Abstract
Purpose:
There has been an increase in the incidence of rectal cancer diagnosed in young adults (age < 50 years). We evaluated outcomes among young adults treated with pre-operative long course chemoradiation (CRT) and total mesorectal excision (TME).
Methods:
The medical records of 219 patients, age 18–49, with non-metastatic, cT3–4, or cN1–2 rectal adenocarcinoma treated from 2000–2017 were reviewed for demographic and treatment characteristics, as well as pathologic and oncologic outcomes. Kaplan-Meier test, log-rank test, and Cox regression analysis were used to evaluate survival outcomes.
Results:
The median age at diagnosis was 44 years. CRT followed by TME and post-operative chemotherapy was the most frequent treatment sequence (n=196), with FOLFOX (n=115) as the predominant adjuvant chemotherapy. There was no difference in sex, stage, MSS/pMMR, or pCR by age (< 45 years [n=111] vs. ≥ 45 years [n=108]). The 5-year rates of DFS were 77.2% for all patients, 69.8% for age < 45 years and 84.7% for age ≥ 45 years (P=0.01). The 5-year rates of OS were 89.6% for all patients, 85.1% for patients with age < 45 years and 94.3% for patients with age ≥ 45 years (P=0.03). Age ≥ 45 years was associated with a lower risk of disease recurrence or death on multivariable Cox regression analysis (HR=0.55, 95% CI 0.31–0.97, P=0.04).
Conclusion:
Among young adults, patients with age < 45 years had lower rates of DFS and OS, compared to those with age ≥ 45 years. These outcomes could serve as a benchmark by which to evaluate newer treatment approaches.
Keywords: rectal cancer, young onset, locally advanced
Micro Abstract:
Among young adult patients treated with long course chemoradiation and surgery, patients with age < 45 experience a similar rate of pathologic complete response, lower rate of nodal downstaging, and lower rate of disease-free survival, compared to those with age ≥ 45 years. These results could serve as a benchmark by which to evaluate newer treatment approaches.
Introduction
Cancers of the colon and rectum (CRC) constitute the third leading cause of cancer diagnosis and death in the United States 1,2. In contrast to the overall decrease in CRC among adults age 50 years and older during recent decades, multiple studies have demonstrated an increase in the incidence of CRC among adults less than 50 years of age since the mid-1990s, with a current rate of increase of 2.2% per year 1,3. Cancers of the rectum, the risk of which doubled from 2.6 cases per 100,000 persons in 1994 to 5.2 cases of per 100,000 in 2014, are disproportionately responsible for the worsening CRC burden and constitute nearly 40% of diagnoses for this age group 3,4. As CRC patients with age 49 years or less were diagnosed prior to the screening age of 50 years, they are generally referred to as having “young-onset” rectal cancer 5. However, more contemporary data suggest that the CRC risk among adults age 45 to 49 may be greater than evidenced in the literature 4. Therefore, the 2018 guidelines from the American Cancer Society and 2020 draft guidelines from the United States Preventative Services Task Force recommend initiation of CRC screening at age 45 years 4,6.
When compared to adults 50 years of age and older, adults less than 50 years of age are more likely to be diagnosed with late-stage rectal cancer 7. Pre-operative long course chemoradiotherapy (CRT) followed by total mesorectal excision (TME) has been the standard of care for locally advanced disease for many years, based on the German CAO/ARO/AIO-94 trial 8,9. However, distant disease relapse remains a source of treatment failure—even with the standard treatment sequence of pre-operative CRT, TME, and post-operative chemotherapy10,11. In recent years, the delivery of radiotherapy over the course of 1 week (short course radiotherapy) rather than 5 to 6 weeks and the delivery of all radiotherapy and chemotherapy treatments prior to TME (total neoadjuvant therapy [TNT]) have been investigated as mechanisms to shorten the time to systemic therapy and improve treatment compliance, with the goal of decreasing the likelihood of distant failure without compromising locoregional control 12–15. The RAPIDO study investigated TNT with short course radiotherapy and demonstrated a lower rate of disease-related treatment failure with pre-operative short course radiotherapy followed by chemotherapy (either folinic acid, fluorouracil, and oxaliplatin [FOLFOX] or capecitabine and oxaliplatin [CAPOX]) and TME compared to long course CRT followed by TME and post-operative chemotherapy 16. Further and with respect to neoadjuvant therapies, the UNICANCER-PRODIGE 23 trial was notable for a higher rate of disease-free survival following pre-operative chemotherapy (leucovorin, fluorouracil, irinotecan, oxaliplatin [FOLFIRINOX]) followed by long course CRT compared to long course CRT alone17. However, no study has established benchmark outcomes for patients with young-onset rectal cancer by which to compare these novel treatment approaches 18–20. Therefore, the goals of this study were—for locally advanced, young-onset rectal cancer (age < 50 years) in patients without a predisposing or heritable condition—to 1) evaluate pathologic response, disease recurrence, and survival outcomes following long course CRT and TME; 2) compare these outcomes for patients with age < 45 years to patients with age 45–49 years (non-screening eligible vs. newly screening-eligible); and 3) determine factors associated with these outcomes.
