Originally published as JCO Early Release 10.1200/JCO.2008.17.5299 on October 20 2008

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Pathologic Response to Preoperative Chemotherapy: A New Outcome End Point After Resection of Hepatic Colorectal Metastases

Dan G. Blazer, III, Yoji Kishi, Dipen M. Maru, Scott Kopetz, Yun Shin Chun, Michael J. Overman, David Fogelman, Cathy Eng, David Z. Chang, Huamin Wang, Daria Zorzi, Dario Ribero, Lee M. Ellis, Katrina Y. Glover, Robert A. Wolff, Steven A. Curley, Eddie K. Abdalla, Jean-Nicolas Vauthey

From the Departments of Surgical Oncology, Gastrointestinal Medical Oncology, and Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX

Corresponding author: Jean-Nicolas Vauthey, MD, The University of Texas M. D. Anderson Cancer Center, Department of Surgical Oncology, Unit 444, 1515 Holcombe Blvd, Houston, TX 77030-4009; e-mail: jvauthey{at}mdanderson.org

	ABSTRACT

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Purpose The primary goal of this study was to evaluate whether pathologic response to chemotherapy predicts patient survival after preoperative chemotherapy and resection of colorectal liver metastases (CLM). The secondary goal of the study was to identify the clinical predictors of pathologic response.

Patients and Methods A retrospective review was performed of 305 patients who underwent preoperative irinotecan- or oxaliplatin-based chemotherapy, followed by resection of CLM. Pathologic response was systematically evaluated and reported as the mean of the percentage of cancer cells remaining within each tumor. Univariate and multivariate analyses were performed to identify the predictors of pathologic response and survival.

Results Cumulative 5-year overall survival rates by pathologic response status were as follows: 75% complete response (no residual cancer cells), 56% major response (1% to 49% residual cancer cells), and 33% minor response ( 50% residual cancer cells; complete v major response, P = .037; major v minor response, P = .028). Multivariate analysis revealed that only surgical margin status (P = .050; hazard ratio [HR], 1.77) and pathologic response (major response: P = .034; HR, 4.80; minor response: P = .007; HR, 6.93) were independent predictors of survival. Multivariate analysis of the predictors of pathologic response revealed that carcinoembryonic antigen level 5 ng/mL, tumor size 3 cm, and chemotherapy with fluoropyrimidine plus oxaliplatin and bevacizumab were independent predictors of pathologic response.

Conclusion Pathologic response predicts survival after preoperative chemotherapy and resection of CLM. Degree of pathologic response represents a new outcome end point for prognosis after resection of CLM.

	INTRODUCTION

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Hepatic resection offers the best chance for long-term survival in patients with liver metastases from colorectal cancer (CLM). With this treatment approach, 5-year overall survival rates as high as 58% have been reported in several recent studies.^1-3 Improvements in the outcome of patients with CLM have been attributed not only to advances in surgical technique but also to the emergence of more effective chemotherapy. Systemic chemotherapy is increasingly used in the preoperative setting for several reasons: (1) chemotherapy may downsize tumors preoperatively and increase rates of curative resection,⁴ (2) chemotherapy can convert disease from unresectable to resectable,⁵ (3) preoperative chemotherapy in patients at high risk for recurrence may identify responders so that therapy can be tailored postoperatively,⁶ and (4) in patients with multiple tumors, chemotherapy can identify nonresponders who may not benefit from resection.⁷

Although independent risk factors such as carcinoembryonic antigen (CEA) level, tumor size, and tumor number have been reported to predict outcome after resection of CLM, different authors have used different cutoff values to discriminate between patient groups with different prognoses.^8-11 The most common factors associated with an increased risk of recurrence have included node-positive primary tumor, disease-free interval (DFI) less than 1 year, CEA level more than 200 ng/mL, tumor size more than 5 cm, and multiple tumors.⁸ However, as the strategy to treat CLM has been evolving toward a more multidisciplinary approach, recent studies suggest that these classically recognized prognostic factors may not predict prognosis after hepatic resection.^12-15

