|Ahead of print
Clinical characteristics and survival profile of young versus old colorectal cancer patients at a tertiary cancer center in North India over a period of 5 years
Smreti Vasudevan1, Anurag Mehta2
1 Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Delhi, India
2 Department of Laboratory and Transfusion Services, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Delhi, India
|Date of Submission||28-Mar-2020|
|Date of Decision||25-Apr-2020|
|Date of Acceptance||28-Apr-2020|
|Date of Web Publication||17-Oct-2020|
Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Delhi
Source of Support: None, Conflict of Interest: None
Background: Colorectal cancer (CRC) is mostly considered a disease of the elderly. But the rate is increasing among young adults and is associated with different clinical patterns. The objective was to study the frequency of CRC in young patients and compare the clinicopathological profile and survival with the older cohort.
Methods: Five-year (2012–2016) data of the 912 consecutive CRC cases treated at the center were analyzed. Clinical and histopathological characteristics were compared in young (≤40) and older (>40) patients. Descriptive statistics were used for data presentation. Categorical data were compared by the Chi-square test; survival analyses were performed by Kaplan-Meier method.
Results: In total, 231 (25.3%) and 681 (74.7%) cases were in the young and older age groups, respectively. Male predominance was noted. Young patients presented predominantly in stage III (46%). Majority of the young patients harbored left-sided tumors (75.8% vs 63.7% in old patients, P = 0.001) and rectum was the favored site in young patients (53.7% vs 37%; P < 0.001). Poorly differentiated adenocarcinoma was more common in the young age group (46.88% vs 24.16% in old patients, P < 0.001), also signet-ring cell morphology occurred more often in young patients (11.7% vs 4%, P < 0.001). Survival was inferior in the patients presenting at an advanced stage or with adverse histology or poor tumor grade. However, stage-specific survival showed no significant difference between both groups.
Conclusion: This study shows that though young CRC patients present with higher stage, aggressive morphology, and predominantly rectal localization, the overall survival and stage-specific survival did not differ significantly from the older patients.
Keywords: Rectal cancer, signet-ring cell carcinoma, stage-for-stage survival analysis
Key Message: Young colorectal cancer patients usually present at an advanced stage and poor tumor differentiation, but overall survival is not inferior to the older cohort. Young colorectal cancer patients could derive better benefit from therapeutic interventions.
|How to cite this URL:|
Vasudevan S, Mehta A. Clinical characteristics and survival profile of young versus old colorectal cancer patients at a tertiary cancer center in North India over a period of 5 years. Indian J Cancer [Epub ahead of print] [cited 2020 Oct 20]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=298287
| » Introduction|| |
Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related deaths that accounted for about 1.8 million new cases and 881,000 deaths worldwide in the year 2018. There is a wide geographical variation in the incidence rate and 55% of the cases occur in developed countries.,, Despite the lesser incidence of cancer in the developing and underdeveloped countries, mortality rates are higher due to late diagnosis and inadequate health care infrastructure. India is a low-incidence country with an age-standardized incidence rate of 5.8/100,000 and 3.1/100,000 population in men and women, respectively. CRC is the seventh leading cancer in India with a mortality rate of 3.4/100,000 population.
Traditionally, CRC has been regarded as a disease of older adults and is usually diagnosed after the fifth decade of life. The incidence increases with age and 90% of the cases occur in the age group of >1 years. Its presentation before 40 years is less common and represents less than 10% of the total CRC., Young-onset CRC is associated with a genetic predisposition or conditions such as chronic inflammatory bowel disease. But recent reports have shown a steady increase in the incidence of sporadic CRC in young adults and a comparative decline in the older age group. The reasons for this rise in younger people are poorly defined. High-calorie, low-fiber, low fruit and vegetable diet coupled with a sedentary lifestyle are some of the explanations that have been put forth., Low index of clinical suspicion in young symptomatic individuals often delays diagnosis to the advanced stage., Further, it is not clearly understood whether survival differs stage-for-stage among the young and older-CRC patients. Several reports suggest that young-onset CRC is associated with different clinical and pathological profiles but disagreement prevails. Although left-sided tumor location is most common, a few Western studies document a changing subsite distribution of the tumors to proximal colon.,, Contrarily, studies from Asia and Africa report majority of left-sided CRC cases.,,,, In brief, the common thread of CRC in young can be surmised as i) poor histologic morphology, ii) late-stage diagnosis, and iii) a preponderance of rectal and distal left-sided colonic tumors at least in Asian cohort.