Methods
After Institutional Review Board approval was obtained, a clinical database of the Department of Radiation Oncology was queried for patients treated with radiotherapy for rectal cancer. Inclusion criteria were newly diagnosed, rectal adenocarcinoma; at least 18 years and no more than 49 years of age at the time of diagnosis; clinical T3, T4, or N1-N2 disease; receipt of pre-operative long course CRT followed by TME at our institution; no evidence of metastatic disease prior to treatment initiation; and a minimum of 3 years post-surgical follow-up. Of the resulting 258 eligible patients, 39 were excluded due to predisposing or heritable condition (i.e., inflammatory bowel disease [IBD], familial adenomatous polyposis [FAP], hereditary non-polyposis colorectal cancer [HNCC]; n=27), synchronous primaries (n=6), distal extent of tumor more than 12 cm from the anal verge (n=4), and prior pelvic malignancy (n=2). Two hundred nineteen patients treated from April 2000 to December 2017 are the subject of this investigation.
Tumor Staging
A comprehensive review of medical records for patient, tumor, and treatment characteristics was performed. All patients underwent multidisciplinary consultation with a dedicated team of surgical oncologists, radiation oncologists, and medical oncologists. Pre-treatment assessment included digital rectal examination, endoscopic evaluation of the primary tumor with measurement of the distance from the distal extent of the tumor to the anal verge, and radiographic imaging (ultrasound, computed tomography [CT] scan, magnetic resonance imaging [MRI], and/or X-ray) of the chest, abdomen, and pelvis. Prior to 2011, endoscopic ultrasound was the primary method of staging the locoregional extent of disease. Thereafter, pelvic MRI scans were routinely performed. Treatment decisions were based on multidisciplinary consensus.
Evaluation of Pathology
Diagnostic pathology reports were evaluated for tumor histology, tumor grade, and microsatellite stability status. Microsatellite stable (MSS) disease was defined as inclusive of microsatellite stable and microsatellite instability-low findings 21. As microsatellite testing was not uniformly performed during the study period, deoxyribonucleic acid (DNA) mismatch repair status was also evaluated. Mismatch repair proficient (pMMR) was defined as tumor expression of hMLH1, hPMS2, hMSH2, and hMSH6 on immunohistochemistry 21. Surgical pathology reports were reviewed for pathologic response to pre-operative therapies. Pathologic complete response (pCR) was defined as the absence of tumor cells in the primary surgical specimen, dissected lymph nodes, and perirectal tissue (i.e., ypT0N0). A tumor was considered to have undergone pathologic downstaging when a decrease in the tumor (T) or nodal (N) classification occurred on the TME pathology specimen when compared to the pre-treatment clinical classification.
Statistical Analysis
Summary statistics were used to assess the patient cohort by age, sex, race, staging modality, clinical stage, tumor histology, tumor grade, baseline carcinoembryonic antigen (CEA) level, MSS/DNA pMMR status, and presenting symptoms. The Chi-Square test and Mann-Whitney U test were used to evaluate the relationship between age and clinical variables. Medical records were reviewed for the development of locoregional recurrence (LRR), distant metastasis (DM), and non-rectal, pelvic malignancy during the follow-up period. The Kaplan-Meier method used to determine overall survival (OS) and disease-free survival (DFS) rates from the date of TME based on clinical information gathered from patients’ most recent clinical encounters. Tumor registry data (when available) were used in OS calculations for patients with no clinical encounters for a minimum of two consecutive years. The log-rank test, Cox univariable regression models, and Cox multivariable regression models were used to evaluate the association of clinical and pathologic characteristics with OS and DFS rates. A p-value of < 0.05 was indicative of statistical significance. All statistical analyses were performed with IBM SPSS Statistics 26.
Results
Patient and Treatment Characteristics
Patient and tumor characteristics are presented in Table 1. The median age at diagnosis was 44 years and there was no sex predominance. Common presenting symptoms included rectal bleeding (91%), change in bowel habits (constipation, diarrhea, frequency, urgency, tenesmus, change in stool caliber or consistency, mucus, and/or incomplete evacuation; 49%), rectal pain/pressure (18%), and abdominal complaints (pain, bloating, and/or cramping; 14%). The median time from symptom presentation to diagnosis was 5 months (interquartile range 3–11.5 months).