Pathologic tumor response to chemotherapy has recently been recognized as an important prognostic factor in patients treated with preoperative chemotherapy for breast,¹⁶ esophageal,^17,18 gastric,¹⁹ and colorectal cancer.^20,21 In a recent European study, Rubbia-Brandt et al²² reported a correlation between histologic response to chemotherapy for CLM and overall survival in 112 patients primarily treated with oxaliplatin-based chemotherapy. We recently reported that the addition of bevacizumab to fluoropyrimidine and oxaliplatin-based chemotherapy improved pathologic response in 285 CLM in 105 consecutive patients.²³ However, that study was limited to patients treated with fluoropyrimidine and oxaliplatin-based chemotherapy only, and the impact of chemotherapy on prognosis was not evaluated.

In the current study, we review our experience with oxaliplatin- and irinotecan-based chemotherapy, with or without bevacizumab, administered before hepatic resection in order to determine whether pathologic response predicts survival in patients with CLM treated with modern chemotherapy regimens preoperatively, followed by hepatic resection independent of currently recognized clinical predictors. Secondarily, we evaluated the clinical predictors of pathologic response in our patient population.

	PATIENTS AND METHODS

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This retrospective study was approved by The University of Texas M. D. Anderson Cancer Center review board (IRB# LAB07-0321). Between September 1997 and November 2007, a total of 312 patients underwent hepatic resection for CLM following preoperative chemotherapy with either a fluoropyrimidine and irinotecan-based regimen, or a fluoropyrimidine and oxaliplatin-based regimen, with or without bevacizumab. Patients who received more than one regimen were not included in the study. Patients who received cetuximab were excluded. Seven of the 312 patients were excluded because curative resection could not be performed. The remaining 305 patients were the participants of this study. Of note, adjuvant chemotherapy was administered in 197 out of 305 patients (64.6%). The median interval from hepatic resection and the administration of adjuvant chemotherapy was 7 weeks (range, 3 to 30 weeks). The median duration of adjuvant chemotherapy was 12 weeks (range, 5 to 71 weeks). The majority of patients who did not receive additional adjuvant chemotherapy did receive additional chemotherapy after tumor recurrence.

The primary end point was overall survival. In each patient, demographic and clinicopathologic factors, including age, sex, lymph node status of the primary, DFI, CEA level before hepatic resection, type of hepatic resection, performance (or not) of concomitant radiofrequency ablation, maximal tumor size, tumor number, surgical margin status, and pathologic response to preoperative chemotherapy, were reviewed. For the category of hepatic resection, hemihepatectomy and extended hepatectomy were defined as major hepatectomy, and other procedures were defined as minor hepatectomy.²⁴ As previously described, a positive surgical margin was defined as the presence of exposed tumor along the line of transection, the presence of tumor cells at the line of transection detected by histologic examination, or less than 1 mm microscopic margin.³

Evaluation of Pathologic Response
Residual carcinoma was determined in each liver resection specimen. All CLM were macroscopically localized after correlation with radiologic findings, including the number of nodules seen on preoperative radiographic studies. The hepatectomy specimens were sectioned in 5 mm-thick slices. In patients with multiple liver metastases, each lesion was extensively sampled from the center to the periphery to include multiple sections of tumor and nonneoplastic liver parenchyma. Sampling of the tumor nodules in the pathology suite was directed at the most viable section of the tumor nodule. More than one section per centimeter was reviewed from each tumor nodule. The mean number of hematoxylin-eosin slides reviewed per tumor nodule was four (range, one to 14 slides). More than 95% of the sections from tumors with residual adenocarcinoma showed tumor cells in the sections. All tumors measuring less than 1.5 cm and the majority of tumors with complete pathologic response were entirely submitted for microscopic examination. Hematoxylin-eosin stained sections were reviewed by two gastrointestinal pathologists (D.M.M. and H.W.). The pathologists were blinded with respect to clinical information, treatment regimen, and outcome. The extent of residual carcinoma was assessed semiquantitatively by estimating the proportion of residual cancer cells in relation to the total tumor area as previously described.²³ The tumor area included areas of chemotherapy-related tissue injury, tumor necrosis, fibro-collagenous proliferation, and other reparative changes. For this study, three subsets were analyzed: no residual cancer cells (complete response), 1% to 49% residual cancer cells remaining (major response), and 50% residual cancer cells remaining (minor response; Fig 1). Patients with no response (100% residual cancer cells) were included in the minor response group. In patients with multiple tumor nodules, the mean of the values for the various tumor nodules was used to define the pathologic response.²³

