Oncologic Outcomes After Neoadjuvant Chemoradiation Followed by Curative Resection With Tumor-Specific Mesorectal Excision for Fixed Locally Advanced Rectal Cancer

Abstract

Objective:

The purpose of this study was to determine the oncologic outcomes and clinical factors affecting survival in patients who underwent neoadjuvant chemoradiotherapy following tumor specific mesorectal excision for locally advanced, fixed rectal cancer.

Summary Background Data:

Neoadjuvant chemoradiation therapy has resulted in significant tumor downstaging, which enhances curative resection and subsequently improves local disease control for rectal cancer. However, oncologic outcomes, according to clinical factors, have not yet been fully understood in locally advanced and fixed rectal cancer.

Methods:

A total of 114 patients who had undergone neoadjuvant chemoradiation for advanced rectal cancer (T3 or T4 and node positive) were investigated retrospectively. Chemotherapy was administered intravenously with 5-FU and leucovorin during weeks 1 and 5 of radiotherapy. The total radiation dose was 5040 cGY in 25 fractions delivered over 5 weeks. Tumor-specific mesorectal excision was done 4 to 6 weeks after the completion of neoadjuvant chemoradiation. Survival and recurrence rates, according to the pathologic stage, were evaluated. Moreover, factors affecting survival were investigated.

Results:

The 5-year survival rates according to pathologic stage were: 100% in pathologic complete remission (n = 10), 80% in stage I (n = 23), 56.8% in stage II (n = 34), and 42.3% in stage III (n = 47) (P = 0.0000). Local, systemic, and combined recurrence rates were 11.4%, 22.8%, and 3.5%, respectively. Multivariate analysis showed that the pathologic N stage and operation method were the independent factors affecting survival rate.

Conclusion:

Pathologic complete remission showed excellent oncologic outcomes, and the pathologic N stage was the most important factor for oncologic outcomes.

The aim of this study was to evaluate the oncologic outcomes and clinical factors affecting survival in patients who underwent neoadjuvant chemoradiotherapy following curative resection for locally advanced, fixed rectal cancer. Pathologic complete remission showed excellent oncologic outcomes, and the pathologic N stage was the most important clinical factor for oncologic outcomes.

Continued efforts have been made to improve local control and survival in rectal cancer. Postoperative adjuvant chemoradiation therapy has been recommended and has become the standard of care for stage II and stage III rectal adenocarcinomas.¹ With the introduction of pelvic sharp dissection and tumor specific mesorectal excision, the rate of local recurrence markedly reduced to 5% to 10% for resectable rectal cancer.^2,3 Total mesorectal excision, defined as a sharp pelvic dissection under clear vision with the excision of the rectum and mesorectum within the mesorectal fascia, has been emphasized. However, local recurrence still remains a problem in locally advanced, fixed rectal cancers. The current strategy for the management of locally advanced, fixed rectal cancer is the multimodality approach. Neoadjuvant chemoradiation therapy has been regarded as a good modality for increasing resectability, decreasing the rate of locoregional recurrence, and improving survival rate.

In neoadjuvant chemoradiation therapy, the clinical implications of this modality for unresectable, fixed rectal cancer were: tumor size reduction; increased tumor mobility, which enhances sphincter saving curative resection; and histopathologic downstaging, which is more important for long-term oncologic outcomes. A variable range of tumor responses has been observed from a complete response to nonresponse. Pathologic complete remission was reported to range from 8% to 29%, depending on the stage at presentation, regimen of chemotherapy, and dose of radiation administered.^4–7

The status of downstaged pathologic stage after neoadjuvant chemoradiation was an important factor for oncologic outcomes. However, to date, few studies have investigated oncologic outcomes according to postirradiated, postoperative pathologic stages and clinical factors affecting survival in locally advanced and fixed rectal cancer. Therefore, the purpose of this study was to determine oncologic outcomes according to pathologic stages and the clinical factors affecting survival in patients who underwent neoadjuvant chemoradiotherapy following curative resection for locally advanced, fixed rectal cancer.