While many of the large epidemiological studies for young-onset CRC have been conducted in developed countries, the data from the Indian subcontinent is sparse and is limited to different regions. These have been conducted on a small patient number, making it difficult to clearly understand the prevalence of young-onset CRC in India and its defining features such as presenting stage, tumor laterality, tumor histology, and the survival attributes. Only one study from north India by Saluja et al. has addressed the stage-specific survival in the young and the older CRC patients. Depending on the disease stage and histology, the young and old patients can show variable survival pattern.
Hence, this study was performed to examine young-onset CRC cases at our center. More specifically, our objective was to compare the clinicopathological differences with respect to gender, stage at disease presentation, tumor histopathology, anatomic subsite location, and comorbidities in young and elderly CRC patients. Further, to understand the survival patterns, we performed survival analyses of patients as per the age groups, tumor histology and carried out a stage-wise survival analysis of the patients who had undergone cancer-directed treatment at our center.
| » Materials and Methods|| |
Research setting, subjects, and treatment
The study has been conducted in a high-volume comprehensive cancer care center in north India. About 12,000 new patients visit the hospital annually (5-year average) and approximately one-fourth are diagnosed with gastrointestinal cancers.
2019 patients sought treatment for CRC in 5 years from January 1, 2012, through December 31, 2016. Of these, 912 patients (about 45%) underwent complete treatment and follow-up at this center. The remaining 55% chose to be treated at facilities near home following the diagnosis and establishment of treatment plans. To ensure complete integrity of clinical information and follow-up data, the study has been restricted to those 912 patients who received complete treatment and were followed up at this center. The patients availing the services belonged to all income groups and were drawn primarily from the northern parts of India including Delhi, Punjab, Chandigarh, Haryana, Himachal Pradesh, Jammu and Kashmir, and Northeast India.
The patients were treated according to the standard protocol. Colon cancer patients were managed by surgery and adjuvant chemotherapy. Rectal cancer cases either underwent upfront surgery or were referred for neoadjuvant chemoradiotherapy followed by surgery. Palliative chemotherapy was rendered to the patients at the advanced disease stage. As first-line chemotherapy, patients were administered with the FOLFOX regimen (5-fluorouracil, leucovorin, and oxaliplatin), while the FOLFIRI regimen (leucovorin, 5-fluorouracil, and irinotecan) was given as second-line. Advanced CRC patients who tested negative for KRAS mutation (75 cases) were treated additionally with Erbitux till progression.
The study was approved by our Institutional Review Board (RGCIRC/IRB/156/2018, dated 15th March, 2018) and was conducted in accordance with the Declaration of Helsinki.
Medical records of CRC patients were retrospectively reviewed from the electronic database (computerized patient record system). Information pertaining to age, gender, date of diagnosis, anatomical site of the primary tumor, histopathology, tumor grade, stage of disease at presentation (American Joint Committee on Cancer (AJCC), 7th edition guidelines), and co-occurring disease(s) was collected.
According to the age of CRC onset, the patients were placed into the two following groups: (i) ≤40 years (young-onset/young group) and (ii) >1 years (older group). Further, according to the anatomical site, tumors were classified as right-sided (tumors located in the cecum, ascending colon, hepatic flexure, and transverse colon) or left-sided (tumors near the distal segment including splenic flexure, descending colon, sigmoid colon, rectosigmoid junction, and the rectum).
Follow-up was maintained until the end of December 2017 by tracking the hospital check-up visits/telephonic contacts.
Descriptive statistics were employed in the study. Pearson's Chi-squared test/Fisher's exact test was used to compare the categorical data. P value <0.05 was considered statistically significant. Survival curves were drawn by the Kaplan–Meier method and the difference between outcomes was tested using the log-rank test. Overall survival was defined as the time interval between the date of diagnosis till death/last contact.