Table 1:
Patient and tumor clinical characteristics for all patients (N=219), patients with age < 45 years (n=111) and patients with age ≥ 45 years (n=108).
| Characteristic | All n, % |
Age < 45 years n, % |
Age ≥ 45 years n, % |
P |
|---|---|---|---|---|
| Median age [IQR range], y | 44 [39–47] | 39 [35–43] | 46 [47–48] | |
| Sex | 0.64 | |||
| Male | 113 (51.6) | 59 (53.2) | 54 (50.0) | |
| Female | 106 (48.4) | 52 (46.8) | 54 (50.0) | |
| Race | 0.82 | |||
| Non-Hispanic White | 171 (78.1) | 85 (76.6) | 86 (79.6) | |
| Hispanic White | 22 (10.0) | 12 (10.8) | 10 (9.3) | |
| Asian | 14 (6.4) | 8 (7.2) | 6 (5.6) | |
| Black | 11 (5.0) | 5 (4.5) | 6 (5.6) | |
| Other | 1 (0.5) | 1 (0.9) | 0 (0.0) | |
| Pelvic staging modality | 0.97 | |||
| Ultrasound | 114 (52.1) | 57 (51.4) | 57 (52.8) | |
| MRI | 86 (39.3) | 44 (39.6) | 42 (38.9) | |
| CT | 19 (8.7) | 10 (9.0) | 9 (8.3) | |
| Clinical tumor classification | 0.15 | |||
| cT1 | 1 (0.5) | 1 (0.9) | 0 (0.0) | |
| cT2 | 8 (3.7) | 1 (0.9) | 7 (6.5) | |
| cT3 | 191 (87.2) | 101 (91.0) | 90 (83.3) | |
| cT4 | 16 (7.3) | 7 (6.3) | 9 (8.3) | |
| cTX | 3 (1.4) | 1 (0.9) | 2 (1.9) | |
| Clinical lymph node classification | 0.50 | |||
| N0 | 38 (17.4) | 18 (16.2) | 20 (18.9) | |
| N1-N2 | 174 (79.5) | 88 (79.3) | 86 (79.6) | |
| NX | 7 (3.2) | 5 (4.5) | 2 (1.9) | |
| Median distance from anal verge [IQR range], cm | 6 [3–8] | 6 [4–9] | 6 [3–8] | 0.31 |
| Grade | ||||
| Well differentiated | 3 (1.4) | 0 (0.0) | 3 (2.8) | 0.12 |
| Moderately differentiated | 195 (89.0) | 97 (87.4) | 98 (90.7) | |
| Poorly differentiated | 20 (9.1) | 13 (11.7) | 7 (6.5) | |
| Not specified | 1 (0.5) | 1 (0.9) | 0 (0.0) | |
| Histology | 0.29 | |||
| Adenocarcinoma | 208 (95.0) | 104 (93.7) | 107 (96.3) | |
| Adenocarcinoma with signet ring features | 8 (3.7) | 6 (5.4) | 2 (1.9) | |
| Adenocarcinoma with neuroendocrine component | 1 (0.5) | 0 (0.0) | 1 (0.9) | |
| Adenocarcinoma with carcinoid component | 1 (0.5) | 0 (0.0) | 1 (0.9) | |
| Adenosquamous carcinoma | 1 (0.5) | 1 (0.9) | 0 (0.0) | |
| Median pretreatment CEA [IQR range], ng/mL | 2.1 [<1.0–6.1] | 2.1 [<1.0–5.6] | 2.2 [1.1–6.2] | 0.70 |
| Microsatellite / DNA mismatch repair testing | 0.23 | |||
| MSS/pMMR | 161 (73.5) | 84 (75.7) | 77 (71.3) | |
| MSI-H/dMMR | 8 (3.7) | 6 (5.4) | 2 (1.9) | |
| Indeterminate | 1 (0.5) | 0 (0.0) | 1 (0.9) | |
| No testing performed | 49 (22.4) | 21 (18.9) | 28 (25.9) | |
| Median time to diagnosis [IQR range], m | 5 [3–12] | 6 [3–12] | 5 [3–12] | 0.99 |
Abbreviations: CEA, carcinoembryonic antigen; cm, centimeters; DNA, deoxyribonucleic acid; dMMR, DNA mismatch repair deficient; IQR, interquartile range; m, months; MSI-H, microsatellite instability-high; MSS, microsatellite stable; pMMR, DNA mismatch repair proficient; y, years
The median distance from the anal verge to the distal extent of the tumor was 6 cm. Findings consistent with MSS/pMMR were present for 95% of tumors on which testing was performed. Clinical tumor/nodal categories were cT1-T2 in 4%, cT3 in 87%, cT4 in 7%, cN0 17%, and cN1-N2 in 80% of patients. The majority of patients (n=164, 75%) met both T classification and N classification criteria for locally advanced disease. When patients with age < 45 years were compared to those with age ≥ 45 years, there was no difference in sex, T classification, N classification, time from symptom presentation to diagnosis, distance from anal verge to distal extent of the tumor, tumor grade, tumor histology, baseline CEA, or MSS/pMMR status.
Treatment characteristics are presented in Table 2. All patients received long course, pre-operative CRT. Pre-operative CRT followed by TME and post-operative chemotherapy was the most frequent treatment sequence and delivered to 90% of patients. Seventeen patients (8%) received pre-operative chemotherapy before or after CRT, and 6 patients (3%) received pre-operative CRT followed by TME without post-operative chemotherapy. The median radiation dose was 50.4 Gy, typically administered in 1.8–2.0 Gy daily fractions (n=185), with 215 (98%) patients receiving 45.0–54.0 Gy. Capecitabine (81%) was the predominant concurrent chemotherapy, and FOLFOX was delivered to 53% of patients post-operatively. Low anterior resection and proctectomy with coloanal anastomosis accounted for 79% of TME procedures, 18% of patients received abdominal perineal resection, and pelvic exenteration was performed in a minority of patients (n=6). When patients with age < 45 years were compared to those with age ≥ 45 years, there was no difference in treatment sequence, radiotherapy dose, surgical procedure, or concurrent chemotherapy regimen. However, there was a trend toward differences in post-operative chemotherapy regimen by age group.