MATERIALS AND METHODS

Eligibility

Between January 1989 and December 2000, 142 patients diagnosed with locally advanced, unresectable carcinoma of the rectum were treated at Severance Hospital's Department of Surgery at Yonsei University with a regimen of combined preoperative chemotherapy and radiotherapy, followed by surgical resection. The clinicopathologic data of these patients were accumulated prospectively and among these patients, a total of 114 patients who underwent curative resection were investigated retrospectively; 28 patients were excluded because positive circumferential resection margin was reported in 26 patients and positive distal resection margin was reported in 2 patients.

The patients were confirmed as having an adenocarcinoma by sigmoidoscopic biopsy (and staged as T3 or T4), and regional lymph node enlargement by transrectal ultrasonography (TRUS) and pelvic MRI. Most of the patients showed fixation to the rectal wall and/or invasion to the surrounding pelvic organs. Bulky and/or tethered tumors were staged by TRUS and pelvic MRI as T3 to T4 and showed enlarged lymph nodes (marginally or unresectable rectal cancer by digital rectal examination). The patients between January 1989 and December 1993 were staged by using TRUS only, and the patients between 1994 and 2000 were staged by using both TRUS and MRI. In the later period between 1994 and 2000, we excluded the patients who were staged lower than T3 to T4 and N+ by only one of both examinations. All patients were evaluated with CT scan for evaluation of distant metastasis.

Neoadjuvant Chemoradiotherapy

Chemotherapy was administered intravenously with 5-fluorouracil, 425 mg/m² per day and leucovorin, 20 mg/m² per day during weeks 1 and 5 of radiotherapy. Radiation treatment was administered with a 6 MV/10 MV dual photon linear accelerator using a 4-field box technique. The total radiation dosage was 5040 cGY in 25 fractions delivered over 5 weeks. The radiation field was as follows: upper margin was 1.5 cm above the sacral promontory (L5 level), lateral margin was 1.5 cm laterally from the pelvic lateral wall, and lower margin was 3 cm below the lower margin of the tumor.

Surgical Resection

Surgery was performed 4 to 6 weeks after the completion of chemoradiation. The method of operation was tumor specific mesorectal excision with pelvic autonomic nerve preservation. Tumor specific mesorectal excision was defined as the surgical method, which was transaction of the mesorectum with the surrounding mesorectum enclosed by the rectal proper fascia at 4 cm distal from the lower edge of the rectum. Thus, all surgery was performed using sharp pelvic dissection under direct vision along the plane of the rectal proper fascia. Tumor-specific mesorectal excision was performed according to the tumor level. In upper rectal cancers, the mesorectum was excised 4 cm distal from the lower edge of the tumor. Total mesorectal excision was performed in the middle and distal rectal cancer. Curative resection defined no gross residual disease, and distal and circumferential resection margins were negative in standard hematoxylin and eosin stain by histopathologic examination.

Pathologic Evaluation

The patients were staged according to the 6th UICC pTNM staging system after the final histopathologic examination. Pathologic complete remission (pCR) was defined as the absence of residual microscopic tumors upon histopathologic examination.

Pathologic evaluation was performed by one pathologist (H.K.), who was unaware of the clinical or radiologic findings. Postirradiated resection specimens were evaluated for depth of tumor penetration, lymph node metastases, and differentiation. Postoperative adjuvant systemic chemotherapy, consisting of 400 to 425 mg/m² of 5-fluorouracil plus 20 mg/m² leucovorin for 5 days, was administered every 28 days for 6 cycles in all enrolled patients.

Follow-up Evaluation

All patients have been closely followed by the surgeons, medical oncologists, and radiation oncologists in the Colorectal Cancer Clinic at Severance Hospital. All patients were followed up every 3 months for 2 years after surgery. Clinical examination, measurement of serum carcinoembryonic antigen levels, and chest x-ray were performed during each follow-up. After 2 years, patients were followed up every 6 months. Abdominopelvic CT and whole body bone scan were checked every year. Recurrences were documented by clinical and/or radiologic assessment and categorized as a local, systemic, or combined (local plus systemic) recurrence.

Statistical Analyses

Statistical analyses were performed using the statistical software package SPSS version 11.5 (SPSS, Chicago, IL). Survival and disease-free survival were calculated using the Kaplan-Meier method, and prognostic factors were compared with the log-rank test. Multivariate survival analysis was with the Cox proportional hazards mode, entering pathologic N stage, pathologic T stage, operation method, preoperative carcinoembryonic antigen, and histologic type. Cox proportional hazard model was done by a forward stepwise selection of variables, and a P value of 0.1 was adopted as the limit for inclusion of a covariant. Values of P < 0.05 were considered statistically significant.

