Oncologic Outcomes
O RIGINAL A RTICLES
Oncologic Outcomes After Neoadjuvant Chemoradiation Followed by Curative Resection With Tumor-Specific Mesorectal Excision for Fixed Locally Advanced
Rectal Cancer
Impact of Postirradiated Pathologic Downstaging on Local
Recurrence and Survival
Nam Kyu Kim,MD,PhD,*?Seung Hyuk Baik,MD,*?Jin Sil Seong,MD,PhD,*§
Hoguen Kim,MD,PhD,*?Jae Kyung Roh,MD,PhD,*?Kang Young Lee,MD,*?Seung Kook Sohn,MD,PhD,?and Chang Hwan Cho,MD,PhD*?
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 speci?c mesorectal excision for locally advanced,?xed rectal cancer. Summary Background Data:Neoadjuvant chemoradiation therapy has resulted in signi?cant tumor downstaging,which enhances curative resection and subsequently improves local disease control for rectal cancer.However,oncologic outcomes,according to clin-ical factors,have not yet been fully understood in locally advanced and?xed rectal cancer.
Methods:A total of114patients who had undergone neoadjuvant chemoradiation for advanced rectal cancer(T3or T4and node positive)were investigated retrospectively.Chemotherapy was ad-ministered intravenously with5-FU and leucovorin during weeks1 and5of radiotherapy.The total radiation dose was5040cGY in25 fractions delivered over5weeks.Tumor-speci?c mesorectal exci-sion was done4to6weeks after the completion of neoadjuvant chemoradiation.Survival and recurrence rates,according to the pathologic stage,were evaluated.Moreover,factors affecting sur-vival were investigated.
Results:The5-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),and42.3%in stage III (n?47)(P?0.0000).Local,systemic,and combined recurrence rates were11.4%,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 on-cologic outcomes,and the pathologic N stage was the most impor-tant factor for oncologic outcomes.
(Ann Surg2006;244:1024–1030)
C ontinued efforts have been made to improve local control
and survival in rectal cancer.Postoperative adjuvant chemoradiation therapy has been recommended and has be-come the standard of care for stage II and stage III rectal adenocarcinomas.1With the introduction of pelvic sharp dissection and tumor speci?c mesorectal excision,the rate of local recurrence markedly reduced to5%to10%for resect-able rectal cancer.2,3Total mesorectal excision,de?ned 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,?xed rectal cancers.The current strategy for the management of locally advanced,?xed rectal cancer is the multimodality approach.Neoadjuvant chemora-diation 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,?xed rectal cancer were:tumor size reduction;increased tumor mobil-ity,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 re-sponse to nonresponse.Pathologic complete remission was reported to range from8%to29%,depending on the stage
From the*Colorectal Cancer Clinic,Severance Hospital,Yonsei University
Medical Center,and the Departments of?Surgery,?Medical Oncology,
§Radiation Oncology,and?Pathology,Yonsei University College of
Medicine,Seoul,Korea.
Reprints:Nam Kyu Kim,MD,PhD,Department of Surgery,Division of
Colorectal Surgery,Yonsei University College of Medicine,Seoul,
Korea.E-mail:namkyuk@yumc.yonsei.ac.kr.
Copyright?2006by Lippincott Williams&Wilkins
ISSN:0003-4932/06/24406-1024
DOI:10.1097/01.sla.0000225360.99257.73
Annals of Surgery?Volume244,Number6,December2006 1024
at presentation,regimen of chemotherapy,and dose of radiation administered.4–7
The status of downstaged pathologic stage after neoad-juvant 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?xed rectal cancer.Therefore,the purpose of this study was to determine oncologic outcomes according to patho-logic stages and the clinical factors affecting survival in patients who underwent neoadjuvant chemoradiotherapy fol-lowing curative resection for locally advanced,?xed rectal cancer.
MATERIALS AND METHODS Eligibility
Between January1989and December2000,142pa-tients diagnosed with locally advanced,unresectable carci-noma 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 of114patients who underwent curative resection were investigated retrospectively;28patients were excluded because positive circumferential resection margin was reported in26patients and positive distal resection margin was reported in2patients.