Table 2:
Treatment characteristics for all patients (N=219), patients with age < 45 years (n=111) and patients with age ≥ 45 years (n=108).
| Characteristic | All n, % |
Age < 45 years n, % |
Age ≥ 45 years n, % |
P |
|---|---|---|---|---|
| Treatment sequence | 0.55 | |||
| CRT, TME | 6 (2.7) | 4 (3.6) | 2 (1.9) | |
| CRT, TME, chemotherapy | 196 (89.5) | 95 (85.6) | 101 (93.5) | |
| CRT, chemotherapy, TME | 1 (0.5) | 1 (0.9) | 0 (0.0) | |
| CRT, chemotherapy, TME, chemotherapy | 3 (1.4) | 2 (1.8) | 1 (0.9) | |
| Chemotherapy, CRT, TME | 1 (0.5) | 1 (0.9) | 0 (0.0) | |
| Chemotherapy, CRT, TME, chemotherapy | 11 (5.0) | 7 (6.3) | 4 (3.7) | |
| Chemotherapy, CRT, chemotherapy, TME, chemotherapy | 1 (0.5) | 1 (0.9) | 0 (0.0) | |
| Median radiotherapy dose [IQR], Gy | 50.4 [50.4–50.4] | 50.4 [50.4–50.4] | 50.4 [50.4–50.4] | 0.31 |
| Concurrent chemotherapy | 0.25 | |||
| Capecitabine | 178 (81.3) | 87 (78.4) | 91 (84.3) | |
| 5-FU | 24 (11.0) | 16 (14.4) | 8 (7.4) | |
| Capecitabine with other agents | 17 (7.8) | 8 (7.2) | 9 (8.3) | |
| Post-operative chemotherapy | 0.056 | |||
| FOLFOX | 115 (52.5) | 59 (53.2) | 56 (51.9) | |
| Capecitabine | 39 (17.8) | 12 (10.8) | 27 (25.0) | |
| XELOX | 26 (11.9) | 15 (13.5) | 11 (10.2) | |
| 5-FU, leucovorin, with or without other agents | 21 (9.6) | 14 (12.6) | 7 (6.5) | |
| Other | 10 (4.6) | 5 (4.5) | 5 (4.6) | |
| None | 8 (3.7) | 6 (5.4) | 2 (1.9) | |
| Surgery | 0.86 | |||
| Low anterior resection | 101 (46.1) | 52 (46.8) | 49 (45.4) | |
| Proctectomy with coloanal anastomosis | 73 (33.3) | 36 (32.4) | 37 (34.3) | |
| Abdominoperineal resection | 39 (17.8) | 19 (17.1) | 20 (18.5) | |
| Pelvic exenteration | 6 (2.7) | 4 (3.6) | 2 (1.9) |
Abbreviations: 5-FU, 5-fluorouracil; CRT, chemoradiotherapy; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; Gy, gray; IQR, interquartile range; TME, total mesorectal excision; XELOX, capecitabine and oxaliplatin
Pathologic Response to Pre-Operative Therapies
Pathologic tumor/nodal classifications were ypT0 in 17%, ypT1 in 10%, ypT2 in 29%, ypT3 in 40%, ypT4 in 4%, ypN0 in 55%, and ypN1-N2 in 45% of patients. Tumor/nodal classification downstaging occurred in 57% of patients with known clinical T classification and 53% of patients with clinically node-positive disease, respectively (Table 3). Patients with age < 45 years were less likely to undergo N classification downstaging than patients with age ≥ 45 years (39.8% vs 52.6%, P=0.00). There was a trend toward an association between age < 45 years and a lower rate of T classification downstaging (50% vs 56.5%, P=0.05). Pathologic compete response occurred in 33 cases (15%), with no statistically significant difference in pCR rates when patients with age < 45 years were compared to patients with age ≥ 45 years.
