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Annals of Surgical Oncology 8:801-806 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Complete Response to Neoadjuvant Chemoradiation for Rectal Cancer Does Not Influence Survival

Mark W. Onaitis, MD, Robert B. Noone, MD, Ryan Fields, BS, Herbert Hurwitz, MD, Michael Morse, MD, Paul Jowell, MB, ChB, Kevin McGrath, MD, Catherine Lee, MD, Mitchell S. Anscher, MD, Bryan Clary, MD, Christopher Mantyh, MD, Theodore N. Pappas, MD, Kirk Ludwig, MD, Hilliard F. Seigler, MD and Douglas S. Tyler, MD

From the Departments of Surgery (MWO, RBN, RF, BC, CM, TNP, KL, HFS, DST), Medicine (HH, MM, PJ, KM), and Radiation Oncology (CL, MSA), Duke University Medical Center, Durham, North Carolina.

Correspondence: Address correspondence and reprint requests to: Douglas S. Tyler, MD, Department of Surgery, Duke University Medical Center, DUMC Box 3118, Durham, NC 27710; Fax: 919-681-8701; E-mail: tyler002{at}acpub.duke.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Up to 30% of patients with locally advanced rectal cancer have a complete clinical or pathologic response to neoadjuvant chemoradiation. This study analyzes complete clinical and pathologic responders among a large group of rectal cancer patients treated with neoadjuvant chemoradiation.

Methods: From 1987 to 2000, 141 consecutive patients with biopsy-proven, locally advanced rectal cancer were treated with preoperative 5-fluorouracil-based chemotherapy and radiation. Clinical restaging after treatment consisted of proctoscopic examination and often computed tomography scan. One hundred forty patients then underwent operative resection, with results tracked in a database. Standard statistical methods were used to examine the outcomes of those patients with complete clinical or pathologic responses.

Results: No demographic differences were detected between either clinical complete and clinical partial responders or pathologic complete and pathologic partial responders. The positive predictive value of clinical restaging was 60%, and accuracy was 82%. By use of the Kaplan-Meier life table analysis, clinical complete responders had no advantage in local recurrence, disease-free survival, or overall survival rates when compared with clinical partial responders. Pathologic complete responders also had no recurrence or survival advantage when compared with pathologic partial responders. Of the 34 pathologic T0 tumors, 4 (13%) had lymph node metastases.

Conclusions: Clinical assessment of complete response to neoadjuvant chemoradiation is unreliable. Micrometastatic disease persists in a proportion of patients despite pathologic complete response. Observation or local excision for patients thought to be complete responders should be undertaken with caution.

Key Words: Rectal cancer • Neoadjuvant chemoradiation • Complete response • Total mesorectal excision


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Adjuvant or neoadjuvant therapy has improved outcomes for patients with locally advanced rectal cancer.1–6 The neoadjuvant approach is favored by many over the adjuvant approach for a number of reasons: facilitation of resection because of tumor shrinkage, reduction of risk of small-bowel toxicity, improvements in functional results because of a nonirradiated neorectum, increases in patient tolerance, and enhancements of biological response to treatment.

Pathologic complete response (CR) rates by using a neoadjuvant approach range from 3% to 30%.7–14 Complete clinical response after treatment has been judged by combinations of examination, proctoscopy, computed tomography (CT) scan, endorectal ultrasound, and biopsy. Despite what seems to be a complete clinical response, these patients are typically treated with definitive resection via either abdominoperineal resection or low anterior resection. However, some have attempted nonoperative or local management of these patients.9,15,16 An understanding of the clinical course of the complete pathologic responders would be helpful in choosing a rational operative course for patients thought to be CRs. We have treated 141 consecutive patients with neoadjuvant chemoradiation for locally advanced rectal cancer since 1987.17 The purpose of this study is to examine in detail the characteristics and outcomes of the clinical and pathologic CRs to this neoadjuvant treatment.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From 1987 to 2000, patients with biopsy-proven suspected T3 or N1 rectal cancer have been treated with neoadjuvant chemotherapy and radiation. All patients in the series were staged by abdominal and pelvic CT scans and chest roentgenograms. For the past 5 years, local tumor stage has been determined by using endorectal ultrasound or magnetic resonance imaging with an endorectal probe. Lymph nodes were considered ultrasonically positive if they were enlarged, round rather than oval, irregular in border, or hypoechoic.

