Abstract
BACKGROUND:
Preoperative staging of clinical stage I rectal cancer can fail to diagnose T3 or nodal disease. Adjuvant treatment of these upstaged patients remains controversial.
Objective:
The objective was to identify predictors of clinical stage I rectal cancer upstaging and quantify rates of local and systemic recurrence.
Design:
This was a retrospective cohort study.
Settings:
The study was conducted using the data from the United States Rectal Cancer Consortium, a registry of 1,881 rectal cancer resections performed at six academic medical centers.
Patients:
There were a total of 94 clinical stage I rectal cancer patients who underwent proctectomy without preoperative therapy
Main Outcome Measures:
The primary measures were incidence of pathologic upstaging, recurrence (local and systemic), and overall survival.
Results:
Among 94 clinical stage I patients who underwent proctectomy without preoperative therapy, 23 (24.5%) were upstaged by surgical pathology. There were 6 pT3N0 patients, 8 pT1–2N+, and 9 pT3N+. There were no significant differences in demographic or clinical characteristics between upstaged and non-upstaged patients. Of the 6 patients who were upstaged to T3N0 disease, none received adjuvant therapy and none recurred. Of the 17 patients who were upstaged to N+ disease, 14 (82%) received adjuvant chemotherapy and 6 (35%) received adjuvant chemoradiation. None developed a local recurrence, but 4 (24%) developed systemic recurrence, and 2 (12%) died of disease over a mean of 36 months follow-up. Among the 9 pT3N+ patients, the systemic recurrence rate was 33%, despite 8 of 9 patients receiving adjuvant fluorouracil, leucovorin, and oxaliplatin.
Limitations:
Small sample size hinders ability to draw significant conclusions.
Conclusions:
One in four patients with stage I rectal cancer had unrecognized T3 or nodal disease found on operative pathology. Occult nodal disease was associated with worse outcomes, despite receiving adjuvant therapy. Systemic recurrence was more common than local recurrence. See Video Abstract at http://links.lww.com/DCR/Bxxx.
Keywords: Adjuvant therapy, Rectal cancer, Stage I, Upstaging
Abstract
ANTECEDENTES:
La estadificación preoperatoria del cáncer de recto en estadio clínico I puede fallar en el diagnóstico de T3 o enfermedad ganglionar. El tratamiento adyuvante de estos pacientes eclipsados sigue siendo controvertido.
Objetivo:
El objetivo fue identificar factores predictivos del estadio clínico I del cáncer de recto y cuantificar las tasas de recurrencia local y sistémica.
Diseño:
Este fue un estudio de cohorte retrospectivo.
Ajuste:
El estudio se realizó utilizando los datos del Consorcio de Cáncer de Recto de los Estados Unidos, un registro de 1.881 resecciones de cáncer de recto realizadas en seis centros médicos académicos.
Pacientes:
Hubo un total de 94 pacientes con cáncer de recto en estadio clínico I que se sometieron a proctectomía sin terapia preoperatoria.
Principales medidas de resultado:
Las medidas primarias fueron la incidencia de eclipsamiento patológico, la recurrencia (local y sistémica) y la supervivencia general.
Resultados:
Entre 94 pacientes en estadio clínico I que se sometieron a proctectomía sin terapia preoperatoria, 23 (24,5%) fueron eclipsados por patología quirúrgica. Hubo 6 pacientes pT3N0, 8 pT1–2N + y 9 pT3N +. No hubo diferencias significativas en las características demográficas o clínicas entre los pacientes eclipsados y no eclipsados. De los 6 pacientes que fueron adelantados a la enfermedad T3N0, ninguno recibió terapia adyuvante y ninguno recidivó. De los 17 pacientes que fueron adelantados a la enfermedad N +, 14 (82%) recibieron quimioterapia adyuvante y 6 (35%) recibieron quimiorradiación adyuvante. Ninguno desarrolló una recidiva local, pero 4 (24%) desarrollaron recidiva sistémica y 2 (12%) murieron a causa de la enfermedad durante un seguimiento medio de 36 meses. Entre los 9 pacientes con pT3N +, la tasa de recurrencia sistémica fue del 33%, a pesar de que 8 de 9 pacientes recibieron fluorouracilo, leucovorina y oxaliplatino como adyuvantes.
Limitaciones:
El tamaño pequeño de la muestra dificulta la capacidad de sacar conclusiones significativas.