The patients were con?rmed as having an adenocarci-noma by sigmoidoscopic biopsy(and staged as T3or T4), and regional lymph node enlargement by transrectal ultra-sonography(TRUS)and pelvic MRI.Most of the patients showed?xation 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 T3to T4and showed enlarged lymph nodes(marginally or unresectable rectal cancer by digital rectal examination).The patients between January1989and December1993were staged by using TRUS only,and the patients between1994and2000 were staged by using both TRUS and MRI.In the later period between1994and2000,we excluded the patients who were staged lower than T3to T4and 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-?uorouracil,425mg/m2per day and leucovorin,20mg/m2 per day during weeks1and5of radiotherapy.Radiation treatment was administered with a6MV/10MV dual photon linear accelerator using a4-?eld box technique.The total radiation dosage was5040cGY in25fractions delivered over 5weeks.The radiation?eld was as follows:upper margin was1.5cm above the sacral promontory(L5level),lateral margin was1.5cm laterally from the pelvic lateral wall,and lower margin was3cm below the lower margin of the tumor.Surgical Resection
Surgery was performed4to6weeks after the comple-tion of chemoradiation.The method of operation was tumor speci?c mesorectal excision with pelvic autonomic nerve preservation.Tumor speci?c mesorectal excision was de?ned as the surgical method,which was transaction of the meso-rectum with the surrounding mesorectum enclosed by the rectal proper fascia at4cm 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-speci?c mesorectal excision was per-formed according to the tumor level.In upper rectal cancers, the mesorectum was excised4cm distal from the lower edge of the tumor.Total mesorectal excision was performed in the middle and distal rectal cancer.Curative resection de?ned no gross residual disease,and distal and circumferential resec-tion margins were negative in standard hematoxylin and eosin stain by histopathologic examination.
Pathologic Evaluation
The patients were staged according to the6th UICC pTNM staging system after the?nal histopathologic exami-nation.Pathologic complete remission(pCR)was de?ned as the absence of residual microscopic tumors upon histopatho-logic examination.
Pathologic evaluation was performed by one patholo-gist(H.K.),who was unaware of the clinical or radiologic ?ndings.Postirradiated resection specimens were evaluated for depth of tumor penetration,lymph node metastases,and differentiation.Postoperative adjuvant systemic chemother-apy,consisting of400to425mg/m2of5-?uorouracil plus20 mg/m2leucovorin for5days,was administered every28days for6cycles in all enrolled patients.
Follow-up Evaluation
All patients have been closely followed by the sur-geons,medical oncologists,and radiation oncologists in the Colorectal Cancer Clinic at Severance Hospital.All patients were followed up every3months for2years after surgery. Clinical examination,measurement of serum carcinoembry-onic antigen levels,and chest x-ray were performed during each follow-up.After2years,patients were followed up every6months.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 version11.5(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 propor-tional hazard model was done by a forward stepwise selection of variables,and a P value of0.1was adopted as the limit for
Annals of Surgery?Volume244,Number6,December2006Neoadjuvant Chemoradiation for Rectal Cancer
inclusion of a covariant.Values of P?0.05were considered statistically signi?cant.
RESULTS
Patient Characteristics
Patients included80males and34females with a median age of55.0years(range,26–81years).Median follow-up period was39.4months(range, 2.2–151.6 months),and the rate of follow-up was93%.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 in38patients (33.3%),low anterior resection in54patients(47.3%),Hart-mann’s procedure in17patients(14.9%),ultra-low anterior resection with coloanal anastomosis in2patients(1.8%),and total pelvic exenteration in3patients(2.6%)(Table1). Postoperative Complications
Eleven patients had postoperative wound complications (9.6%).Anastomotic leakage was noted in3patients(2.6%) and stenosis in1patient(0.9%).Intestinal obstruction devel-oped in3patients(2.6%)(Table2).
Tumor Response
Margin free resections without microscopic disease at the radial or pelvic side wall margin were achieved in all114 patients.Pathologic complete response(pCR)of the primary rectal cancer was observed in10patients(8.8%).Three patients(2.6%)were downstaged to pT1N0M0,20patients (17.5%)to pT2N0M0,and3patients(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),3patients(2.6%)in T4N0M0,and1 patient(0.9%)in T4N1-2M0(Table3).
Five-Year Survival and5-Year Disease-Free Survival Rates
The5-year survival rate was58.1%.The5-year dis-ease-free survival was52%.Five-year survival rates accord-ing 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),and42.3%in stage III(n?47)(P?0.0000)(Fig.1).The5-year disease-free survival rates,ac-cording to pathologic stage,were:100%in pCR,72.3%in stage I,49.7%in stage II,and33.6%in stage III(P?0.0002) (Fig.2).The5-year disease-free survival rate,according to pathologic T stage,pathologic N stage,and operation meth-ods,is shown in Figures3to5.