View larger version (82K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Representative photomicrographs of metastases demonstrating (A) complete response (0% residual tumor cells), (B) major response (1% to 49% residual tumor cells), and (C) minor response ( 50% residual tumor cells).

	RESULTS

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Overview
The median age of the 305 patients in the study was 57 years (range, 26 to 85 years); 179 patients (59%) were men. Preoperative chemotherapy regimens were as follows: fluoropyrimidine and irinotecan without bevacizumab in 141 patients (46%); fluoropyrimidine and irinotecan with bevacizumab in 28 patients (9%); fluoropyrimidine and oxaliplatin without bevacizumab in 50 patients (16%); and fluoropyrimidine and oxaliplatin with bevacizumab in 86 patients (28%). The median number of cycles administered was five (range, two to 32 cycles). In all cases, chemotherapy was discontinued 4 to 8 weeks before hepatic resection.

The primary cancer was located in the colon in 231 patients (76%), and in the rectum in 74 patients (24%). Two hundred ten patients (73%) had lymph node metastases from primary colorectal cancer. The DFI was less than 1 year in 237 patients (78%). Two-stage hepatectomy²⁵ was performed in 17 patients (5.6%) with a median interval of 50 days (range, 13 to 225 days). Preoperative portal vein embolization was performed in 24 patients (8%). Major hepatectomy was performed in 212 patients (70%), and radiofrequency ablation was concomitantly performed in 100 patients (33%). The median tumor size was 2.5 cm (range, 0.1 to 13.0 cm), and the median number of tumors was two (range, one to 21 tumors). All patients underwent macroscopically curative resection, but 31 patients (10%) had positive surgical margins. The median follow-up period was 25.0 months (range, 0.3-114.5 months). Three patients (1%) died within 30 days of surgery, eight patients (3%) died within 60 days of surgery, and 11 patients (4%) died within 90 days of surgery.

Pathologic Response
Pathologic response was evaluated in the specimens of 271 patients (89%). Twenty-five patients (9%) had a complete response, 97 patients (36%) had a major response, and 149 patients (55%) had a minor response. There were very few tumor nodules with no response (100% residual cancer), and, in fact, only six of 149 (4%) patients showed 10% response. Therefore, all patients with 0% to 50% response were included in the minor response group.

Predictors of Survival
Survival curves for each response group are illustrated in Figure 2. Cumulative 1-, 3-, and 5-year overall survival rates by response were as follows: complete response, 100%, 100%, and 75%; major response, 95%, 69%, and 56%; and minor response, 91%, 58%, and 33%, respectively. The survival differences between complete and major response (P = .037) and between major and minor response (P = .028) were both statistically significant by log-rank test.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival curves by the degree of pathological response.

Predictors of Pathologic Response
Figure 3 demonstrates the frequency of complete and major pathologic response according to CEA level, tumor size, and tumor number. Among the 25 patients with complete response, 22 patients (88%) had a normal CEA level ( 5.0 ng/mL), 17 patients (68%) had small tumors ( 3 cm), and 21 patients (84%) had a small number ( 3) of tumors. Similarly, among the 97 patients with major response, 74 patients (76%) had a normal CEA level, 73 patients (75%) had small tumors, and 65 patients (67%) had a small number of tumors.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Rates of complete and major response according to (A) carcinoembryonic antigen (CEA) value, (B) tumor size, and (C) tumor number.

