Research ArticleClinical Studies

Better Cancer-specific Survival in Younger Patients With Stage III Colorectal Cancer: A Propensity Score Matching Study From Japan

LIMING WANG, YASUMITSU HIRANO, GREGORY HENG, TOSHIMASA ISHII, HIROKA KONDO, KIYOKA HARA, NAO OBARA, MASAHIRO ASARI and SHIGEKI YAMAGUCHI
Anticancer Research August 2020, 40 (8) 4365-4372; DOI: https://doi.org/10.21873/anticanres.14439

Abstract

Background/Aim: The purpose of this study was to explore the perioperative, short-term, and long-term prognostic differences in colorectal cancer (CRC) between young and older patients. Patients and Methods: A total of 3095 patients were divided into young (≤45 years; n=139) and older (>45 years; n=2956) groups. Then, propensity score matching was performed for patients in stage I to III according to a ratio of 1:1. The clinicopathological factors and prognosis of the two groups were studied. Results: Young patients with CRC account for 4.49% of the total number of patients with CRC. Younger patients with CRC in stage I to III showed better cancer-specific survival (CSS). Older age was an independent risk factor for CSS prognosis. The CSS of the younger group was significantly better in stage I to III as a whole, but there was no difference in stage I and II subgroups – only in stage III. The proportion of young patients with stage III disease receiving first-line adjuvant chemotherapy was significantly higher. When young patients relapsed, they were more likely to receive second-line adjuvant chemotherapy or reoperation than older patients. Conclusion: Younger patients with stage III colorectal cancer had better CSS rates.

The incidence of colorectal cancer (CRC) in young patients is increasing in the United States (1). Despite advances in screening technology and treatment, CRC is the second leading cause of cancer-related deaths in Japan; more than 50,000 people died of CRC in 2016, many of whom were young patients (2).

CRC is relatively unique in that it affects a large age span, from young to old. There are few studies on young patients diagnosed with CRC and the clinical outcome of these patients is not clear. Previous reports have shown that younger patients with CRC are more likely to develop progressive disease and have a worse prognosis than older patients (3). However, other reports have suggested that young patients' survival rates are similar to those of older patients (4). The reason for this contradiction may be related to the individual study's definition of a “young” patient. Some studies classify any patients ≤50 years old (5, 6) as young, whereas other studies classify patients ≤45 years of age (7, 8) as young. In addition, the different clinical characteristics of the young and older patients may also lead to inconsistent results.

In recent years, propensity score matching (PSM) has been widely used in clinical studies to reduce differences between study groups (9, 10). The purpose of our study was to analyze, using PSM, the difference in prognosis between young and older patients with CRC during the perioperative, short-term, and long-term period.

Patients and Methods

This was a 10-year retrospective cohort study of a high-volume cancer center in Japan. Cases were selected from 3570 patients with CRC who underwent surgical resection at the Saitama Medical University International Medical Center from October 2007 to December 2016. Patients with neuroendocrine colon tumors or without indications for surgery were excluded. All patients signed a written, informed consent form. The ethics committee of the Saitama Medical University International Medical Center approved the study.

The patients with CRC were divided into young (≤45 years; n=139) and old (>45 years; n=2,956) groups (Figure 1). The basic medical history and preoperative comorbidities of the patients were collected from the outpatient medical records, and short-term postoperative comorbidities were screened from the discharge summary. Resection specimens were classified pathologically according to the seventh edition of the International Union Against Cancer TNM classification. Propensity score weights were used to balance the basic variable logistic regression model using polynomials for comparative analysis. Sex, family history, tumor location, postoperative complications, preoperative carcinoembryonic antigen (CEA) levels, surgical methods, tumor morphology, pathological type, peritoneal metastasis, depth of invasion, lymphatic infiltration, peripheral nerve invasion, blood vessel infiltration, and lymph node metastasis were included in the matching model. Independent risk factors for relapase-free survival (RFS) and cause-specific survival (CSS) were determined by Cox regression analysis and the Wald test.

All statistical analyses were performed using the SPSS software package version 22.0 for Macintosh (IBM Japan, Tokyo, Japan). Survival rates were drawn using the Kaplan-Meier method and log-rank test. A p-value <0.05 was considered statistically significant.