RESULTS

Patient Characteristics

Patients included 80 males and 34 females with a median age of 55.0 years (range, 26–81 years). Median follow-up period was 39.4 months (range, 2.2–151.6 months), and the rate of follow-up was 93%. The distribution of tumor location was: upper (n = 20, 17.5%), middle (n = 38, 33.3%), and lower (n = 56, 49.1%). The type of surgery performed was: abdominoperineal resection in 38 patients (33.3%), low anterior resection in 54 patients (47.3%), Hartmann's procedure in 17 patients (14.9%), ultra-low anterior resection with coloanal anastomosis in 2 patients (1.8%), and total pelvic exenteration in 3 patients (2.6%) (Table 1).

TABLE 1. Patient Characteristics (n = 114)

Postoperative Complications

Eleven patients had postoperative wound complications (9.6%). Anastomotic leakage was noted in 3 patients (2.6%) and stenosis in 1 patient (0.9%). Intestinal obstruction developed in 3 patients (2.6%) (Table 2).

TABLE 2. Postoperative Morbidity (n = 114)

Tumor Response

Margin free resections without microscopic disease at the radial or pelvic side wall margin were achieved in all 114 patients. Pathologic complete response (pCR) of the primary rectal cancer was observed in 10 patients (8.8%). Three patients (2.6%) were downstaged to pT1N0M0, 20 patients (17.5%) to pT2N0M0, and 3 patients (2.6%) to pT2N1-2M0. Thirty-one patients (27.2%) were downstaged to stage II (T3N0M0). Forty-three patients (37.7%) were found to be stage III (T3N1-2M0), 3 patients (2.6%) in T4N0M0, and 1 patient (0.9%) in T4N1-2M0 (Table 3).

TABLE 3. Correlation of pT Stage and pN Stage (n = 114)

Five-Year Survival and 5-Year Disease-Free Survival Rates

The 5-year survival rate was 58.1%. The 5-year disease-free survival was 52%. Five-year survival rates according to pathologic stage were: 100% in pathologic complete remission (pCR) (n = 10), 80% in stage I (n = 23), 56.8% in stage II (n = 34), and 42.3% in stage III (n = 47) (P = 0.0000) (Fig. 1). The 5-year disease-free survival rates, according to pathologic stage, were: 100% in pCR, 72.3% in stage I, 49.7% in stage II, and 33.6% in stage III (P = 0.0002) (Fig. 2). The 5-year disease-free survival rate, according to pathologic T stage, pathologic N stage, and operation methods, is shown in Figures 3 to 5.

FIGURE 1. Five-year survival rates according to stage (n = 114).

FIGURE 2. Five-year disease-free survival rates according to stage (n = 114).

FIGURE 3. Five-year disease-free survival rates according to pT stage (n = 114).

FIGURE 4. Five-year disease-free survival rates according to node metastasis (n = 114).

FIGURE 5. Five-year survival according to operation method. LAR, low anterior resection and ultra low anterior resection with coloanal anastomosis; APR, abdominoperineal resection and total pelvic exenteration (n = 114).

Pattern of Recurrence

Overall recurrence was noted in 44 patients (38.6%). The 5-year local recurrence rate was 0% in pCR, 9.6% in stage I, 10.3% in stage II, and 24% in stage III (P = 0.226) (Fig. 6). The 5-year systemic recurrence rate was 0% in pCR, 10.1% in stage I, 22.3% in stage II, and 42.8% in stage III (P = 0.009). The 5-year local and systemic recurrence was 0% in pCR and stage I, 4.0% in stage II, and 7.2% in stage III (P = 0.437).

FIGURE 6. Five-year local recurrence rate according to stage (n = 114).

Prognostic Factors Affecting Survival

Univariate analyses of factors affecting survival showed perioperative serum carcinoembryonic antigen level and pathologic T and N stages to be significant factors. Operation method and histologic differentiation were marginally significant factors (Table 4). Multivariate analysis of these factors showed that pathologic N stage and operation method were the independent factors affecting survival rates (Table 5).