Table 3:
Tumor pathologic characteristics for all patients (N=219), patients with age < 45 years (n=111) and patients with age ≥ 45 years (n=108).
| Characteristic | All n, % |
Age < 45 years n, % |
Age ≥ 45 years n, % |
P |
|---|---|---|---|---|
| Pathologic T classification | 0.14 | |||
| ypT0 | 37 (16.9) | 17 (15.3) | 20 (18.5) | |
| ypT1 | 22 (10.0) | 9 (8.1) | 13 (12.0) | |
| ypT2 | 63 (28.8) | 28 (25.2) | 35 (32.4) | |
| ypT3 | 87 (39.7) | 51 (45.9) | 36 (33.3) | |
| ypT4 | 8 (3.7) | 6 (5.4) | 2 (1.9) | |
| ypTX | 2 (0.9) | 0 (0.0) | 2 (1.9) | |
| Pathologic N classification | < 0.001 | |||
| ypN0 | 120 (54.8) | 49 (44.1) | 71 (65.7) | |
| ypN1-N2 | 99 (45.2) | 62 (55.9) | 37 (34.3) | |
| T classification downstaging (n=216) | 0.050 | |||
| yes | 122 (56.5) | 55 (50.0) | 67 (63.2) | |
| no | 94 (43.5) | 55 (50.0) | 39 (36.8) | |
| N classification downstaging (n=174) | < 0.001 | |||
| yes | 91 (52.6) | 35 (39.8) | 56 (65.9) | |
| no | 82 (47.4) | 53 (60.2) | 29 (34.1) | |
| Pathologic response | 0.30 | |||
| Complete | 33 (15.1) | 14 (12.6) | 19 (17.6) | |
| Incomplete | 186 (84.9) | 97 (87.4) | 89 (82.4) |
Survival Outcomes
The median follow-up time for evaluation of DFS was 5.0 years (range 0–18.1 years), during which there were 11 LRR, 40 DM, and 1 synchronous presentation of LRR and DM as initial sites of disease recurrence. Eleven (28%) of the DM were detected prior to/at the time of TME. Of these 11 patients, 8 (20%) presented with isolated liver metastases. All underwent resection of the metastasis followed by chemotherapy and 3 had no evidence of disease at last follow-up. The remaining 3 of these 11 patients were found to have metastatic disease to the lung, including 1 patient with both liver and lung involvement. All experienced disease progression following systemic therapy, including one patient who received systemic therapy followed by resection of lung and liver metastases. The 5-year rates of DFS were 77.2% for all patients, 69.8% for patients with age < 45 years, and 84.7% for patients with age ≥ 45 years (P=0.01, Figure 1).
Figure 1.
Kaplan Meier estimates of disease-free survival for patients with age < 45 years and ≥ 45 years. Abbreviations: y, years
On Cox univariable regression analysis, patients who did not achieve T classification downstaging were more likely to experience disease recurrence or death (DFS hazard ratio [HR]=2.8, 95% CI 1.6–5.0 P<0.001). Similarly, patients who did not achieve N classification downstaging were more likely to experience disease recurrence or death during the follow-up period (Table 4). When compared to age < 45 years, age ≥ 45 years was associated with a lower risk of disease recurrence or death. This association remained significant on multivariable Cox regression analysis that included T classification downstaging and N classification downstaging (HR=0.55, 95% CI 0.31–0.97, P=0.04).
Table 4:
Univariable and multivariable Cox regression models of clinical and pathological characteristics associated with disease-free survival and overall survival.
| Characteristic | Univariable Regression for DFS | Multivariable Regression for DFS | Univariable Regression for OS | Multivariable Regression for OS | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
| ||||||||||||
| HR | 95% CI | P | HR | 95 % CI | P | HR | 95% CI | P | HR | 95 % CI | P | |
| Sex | 0.84 | 0.30 | ||||||||||
| Male | [Ref] | [Ref] | ||||||||||
| Female | 1.06 | 0.62–1.80 | 0.71 | 0.37–1.35 | ||||||||
|
| ||||||||||||
| Age, y | 0.008 | 0.04 | 0.03 | 0.07 | ||||||||
| < 45 | [Ref] | [Ref] | [Ref] | [Ref] | ||||||||
| ≥ 45 | 0.47 | 0.27–0.82 | 0.55 | 0.31–0.97 | 0.48 | 0.24–0.93 | 0.52 | 0.26–1.05 | ||||
|
| ||||||||||||
| Clinical tumor classification (n=216) | 0.29 | 0.40 | ||||||||||
| cT1-T2 | [Ref] | [Ref] | ||||||||||
| cT3-T4 | 2.48 | 0.34–17.98 | 21.49 | 0.02–26406.57 | ||||||||
|
| ||||||||||||
| Clinical lymph node classification (n=212) | 0.44 | 0.89 | ||||||||||
| cN0 | [Ref] | [Ref] | ||||||||||
| cN1-N2 | 1.35 | 0.63–2.9 | 0.95 | 0.43–2.08 | ||||||||
|
| ||||||||||||
| Distance from anal verge, cm | 0.42 | 0.82 | ||||||||||
| ≤ 6 | [Ref] | [Ref] | ||||||||||
| > 6 | 1.25 | 0.73–2.13 | 0.93 | 0.49–1.77 | ||||||||
|
| ||||||||||||
| Pretreatment CEA, ng/mL | 0.153 | 0.64 | ||||||||||
| ≤ 2.1 | [Ref] | [Ref] | ||||||||||
| > 2.1 | 1.48 | 0.86–2.54 | 0.64 | 0.34–1.22 | ||||||||
|
| ||||||||||||
| T classification downstaging (n=216) | < 0.001 | 0.008 | 0.002 | 0.01 | ||||||||
| yes | [Ref] | [Ref] | [Ref] | [Ref] | ||||||||
| no | 2.82 | 1.60–4.99 | 2.27 | 1.244.14 | 2.85 | 1.45–5.61 | 0.40 | 0.19–0.81 | ||||
|
| ||||||||||||
| N classification downstaging (n=174) | 0.001 | 0.02 | 0.03 | 0.20 | ||||||||
| yes | [Ref] | 1.00 | [Ref] | [Ref] | ||||||||
| no | 3.10 | 1.60–6.04 | 2.24 | 1.13–4.47 | 2.35 | 1.10–5.00 | 0.60 | 0.27–1.30 | ||||
Abbreviations: CEA, carcinoembryonic antigen; CI, confidence interval; cm, centimeters; DFS, disease-free survival; HR, hazard ratio; OS, overall survival; y, years