Results

A total of 3095 patients with primary CRC were included in this study, of which 2956 (95.51%) were >45 years of age, and 139 patients (4.49%) were ≤45 years. First, the patients were analyzed by single factor analysis. There was a 20-year difference in the mean age of the 2 groups [mean (y) ± SD, 40±0.48 vs. 60±0.007; p<0.001]. Compared to the older patients, the young CRC group had 1) more female patients (48.2% vs. 39.0%; p=0.033); 2) greater family history of CRC (29.5% vs. 18.4%; p=0.002); 3) more rectal cancer (54.0% vs. 39.8%; p=0.001); 4) a higher proportion of signet ring, mucinous, and low-differentiated adenocarcinoma (7.9% vs. 4.1%; p=0.048); 5) more protruding-proliferative type (36.7% vs. 25.2%; p=0.004); and 6) more shallow infiltration (T1: 29.5% vs. 19.1%; p=0.017) than the older CRC group. Shallow infiltration was more easily detected in the early stage (stage I: 35.3% vs. 25.9%; p=0.044). However, there were no significant differences in CEA ≥5 ng/ml (31.7% vs. 37.6%; p=0.178), peritoneal metastasis (43.2% vs. 40.8%; p=0.597), and lymphatic infiltration (37.4% vs. 31.6%; p=0.162). Regarding surgery type, there was no difference in whether the operation was open or laparoscopic between the 2 groups (p=0.331) (Table I).

Next, we performed multivariate analysis on the 2 groups before matching. It was found that patients with rectal cancer [hazard ratio (HR)=0.755; 95% confidence interval (CI)=0.613-0.931; p=0.009] and ulcerative and infiltrating proliferation (HR=0.495; 95%CI=0.34-0.720; p<0.001) were more prone to relapse than those with colon cancer. Patients with pathology revealing signet ring cell carcinoma, mucinous adenocarcinoma, and poorly differentiated adenocarcinoma were more likely to relapse than those with adenocarcinoma (HR=0.592; 95%CI=0.395-0.888; p=0.011).

In the group with CEA level ≥5 ng/ml, recurrence rates increased (HR=0.548; 95%CI=0.443-0.676; p<0.001), and CSS decreased significantly (HR=0.596; 95%CI=0.459-0.774; p<0.001). Lymphatic invasion, vascular invasion, and lymph node metastasis were also independent risk factors for both RFS and CSS: 1) lymphatic invasion for RFS (HR=0.706; 95%CI=0.564-0.883; p=0.002) and CSS (HR=0.639; 95%CI=0.485-0.841; p=0.001); 2) vascular invasion for RFS (HR=0.554; 95%CI=0.423-0.725; p<0.001) and CSS (HR=0.529; 95%CI=0.386-0.726; p<0.001); and 3) lymph node metastasis for RFS (HR=0.376; 95%CI=0.264-.536; p<0.001) and for CSS (HR=0.559; 95%CI=0.339-0.923; p=0.023) (Table III).

We then matched the 2 groups with a propensity score of 1:1. A total of 139 young patients were compared with 139 older patients. Initially, we matched all cases of stage I to IV and found no differences in CSS between the 2 groups, as well as in stage IV (before PSM, p=0.392; after PSM, p=0.257).

Then we matched 114 patients in stage I to III again, with a mean age difference of about 27 years (40±0.48 vs. 67±0.54; p<0.001). There was no statistical difference in patient clinical characteristics between the 2 groups, including the number of lymph nodes removed (Table II).

We analyzed the prognosis of patients before PSM. There was no difference in overall CSS and RFS rate. The younger patients with CRC had a better CSS rate for stage I to III, and after matching, the difference became more obvious (before PSM, p=0.046; after PSM, p=0.005) (Figure 2A and 3A). There was no difference between the younger and older patients with CRC in stage II (before PSM, p=0.410; after PSM, p=0.983) (Figure 2B and 3B). There was no difference in RFS among the various stages. Interestingly, there was no significant difference between the 2 groups in the prematching stage III, but after matching, the CSS prognosis in the older group was significantly worse (before PSM, p=0.405; in PSM, p=0.031) (Figure 2C and 3C).