Conclusiones:
Uno de cada cuatro pacientes con cáncer de recto en estadio I tenía enfermedad ganglionar o T3 no reconocida encontrada en la patología operatoria. La enfermedad ganglionar oculta se asoció con peores resultados, a pesar de recibir terapia adyuvante. La recurrencia sistémica fue más común que la recurrencia local. Consulte Video Resumen en http://links.lww.com/DCR/Bxxx. (Pre-proofed version)
INTRODUCTION
Preoperative staging of rectal cancer is imperfect.1,2 Determining the T stage of rectal tumors is dependent on magnetic resonance imaging (MRI) and endorectal ultrasound (ERUS) but these modalities fail to accurately predict pathologic stage up to 31% of the time in patients with clinical stage I rectal cancer.2–4 This may have serious implications for pathologically upstaged clinical stage I rectal cancer patients who do not receive guideline-recommended neoadjuvant chemoradiation.5,6 These upstaged patients may have worse oncologic outcomes and the value of adjuvant chemoradiation is controversial.7,8
Previous studies have shown improved overall survival in upstaged patients who receive adjuvant therapy, though due to limitations in the National Cancer Database, they were not able to describe local versus systemic recurrence.7,9 Elucidating the local and systemic recurrence rates could inform the decision to provide adjuvant radiation.10 Although current guidelines recommend adjuvant chemoradiation in clinical Stage I rectal cancer patients who are pathologically upstaged, there is little evidence to suggest that this is advantageous over adjuvant chemotherapy.6
In this context, using a multi-institutional registry, we sought to identify predictive patient characteristics for pathologic upstaging and to determine their oncologic outcomes including rates of overall survival and recurrence (local and systemic).
MATERIALS AND METHODS
Data set and analytic cohort
We performed a retrospective review using the data from the United States Rectal Cancer Collaborative, a registry of 1,881 rectal cancer patients treated at six academic medical centers including Emory University, University of Michigan, University of Pittsburgh Medical Center, Ohio State University, Vanderbilt University Medical Center, and Washington University School of Medicine in St Louis. Institutional Review Board (IRB) approval was obtained at each institution prior to data collection and the requirement for patient consent was waived. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Analysis was limited to patients with clinical stage I disease who underwent elective proctectomy for rectal cancer. All patients were staged with either MRI or ERUS preoperatively. Patients were excluded if they had a history of prior pelvic radiation, recurrent or metastatic disease, preoperative T-stage of T3/T4 or if T-stage could not be determined/missing, preoperative N-stage of 1 or if N-stage could not be determined/missing, received neoadjuvant treatment of any kind (chemotherapy, radiation, chemoradiation), or underwent urgent or palliative surgery. In addition, patients were excluded if they underwent endoscopic mucosal resection or local excision because their regional nodal status could not be staged pathologically (Fig. 1). Upstaged patients were identified based on the pathologic report of their operative specimen and defined as those who had T3/T4 tumors and/or evidence of nodal disease. Patients found to have pathologic stage IV disease at surgery were excluded. All patients in the final analytic cohort had complete data.
Figure 1.
Participant flow chart.
Statistical analyses
Descriptive statistics were used to compare patient demographics and preoperative clinical variables between upstaged patients and those who were not upstaged. Postoperative outcomes were compared between those upstaged to pT3N0 and those with nodal disease (N+). We used a t-test to compare two continuous variables and chi-square tests to evaluate the level of association between categorical variables. All analyses were performed using SAS, version 9.4 and a p value of < 0.05 was considered statistically significant.
RESULTS
Of 1,881 patients who underwent rectal cancer resection, 94 (5.0%) had clinical stage I and underwent proctectomy without neoadjuvant therapy. In total, 23/94 (24.5%) patients were upstaged by surgical pathology. Of these 23 patients, 52% were male, the average was 59.8 years and 100% were of White race. There were no significant differences in demographic characteristics between upstaged and non-upstaged patients (Table 1). Upstaged patients had a lower BMI (p = 0.01) and a shorter time between diagnosis and surgery (p = 0.02). Of the 23 patients who were upstaged, 9 (39%) were initially staged with ERUS, 11 (48%) with MRI and 3 (13%) via both imaging modalities. There was not a statistically significant difference in imaging modality used for staging between upstaged patients and non-upstaged patients. A full comparison of clinical characteristics between cohorts can be seen in Table 2.