Pattern of Recurrence
Overall recurrence was noted in44patients(38.6%).The 5-year local recurrence rate was0%in pCR,9.6%in stage I, 10.3%in stage II,and24%in stage III(P?0.226)(Fig.6).The 5-year systemic recurrence rate was0%in pCR,10.1%in stage I,22.3%in stage II,and42.8%in stage III(P?0.009).The 5-year local and systemic recurrence was0%in pCR and stage I,4.0%in stage II,and7.2%in stage III(P?0.437).
TABLE1.Patient Characteristics(n?114)
No.(%)
Sex
Male80(70.2) Female34(29.8) Median age(yr)(range)55.0(26–81) Median follow-up period(mo)39.4(2.2–151.6) Follow-up rate(%)93 Tumor level
Upper20(17.5) Middle38(33.3) Lower56(49.1) Type of surgery
Abdominoperineal resection38(33.3) Low anterior resection54(47.3) Hartmann’s procedure17(14.9) Ultra low anterior resection with coloanal
anastomosis
2(1.8) Total pelvic exenteration3(2.6) Pathologic stage
Complete response10(8.8) Stage I23(20.2) Stage II34(29.8) Stage III47(41.2)TABLE2.Postoperative Morbidity(n?114)
Morbidity No.(%)
Wound infection11(9.6) Anastomotic leakage3(2.6) Intestinal obstruction3(2.6) Intraabdominal abscess1(0.9) Anastomotic stricture1(0.9)
TABLE3.Correlation of pT Stage and pN Stage(n?114) Stage No.(%)Total No.(%)
pT0
pN010(8.8)10(8.8)
pN1-20(0)
pT1
pN03(2.6)3(2.6)
pN1-20(0)
pT2
pN020(17.5)23(20.2) pN1-23(2.6)
pT3
pN031(27.2)74(64.9) pN1-243(37.7)
pT4
pN03(2.6)3(3.5)
pN1-21(0.9)
Kim et al Annals of Surgery?Volume244,Number6,December2006
Prognostic Factors Affecting Survival
Univariate analyses of factors affecting survival showed perioperative serum carcinoembryonic antigen level and pathologic T and N stages to be signi?cant factors.Operation method and histologic differentiation were margin-ally signi?cant 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).
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 bene?ts.8In addition,neoadjuvant chemoradiotherapy has been applied for resectable rectal cancer cases to improve anal sphincter preservation.When rectal cancer is ?xed 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.9–11Neoadjuvant 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 im-prove resectability,local control,and overall survival bene-?ts.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
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).
Annals of Surgery ?Volume 244,Number 6,December 2006Neoadjuvant Chemoradiation for Rectal Cancer
outcomes.Interestingly,we observed that more than a 50%tumor volume reduction shows no correlation with T and N staging.12Therefore,improved resectability does not confer a pathologic downstaging effect.Some studies have reported on the oncologic outcomes regarding local control and dis-ease-free survival in resectable rectal cancer patients who received preoperative chemoradiation therapy.13–17However,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 T3to T4with multiple enlarged lymph nodes by transrectal ultrasonography and pelvic MRI.9,11In 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 ?xed locally advanced rectal cancer staged at least T3plus N
positive.
FIGURE 5.Five-year survival according to operation https://www.wendangku.net/doc/035255289.html,R,low anterior resection and ultra low anterior resection with coloanal anastomosis;APR,abdominoperineal resection and total pelvic exenteration (n ?
114).
FIGURE 6.Five-year local recurrence rate according to stage (n ?114).
TABLE 4.Univariate Analysis of Prognostic Factors for 5-Year Survival (n ?114)
No.
5-Year Survival (%)
P Sex 0.214
Male 8063.2Female 3454.1
Age
0.567
?55yr 5863.4?55yr
5657.6
Histologic type
0.070
Well differentiated
766.7Moderately differentiated 8468.1Poorly differentiated 1347.2Mucinous,others 1022.5
Location of tumor 0.259
Upper 2058.8Mid 3866.6Lower
5653.7
Pathologic N stage ?0.001
N06773.8N12947.6N2
1831.5
Pathologic T stage 0.005
T010100T13100T22380.2T37449.5T4
425.0
Operation method 0.069
LAR 4177.4APR
5660.1Hartmann’s procedure 1733.0Preoperative CEA ?5ng/mL 2648.80.028?5ng/mL
88
64.1
LAR indicates low anterior resection and ultra low anterior resection with coloanal anastomosis;APR,
abdominoperineal resection and total pelvic exenteration.