Chemotherapeutic regimens for all patients were 5-fluorouracil (5-FU)-based. The first 54 patients received 5-FU and cisplatin, which were begun at the onset of the radiation treatments. The dose of 5-FU was 500 mg/m2/day administered as a rapid infusion on five consecutive days. This was immediately followed by a 30-minute infusion of 20 mg/m2/day of cisplatin. The same doses and agents were repeated during the last week of radiotherapy. The remaining 87 patients received 5-FU alone in one of various regimens. Seventy-seven patients were treated with continuous-infusion 5-FU in one of three dosing regimens: 800 to 1000 mg/m2 for 5 days in weeks 1 and 5; 100 mg/m2 for 4 days in weeks 1 and 5; or 225 mg/m2 for all 35 days. Ten of the 87 received an experimental oral 5-FU formulation along with eniluracil as part of a research protocol.

Radiotherapy was administered by photon radiation generated by a 6-mV or greater linear accelerator with attempts to exclude small bowel from the fields. A three-field technique was used, with one anterior-posterior (AP) and two lateral wedge fields. The superior border of the AP field was the top of the fifth lumbar vertebra, and the inferior limit was the inferior border of the ischial tuberosities or 2 cm inferior to the most inferior aspect of the tumor. The lateral border of the AP field was 1.5 cm lateral to the pelvic brim. The anterior border of the lateral fields was the posterior edge of the pubic symphysis. For the first 54 patients, treatment was administered five times per week with a daily fraction of 180 cGy. Twenty-five treatments were administered for a total pelvic dose of 4500 cGy. For the remaining 87 patients, a boost of 540 cGy was added for a total pelvic dose of 5040 cGy.

All patients underwent postchemoradiation examination and proctoscopy, and many underwent CT scan. Complete clinical response was defined as absence of disease on examination, proctoscopy, and CT scan. Operative treatment of the tumors was performed 4 to 8 weeks after completion of the chemoradiation. Pathologic response on postoperative staging was standardized such that the deepest bowel layer with microscopic viable tumor cells determined the T stage. Pathologic CR was defined as the absence of viable tumor cells in the specimen. Postoperative complications were tracked and entered into a database. A small proportion of patients with node-positive tumors or liver metastases underwent postoperative systemic chemotherapy with a variety of regimens. Subset analyses of these small subgroups were not undertaken.

For the purposes of power and sample size calculations, a CR to preoperative chemoradiation was assumed to yield a 5-year survival increase of 10% (from 50% to 60%). In a prospective study, given the approximately 50-patient-per-year accrual rate and a 25% CR rate, a sample size of 720 patients would be necessary to produce such a difference with a power of .8. Retrospectively, the power of this study to reveal such a difference was .25. The computer program Statistica for Windows Version 5TM (Statsoft, Tulsa, OK) was used for all statistical calculations and Kaplan-Meier curve generation. The Mantel-Cox log-rank test was used to compare curves, with a P value of <.05 considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 141 locally advanced rectal cancer patients treated with our neoadjuvant protocol, clinical response assessment (complete records of proctoscopy, CT scan, or both) was available in 134 cases. Median follow-up was 27 months. The mean age of the 30 clinical CRs was 61.5 ± 12.7 years, whereas that of the 104 with residual clinical disease was 58.3 ± 11.8 years (P = not significant by Student’s t-test). Men outnumbered women by 18 to 12 in the clinical CRs and 66 to 38 in those with residual disease clinically (P = not significant by {chi}2). The mean distance of the tumors from the anal verge was 4.4 ± 4.1 cm for clinical CRs and 5.2 ± 4.1 cm for those with residual disease clinically (P = not significant by t-test). Of the 30 complete clinical responders, 29 underwent resection, with 19 specimens revealing complete pathologic T-stage response. Lymph node metastases were present in two of these. One patient refused operation, is alive without disease at 8 years follow-up, and is considered a complete pathologic responder for the purposes of this analysis. The positive predictive value of our clinical assessment for a complete clinical response was thus 60% (Table 1). Those staged clinically after therapy to have residual disease numbered 104, 14 of which had complete pathologic T-stage responses. Of these, two had lymph node metastases. The negative predictive value of clinical assessment of CR was 88%.