TABLE 4. Univariate Analysis of Prognostic Factors for 5-Year Survival (n = 114)

TABLE 5. Multivariate Analysis of Prognostic Factors for 5-Year Survival (n = 114)

DISCUSSION

Neoadjuvant multimodality therapy for advanced rectal adenocarcinoma continues to gain wide acceptance. Short course preoperative radiotherapy treatment combined total mesorectal excision for resectable rectal cancer improved local control more than TME alone. However, this therapy did not show any survival benefits.⁸ In addition, neoadjuvant chemoradiotherapy has been applied for resectable rectal cancer cases to improve anal sphincter preservation. When rectal cancer is fixed at the time of presentation, recurrence after surgical resection has been reported to range from 50% to 70% and is characterized by poor survival rates and early distant metastasis.^9–11 Neoadjuvant chemoradiation therapy is now a well-established treatment of locally advanced middle to lower rectal cancer. In locally advanced rectal cancer, this multimodality therapy has been known to improve resectability, local control, and overall survival benefits. The ultimate goal of this treatment is to obtain tumor downstaging and tumor volume reduction which is related to curative surgical resection and long-term favorable oncologic outcomes. Interestingly, we observed that more than a 50% tumor volume reduction shows no correlation with T and N staging.¹² Therefore, improved resectability does not confer a pathologic downstaging effect. Some studies have reported on the oncologic outcomes regarding local control and disease-free survival in resectable rectal cancer patients who received preoperative chemoradiation therapy.^13–17 However, there have been few series regarding oncologic outcomes for patients with marginally resectable or unresectable rectal cancers diagnosed by digital rectal examination and assessed as stage T3 to T4 with multiple enlarged lymph nodes by transrectal ultrasonography and pelvic MRI.^9,11 In this study, preoperative staging of the rectal cancer was performed by digital rectal examination, transrectal ultrasonography, and MRI. We considered all patients enrolled in our study to be homogenously categorized as fixed locally advanced rectal cancer staged at least T3 plus N positive.

A previous study showed that the accuracy of TRUS and MRI for assessing the depth of invasion ranged from 81% to 95%.^18,19 The accuracy of these methods to assess metastatic lymph nodes ranged from 63% to 87%.^20,21

In our study, TRUS staging has been made since January 1989 and MRI staging has been made since January 1994. The period of this study was 11 years. Thus, there is little doubt that the reliability of the initial study groups staging may have varied with current techniques. However, in 1985, Hidebrandt and Feifel²² reported that accuracy of preoperative staging of rectal cancer TRUS was 92%. Moreover, Beynon et al²⁰ reported the accuracy of TRUS was 91% in 1986. In 1989, accuracy of preoperative assessment of mesorectal lymph node involvement in rectal cancer was 83%.²¹ In 1999, Kim et al¹⁹ reported the overall accuracy of T stage was 81.1% by TRUS and 81% by MRI, and the overall accuracy of N stage 63.5% by TRUS and 63% by MRI. Thus, we thought that staging had been consistent over time.

The level of tumor response to preoperative chemoradiation therapy for fixed locally advanced rectal cancer has been reported to improve 5-year survival rates.^23–25 Regarding pathologic complete remission, 10 patients (8.8%) had a pathologic complete response. Grann et al²⁶ reported a 9% pathologic complete response, Medichi et al²⁷ also reported an 8% pathologic complete response, and Janjan et al^14,15 reported 27% pathologic complete remission by continuous intravenous infusion. The pathologic T and N downstaging effects have been recognized as important factors for determining a long-term prognosis. Ruo et al¹³ reported on 69 patients, preoperatively staged as T3 to T4 N1 who underwent preoperative chemoradiation therapy. They observed that patients who showed a marked tumor response tended to show good long-term outcomes.