TABLE 5.Multivariate Analysis of Prognostic Factors for 5-Year Survival (n ?114)
RR
95%CI
P Pathologic N stage ?0.001
N0 1.000N1 2.2520.960–4.655N2
6.495 3.698–21.231
Operation method 0.017
LAR 1.000APR
2.866 1.265–6.494Hartmann’s procedure
2.963
1.229–7.143
LAR indicates low anterior resection and ultra low anterior resection with coloanal anastomosis;APR,abdominoperineal resection and total pelvic exenteration.
Kim et al Annals of Surgery ?Volume 244,Number 6,December 2006
A previous study showed that the accuracy of TRUS and MRI for assessing the depth of invasion ranged from81% to95%.18,19The accuracy of these methods to assess meta-static lymph nodes ranged from63%to87%.20,21
In our study,TRUS staging has been made since January 1989and MRI staging has been made since January1994.The period of this study was11years.Thus,there is little doubt that the reliability of the initial study groups staging may have varied with current techniques.However,in1985,Hidebrandt and Feifel22reported that accuracy of preoperative staging of rectal cancer TRUS was92%.Moreover,Beynon et al20reported the accuracy of TRUS was91%in1986.In1989,accuracy of preoperative assessment of mesorectal lymph node involvement in rectal cancer was83%.21In1999,Kim et al19reported the overall accuracy of T stage was81.1%by TRUS and81%by MRI,and the overall accuracy of N stage63.5%by TRUS and 63%by MRI.Thus,we thought that staging had been consistent over time.
The level of tumor response to preoperative chemora-diation therapy for?xed locally advanced rectal cancer has been reported to improve5-year survival rates.23–25Regard-ing pathologic complete remission,10patients(8.8%)had a pathologic complete response.Grann et al26reported a9% pathologic complete response,Medichi et al27also reported an8%pathologic complete response,and Janjan et al14,15 reported27%pathologic complete remission by continuous intravenous infusion.The pathologic T and N downstaging effects have been recognized as important factors for deter-mining a long-term prognosis.Ruo et al13reported on69 patients,preoperatively staged as T3to T4N1who under-went 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 signi?cant factor affecting recurrence and survival.Our re-sults showed that the5-year survival rate of patients with positive lymph nodes was42.3%and negative lymph nodes was73.8%(P?0.0004).Multivariate analysis revealed that the pathologic N stage and operation method in postirradiated specimens were the independent prognostic factor.The op-eration 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 al28analyzed141consecutive patients who received neoadjuvant chemoradiotherapy for locally ad-vanced 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 al16reported that the?nal pathologic stage after surgical resection following neoadju-vant 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 dis-ease-free survival according to pathologic stage.In our study, pCR and stage I showed good disease-free survival rates and stages II and III showed49.7%and33.6%,respectively.However,Garcia-Aguilar et al29reported that only patients with pCR showed lower local recurrence and improved sur-vival rates;whereas in patients without pCR,the?nal patho-logic stage did not show any prognostic signi?cance.
The prognostic signi?cance of complete remission in patients who undergo surgical resection after chemoradiation therapy is still unclear.In general,in advanced?xed rectal cancer,preoperative chemoradiotherapy can provide bene-?ts-related resectability and improving oncologic outcomes if the tumor showed pathologic downstaging evidence.Patho-logic complete remission is an ultimate goal of preoperative chemoradiation therapy.Pucciarelli et al30reported 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 de?nitely conclude that a pathologic complete remission confers a favorable prognosis.Moreover,Pucciarelli et al31 reported that pathologic complete remission following pre-operative chemoradiotherapy for middle to distal rectal can-cer 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 al32reported7patients (18.5%)with postoperative complications such as anasto-motic suture dehiscence or abscess.These?gures were not signi?cantly different from those reported in retrospective studies.Our results showed that postoperative complications developed in19patients(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.7,9–11The reasons for this wide variability in tumor responses are unclear.The results of studies reporting predictive clinicopathologic fac-tors 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.27,29Some molecular biomarkers,such as PCNA-labeling index,p21or p53expression,may predict tumor response to chemoradiation.33–35Moreover,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 chemora-diation in rectal cancer.36Neoadjuvant chemoradiation ther-apy has played a signi?cant 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.
Annals of Surgery?Volume244,Number6,December2006Neoadjuvant Chemoradiation for Rectal Cancer
CONCLUSION
Neoadjuvant chemoradiotherapy is a safe multimodal-ity treatment of?xed,locally advanced rectal cancer.In this study,the pathologic complete remission using this combined modality was8.8%.The pathologic downstaging effect was 58.8%,including pathologic complete response.Patients who showed pathologic complete remission had an excellent prog-nosis.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 mo-dalities enhancing the downstaging should be investigated.
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Kim et al Annals of Surgery?Volume244,Number6,December2006