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  		TABLE 1. Response data
 
Of the 141 treated patients, 140 underwent operation, with 34 having complete pathologic T-stage responses. Of these 34, 4 had positive lymph nodes on pathologic assessment. The mean age of the pathologic CRs was 59.1 ± 13.9 years, whereas that of those with residual disease at resection was 59.9 ± 11.4 years (P = not significant by t-test). Men outnumbered women 21 to 9 in the group of complete T-stage responders and 69 to 41 in the group with residual disease (P = not significant by {chi}2). The mean distance of the tumor from the anal verge was 5.2 ± 4.3 cm for the complete pathologic T-stage responders versus 5.1 ± 4.0 cm for those with residual disease (P = not significant by t-test). Of the 30 pathologic T-stage CRs, 29 proctoscopic records were available for review. Of these 29, 18 were clinical CRs (62%). Of the 110 patients with pathologic residual tumor, 104 proctoscopic records were available for review. Of these 104, 12 had complete clinical responses (12%; P < .0001 vs. pathologic CRs by {chi}2). The sensitivity and specificity of proctoscopy and CT in this posttreatment, presurgical setting are listed in Table 1.

Of the 30 pathologic CRs, 12 underwent abdominoperineal resection (40%), 17 underwent low anterior resection (57%), and 1 underwent transanal local excision (3%). Of the patients with residual disease at operation, 56 underwent abdominoperineal resection (51%), 49 underwent low anterior resection (44%), 2 underwent Hartmann’s procedure (2%), 2 underwent exploratory laparotomy (2%), and 1 underwent transanal local excision (1%). None of these differences between the two groups was significant by {chi}2.

Outcome of the clinical and pathologic CRs were next examined in comparison with those of patients with residual disease. Kaplan-Meier analysis was performed with local recurrence, disease-free survival, and overall survival as end points. Comparing the outcomes of clinical CRs with those with clinical residual disease, no significant differences were seen in local recurrence, distant recurrence, or survival (data not shown). Next, complete pathologic responders were compared with those with pathologic residual disease. As the curves in Figs. 1A–1C reveal, no differences were seen between the two groups in freedom from local recurrence, disease recurrence, or death. However, closer analysis of the disease-specific (Fig. 1B) and overall (Fig. 1C) survival curves reveals early survival advantages in the T0 group. These advantages disappear by 40 to 50 months.



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  		FIG.1. (A) Local recurrence in patients with sterile specimens versus residual disease on postoperative pathologic analysis. (B) Disease-free survival in patients with sterile specimens versus residual disease on postoperative pathologic analysis. (C) Overall survival in patients with sterile specimens versus residual disease on postoperative pathologic analysis.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although patients treated with combined preoperative chemoradiation have done better than untreated controls,4–6,12,13,18–21 few studies have achieved sufficient patient numbers and follow-up to examine differences in outcomes among the treated group.

Reported factors predictive of significant tumor downstaging and sterilization have varied. Janjan et al.10 from M. D. Anderson have found a correlation between tumor size <5 cm and CR, whereas Berger et al.22 have associated higher radiation doses, tumor differentiation, preoperative stage, and length of time between completion of preoperative therapy and operation with downstaging, but no factor correlated with CR. In our series, no factor examined was predictive of complete T-stage response to treatment.