The median follow-up time for evaluation of OS was 7.5 years (range 0.9–19.8 years), during which there were 38 deaths. Four of 38 patients were without documented evidence of disease recurrence at time of death. The majority of deaths (n=23) among the remaining 34 patients were due to progressive disease, with a median time from development of disease recurrence to death of 1.9 years (range 0.4–5.2 years). Three patients died from treatment-related complications including sepsis secondary to chronic enterocutaneous fistula, neutropenia in the setting of chemotherapy-related myelodysplastic syndrome, and progressive, radiation-related spindle cell sarcoma of the pelvis. The 5-year rates of OS were 89.6% for all patients, 85.1% for patients with age < 45 years and 94.3% for patients with age ≥ 45 years (P=0.03, Figure 2).
Figure 2.
Kaplan Meier estimates of overall survival for patients with age < 45 years and ≥ 45 years. Abbreviations: y, years
On Cox univariable regression analysis, patients who did not achieve T classification downstaging were more likely to experience death (OS HR=2.9, 95% CI 1.5–5.6, P=0.002). Additionally, patients who did not achieve N classification downstaging were more likely to experience death during the follow-up period. There was no statistically significant association between sex, clinical T classification, clinical N classification, distal extent of tumor (≤ 6 cm vs. > 6 cm), CEA level (≤ 2.1 ng/mL vs. > 2.1 ng/mL), or age (< 45 years vs. ≥ 45 years) and OS on Cox univariable regression analysis. On Cox multivariable regression analysis, T classification downstaging was the only factor significantly associated with OS.
Secondary Malignancies
Two patients developed malignancies in the irradiated pelvis during the follow-up period. A male patient was found to have a high-grade, spindle-cell sarcoma at the surgical anastomosis at 6.3 years follow-up. As the disease was surgically unresectable, he was treated with chemotherapy. He was deceased within 1 year of recurrence diagnosis. A female patient was found to have endometrioid/serous carcinoma of the uterus at 9.3 years follow-up and underwent total laparoscopic hysterectomy with bilateral salpingo-oopherectomy, adjuvant chemotherapy, and vaginal cuff brachytherapy. She was noted to have recurrent disease to the inguinal lymph nodes at 9 months following completion of treatment for her recurrence and was receiving chemotherapy at last follow-up.
Discussion
We sought to establish benchmark outcomes for sporadic, young-onset rectal cancer (age < 50 years) by evaluating patient, treatment, and survival outcomes following treatment with pre-operative long course CRT and TME. As the majority of young-onset rectal cancer patients are stage III or IV at presentation, we focused specifically on those diagnosed with non-metastatic, locally advanced disease and were treated with curative intent 22,23. Additionally, we compared outcomes between patients less than 45 years of age and those 45–49 years of age (screening ineligible vs. newly screening-eligible).
We found that the majority of patients demonstrated evidence of both high T classification and nodal positivity on baseline staging studies. Further, the rates of poor tumor differentiation and mucinous or signet ring histology in our study were low. When patients with age < 45 years were compared to those with age ≥ 45 years, there was no difference in patient or tumor characteristics. While our study excluded patients with a predisposition for CRC (i.e., IBD, FAP, HNCC), we identified findings consistent with microsatellite instable/mismatch repair deficient disease in 5% of patients, with no difference between patients with age < 45 years and those with age ≥ 45 years. Among both heritable and sporadic locally advanced rectal cancers, microsatellite instability is associated with a favorable rate of response to pre-operative therapies 24. In our study we observed a pCR rate of 15%, comparable to pCR rates reported in other publications of the outcomes of the overall rectal cancer population following pre-operative long course CRT 16,25.
Our institution has been delivering neoadjuvant CRT to patients with locally advanced rectal cancer since the early 1990s, thereby providing a unique opportunity to evaluate the outcomes of this population within the context of a consistent treatment practice. In our study, all patients received long course CRT, the majority were treated with long course CRT followed by TME and adjuvant chemotherapy, and only 6% received chemotherapy prior to TME. However, as new evidence emerges regarding the roles of TNT and short course radiotherapy for rectal cancer, our observed treatment sequences may not fully represent evolving practice patterns 14,16,17,26–29. Both the RAPIDO and UNICANCER-PRODIGE 23 trials reported higher rates of pCR and DFS-related outcomes with short course TNT and FOLFIRINOX-based TNT, respectively, compared to control arms. As further investigation is needed to specifically evaluate these treatment approaches among patients with young-onset rectal cancer, our study could serve as a benchmark for such comparisons 16,17.