Cox regression analysis after matching showed that the older group (HR=0.247; 95%CI=0.085-0.719; p=0.010) and higher CEA level were independent risk factors (HR=0.108; 95%CI=0.027-0.430; p=0.002) for CSS (Table IV).

Considering that the patient's underlying disease and postoperative recovery may affect the prognosis, we compared the perioperative factors between the 2 groups. As expected, the background of the patients after matching showed that the older group had more diabetes mellitus (14.9% vs. 1.8%; p<0.001) and hypertension diagnoses (43.8% vs 6.1%; p<0.001) and preoperative surgical history (28.9% vs. 12.2%; p<0.001). However, there was no significant difference in operation time, blood loss, postoperative food intake, hospital stay, length of specimen resection, postoperative complications (e.g., anastomotic leakage) and recurrence (Table IV). We further investigated the postoperative adjuvant chemotherapy in patients with stage III, and we found that the proportion receiving adjuvant chemotherapy in the younger group was much higher (76.9% vs. 38.5%; p<0.001). The proportion of the 2 groups receiving second-line chemotherapy or reoperation after relapse was significantly higher in the younger group than in the older group (81.8% vs. 40%; p<0.001) (Table V). Eleven patients (28.2%) in the young group relapsed, 6 patients (54.5%) had additional targeted drug chemotherapy, and 3 patients (27.3%) had reoperation performed. However, in the older group, 15 (38.5%) patients relapsed, 8 patients (53.3%) chose hospice, 5 (33.3%) received second-line chemotherapy, and just 1 (6.7%) patient elected to have surgery.

View this table:
Table I.

Clinicopathological parameters for patients before matching.

Discussion

Current European guidelines recommend CRC screening from the age of 50. In 2018, the American Cancer Society recommended screening from the age of 45 (11). This study is based on the new American colorectal screening guidelines. Patients under the age of 45 were defined as the young group. The average age of patients in the young group was 40 years old, and their family history of CRC was close to 30%, which is much higher than that of the older group. Therefore, this reinforces the need to screen for a family history of CRC in patients from 40 years of age. Unlike previous reports (12), our study found that compared with older patients, invasive proliferative CRC in young patients was less common, and the number of patients in stage T1 was relatively high. This may explain why our findings indicated that the CSS prognosis was better in the young group in stage I to III. Contrary to some reports, we did not find any statistically significant differences in DFS before or after the match between the 2 groups (12, 13). This is also possibly due to the fact that 35.3% of the young patients were in stage I, which is 10% more than the older group, or may also be related to stable postoperative performance.

View this table:
Table II.

Clinicopathological parameters for patients in stage I-III after matching.

View this table:
Table III.

Cox regression model comparing the prognosis of patients in stage I-III before matching.

View this table:
Table IV.

Cox regression model comparing the prognosis of patient in stage I-III after matching.

In Cox regression analysis, vascular infiltration and lymphatic invasion are considered to be independent risk factors for RFS and CSS. However, in this study, we did not find any difference between the 2 groups for RFS and CSS. There are reports in the literature that the number of lymph nodes removed is related to the prognosis of tumor treatment (14, 15). Considering that lymph node metastasis was a common independent risk factor for RFS and CSS before matching, we aimed to keep the number of resected lymph nodes similar when performing PSM. In Japan, surgeons generally dissect the lymph nodes after surgery instead of handing the specimens to the pathologist. This makes it easier to collect smaller lymph nodes while the specimens are still fresh. The number of harvested lymph nodes is approximately 30, which is more conducive to lymph node analysis.

In the matched Cox regression analysis, we surprisingly found that older age was an independent high risk factor for CSS. This is also one of the interesting findings of our study which indicates that, when keeping all patient variables constant, older patients were more likely to have a worse prognosis. This finding coincides with previous reports (5, 16).

Figure 1.
Figure 1.

Research flow chart. CRC: Colorectal cancer.