Statistical analysis was performed using SPSS version 23.0 software package (IBM Corp, Armonk, NY).
| » Results|| |
Data of 912 CRC patients who were managed at the center in a 5-year span (2012–2016) was analyzed. A flow diagram of the study is shown in [Figure 1].
|Figure 1: Flow diagram from registration to the final outcome (2012–2016)|
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There were 601 (65.9%) males, the median age was 53 years (range: 14–87). The baseline features have been presented in [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. As noted in [Figure 2]a, the advanced stage of CRC at presentation was observed in the cohort. The majority of the patients (334/912; 36.6%) presented at stage IV (metastatic) disease and almost similar number of cases were in stage III (322/912; 35.3%).
|Figure 2: Baseline characteristics of the study group (n = 912). Bar diagrams present (a) number of colorectal cancer (CRC) cases and their presenting stage, (b) age distribution with breakout per stage. Pie charts depict (c) tumor histology. Here “other types” include gastrointestinal stromal tumors, neuroendocrine tumors, melanoma, and undifferentiated carcinomas, (d) comorbidities in the study group. Here “Others” category includes co-morbid conditions such as asthma, chronic obstructive pulmonary disease (COPD), hepatitis, hypo/hyperthyroidism, tuberculosis, vitiligo, and vertigo in the CRC patients|
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Around 25% of the cases (231/912) were in the young-onset group. Most of the young patients (46%) presented with stage III CRC [Figure 2]b. Adenocarcinoma (not otherwise specified) was the most common histological type observed (82.8%), signet-ring cell carcinoma was reported in 54 cases (5.9%) [Figure 2]c. Comorbid conditions were present in more than one-third of patients, wherein a majority of the cases had hypertension (212/912, 23.25%) and Type 2 diabetes mellitus (147/912, 16.12%) [Figure 2]d. Moreover, colon and rectal cancers (including anorectum) accounted for 52.52% (479/912) and 41.23% (376/912) of the cases, respectively. The substantial number of patients (609/912, 66.8%) harbored left-sided tumors.
Furthermore, to understand the differences, the two age groups were compared with respect to the identified clinical parameters (summarized in [Table 1]). It was observed that, in the cohort, the frequency of colon cancer was high, noticeably; rectal cancer significantly predominated in the young-onset group (53.7%). While colon cancer was more common (56.7%) in the older CRC group (P < 0.001) [Table 1]. Moreover, in the young group, left-sided tumors were significantly common as compared to the older group (P = 0.0001) [Table 1]. The majority of the left-sided tumors were located in the rectum/anorectal junction [Table 2]. Concerning right-sided tumors, cecum was the commonest primary tumor site in both the groups [Table 2].
Tumor histology differed significantly among young and older patients [Table 1]. More patients showed signet-ring cell morphology in the young-onset group than in the older group (11.7 vs 4%, P < 0.001). A significant proportion of patients in the young group showed poorly differentiated tumors. For adenocarcinomas, the tumor differentiation proportion in young group vs older group was well differentiated, 4.91% vs 5.96%; moderately differentiated, 48.21% vs 69.88%; poorly differentiated, 46.88% vs 24.16% (P < 0.001). Also, the frequency of stage III tumors was higher in the young group than the comparison group (45.9% vs 31.7%, P = 0.002). With respect to the associated comorbidities, it was observed that they increased with advancing age. In the younger age group, only three cases had a comorbid condition. Among them, two CRC patients had type 2 diabetes mellitus and one had both diabetes and hypertension. Importantly, type 2 diabetes mellitus was more common in older patients as compared to the younger patients (21.1% vs 1.3%, P < 0.001, [Table 1]).
[Table 3] details the treatment modalities received by the subjects in both the groups. The treatment in the young and older cohort was alike and was as per the National Comprehensive Cancer Network (NCCN) 2012 guidelines. The only noteworthy difference was that more older colon cancer patients at stage III and stage IV were offered supportive care due to their falling performance status [Table 3].