In our study, we excluded patients who declined TME and elected to pursue a “watch and wait” approach. There has been increased interest in non-operative management for locally advanced rectal cancer in an effort to potentially avoid the long-term bowel, urinary, and sexual side effects associated with TME. “Watch and wait” entails a strategy of close clinical surveillance following complete clinical response to neoadjuvant therapy, with surgical intervention upon evidence of tumor regrowth. van der Valk et al. reported the outcomes of approximately 1,000 patients with locally advanced rectal cancer who were enrolled in the International Watch & Wait Database. With a median follow-up time of 3.3 years, the 2-year local re-growth rate was 25.2% 30. To evaluate the optimal “watch and wait” neoadjuvant sequence, the “Organ Preservation of Rectal Adenocarcinoma (OPRA)” trial randomized patients with stage II or stage III rectal cancer to either induction chemotherapy followed by long course CRT or long course CRT followed by consolidative chemotherapy. Early results of 307 enrolled patients with a median follow-up of 2.1 years demonstrated comparable rates of DFS between treatment groups but a higher rate of organ preservation following consolidative chemotherapy (58% vs. 43% P=0.01) 31. Especially in the absence of randomized data, the role of organ preservation strategies for young rectal cancer patients remains to be elucidated. However, avoidance of long-term gastrointestinal and sexual toxicity with a “watch and wait” approach would likely be of great interest to these patients. Our study could also serve as a benchmark by which to evaluate “watch and wait” studies of young-onset rectal cancer.
The German CAO/ARO/AIO-94 trial established the role of pre-operative CRT in the management of locally advanced (clinical T3, T4, or node positive disease) rectal cancer with respect to local disease control. At 5 years’ follow-up, the authors reported a local relapse rate 6% with pre-operative CRT, compared to 13% with post-operative CRT (P=0.006) 8,9. Using the same inclusion criteria and with a median follow-up of 5 years, we found a comparable local recurrence rate of 5% with pre-operative CRT. There was no difference in DFS or OS by clinical T classification or N classification. However, less than 5% of patients had cT1–2 disease and the majority of patients met both T classification and N classification characteristics for locally advanced disease, thereby confounding our ability to assess associations between tumor/nodal classifiers and survival outcomes.
Limited data exist regarding the prognostic implications of lymph node positivity for young-onset rectal cancer patients. In the assessment of approximately 56,000 patients with non-metastatic rectal cancer included in the Surveillance, Epidemiology, and End Results (SEER) database and treated with primary surgical resection (without neoadjuvant therapies), Meyer et al. found that age at diagnosis was inversely associated with metastatic involvement of lymph nodes on surgical pathology for all T classifications 32. This association persisted for T1-T3 disease after adjusting for pertinent variables, including number of lymph nodes examined. We found no difference in clinical nodal positivity by age group. However, when compared to patients with age ≥ 45 years, patients with age < 45 years were less likely to undergo N classification downstaging following neoadjuvant therapies. When compared to age ≥ 45 years, age < 45 years was also associated with a lower rate of DFS in our study. This association remained significant on multivariable analysis that adjusted for other factors associated with worse DFS outcomes, including the absence of N classification downstaging and the absence of T classification downstaging. Although the exact roles of genetic alterations in disease carcinogenesis and prognosis of sporadic cancers remain to be elucidated, we hypothesize that more aggressive tumor biology may be responsible for the lower rates of N classification downstaging and DFS observed among patients with age < 45 years. The chromosomal instability pathway (CIN) is involved in 80–85% of young-onset CRC and is believed to be a main driver of disease 33. It is notable for activation of KRAS and C-MYC, inactivation of APC and p53, and mutations in TGFBR and PIK3CA.
Despite data to suggest a more aggressive molecular phenotype of young-onset CRC, current guidelines do not consider age of onset in treatment decisions. However, population databases suggest that young-onset rectal cancer patients may receive more aggressive therapy in clinical practice. An analysis of approximately 16,000 stage III CRC cases included in the National Cancer Database (NCDB) noted that patients with age 18–49 years were more likely than those with age 65–75 years to receive systemic therapy (OR=2.42, 95% CI, 2.18–2.68), with a marginal benefit in OS (relative risk=0.89, 95% CI, 0.81–0.97) 18. We found a trend toward differences in adjuvant chemotherapy between patients age < 45 years versus ≥ 45 years, including greater use of combination, non-FOLFOX regimens among patients < 45 years. Taken together, these data suggest that 1) young-onset rectal cancers are more likely to present with node-positive disease and less likely to experience N classification downstaging; 2) age < 45 years is an independent predictor of lower DFS following definitive treatment; 3) aberrant genetic pathways may account for the lower pathologic downstaging and worse survival outcomes among these patients; and 4) further studies are needed on the role of intensified treatment regimens in the management of young-onset rectal cancer, particularly for patients < 45 years of age.