	DISCUSSION

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Recently, Rubbia-Brandt et al²² correlated the degree of pathologic response with survival in patients with CLM treated with preoperative chemotherapy and hepatic resection. They analyzed the pathologic response on a scale of 1 to 5 and found results similar to ours. Because the degree of pathologic response in their study was based on semiquantitative analysis of the proportion of viable cancer cells remaining, it was subject to variability in interpretation. Therefore, for our study, we used an approach less subject to variability (complete, major, and minor response, with strictly defined cut-offs). Recent work from our institution reported a similar correlation between pathologic response and survival in patients with esophageal cancer treated with preoperative chemoradiotherapy when pathologic response was evaluated using this three-tiered pathologic response scale.¹⁸

Our study also confirms the low complete pathologic response rates after systemic chemotherapy previously reported by Benoist et al.²⁶ It also suggests a lack of additional benefit with the use of bevacizumab, although patient numbers were small. However, the study indicates clear differences in the ability of various regimens to produce at least major responses. The multivariate analysis confirmed that fluoropyrimidine plus oxaliplatin and bevacizumab is an independent predictor of more than a 50% response rate. It is notable that this result was achieved despite a short duration of preoperative treatment (median, 10 weeks). This result confirms our recent report indicating that two to four cycles of the combination of fluoropyrimidine plus oxaliplatin and bevacizumab is effective, and that additional response is not seen with more treatment cycles.²³ These data are important in the context of recent studies indicating an association between surgical morbidity and prolonged use of preoperative chemotherapy.^27-30 Although we did not specifically evaluate this issue in the present study, further studies regarding the association between the dose or duration of chemotherapy and the pathologic response are expected.

Besides fluoropyrimidine plus oxaliplatin and bevacizumab-based chemotherapy, CEA level 5 ng/mL and tumor size 3 cm were independent predictors of more than 50% pathologic response. Rubbia-Brandt et al²² found that tumor size was not correlated with pathologic response; however, they did find that a major response was seen in 129 (75%) of 172 tumors less than 1 cm and that there were no complete responses of tumors of more than 2 cm. Another study by Wicherts et al³¹ showed a complete pathologic response rate of 4% (31 of 791 patients) among patients with CLM treated with preoperative chemotherapy and revealed that independent predictors of complete pathologic response were age 60 years, CEA level 40 ng/mL, tumor size 3 cm, and objective response. Low CEA level most likely reflects less aggressive CLM. Although the correlation between tumor size and pathologic response may be controversial, these results suggest that it is difficult to achieve complete or major pathologic response in large tumors with current chemotherapy regimens. We recently compared the pathologic response of fluoropyrimidine and oxaliplatin plus bevacizumab to the pathologic response of fluoropyrimidine and oxaliplatin alone. We found that the addition of bevacizumab improved the pathologic response rate only in tumors 4 cm.²³

Finally, in this study, 45% of the patients achieved a major response, and major response independently predicted improved patient survival. These results suggest that pathologic response based on careful analysis of the surgical specimen can be used as a new outcome end point to predict prognosis immediately after surgery. Pathologic response could also emerge as an important tool in the evaluation of new targeted therapies for CLM and may make it unnecessary to wait for survival data. Additionally, radiologic response to chemotherapy for CLM is an unsatisfactory predictor of survival.³² In this context, pathologic response may provide a standard against which new criteria for radiologic response could be developed.

