlying peritoneal malignancies which resulted in delayed presentation to primary care. Findings from our study similarly highlight the importance of early patient recognition of symptoms and early appropriate clinical evaluation in optimizing treatment outcomes for peritoneal surface malignancies.

This study’s findings on the association between delayed presentation and poorer overall survival and disease-free survival must be interpreted with due consideration given to the limited sample size and relatively short follow up duration of 12.4 months post CRS-HIPEC, also taking into consideration the effects of disease biology on symptom progression and presentation. The detrimental effect of delayed presentation on survival outcomes may potentially be attributable to poorer disease biology, with more indolent biology presenting with more clinically occult symptoms (28, 29) which translates to a delayed presentation to medical attention, and ultimately poorer survival outcomes. However, our study notably demonstrated that tumor histology and patient comorbidities appear relatively consistent in both non-delayed and delayed time to treatment groups ( Table 2 ), suggesting that such factors were not likely to have influenced the duration of time to treatment. This study further demonstrated an independent association between delayed presentation and reduced disease free survival which persisted after correction for tumor histology (HR 4.67, 95% CI 1.11-19.69, p=0.036), which suggests that delayed presentation of more than 60 days may adversely impact disease outcomes in PSM regardless of the contributory primary histology. The persistent correlation between delayed presentation and poorer survival outcomes after correction for histology would, however, suggest that delayed presentation results in poorer survival due to other independent factors, which has been similarly demonstrated for some other biologically distinct malignancies, delayed presentation in soft tissue sarcoma for instance having demonstrated to be associated with higher likelihood of distal metastases on diagnosis, portending poorer prognoses and poorer survival outcomes (23).

While age does not appear to significantly influence survival outcomes in patients with PM based on our data, older patients 60 years of age and above with peritoneal malignancies demonstrate a tendency towards poorer survival (HR 5.39, 95% CI 0.84-34.72, p=0.076) and lower DFS (HR 3.76, 95% CI 0.92-15.30) compared to younger patients ( Table 3 ). This emphasizes the importance of early detection of PM in particular for older patients, although more studies with a longer follow up duration would be required to prove a significant correlation between age and oncological outcomes in PM.

This study bears several other limitations. Firstly, data collected on pre-hospital symptoms relies on patient-reported duration and severity of symptoms which may bear an inherent recall bias at the time of consult. Secondly, median follow up time was relatively short (12.4 months) with a small sample size of 58, which also did not include any patients previously treated with neoadjuvant chemotherapy or patients with PSM secondary to previously treated primary tumors, thus limiting the analytic power of this study as well as generalizability of results to a small subset of patients with primary PSM who received upfront CRS-HIPEC. Thirdly, this study does not account for the impact of adjuvant treatment regimens on the overall outcomes of patients undergoing CRS-HIPEC. With greater amounts of data obtained from further follow up, further studies can be conducted on the individual treatment outcomes tailored to peritoneal malignancies of each subtype with further subgroup analyses being performed these cases.

Treatment delays are predominantly contributed by healthcare-provider related factors which can be further optimized by streamlined referral processes and wider awareness towards evaluation and management of peritoneal malignancies among healthcare workers. Delayed presentation of >60 days appears to be associated with poorer disease free survival in index-presentation peritoneal surface malignancies receiving upfront CRS-HIPEC. Further studies evaluating the effects of treatment delays on survival outcomes in peritoneal malignancies would be useful in improving treatment protocols and optimizing outcomes.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Centralized Institutional Review Board (CIRB) of Singapore Health Services, CIRB reference number 2018/2638. The patients/participants provided their written informed consent to participate in this study.

JKT, JSM and CSC contributed to conception and design of the study. JKT, JCO and JSM organized the database. JKT and CL performed the statistical analysis. JKT and JSM wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.