Surgical treatment is a vital part of colorectal treatment. In our study, there were no differences in postoperative results between the 2 groups due to age differences. We found that patients in stage I and II can have better CSS after rigorous surgical resection. In other words, regardless of age, early screening is extremely important. Only in stage III we found that when the number of lymph nodes cleared was equal, CSS in the young group was far better than that in the older group. This highlights the fact that, although the young group of patients had an earlier onset, the prognosis may not be necessarily poor. In addition to the homogeneous perioperative performance, we found that for patients in stage III, the proportion of postoperative adjuvant chemotherapy may directly affect the long-term survival rate of patients. We found that 53.3% of young patients chose oxaliplatin-containing chemotherapy after central vein chemotherapy pump implantation. In contrast, 66.7% of older patients were more inclined to take orally chemotherapy drugs. Discovering how to improve the adjuvant chemotherapy introduction rate in older patients will be critical for improving the clinical outcome of CRC in that population. Young patients were more tolerant of second-line chemotherapy or reoperation in this research, which may also be one of the reasons for the difference in prognosis between the 2 groups.

This study does have some limitations. Some studies have reported that there are differences in microsatellite instability and KRAS and BRAF gene variations in young and older patients with CRC (4, 5, 17), which can also guide future clinical targeted therapy and immunotherapy. Secondly, although PSM reduced the differences between groups, it also greatly reduced the sample size, and it was impossible to completely match the preoperative comorbidities, which may also have caused some statistical bias. Further, despite follow-up results from high volumn cancer centers over the past decade, the number of young patients was still small, so we hope that additional multi-center international research on young patients with CRC will be conducted in the future.

Figure 2.
Figure 2.

Cancer-specific survival rate before matching. A. Cancer-specific survival rate for patients in stage I to III before matching. B. Cancer-specific survival rate for patients in stage II patients before matching. C. Cancer-specific survival rate for patients in stage III patients before matching.

Figure 3.
Figure 3.

Cancer-specific survival rate after matching. A. Cancer-specific survival rate for patients in stage I-III patients after matching. B. Cancer-specific survival rate for patients in stage II patients after matching. C. Cancer-specific survival rate for patients in stage III patients after matching.

View this table:
Table V.

Characters of patients after matching.

In summary, this study found that age higher that 45 years was an independent risk factor for CRC, and young patients with stage III CRC have better CSS. Young patients have higher compliance with postoperative adjuvant chemotherapy and have a better chance of having second-line adjuvant chemotherapy or reoperation when they relapse.

Conclusion

Younger patients with stage III CRC have better CSS rates, and improving postoperative adjuvant chemotherapy compliance may be a critical area to target for improving outcomes.

Acknowledgements

Thanks are extended to BioMed Proofreading LLC for English copyediting.

Footnotes

  • Authors' Contributions

    LMW drafted the manuscript. YH, GH, TI, HK, KH, NO, MA and SY reviewed its content. All authors have read and approved the final submission.

  • Conflicts of Interest

    The Authors have no competing interests to declare with respect to this study.

  • Received June 3, 2020.
  • Revision received June 22, 2020.
  • Accepted June 23, 2020.