Methods of ascertaining preoperative response to therapy have been shown to be inaccurate. The group at Jefferson retrospectively examined the preoperative staging of their 25 pathologic CRs. This staging consisted of various regimens of digital rectal examination, sigmoidoscopy, CT scan, endorectal ultrasound, and magnetic resonance imaging. All of the regimens overstaged these patients at least 75% of the time.23 Other studies examining CT scan in this context also reveal fatty changes and mesenteric streaking that limit accuracy.24,25 Likewise, the accuracy of endorectal ultrasound after radiotherapy has been documented to decrease to 47% to 58%.25–27 Even proctoscopic biopsy of residual tumor is disappointing. The M. D. Anderson group examined 16 patients who underwent proctoscopic biopsy postchemoradiation. Although 14 of these patients had no evidence of tumor on biopsy, only 5 of these were true pathologic CRs (36%).28 In this series, there was an 82% accuracy rate in predicting complete pathologic response to the neoadjuvant treatments. However, 18% are still staged incorrectly. Perhaps newer modalities such as positron emission tomography, which has shown promise in this scenario in a pilot study,29 will prove useful in the future.

There are conflicting data as to the importance of downstaging for local recurrence and survival. With the use of sharp mesorectal excision in the majority of these patients, local recurrence rates can be expected to be <10%.30–32 As noted in Methods, this study is clearly underpowered to ascertain small differences between the CRs and those with residual disease in terms of local recurrence and survival. Reviewing the literature, the series from M. D. Anderson33 reported improved disease-free but not overall survival in those with any response as compared with no response to neoadjuvant therapy. However, CR was not an independent predictor of either disease-free or overall survival. In contrast, the Florida group revealed statistically significant survival advantages for CR.9 Possible explanations for these differences include different patient populations, different treatment protocols, and different lengths of follow-up. The 13% complete pathologic response rate of the Florida series may point to a less effective treatment regimen when compared with the 22% rate in this series and the 27% rate from M. D. Anderson.

What is the biological mechanism for the lack of survival advantage for the CR? Because local recurrence rates were low and similar between the two groups, a similar proportion of patients in each group must harbor micrometastatic cells outside the pelvis after neoadjuvant treatment. Many of these metastatic cells may be phenotypically different from those in the primary tumor in that they are relatively insensitive to 5-FU. Perhaps complete pelvic responders have a higher proportion of metastatic cells that are 5-FU sensitive. This could account for the early survival benefit seen in this group of patients in terms of disease-free and overall survival. The addition of new chemotherapeutic agents may improve outcomes, and correlation of molecular markers with outcome may aid in further defining groups with improved chances of survival.

Given the inability to accurately restage patients after neoadjuvant treatment, and assuming that the lack of survival improvement is explained by micrometastatic disease at the time of operation, what is the best course of therapy for these patients? Considering the preoperative regimen first, we prefer continuous infusion 5-FU over bolus 5-FU because of the ability to titrate infusion rate in response to side effects and because oral 5-FU is no longer clinically available. Although the Europeans have achieved survival increases with 2500 cGy of radiation, we have used only 4500 to 5040 cGy. We believe that we achieve significant downstaging and acceptable morbidity with this regimen. Turning to operative decision-making, if postneoadjuvant treatment staging can be optimized, perhaps clinical CRs can be spared aggressive surgical resection. Some have offered selected downstaged patients local scar excision or transanal endoscopic microsurgical resection.9,16 Habr-Gama et al.15 have used such an approach in a cohort of 118 patients treated with preoperative 5-FU and radiation for stage I, II, and III rectal cancer. Of these, 36 were clinical CRs, and 30 were initially managed nonoperatively. However, during follow-up, eight patients showed evidence of persistent tumor and were resected. Thus, in this preliminary study, 28 patients were spared resection. However, the 13% rate of lymph node metastases seen in this study in those with complete pathologic responses warrants caution and close follow-up of those treated conservatively. Further study of this issue is necessary to answer this difficult question.


   Footnotes
 
Presented in part at the 54th Annual Cancer Symposium of the Society of Surgical Oncology, Washington, DC, March 15–18, 2001.

Received for publication March 16, 2001. Accepted for publication June 20, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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