Does Waiting Time from Diagnosis to Treatment Affect Outcome in Locally Advanced Rectal Cancer? Real World Data Analysis

Introduction: Rectal cancer is a common and lethal disease, with approximately 44,180 new cases of
diagnosed annually in the United States and a five-year survival of 67% [1, 2]. The interval from diagnosis
to chemoradiation treatment, or waiting time (WT), is considered to be an important quality indicator for
cancer care and has been demonstrated to be associated with oncologic outcomes in various cancers [3, 4].
The current recommendation for pre-treatment staging evaluation includes rigid proctoscopy, PET CT,
transrectal ultrasound (TRUS) and often rectal MRI. These diagnostic procedures may significantly
postpone the start of treatment. We aim to examine the effect of WT on overall survival (OS) and disease
free survival (DFS) of rectal cancer patients.
Methods: Retrospective analysis was performed in a detailed database of patients with resectable primary
rectal cancer who underwent chemoradiation between January 2000 and January 2019. Univariate and
multivariate cox proportional hazard regressions were conducted in order to evaluate the effect of WT on
oncological outcomes.
Results: 387 patients were enrolled in our database; of them 297 patients were eligible by the inclusion
criteria. Median WT was 6.3 weeks (IQR 4.3-8.7). Multivariate analysis showed adjusted Hazard Ratio
(HR) for OS increases by 1.07 for each additional week of therapeutic delay in all age groups (p=0.025).
Furthermore, focusing on the majority of patients in the age group 45 - 70 years, adjusted HR for OS
increases by 1.12 for each additional week of therapeutic delay (p=0.011). Adjusted HR for DFS increases
by 1.06 for each additional week of therapeutic delay in all age groups (p=0.045) and an increment by 1.09
for each additional week of therapeutic delay in age group 45-70 years (p=0.02).
Conclusion: Prolonged WT leads to significant poorer overall survival in patients with primary rectal cancer
who underwent chemoradiation and curative surgical treatment. This marks the importance of efficient
diagnostic evaluation and clinical multidisciplinary decision making in a timeframe of 6 weeks in order to
not jeopardize oncological outcomes.


A B S T R A C T
Introduction: Rectal cancer is a common and lethal disease, with approximately 44,180 new cases of diagnosed annually in the United States and a five-year survival of 67% [1,2]. The interval from diagnosis to chemoradiation treatment, or waiting time (WT), is considered to be an important quality indicator for cancer care and has been demonstrated to be associated with oncologic outcomes in various cancers [3,4].
The current recommendation for pre-treatment staging evaluation includes rigid proctoscopy, PET CT, transrectal ultrasound (TRUS) and often rectal MRI. These diagnostic procedures may significantly postpone the start of treatment. We aim to examine the effect of WT on overall survival (OS) and disease free survival (DFS) of rectal cancer patients. Furthermore, focusing on the majority of patients in the age group 45 -70 years, adjusted HR for OS increases by 1.12 for each additional week of therapeutic delay (p=0.011). Adjusted HR for DFS increases by 1.06 for each additional week of therapeutic delay in all age groups (p=0.045) and an increment by 1.09 for each additional week of therapeutic delay in age group 45-70 years (p=0.02).

Conclusion:
Prolonged WT leads to significant poorer overall survival in patients with primary rectal cancer who underwent chemoradiation and curative surgical treatment. This marks the importance of efficient diagnostic evaluation and clinical multidisciplinary decision making in a timeframe of 6 weeks in order to not jeopardize oncological outcomes.
© 2020 Shira Peleg Hasson. Hosting by Science Repository. All rights reserved.

Background
Rectal cancer is a common and lethal disease, with approximately 44,180 new cases diagnosed annually in the United State and a five-year survival of 67% [1,2]. According to current guidelines, the recommended treatment for stage III rectal cancer includes long-term neoadjuvant chemotherapy and radiation therapy (hereafter, chemoradiotherapy) followed by surgery. Diagnostic procedure recommended prior to the initiation of CRT include trans-rectal US and pelvic MRI, aiming at local assessment of the tumor and FDG-PET CT aiming at the assessment of metastatic spread [6]. Adverse effects of delaying radiation treatment on survival is well known in various malignancies, including small cell lung cancer and breast cancer [8,9].
Over the past three decades, the association between WT and mortality has been the subject of several studies based on data from symptomatic colon and/or rectal cancer patients [10,12,13,15,16]. The studies report either no statistically significant association or the waiting time paradox (findings of higher mortality for short delays was caused by hidden confounders like the tumor's speed of growth and/or its ability to spread) [17,20]. According to this theory, aggressive tumors are associated with shorter delays because they are easier to appraise [3]. Most of the studies focus on diagnostic intervals from symptoms to biopsy rather than WT from biopsy to initiation of chemoradiation. A recent study found that prolonged treatment delay does not lead to poorer overall or cancerfree survival in patients with primary colorectal cancer who underwent curative surgical treatment [21].
In Israel, all required diagnostic procedures are accessible and universally reimbursed. Yet, their completion is often prolonged due to long waiting times, thus delaying the start of chemoradiotherapy. We report here on the association between time to treatment and survival in a consecutive population of stage III rectal cancer patients, treated at a single institution.