This study has several limitations. It was a retrospective analysis of patients treated with four different chemotherapy protocols. It should be noted, however, that patients who received multiple chemotherapy regimens were excluded from this study. Interobserver variability in evaluation of pathologic response may be a factor. However, our group has demonstrated good reproducibility in assessment of residual cancer in the esophagus, and the diagnostic criteria followed to evaluate residual tumor in CLM were to a large extent similar to those used for esophageal carcinoma.³³ In this study, the two pathologists who analyzed the pathology material were blinded to treatment and outcomes, increasing the strength of the study. Sampling of the tumor nodules in the pathology suite was directed at the most viable section of the tumor nodule; thus, if anything, the study was biased towards underestimation of response. Our study confirms the correlation between residual tumor cells and survival reported by Rubbia-Brandt et al²² for CLM and reported by others for other disease sites.^16,17,19-21 It will be important, however, for future studies to analyze the interobserver variability in the percentage of residual tumor cells to determine consistent percentage cut-offs in CLM.

In conclusion, in patients with CLM treated with preoperative chemotherapy followed by hepatic resection, pathologic response predicted postoperative survival. Major pathologic response was associated with preoperative CEA level 5 ng/mL, tumor size 3 cm, and chemotherapy combining oxaliplatin and bevacizumab. Pathologic response may provide the new standard against which chemotherapeutic and radiologic response can be evaluated and may serve as a new outcome end point after hepatic resection of CLM.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Scott Kopetz, Sanofi-aventis (C), Roche (C); Cathy Eng, Pfizer (C); Jean-Nicolas Vauthey, Sanofi-aventis (C), Genentech (C) Stock Ownership: None Honoraria: Scott Kopetz, Pfizer Inc; Cathy Eng, Pfizer Inc; Lee M. Ellis, Genentech; Eddie K. Abdalla, Sanofi-aventis; Jean-Nicolas Vauthey, Sanofi-aventis, Genentech Research Funding: Scott Kopetz, Bristol-Myers Squibb Co, Genentech, Pfizer Inc, BiPar Sciences Inc, Taiho Pharmaceutical Co Ltd; Michael J. Overman, Sanofi-aventis; Cathy Eng, Bristol-Myers Squibb Co, Genentech, Sanofi-aventis, Pfizer Inc; Lee M. Ellis, Sanofi-aventis; Robert A. Wolff, Genentech, Eli Lilly & Co., Sanofi-aventis; Eddie K. Abdalla, Sanofi-aventis; Jean-Nicolas Vauthey, Cancer Fighters of Houston Inc, Sanofi-aventis Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Dipen M. Maru, Eddie K. Abdalla, Jean-Nicolas Vauthey

Financial support: Jean-Nicolas Vauthey

Administrative support: Yun Shin Chun, Cathy Eng, Jean-Nicolas Vauthey

Provision of study materials or patients: Dipen M. Maru, Scott Kopetz, David Fogelman, Huamin Wang, Daria Zorzi, Lee M. Ellis, Robert A. Wolff, Steven A. Curley, Eddie K. Abdalla, Jean-Nicolas Vauthey

Collection and assembly of data: Dan G. Blazer III, Dipen M. Maru, Huamin Wang, Daria Zorzi, Dario Ribero, Jean-Nicolas Vauthey

Data analysis and interpretation: Dan G. Blazer III, Yoji Kishi, Dipen M. Maru, Scott Kopetz, Daria Zorzi, Steven A. Curley, Eddie K. Abdalla, Jean-Nicolas Vauthey

Manuscript writing: Dan G. Blazer III, Yoji Kishi, Yun Shin Chun, Lee M. Ellis, Eddie K. Abdalla, Jean-Nicolas Vauthey

Final approval of manuscript: Dan G. Blazer III, Scott Kopetz, Michael J. Overman, David Fogelman, Cathy Eng, David Z. Chang, Daria Zorzi, Dario Ribero, Lee M. Ellis, Katrina Y. Glover, Robert A. Wolff, Steven A. Curley, Eddie K. Abdalla, Jean-Nicolas Vauthey

	NOTES

 
published online ahead of print at www.jco.org on October 20, 2008.

D.G.B. III and Y.K. contributed equally to this work.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted April 3, 2008; accepted June 2, 2008.

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