Table 1:
Demographics non-upstaged vs. upstaged
| Patient Demographics | Non-upstaged (N = 71) | Upstaged (N = 23) | P-value |
|---|---|---|---|
| Mean age (SD) | 60.6 (11.8) | 59.8 (13.9) | 0.30 |
| Gender | |||
| Male | 39 | 12 | 0.18 |
| Female | 32 | 11 | |
| Race | |||
| White | 64 | 23 | 0.29 |
| Black | 5 | 0 | |
| Unknown | 2 | 0 |
Table 2:
Clinical characteristics non-upstaged patients vs. upstaged
| Patient Clinical Characteristics | Non-upstaged (N = 71) | Upstaged (N = 23) | P-value |
|---|---|---|---|
| Mean BMI (SD) | 30.4 | 26.9 | 0.01 |
| Mean CEA (SD) | 1.8 (2.6) | 2.2 (2.2) | 0.47 |
| Imaging modality | |||
| ERUS | 34 | 9 | 0.75 |
| MRI | 30 | 11 | |
| Both | 7 | 3 | |
| Tumor characteristics | |||
| Mean diameter cm (SD) | 2.4 (2.4) | 3.1 (1.6) | 0.23 |
| Mean length cm (SD) | 2.2 (1.6) | 2.9 (1.2) | 0.27 |
| Location | |||
| Unknown | 18 | 3 | 0.55 |
| Low rectum | 15 | 6 | |
| Mid rectum | 26 | 11 | |
| Upper rectum | 12 | 3 | |
| Clinical T-stage | 0.13 | ||
| T1 | 31 | 6 | |
| T2 | 40 | 17 | |
| Mean distance from anal verge cm (SD) | 8.6 (3.4) | 7.7 (3.1) | 0.62 |
| Mean distance from anal sphincter cm (SD) | 3.7 (3.2) | 2.6 (2.5) | 0.77 |
| Mean time from diagnosis to surgery - days (SD) | 54 (49) | 51 (30) | 0.02 |
| Operation type | |||
| LAR | 58 | 17 | 0.07 |
| APR | 4 | 4 | |
| Total Proctocolectomy | 0 | 1 | |
| Unknown | 9 | 1 | |
| Positive margin (proximal, distal or circumferential) | 0.58 | ||
| Yes | 1 | 1 | |
| No | 64 | 21 | |
| Could not be assessed | 6 | 1 | |
| Mean lymph nodes harvested (SD) | 16.5 | 17.7 | |
| Degree of differentiation | |||
| Well differentiated | 10 | 1 | 0.13 |
| Moderately differentiated | 30 | 16 | |
| Poorly differentiated | 2 | 0 | |
| Undifferentiated | 0 | 0 | |
| Not recorded | 29 | 6 | |
| Quality of TME | 0.07 | ||
| Complete | 48 | 14 | |
| Near complete | 1 | 1 | |
| Incomplete | 0 | 2 | |
| Not recorded | 22 | 6 |
Of the 23 upstaged patients, 6 were upstaged to pT3N0, 8 to pT1–2N+, and 9 to pT3N+. Of the 6 patients who were upstaged to T3N0 disease, none received adjuvant therapy and none recurred. Among the 17 patients who were upstaged to N+ disease, the average number of positive lymph nodes was 2.2. 14 (82%) received adjuvant chemotherapy and 6 (35%) received adjuvant chemoradiation (all patients who received chemoradiation also received chemotherapy). None developed a local recurrence, 4 (24%) developed distant recurrence and 2 (12%) died of disease over a mean of 36 months follow-up. Among the 9 pT3N+ patients, the systemic recurrence rate was 33% despite 8/9 (89%) patients receiving adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX, Table 3). In comparison, only 1/71 (1.4%) pathologic stage I patients developed a recurrence over a similar period of follow-up.
Table 3:
Outcomes of upstaged patients
| Outcomes | T3N0 (N = 6) | T1–2/N+ (N = 8) | T3N+ (N = 9) |
|---|---|---|---|
| Mean length of follow up in years (SD) | 3.1 (1.9) | 2.9 (2) | 2.6 (1.9) |
| Postoperative treatment | |||
| None | 6 | 2* | 1** |
| Chemotherapy | 0 | 6 | 8 |
| Chemoradiation | 0 | 3 | 3 |
| Both chemotherapy and chemoradiation | 0 | 3 | 3 |
| Recurrence | |||
| Local recurrence | 0 | 0 | 0 |
| Systemic recurrence | 0 | 1 | 3 |
| Death | 0 | 1 | 1 |
There was no follow up recorded for one of these patients
There was no follow up recorded for this patient
DISCUSSION
In our study, we found that one in four patients with stage I rectal cancer had unrecognized T3 or nodal disease found on operative pathology. Patients who had undetected T3N0 disease did not get adjuvant therapy and none developed recurrence. However, as compared to non-upstaged patients, outcomes were worse among upstaged patients with occult nodal disease despite all patients receiving adjuvant therapy. None developed local recurrence, but one in four had a systemic recurrence and 12% died over a mean follow-up of three years. These results suggest occult nodal disease heralds a poor prognosis despite the receipt of adjuvant therapy.