I Study Design
We performed a retrospective review of a prospectively entered database on 297 consecutive patients with biopsy-proven locally advanced (T3-4 or N1 and/or clinically bulky) low (at or below 5 cm from the anal verge) and mid-(6-11 cm from the anal verge) rectal adenocarcinoma who underwent neoadjuvant therapy followed by radical resection with total mesorectal excision (TME) for curative intent between October 2000 and December 2019.
The examined parameters included date of diagnosis, beginning of radiation therapy, clinical staging, final pathology, imaging modalities, radiation dose and survival data. The pre-treatment staging was based on rigid rectoscopy for localization of the tumor in the rectum, endorectal ultrasonography (EUS), and computerized tomography (CT) of the pelvis for local tumor status, abdominal CT, chest X-ray, and/or chest CT to rule out distant metastases. The neoadjuvant regimen included high-dose radiation therapy of 45-50.4 Gy, usually with concomitant 5fluorouracil (FU)-based chemotherapy. Radiotherapy was administered 5 days per week for 5.5 weeks. Patients were treated with 5-FU either in continuous infusion (180 mg/m2 / day) for 5 days per week during 5 weeks or as oral preparations. Surgery was planned 6-8 weeks following the completion of preoperative therapy but was changed according to bed availability on the surgical ward.
Routine postoperative follow-up of patients included physical examination and serum carcinoembryonic antigen every 3-4 months in the first 2 years after surgery and then every 6 months. Colonoscopy was performed a year after surgery and if normal every 3 years thereafter. CT of the chest, abdomen, and pelvis was done yearly in the first 2 years of follow-up. Survival was considered the interval between surgery and last follow-up or death (OS) or the date of last follow-up or recurrence (DFS). Patterns of disease recurrence (local and/or distant), DFS, and OS were analyzed. Waiting time was defined from day of biopsy to initiation of chemorad (Figure 1). The institutional Helsinki Committee approved this study.

II Statistical Analysis
Data was analyzed using descriptive statistics. OS and DFS were calculated using Kaplan-Meier estimators. P-values for difference in the survival curves were determined using the log-rank test. Univariate and multivariate cox proportional hazards were conducted in order to evaluate the effect of WT on oncological outcomes. For all analyses, two-sided p-values of less than 0.05 were considered statistically significant.

Survival
At a median follow up of 115 months 7.4% of patient population experienced local recurrence and 29.6% deceased. Median DFS and OS were 163 and 170 months, respectively (Figure 3). WT effect on DFS and OS was evaluated using a univariate cox-model which showed a trend to significant HR 1.04 (p =0.067) for OS in age group 45-70. Therefore, a multivariate analysis was conducted and was adjusted to age, clinical stage and surgery waiting time. Adjusted HR for DFS was increased by 1.06 for each additional week of therapeutic delay in all age groups (p=0.045) and a significant increment by 1.09 for each additional week of therapeutic delay in age group 45-70 years (p=0.02) (Figure 4). The effect on overall survival, was also estimated by multivariate analysis adjusted to age, clinical stage and surgery waiting time. Adjusted HR for OS was increased by 1.07 for each additional week of therapeutic delay in all age groups (p=0.025) and an increment by 1.12 for each additional week of therapeutic delay in age group 45-70 years (p=0.011) ( Figure 5).

Discussion
Our study indicates significant association between longer WT and reduced survival in stage III rectal cancer patients. Prolonged diagnostic WT can be attributed to multiple 'second opinions' and inappropriate referral to imaging tests. Potential outcomes of delay could include decreased patient satisfaction, increased patient worry, and inefficient or wasteful use of medical services if inappropriate tests are ordered. Moreover, treatment delay in rectal cancer patients is affected not only by clinicopathological factors, but also by sociocultural ones. Healthcare providers should pay greater attention to social groups with less formal education in order to optimize treatment attention [22].  It is important to differentiate between diagnostic delays, treatment delays and surgery delays which are often discussed together. Diagnostic delays greater than 60 days has been shown to be significantly associated with more advanced stage at diagnosis [23]. On systematic review, 20 of 26 studies on Colorectal cancer (CRC) delays showed no association between diagnostic or treatment delays and survival, and four studies actually showed that longer delay was associated with better prognosis [24]. In a companion meta-analysis, no statistically significant association was found between diagnostic and treatment delays and disease stage when considering colon and rectal cancers collectively. Analyzed separately, longer delays were associated with later stages for rectal cancer, but earlier stages for colon cancer [16,[25][26][27]. The above mixed findings in literature can be attributed in part to method limitations, including analyzing colon and rectal cancers together and having smaller cohort samples. Different health systems abroad have adopted timeliness guidelines. For example, according to UK guidelines, patients with suspected cancer should see a specialist within 2 weeks and treatment should begin within a month of diagnosis [28]. The key strength of this study lies in the large number of cases reflecting real life data of Israeli patients diagnosed, treated and operated by the same team in a tertiary referral center. Contrary to previous studies, our patient population includes primary rectal cancer only. The present study carries a number of limitations that need to be considered for proper interpretation of the results. Perhaps the main limitation of this study is its retrospective design, which makes it vulnerable to information bias from inaccurate clinical records and missing data. Data regarding MRI evaluation was not collected. Other measured confounding variables such as comorbidities or emergency admission may also have influenced the results and were not recorded.
In conclusion, clinicians should complete diagnostic evaluation within scheduled timeframe up to 6 weeks. Our statistical model approves that each additional week of therapeutic delay significantly jeopardizes oncological outcomes and prognosis. Further prospective research on similar combined data sets from longitudinal studies should be conducted to confirm the relative impact of diagnostic intervals on outcomes in patients with rectal cancer.

Conflicts of Interest
None.

Financial Disclosure
None.

Funding
None.