Impact of Neoadjuvant Chemoradiotherapy on Rectal Cancer Recurrence

0
0
0

Impact of Neoadjuvant Chemoradiotherapy on the Local Recurrence and Distant Metastasis Pattern of Locally Advanced Rectal Cancer: A Propensity Score-Matched Analysis

Introduction

Locally advanced rectal cancer (LARC), defined as stage II to III disease, has long been managed with a multimodal approach. Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment, significantly reducing local recurrence rates to below 10%. However, distant metastases remain a critical challenge, occurring in 20%–30% of cases despite treatment. Previous studies suggested that NCRT might alter the predominant sites of metastasis, shifting from the liver (common in untreated cases) to the lung. However, these studies often compared heterogeneous cohorts with differing baseline characteristics, such as tumor location, stage, and adjuvant regimens. This study addressed these limitations by employing propensity score matching (PSM) to evaluate whether NCRT truly influences metastasis patterns and recurrence timing.

Patients and Methods

Study Population
From 2008 to 2015, 1,296 patients with LARC (adenocarcinoma <10 cm from the anal verge) receiving NCRT (n=335) or postoperative chemoradiotherapy (PCRT; n=961) were included. Exclusion criteria included metastatic disease, secondary tumors, familial syndromes, perioperative death, metastases within 6 months of diagnosis, and incomplete data.

Treatment Protocols

  • NCRT Group: Long-course radiotherapy (40–50 Gy) with concurrent 5-fluorouracil-based chemotherapy followed by TME after 7 weeks.
  • PCRT Group: Surgery first, followed by similar chemoradiotherapy starting 4 weeks postoperatively.

Pathological Evaluation
A novel method assessed the initial pathological tumor (ipT) and lymph node (ipN) stages for NCRT patients. Residual cancer cells, fibrosis, or mucinous lakes were considered evidence of pre-treatment tumor extent. For example, fibrosis in the muscularis propria without residual cancer indicated ipT2. Lymph node regression was similarly evaluated, with fibrotic nodes counted as positive pre-NCRT.

Propensity Score Matching
Variables matched included age, sex, tumor distance from the anal verge, treatment period, adjuvant chemotherapy, ipT/pT, ipN/pN, and ipTNM/pTNM stages. A 1:2 matching ratio with a 0.01 caliper minimized baseline differences. Post-matching, 245 NCRT and 408 PCRT patients were analyzed.

Follow-Up and Outcomes
Follow-ups occurred every 3 months (years 1–2), 6 months (years 3–5), and annually thereafter. Outcomes included local recurrence, distant metastasis rates, sites, and timing. Disease-free survival (DFS) and overall survival (OS) were calculated from surgery to recurrence, metastasis, death, or last follow-up (August 2019).

Results

Baseline Characteristics
Before PSM, significant differences existed in tumor location (65.4% of NCRT vs. 45.9% of PCRT had tumors <5 cm from the anus; P<0.001), clinical staging, and treatment periods. After PSM, groups were balanced for age, sex, ipT/pT, ipN/pN, ipTNM/pTNM stages, and tumor location (P>0.05 for all).

Survival Outcomes
Median follow-up was 56.9 months. Five-year OS (80.6% PCRT vs. 80.4% NCRT; P=0.612) and DFS (60.7% vs. 67.7%; P=0.079) showed no significant differences.

Recurrence Patterns

  • Local Recurrence: NCRT reduced local recurrence significantly (4.1% vs. 10.3%; P=0.004), with later median onset (29.2 vs. 18.7 months; P=0.019).

    • PCRT: 42.9% of recurrences occurred in year 2.
    • NCRT: 30% recurred in year 3, with 40% beyond year 3.

  • Distant Metastases: Rates were similar (27.9% PCRT vs. 28.2% NCRT; P=0.924). The lung was the most common site in both groups (13.5% PCRT vs. 12.2% NCRT), followed by the liver (6.9% vs. 6.5%).

    • Timing: Metastases occurred later in NCRT (median 21.2 vs. 16.4 months; P=0.035).
    • Yearly Distribution:
    • Year 2: 34.2% (PCRT) vs. 30.4% (NCRT).
    • Year 3: 13.2% vs. 20.3%.
    • Beyond year 5: 0.9% vs. 1.4%.

Discussion

Key Findings

  1. Metastasis Site Consistency: Contrary to prior studies suggesting NCRT shifts metastasis to the lung, this study found the lung was predominant in both groups. Lower rectal tumors (<5 cm) inherently have higher lung metastasis risk due to venous drainage patterns, independent of NCRT.
  2. Delayed Recurrence: NCRT delayed local recurrence and metastasis by 10.5 and 4.8 months, respectively. This aligns with meta-analyses showing delayed recurrence after NCRT.
  3. Survival Parity: Despite delayed recurrence, 5-year OS and DFS were similar, underscoring the need for improved systemic therapies to address micrometastases.

Clinical Implications

  • Follow-Up Adjustments: Current guidelines recommend intensive follow-up for 2 years. However, 20.3% of NCRT metastases occurred in year 3, suggesting extending intensive monitoring to 3 years.
  • Pathological Staging Innovation: The novel ipT/ipN staging method provided accurate pre-NCRT tumor characterization, addressing inconsistencies in imaging-based clinical staging.

Limitations

  • Retrospective design and single-center data limit generalizability.
  • Heterogeneous chemotherapy regimens over the study period.

Conclusion

This PSM-based analysis demonstrates that NCRT reduces local recurrence and delays recurrence/metastasis without altering metastasis site predilection. The lung remains the primary metastatic site regardless of NCRT, influenced by tumor location rather than treatment. Extended follow-up to 3 years is recommended for NCRT patients to detect delayed recurrences. Future research should focus on personalized surveillance protocols and systemic therapies targeting residual disease.

doi.org/10.1097/CM9.0000000000001641

Was this helpful?

0 / 0