CRC patients with and without diabetes showed no significant difference in mortality in both young and older age-groups (P = 0.570 and P = 0.636, respectively) [Figure 3].
|Figure 3: Mortality in CRC patients with and without diabetes mellitus (DM) in the young (≤40 years) and older (>40 years) age groups (n = 622)|
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The overall survival of the study group was 53.9% at 72 months. To determine whether there is a difference between the survival of the young and older CRC patients, we performed a Kaplan–Meier survival analysis with respect to age-grouping. The median follow-up time was 19 months (range: 0–72). Follow-up information was available for 622 patients (68% cases) (% loss to follow-up cases did not differ significantly between the groups). In total, there were 10 cases of anal canal squamous cell carcinoma; these cases were excluded from the comparative survival analysis. No significant difference was observed in overall survival between the two age groups [Figure 4]a. The overall survival in the young group was 62.8%, while in the older group it was 50.5% at 72 months (P = 0.116).
|Figure 4: Kaplan–Meier curves showing overall survival in CRC patients according to (a) age groups (*n = 902), (b) tumor stage in the young and older age groups (*n = 902), (c) depicted tumor histology (**n = 878), (d) Tumor grade in both age groups (**n = 878). Please note: In the graphs: Y = Younger group, O = Older group, I = Stage I, II = Stage II, III = Stage III and IV = Stage IV. *10 anal canal squamous cell carcinoma cases have been excluded. **16 squamous cell carcinoma cases and 18 other type histology cases have been excluded|
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Next, we examined whether survival differs stage-for-stage among young and older patients [Figure 4]b. It was seen that the overall survival significantly differed for stage I, II, III, and IV patients (P < 0.001). However, the stage-wise comparison showed no significant difference in same stage young and older patients [Figure 4]b. The overall survival in stage I was 81.8% and 83.1% at 56 months in the young and older groups, respectively (P = 0.301). For stage II, the overall survival was 82.1% and 80.5% at 69 months in the respective age groups, young and older (P = 0.749), whereas, for stage III the survival dropped to 70% and 55.3% at 67 months (P = 0.154). Further, the overall survival in stage IV was 32.4% in the young-onset group and 15.7% in the older group at 71 months (P = 0.531) [Figure 4]b. The median overall survival time for stage IV patients (including both groups) was 22 months (95% confidence interval (CI): 17.8–26.2).
The survival differed significantly between the histological subtypes [Figure 4]c. Overall survival was inferior in signet-ring cell carcinoma patients (median overall survival: 24 months; 95% CI: 17.5–30.4) as compared to mucinous adenocarcinoma (median survival time: 39 months) and adenocarcinoma patients (P = 0.003). With respect to tumor differentiation status, the two age groups significantly differed in overall survival (P < 0.001) [Figure 4]d. In both groups the survival was inferior in the patients with poorly differentiated tumors. Notably, young patients with well/moderately differentiated tumors showed significantly better survival than older patients with similar tumor grade (P = 0.002).
| » Discussion|| |
CRC has long been considered as a disease of older adults, afflicting individuals in the later part of their life. This trend is gradually undergoing a worrying shift toward an early age and aggressive tumor biology.
Here we have analyzed the 5-year data of 912 CRC patients treated at a tertiary care cancer center in north India and compared the old patients (>40 years) and the young patients (≤40 years) in terms of disease characteristics and survival. The peak age group was 50–60 years, with the youngest patient being a 14-year-old male. One-fourth of the cases represented young-onset CRC, and were mostly presented at stage III and tended to have rectal tumors. Outcome analysis showed that survival was inferior in the patients presented at an advanced stage or displaying adverse tumor histology. An important finding from this study is that the survival analysis matched for stage showed no significant difference between the young and the old group.