References

  1. ↵
    1. Bailey CE,
    2. Hu CY,
    3. You YN,
    4. Bednarski BK,
    5. Rodriguez-Bigas MA,
    6. Skibber JM,
    7. Cantor SB,
    8. Chang GJ
    : Increasing disparities in the age-related incidences of colon and rectal cancers in the united states, 1975-2010. JAMA Surg 150(1): 17-22, 2015. PMID: 25372703. DOI: 10.1001/jamasurg.2014.1756
    OpenUrl
  2. ↵
    1. Hashiguchi Y,
    2. Muro K,
    3. Saito Y,
    4. Ito Y,
    5. Ajioka Y,
    6. Hamaguchi T,
    7. Hasegawa K,
    8. Hotta K,
    9. Ishida H,
    10. Ishiguro M,
    11. Ishihara S,
    12. Kanemitsu Y,
    13. Kinugasa Y,
    14. Murofushi K,
    15. Nakajima TE,
    16. Oka S,
    17. Tanaka T,
    18. Taniguchi H,
    19. Tsuji A,
    20. Uehara K,
    21. Ueno H,
    22. Yamanaka T,
    23. Yamazaki K,
    24. Yoshida M,
    25. Yoshino T,
    26. Itabashi M,
    27. Sakamaki K,
    28. Sano K,
    29. Shimada Y,
    30. Tanaka S,
    31. Uetake H,
    32. Yamaguchi S,
    33. Yamaguchi N,
    34. Kobayashi H,
    35. Matsuda K,
    36. Kotake K,
    37. Sugihara K,
    38. Japanese Society for Cancer of the C and Rectum
    : Japanese society for cancer of the colon and rectum (jsccr) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol 25(1): 1-42, 2020. PMID: 31203527. DOI: 10.1007/s10147-019-01485-z
    OpenUrl
  3. ↵
    1. Shida D,
    2. Ahiko Y,
    3. Tanabe T,
    4. Yoshida T,
    5. Tsukamoto S,
    6. Ochiai H,
    7. Takashima A,
    8. Boku N,
    9. Kanemitsu Y
    : Shorter survival in adolescent and young adult patients, compared to adult patients, with stage iv colorectal cancer in japan. BMC Cancer 18(1): 334, 2018. PMID: 29587683. DOI: 10.1186/s12885-018-4241-9
    OpenUrl
  4. ↵
    1. Perrott S,
    2. Laurie K,
    3. Laws K,
    4. Johnes A,
    5. Miedzybrodzka Z,
    6. Samuel L
    : Young-onset colorectal cancer in the north east of scotland: Survival, clinico-pathological features and genetics. BMC Cancer 20(1): 108, 2020. PMID: 32041565. DOI: 10.1186/s12885-020-6606-0
    OpenUrl
  5. ↵
    1. Willauer AN,
    2. Liu Y,
    3. Pereira AAL,
    4. Lam M,
    5. Morris JS,
    6. Raghav KPS,
    7. Morris VK,
    8. Menter D,
    9. Broaddus R,
    10. Meric-Bernstam F,
    11. Hayes-Jordan A,
    12. Huh W,
    13. Overman MJ,
    14. Kopetz S,
    15. Loree JM
    : Clinical and molecular characterization of early-onset colorectal cancer. Cancer 125(12): 2002-2010, 2019. PMID: 30854646. DOI: 10.1002/cncr.31994
    OpenUrl
  6. ↵
    1. Rex DK,
    2. Boland CR,
    3. Dominitz JA,
    4. Giardiello FM,
    5. Johnson DA,
    6. Kaltenbach T,
    7. Levin TR,
    8. Lieberman D,
    9. Robertson DJ
    : Colorectal cancer screening: Recommendations for physicians and patients from the u.S. Multi-society task force on colorectal cancer. Gastrointest Endosc 86(1): 18-33, 2017. PMID: 28600070. DOI: 10.1016/j.gie.2017.04.003
    OpenUrl
  7. ↵
    1. Saraste D,
    2. Jaras J,
    3. Martling A
    : Population-based analysis of outcomes with early-age colorectal cancer. Br J Surg 107(3): 301-309, 2020. PMID: 31925793. DOI: 10.1002/bjs.11333
    OpenUrl
  8. ↵
    1. Wolf AMD,
    2. Fontham ETH,
    3. Church TR,
    4. Flowers CR,
    5. Guerra CE,
    6. LaMonte SJ,
    7. Etzioni R,
    8. McKenna MT,
    9. Oeffinger KC,
    10. Shih YT,
    11. Walter LC,
    12. Andrews KS,
    13. Brawley OW,
    14. Brooks D,
    15. Fedewa SA,
    16. Manassaram-Baptiste D,
    17. Siegel RL,
    18. Wender RC,
    19. Smith RA
    : Colorectal cancer screening for average-risk adults: 2018 guideline update from the american cancer society. CA Cancer J Clin 68(4): 250-281, 2018. PMID: 29846947. DOI: 10.3322/caac.21457