There are several limitations to this retrospective report. Because our study included patients who were treated over a time span of approximately 2 decades, there were differences in pre-treatment staging evaluation during the study period. Specifically, endoscopic ultrasound was the predominant staging modality for the earlier part of the study period. Therefore, we were unable to uniformly assess tumor characteristics observed on MRI including extension beyond the muscularis propria, involvement of the circumferential resection margin, and presence of extramural vascular invasion—all of which bear prognostic implications and could have confounded our ability to assess differences in initial disease status and response to pre-operative therapies between age groups. Our ability to evaluate the predictive roles of variables was limited by incomplete information for some patients. As long-term bowel, urinary, and sexual side effects were not captured in a standardized manner, they are not reported in this study.
In conclusion, we report outcomes of patients with sporadic, young-onset, locally advanced rectal cancer and treated with pre-operative long course CRT followed by TME. Most tumors were MSS/pMMR. When compared to patients with age ≥ 45, patients with age < 45 experienced a similar rate of pCR but lower rate of N classification downstaging. Age < 45 years was an independent predictor of a lower rate of DFS. Although future prospective studies are needed on the role of TNT and more aggressive therapies for this population, especially in the era of a screening age of 45 years, our results could serve as a benchmark by which to evaluate these newer treatment approaches.
Clinical Practice Points.
Patients with sporadic, young-onset, locally advanced rectal cancer experience lower rates of disease free survival and overall survival following pre-operative long course chemoradiotherapy and total mesorectal excision Additional studies regarding total neoadjuvant therapy and treatment intensification are needed for this population.
Acknowledgments:
The authors have no acknowledgments.
Funding statement:
No funding was received for this research.
Footnotes
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Ethical Statement: MD Anderson Cancer Center IRB approval was obtained for this retrospective study, with “exempt” as the review level and “secondary research on data or specimens review” as the review category. No animals were involved in this study.
- Dr. Taku is the recipient of research funding from Varian Medical Systems.
- Dr. Smith has an immediate family member who has a relationship with Oncora Medical and has an immediate family member who is the recipient of research funding from Varian Medical Systems.
- Dr. Chang has a consulting/advisory relationship with MORE Health, Medicaroid, 11 Health, and Johnson & Johnson. He the recipient of research funding from Agendia.
- Dr. Koong has stock/other ownership interests in Aravive.
- Dr. Holliday is the recipient of research funding from Merck.
- Dr. Koay has a consulting/advisory relationship with Augmenix and RenovoRx. He has a speakers’ bureau relationship with Oncology Information Group. He has a provisional patent for 3D printed oral stents and receives royalties from Taylor and Francis LLC for a co-authored book. He is the recipient of research funding from Philips Healthcare, Elekta, and GE Healthcare.
- Dr. Dasari has a consulting/advisory relationship with Ipsen, Novartis, Voluntis, Lexicon, Advanced Accelerator Applications, and Hutchison MediPharma. He is the recipient of research funding from Novartis, Eisai, Hutchison MediPharma, Merck, Guardant Health, and Ipsen.
- Dr. Taniguchi has a consulting/advisory relationship with Accuray. He has patents for PHD inhibitors for radio protection of the GI Tract and oral amifostine for radio protection of the intestinal tract. He has received honoraria from and is a consultant for Xerient Pharmaceuticals.
- Dr. Morris has a consulting/advisory relationship Array Biopharma, Incyte, SERVIER, Boehringer Ingelheim, Axiom Healthcare Strategies, BioMedical Insights, Bicara Therapeutics. He has received honoraria from Projects in Knowledge. He or his institution is the recipient of research funding from Bristol-Myers Squibb, EMD Serono, Boehringer Ingelheim, Immatics, Pfizer, and BioNTech AG.
- Dr. Overman has a consulting/advisory relationship with Bristol-Myers Squibb, Roche/Genentech, Gritstone Oncology, MedImmune, Novartis, Promega, Spectrum Pharmaceuticals, Array BioPharma, Janssen, and Pfizer. He is the recipient of research funding from Bristol-Myers Squibb, Merck, Roche, and MedImmune.
- Dr. Kopetz has a consulting/advisory relationship with Roche, Genentech, EMD Serono, Merck, Navire, Symphogen, Holy Stone Healthcare, Amgen, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, EMD Serono, Redx Pharma, Ipsen, Daiichi Sankyo, Natera, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, GlaxoSmithKline, and Jazz Pharmaceuticals. He has stock/other ownership interests in MolecularMatch, Navire, and Lutris. He or hist institution is the recipient of research funding from Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, and Daiichi Sankyo.
- Dr. Raghav has a consulting/advisory relationship with AstraZeneca, Bayer, Eisai, and Daiichi Sankyo.
- Dr. Das has a consulting/advisory relationship with Adlai Nortye and MD Anderson Cancer Center.
Data availability:
Data available on request due to privacy/ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data available on request due to privacy/ethical restrictions.