In our study, the positive node status was a statistically significant factor affecting recurrence and survival. Our results showed that the 5-year survival rate of patients with positive lymph nodes was 42.3% and negative lymph nodes was 73.8% (P = 0.0004). Multivariate analysis revealed that the pathologic N stage and operation method in postirradiated specimens were the independent prognostic factor. The operation method was not the confounding factor that attenuated statistical power of pathologic N stage. Thus, we propose that nodal status in the postirradiated tumor specimen was the strongest factor affecting prediction of long-term oncologic outcomes. Onaitis et al²⁸ analyzed 141 consecutive patients who received neoadjuvant chemoradiotherapy for locally advanced rectal cancer. The postoperative T stage had no effect on oncologic outcomes. However, a positive lymph node status predicted increased local recurrence and decreased survival. Moreover, Habr-Gama et al¹⁶ reported that the final pathologic stage after surgical resection following neoadjuvant chemoradiation therapy is an important prognostic factor in distal rectal cancer following neoadjuvant chemoradiation and correlates with overall and disease-free survival. These results were similar to our oncologic results regarding disease-free survival according to pathologic stage. In our study, pCR and stage I showed good disease-free survival rates and stages II and III showed 49.7% and 33.6%, respectively. However, Garcia-Aguilar et al²⁹ reported that only patients with pCR showed lower local recurrence and improved survival rates; whereas in patients without pCR, the final pathologic stage did not show any prognostic significance.

The prognostic significance of complete remission in patients who undergo surgical resection after chemoradiation therapy is still unclear. In general, in advanced fixed rectal cancer, preoperative chemoradiotherapy can provide benefits-related resectability and improving oncologic outcomes if the tumor showed pathologic downstaging evidence. Pathologic complete remission is an ultimate goal of preoperative chemoradiation therapy. Pucciarelli et al³⁰ reported that pathologic complete remission may ultimately develop a recurrence from a small nest of viable tumor cells. Irradiated rectal cancer patients need a longer follow-up before we definitely conclude that a pathologic complete remission confers a favorable prognosis. Moreover, Pucciarelli et al³¹ reported that pathologic complete remission following preoperative chemoradiotherapy for middle to distal rectal cancer is not a prognostic factor for a better outcome. They also reported that the tumor response is mainly related to the preoperative regimen used and that pretreatment T stage is a prognostic factor for oncologic outcomes such as disease-free and overall survival rates.

Regarding safety after neoadjuvant chemoradiation therapy following curative rectal resection, there were some concerns about high frequent complications because of the effects of radiation. Uzcudun et al³² reported 7 patients (18.5%) with postoperative complications such as anastomotic suture dehiscence or abscess. These figures were not significantly different from those reported in retrospective studies. Our results showed that postoperative complications developed in 19 patients (16.7%). Based on these results, preoperative chemoradiotherapy is considered to be safe in terms of postoperative complications.

A wide range of tumor responses after preoperative chemoradiotherapy has been reported.^7,9–11 The reasons for this wide variability in tumor responses are unclear. The results of studies reporting predictive clinicopathologic factors of tumor response are controversial. Most of the studies showed clinicopathologic characteristics, such as gender, age, tumor size, cellular grade, and proximity to the anal verge etc.^27,29 Some molecular biomarkers, such as PCNA-labeling index, p21 or p53 expression, may predict tumor response to chemoradiation.^33–35 Moreover, variation in the enzyme such as thymidylate synthase may be important in predicting response to chemotherapy. Polymorphism of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging following chemoradiation in rectal cancer.³⁶ Neoadjuvant chemoradiation therapy has played a significant role in improving resectability and downstaging tumors. Decreasing the size of tumors and histopathologic downstaging are important for resection and improving oncologic outcomes, among which pathologic N downstaging represents an important factor for long-term prognosis. A variety of neoadjuvant chemoradiation regimen and radiosensitizer might be used for improving the tumor response after chemoradiation.

CONCLUSION

Neoadjuvant chemoradiotherapy is a safe multimodality treatment of fixed, locally advanced rectal cancer. In this study, the pathologic complete remission using this combined modality was 8.8%. The pathologic downstaging effect was 58.8%, including pathologic complete response. Patients who showed pathologic complete remission had an excellent prognosis. However, overall survival and disease-free survival rates of stage pTNM II and III were low. In a multivariate analysis of clinical factors affecting long-term oncologic outcomes, the pathologic nodal status in postirradiated tumor specimens was the independent prognostic factor. Moreover, the operation method impacted oncologic outcomes. For better oncologic outcomes after neoadjuvant chemoradiation for locally advanced rectal cancer, additional treatment modalities enhancing the downstaging should be investigated.