Our work extends a growing body of literature highlighting the need for improved preoperative staging of rectal cancer. We found that a quarter of patients were upstaged and 18% had occult nodal disease which is similar to that of previous studies.4,8,9,11 When compared to CT and ERUS, some consider MRI to be the superior staging modality, yet MRI is only 60–70% sensitive and 75–85% specific in its ability to detect malignant lymph nodes.1,3 Certainly, technological advances could increase accuracy, but this may not be the only area for improvement. Variation at the hospital-level may also be a contributor toward inaccurate preoperative staging. Becerra et al. showed that despite patient-level risk adjustment, hospitals have been shown to vary in rates of understaging by 24-fold (range 3–72%). Unfortunately, in this study, no identifiable hospital factors were significantly associated with increased rates of understaging, making targeted intervention a challenge.9
Adjuvant chemoradiation for upstaged clinical Stage I rectal cancer patients is controversial. The National Comprehensive Cancer Network guidelines recommend adjuvant chemoradiation for upstaged patients found to have T3 disease or occult nodal disease, with certain select T3N0 patients allowed to pursue observation. Unfortunately, prior work has shown that approximately 23% of upstaged patients do not receive any adjuvant therapy12 and in our study, of the 14 patients who received adjuvant therapy for nodal disease, 8 (57%) did not receive chemoradiation, highlighting the discrepancy between guideline-recommended care and observed practice habits. However, no studies have convincingly compared outcomes following adjuvant chemotherapy against adjuvant chemoradiation. Work in this domain is essential to optimize long-term oncologic outcomes for under-staged patients. In our study, we found that among the 17 patients upstaged to pN+, none had a local recurrence after receiving adjuvant therapy but 4 (24%) developed a systemic recurrence. Our study demonstrated increased rates of systemic recurrence as compared to local recurrence but was not powered to detect a difference between chemotherapy and chemoradiation.
Previous work done by Kang et. al compared 5-year outcomes after adjuvant chemotherapy versus chemoradiation in stage II/III patients who did not receive neoadjuvant therapy. These authors found no significant difference between the 5-year rates of local recurrence in the group that received adjuvant chemotherapy versus chemoradiation (10.8% vs. 14.8%, p = 0.236). Additionally, overall survival (OS) and disease-free-survival were significantly longer in the group that received adjuvant chemotherapy 94.1% vs. 85.4% (p = 0.024) and 72.4% vs. 58.1%, (p = 0.002), respectively.13 Moreover, sub-analysis from work done by Polamraju et al. comparing outcomes in upstaged clinical Stage I rectal cancer patients also supports the use of adjuvant chemotherapy over chemoradiation, except in patients with positive surgical margins. In these patients, though there was a trend toward an improvement in overall survival (54.9 months vs. 47.4 months, p = 0.10), the difference was not statistically significant.7
Although these retrospective studies did not find evidence to support the use of adjuvant chemoradiation, their results must be carefully interpreted within the context of their limitations. As there currently does not exist enough evidence for the use of adjuvant chemoradiation in all upstaged clinical stage I patients, its use will continue to be based on what is likely a combination of factors including patient characteristics, the subjective surgical quality and specimen pathology. To properly understand differences between treatments and better inform guidelines, adequately powered prospective trials are need.
Our results must be interpreted in light of the study’s limitations. First, we were underpowered to draw conclusions, and any attempt to compare outcomes would be confounded by selection bias and surgeon decision-making. Furthermore, our small sample size limits the generalizability of our results. For example, 100% of upstaged patients were of White race (across our entire dataset, 88% were of White race), whereas in other studies, approximately 84% of upstaged patients are of White race.12 The small sample size is partially a consequence of our database being comprised of patients from 6 referral centers which are more likely to treat patients with more advanced disease, and this aspect of our database may also limit the generalizability of our results. However, our exploratory analysis can be used to help guide subsequent in-depth studies. Lastly, this paper does not address any issues with overstaging. Like understaging, the implications of overstaging can also be substantial.
CONCLUSION
Pathologic upstaging of clinical stage I rectal cancer, found in a quarter of clinical stage 1 patients, leads to disruption of guideline recommended stage-specific management. When compared to patients who were not upstaged, patients found to have occult nodal disease had worse outcomes and higher rates of systemic recurrence despite receiving adjuvant therapy.
ACKNOWLEDGMENTS
The authors thank Dr. Scott Regenbogen for his support and thoughtful review of this manuscript.
Funding/Support:
Dr Lussiez is supported by the Surgical Oncology Scientist Fellowship Award administered from the National Cancer Institute T32CA009672. Dr Rivard is supported by the National Institute of Health under grant number T32DK108740.
Footnotes
Financial Disclosures: None reported.
Selected for plenary podium presentation at the 2021 American Society of Colon and Rectal Surgeons Annual Scientific Meeting, April 24 – 28, 2021 at the San Diego, California.
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