Some of the current reports from India,, as well as Western countries, have reported an increased incidence of CRC in young age group. Our study shows 25% of young CRC cases, which is high and is comparable to other Indian studies by Sudarshan et al. and Haleshappa et al. who have reported an incidence of 39.05% and 27.8%, respectively from their tertiary/regional cancer care centers., Moreover, in this study, the ratio of the number of patients under 40 to those above 40 years of age was 0.34. This ratio is on the higher side and is in line with the comparisons made by Gupta et al., which was found to be more than the Indian National Cancer Registry data (0.20) and international average (0.07). This discrepancy could be present because the data from a tertiary cancer center may not be reflective of the population database. The median age of disease presentation in our study was 53 years, which is also significantly lower to the SEER cancer statistics which has reported the median age at diagnosis ranging from 63–73 years. CRC is diverse in incidence and is highly associated with ethnicity and dietary factors. A larger median age in SEER cancer statistics could be because SEER database primarily represents US population and is expected to be different from South Asian population. It is possible that CRC in South Asian patients presents early in contrast to population depicted in the SEER database.
In this study, the gender representation of males was higher than females (1.9), and it is in accordance with the literature where CRC has shown to have a male predilection., The ratio was still higher in the younger group (2.25). Further, left-sided tumors were more common in young patients. Most of these left-sided tumors were located in the rectum. Some hospital-based studies from India have reported a predominance of left-sided tumors in young CRC patients, where the dominance of rectal cancer was observed. A study by Raman et al., relating to two tertiary cancer centers from south India, documented the predominance of rectal cancer in the young CRC patients, which was significantly associated with advanced stage. The authors have reported the median survival for stage IV patients as 21 months (95% CI: 19.0–25.0), which is comparable to that observed in our study (22 months). Of note, the younger patients tended to present at an advanced tumor stage. However, stage-for-stage survival was similar between the two age groups. This finding is consistent with a previous study by Saluja et al. from India, wherein no stage-specific difference in the survival estimates among the young and older CRC patients was observed. However, our findings disagree with summarized findings from literature by O'Connell et al. where the stage-specific overall 5-year survival in Dukes' stages A or B was better in young than the old. Better treatment response in young patients and lesser comorbidities could favorably affect survival in the young group. Another observation of interest is that the number of patients with signet-ring cell carcinoma morphology recognized in our study (5.9%) is comparatively more than its reported prevalence of <1%.,, It is a rare subtype of CRC and is usually diagnosed late, is highly aggressive, and shows a poor prognosis.,, A recent, single-year audit from a referral cancer center in western India on 800 patients reported 13% CRC cases with signet-ring cell morphology, which was significantly associated with young age and late stage of the disease. In our study, three times more signet-ring cell morphology was observed in the young group than the older group (11.7% vs 4.0%). Overall survival was inferior in the patients presented with signet-ring cell morphology and the comparison was unfavorable in both groups. Further, with respect to the associated comorbidities, type 2 diabetes mellitus was found to be co-occurring in about one-sixth (16%) of the CRC cases and was more common in older patients (>40 years). This percentage is high when compared to the overall prevalence of diabetes in India (7.3%). A similar finding in CRC patients has been reported in a retrospective study from eastern India by Patra et al., in which 16.7% of CRC patients had type 2 diabetes and a significant proportion of these were from older age group.
The strength of this study is the large sample size and an accurate follow-up of the patients. Being single-centric, greater homogeneity in the data collection and treatment plan was assured. However, it has the limitation of referral bias because of the tertiary cancer center setting and is inclined to show more advanced cases. Besides, for survival analyses, we have not considered treatment modalities as a variable. The study is retrospective and 32% of the patients were lost to follow-up. Nonetheless, this study explores some of the observed epidemiological and clinicopathological features of CRC at a tertiary cancer center.
| » Conclusions|| |
A fairly large proportion of CRC patients are young (25%). Ominously, they present at a higher stage and frequently with poor differentiation and aggressive signet-ring cell morphology. The overall survival and stage specific survival of the young and older CRC patients do not differ significantly. Because young patients are not so uncommonly afflicted by CRC, a high index of clinical suspicion is needed in this group.
The authors thank the Hospital-Based Cancer Registry Program and Ms. Swarnima Jaitley for providing three years' data (2012, 2013 and 2014).
We also thank Ms. Atika Dogra for helping with the analysis.
The authors are grateful to the patients/their guardians for providing relevant survival information.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]