    OpenUrlCrossRefPubMed
  9. ↵
    1. Hirano Y,
    2. Hiranuma C,
    3. Hattori M,
    4. Douden K,
    5. Yamaguchi S
    : Single-port laparoscopic colectomy in elderly patients with colon cancer: A propensity score-matched comparison with younger patients. Asian J Endosc Surg, 2019. PMID: 31250557. DOI: 10.1111/ases.12719
  10. ↵
    1. Kanda M,
    2. Oba K,
    3. Aoyama T,
    4. Kashiwabara K,
    5. Mayanagi S,
    6. Maeda H,
    7. Honda M,
    8. Hamada C,
    9. Sadahiro S,
    10. Sakamoto J,
    11. Saji S,
    12. Yoshikawa T,
    13. Japanese Foundation for Multidisciplinary Treatment of C
    : Clinical signatures of mucinous and poorly differentiated subtypes of colorectal adenocarcinomas by a propensity score analysis of an independent patient database from three phase III trials. Dis Colon Rectum 61(4): 461-471, 2018. PMID: 29521828. DOI: 10.1097/DCR.0000000000001022
    OpenUrl
  11. ↵
    1. Vuik FE,
    2. Nieuwenburg SA,
    3. Bardou M,
    4. Lansdorp-Vogelaar I,
    5. Dinis-Ribeiro M,
    6. Bento MJ,
    7. Zadnik V,
    8. Pellise M,
    9. Esteban L,
    10. Kaminski MF,
    11. Suchanek S,
    12. Ngo O,
    13. Majek O,
    14. Leja M,
    15. Kuipers EJ,
    16. Spaander MC
    : Increasing incidence of colorectal cancer in young adults in europe over the last 25 years. Gut 68(10): 1820-1826, 2019. PMID: 31097539. DOI: 10.1136/gutjnl-2018-317592
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Taggarshe D,
    2. Rehil N,
    3. Sharma S,
    4. Flynn JC,
    5. Damadi A
    : Colorectal cancer: Are the “young” being overlooked? Am J Surg 205(3): 312-316; discussion 316, 2013. PMID: 23414955. DOI: 10.1016/j.amjsurg.2012.10.016
    OpenUrlPubMed
  13. ↵
    1. Segev L,
    2. Kalady MF,
    3. Plesec T,
    4. Mor E,
    5. Schtrechman G,
    6. Nissan A,
    7. Church JM
    : The location of premalignant colorectal polyps under age 50: A further rationale for screening sigmoidoscopy. Int J Colorectal Dis 35(3): 529-535, 2020. PMID: 31930456. DOI: 10.1007/s00384-020-03504-2
    OpenUrl
  14. ↵
    1. Le Voyer TE,
    2. Sigurdson ER,
    3. Hanlon AL,
    4. Mayer RJ,
    5. Macdonald JS,
    6. Catalano PJ,
    7. Haller DG
    : Colon cancer survival is associated with increasing number of lymph nodes analyzed: A secondary survey of intergroup trial int-0089. J Clin Oncol 21(15): 2912-2919, 2003. PMID: 12885809. DOI: 10.1200/JCO.2003.05.062
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Chen SL,
    2. Bilchik AJ
    : More extensive nodal dissection improves survival for stages i to III of colon cancer: A population-based study. Ann Surg 244(4): 602-610, 2006. PMID: 16998369. DOI: 10.1097/01.sla.0000237655.11717.50
    OpenUrlCrossRefPubMed
  16. ↵
    1. O'Connell JB,
    2. Maggard MA,
    3. Liu JH,
    4. Etzioni DA,
    5. Livingston EH,
    6. Ko CY
    : Do young colon cancer patients have worse outcomes? World J Surg 28(6): 558-562, 2004. DOI: 10.1007/s00268-004-7306-7
    OpenUrlCrossRefPubMed
  17. ↵
    1. Tezcan G,
    2. Tunca B,
    3. Ak S,
    4. Cecener G,
    5. Egeli U
    : Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer. World J Gastrointest Oncol 8(1): 83-98, 2016. PMID: 26798439. DOI: 10.4251/wjgo.v8.i1.83
    OpenUrl
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Better Cancer-specific Survival in Younger Patients With Stage III Colorectal Cancer: A Propensity Score Matching Study From Japan
LIMING WANG, YASUMITSU HIRANO, GREGORY HENG, TOSHIMASA ISHII, HIROKA KONDO, KIYOKA HARA, NAO OBARA, MASAHIRO ASARI, SHIGEKI YAMAGUCHI
Anticancer Research Aug 2020, 40 (8) 4365-4372; DOI: 10.21873/anticanres.14439
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords