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Significance of Histological Response to Preoperative Chemoradiotherapy for Pancreatic Cancer

¹ Department of Surgery, Duke University Medical Center, Box 3118, Durham, North Carolina 27710,
² Department of Pathology, Duke University Medical Center, Box 3118, Durham, North Carolina
³ Department of Radiation Oncology, Duke University Medical Center, Box 3118, Durham, North Carolina
⁴ Department of Medicine, Duke University Medical Center, Box 3118, Durham, North Carolina
⁵ Department of Radiology, Duke University Medical Center, Box 3118, Durham, North Carolina

Correspondence: Address correspondence and reprint requests to: Douglas S. Tyler, MD; E-mail: tyler002{at}mc.duke.edu.

	ABSTRACT

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Background: Neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer offers theoretical advantages over the standard approach of surgery followed by adjuvant CRT. We hypothesized that histological responses to CRT would be significant prognostic factors in patients undergoing neoadjuvant CRT followed by resection.

Methods: Since 1994, 193 patients with biopsy-proven pancreatic adenocarcinoma have completed neoadjuvant CRT, and 70 patients have undergone resection. Specimens were retrospectively examined by an individual pathologist for histological responses (tumor necrosis, tumor fibrosis, and residual tumor load) and immunohistochemical staining for p53 and epidermal growth factor receptor. Factors influencing overall survival were analyzed with the Kaplan-Meier (univariate) and Cox proportional hazards (multivariate) methods.

Results: The estimated overall survival (median ± SE) in the entire group of patients undergoing resection was 23 ± 4.2 months, with an estimated 3-year survival of 37% ± 6.6% and a median follow-up of 28 months. Complete histological responses occurred in 6% of patients. Overexpression of p53 was more common in patients with large residual tumor loads. Tumor necrosis was an independent negative prognostic factor, as were positive lymph nodes, a large residual tumor load, and poor tumor differentiation.

Conclusions: Histological response to neoadjuvant CRT—as measured by residual tumor load—may be useful as a surrogate marker for treatment efficacy. Characterization of the tumor cells that survive neoadjuvant CRT may help us to identify new or more appropriate targets for systemic therapy.

Key Words: Pancreatic cancer • Chemoradiotherapy • Neoadjuvant therapy • Histological response

	INTRODUCTION

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Surgical resection is necessary for the curative treatment of pancreatic cancer. However, long-term (5-year) survival rates—even for patients undergoing "complete" resection—are <20%.¹ Both distant and local/regional patterns of recurrence are common, and this suggests that most patients have occult metastatic disease or local/regional disease (or both) at the time of resection. Postoperative (adjuvant) chemoradiotherapy (CRT) has been shown to improve survival in patients with resected pancreatic cancer,²³ although there is debate over whether radiotherapy is a beneficial component.⁴ The problems with the postoperative adjuvant approach include the fact that at least 25% of patients do not actually receive adjuvant therapy because of complications of surgery or patient refusal.³⁵ A primary advantage of preoperative (neoadjuvant) therapy is therefore the assurance that CRT is received by all patients with resected disease in a timely fashion. Other benefits are the delivery of radiation to well-oxygenated tissues and the avoidance of radiation to fixed loops of intestine within the operative field. Another rationale for preoperative CRT is that occult metastatic disease is given the opportunity to manifest, thus allowing patients to avoid the morbidity of resection or laparotomy. Finally, the potential for preoperative CRT to convert locally advanced lesions to resectable lesions has been realized for other gastrointestinal tumors and could greatly increase the number of patients with pancreatic cancer who might be offered a chance of cure.

For cancers of the esophagus, stomach, and rectum, preoperative CRT has been associated with complete histological response rates in significant percentages of patients. Histological response to preoperative therapy has been found to be a positive prognostic factor for esophageal and gastric cancer,⁶⁷ but an effect of histological response on survival for rectal cancer has not consistently been seen.⁸⁹ Compared with these other gastrointestinal malignancies, complete histological responses for pancreatic cancers to preoperative CRT are much less common, and radiographical responses are generally modest.⁵¹⁰¹¹ Pancreatic cancers are somewhat unique in that even nonirradiated tumors are often characterized by an intense desmoplastic reaction,¹²¹³ and irradiated specimens typically demonstrate replacement of tumor by fibrosis rather than tumor shrinkage.⁵¹⁰¹¹ Tumor necrosis is variably present and is believed to precede fibrosis in the response to radiation, although necrosis may also be found within the hypoxic centers of large, nonirradiated tumors.¹⁴

Histological criteria for grading therapeutic effects are useful for evaluating the efficacy of new therapies. However, grading systems developed for other malignancies do not seem to apply very well to pancreatic cancers. We retrospectively examined pancreatic cancer resection specimens from patients undergoing preoperative CRT and hypothesized that histological responses—including tumor necrosis, tumor fibrosis, and residual tumor load—would be useful as prognostic factors. This study evaluates the effects of histological responses, as well as several other clinical and pathologic factors, on overall survival.

	METHODS

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Since 1994, we have treated 193 patients with biopsy-proven adenocarcinoma of the pancreas by using neoadjuvant CRT. All patients underwent contrast-enhanced, dynamic computed tomography (CT) to exclude distant metastatic disease. On the basis of their initial staging CT, patients were categorized as having locally advanced disease (arterial abutment, venous occlusion, or both) or potentially resectable disease (including venous involvement without occlusion). Exact treatment regimens varied, but 183 patients (95%) received 5-fluorouracil–based chemotherapy delivered concurrently with daily external beam radiotherapy for a planned total dose of 4500 cGy at 180 cGy per fraction over 5 weeks plus a 540-cGy boost to the tumor. Ten patients (5%) received gemcitabine chemotherapy with twice-daily external beam radiotherapy with a planned total dose of 3000 cGy at 150 cGy per fraction over 3 weeks. After CRT, patients were given a 3- to 4-week break for recovery of blood counts and nutrition before restaging CT. Patients without evidence of distant progression or clear evidence of unresectability were offered surgical exploration. Patients with gross distant metastatic disease or regional lymph node involvement confirmed by frozen-section analysis did not undergo resection, but normal-appearing lymph nodes were not routinely sampled.

Seventy patients underwent resection. Patients with proximal lesions (head, uncinate, or neck) underwent standard Whipple pancreaticoduodenectomy, and patients with distal lesions (body or tail) underwent midgland or distal pancreatectomy. Resected specimens were routinely examined for resection margins, lymph node involvement, gross tumor size, tumor differentiation, and perineural invasion. In addition, 54 specimens were available for retrospective examination for histological responses by an individual pathologist (H.B.X.), who was blinded to patient outcome. Tumor necrosis was defined as the presence of lysed cells with necrotic debris within the tumor. Tumor fibrosis was graded qualitatively as mild, moderate, or extensive. Tumor load was a semi-quantitative assessment of the percentage of the tumor composed of viable tumor cells: "large" corresponded roughly to >90% viable tumor cells (<10% destruction or grade I in the M. D. Anderson Cancer Center [MDACC] modification of the Shimosato grading system^14–16), "moderate" spanned 10% to 90% viable tumor cells, "small" represented <10% viable tumor cells, and "minimal" or "none" indicated only scattered foci of tumor cells or no tumor cells, respectively. For 41 patients with fixed, paraffin-embedded tissue available, immunohistochemical staining was performed for epidermal growth factor receptor (EGFR) by using a rabbit anti-human polyclonal antibody at 1/50 dilution (RB-9007-R7; Lab Vision Corporation, Fremont, CA) and for p53 by using a mouse anti-human monoclonal antibody at 1/50 dilution (M7001, clone DO-7; DakoCytomation, Carpinteria, CA). Negative controls were obtained by omitting the primary antibodies. Both nuclear and cytoplasmic immuno-reactivities, either focal or diffuse, were considered positive.

Overall survival was measured from the date of pathologic diagnosis. All 67 patients who survived the postoperative period were included in the analyses of routine clinical and pathologic factors, whereas only the 54 patients whose specimens were available for re-examination were included in the analyses of histological response factors. Factors that influenced overall survival, measured from the time of tissue diagnosis, were analyzed with the Kaplan-Meier (univariate) and Cox proportional hazards (multivariate) methods (Statistica for Windows; StatSoft, Tulsa, OK). Dichotomous variables were used for all univariate analyses; continuous and ranked categorical variables were used for the multivariate analyses where possible. Categorical variables were compared across subgroups by using the two-tailed Fisher’s exact test.

	RESULTS

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Of 102 patients with potentially resectable tumors by initial staging CT, 54 patients (53%) underwent resection, and 16 (18%) of 91 locally advanced tumors on initial staging CT were ultimately resected. Eight patients (11%) required repair or reconstruction of the portal vein, superior mesenteric vein, or both. There were three (4.3%) perioperative deaths, and these patients were excluded from subsequent analyses. The clinical characteristics of the 67 patients who survived the perioperative period are listed in Table 1.

The pathologic characteristics of the resected specimens are listed in Table 2. Negative surgical margins were achieved in 73% of patients, and lymph nodes were uninvolved in 70% of patients. The rates of neither negative margins nor negative lymph nodes were significantly different between initially potentially resectable tumors and initially locally advanced tumors. Gross tumor size was different, however; 88% of initially locally advanced tumors versus 57% of initially potentially resectable tumors were >2 cm (P = .04). Of the 54 specimens retrospectively examined, there were 3 (5.6%) complete responses, whereas there were 4 (6%) complete responses out of the total group of 67 resection specimens. An additional one third of patients had either minimal or small residual tumor loads. Tumor fibrosis was present in all specimens and was extensive in most (76%). Tumor necrosis was present in one third of specimens, and there was no significant relationship between the presence of tumor necrosis and gross tumor size, initial tumor resectability, or residual tumor load. Tumor necrosis was not present in any of the complete responders.

Overall survival was compared between subgroups (Table 3). Neither age nor sex significantly influenced survival. Patients with initially potentially resectable tumors enjoyed a median survival of 39 months, compared with 20 months for patients with initially locally advanced tumors, although this difference did not quite reach statistical significance (Fig. 1; P = .07). Of the routine histological factors (resection margins, lymph nodes, gross tumor size, differentiation, and perineural invasion), only lymph node status was a significant predictor of overall survival (Fig. 2; P < .01). Of the histological response factors, degree of tumor fibrosis was not associated with survival. Patients with large residual tumor load did have worse survival than patients with moderate or smaller tumor loads (Fig. 3; P = .02). Survival curves for patients with none, minimal, small, or moderate tumor loads were very similar and, therefore, were not analyzed separately. Specifically, of the four patients with complete response (no residual tumor load and no lymph node involvement), two died of disease progression at 22 and 29 months. The other two complete responders died without evidence of recurrence at 11 and 16 months, the former because of complications from percutaneous feeding jejunostomy tube replacement and the latter because of recurrent cholangitis. Despite its association with residual tumor load, p53 overexpression was not a significant prognostic factor. Finally, although we had hypothesized that tumor necrosis would be a positive prognostic factor, patients with tumor necrosis had significantly worse survival than patients without tumor necrosis (Fig. 4; P < .02). The extent of necrosis varied from focal to extensive, and none of the three patients with extensive necrosis survived longer than 20 months.

View larger version (14K): [in this window] [in a new window]   FIG. 1. Overall survival in patients with potentially resectable (n = 51) versus locally advanced (n = 16) tumors by prechemoradiotherapy computed tomography (CT).

View larger version (22K): [in this window] [in a new window]   FIG. 2. Overall survival in resected patients with negative lymph nodes (n = 47) versus positive lymph nodes (n = 20).

View larger version (24K): [in this window] [in a new window]   FIG. 3. Overall survival in patients with a large residual tumor load (n = 8) in the resection specimen as compared with patients with moderate, small, minimal, or no tumor load (n = 46).

View larger version (12K): [in this window] [in a new window]   FIG. 4. Overall survival by the presence (n = 17) or absence (n = 37) of tumor necrosis in the resection specimen.

	DISCUSSION

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Median and 5-year survival estimates (23 months and 28%, respectively) for the entire group of patients undergoing neoadjuvant CRT followed by resection are similar to those that we have previously published and reflect a larger and more mature patient population.¹¹ These survival estimates are also similar to those published by MDACC for their series of 132 patients undergoing neoadjuvant CRT followed by resection (21 months and 23%, respectively).¹⁶ Our series differs from the MDACC series in that we offered neoadjuvant CRT not only to patients with potentially resectable tumors by initial staging CT, but also to patients with locally advanced tumors, who comprised almost 25% of our patients with resected disease. If we consider only patients with potentially resectable tumors on initial staging, median and 5-year survival estimates in our study are 39 months and 40%, respectively. Survival rates in these two neoadjuvant series, which are the two largest published experiences, compare favorably to survival rates for patients undergoing resection followed by adjuvant CRT in recent studies, which have ranged from 15 to 20 months.¹³⁴ Selecting out patients with occult metastatic disease before resection is an intended goal of neoadjuvant therapy and would be expected to improve survival in patients with resected disease. Whether the favorable survival seen in patients undergoing neoadjuvant CRT followed by resection is entirely explained by patient selection or whether there is a downstaging effect of neoadjuvant CRT is not yet clear.

The general experience has been that radiographical responses to neoadjuvant CRT are modest and do not correlate well with histological responses.⁵¹⁰¹¹ The replacement of tumor with fibrosis that has typically been observed on histological examination of resected surgical specimens may result in little or no change in radiographical appearance. For instance, approximately 10% of tumors that appear locally advanced on restaging CT because of vascular involvement are found to have sterile fibrosis at exploration and are resected.¹⁷

The purpose of this study was to determine whether histological responses to neoadjuvant CRT could be useful as prognostic factors for pancreatic cancer. We hypothesized that tumor necrosis and fibrosis would be positive prognostic factors and, conversely, that residual tumor load would be a negative prognostic factor. A number of routine clinical and pathologic variables that have been associated with pancreatic cancer prognosis were also included in our analysis, both to verify their importance in our patient population and to examine their relationships to histological responses.

Lymph node status was a powerful prognostic factor, as has been demonstrated in numerous studies of patients with resected pancreatic cancers. Patients with negative lymph nodes had an apparent survival advantage of almost 1 year over patients with positive lymph nodes (29 vs. 18 months, respectively; P < .01). Resection margin status, which is also widely regarded as an important prognostic factor, was not significant in either univariate or multivariate analysis in this study. However, there was clearly a trend toward improved survival in patients with negative margins, and margin status might achieve significance with larger numbers of patients. It is interesting to note that margin status was also not found to be a significant prognostic factor in the MDACC series, in which only 12% of patients had positive margins.¹⁶ Gross tumor size in resected specimens was not a significant prognostic factor in either our series or the MDACC series, although tumor size has been significant in most studies of pancreatic cancer resection in patients without neoadjuvant CRT. Just as radiographical responses to CRT do not correlate well with histological responses, gross tumor size does not seem to correlate well with the amount of residual tumor in patients who have received neoadjuvant CRT. Tumor differentiation was a significant factor in the multivariate model, and patients with poorly differentiated tumors had markedly worse survival than patients with moderately differentiated or well-differentiated tumors. Age, sex, and perineural invasion had no apparent effect on survival.

Patients with locally advanced tumors on initial CT demonstrated a trend toward worse survival than patients with potentially resectable tumors on initial CT, although this trend disappeared in the multivariate analysis. We believe that patients with locally advanced tumors should be offered neoadjuvant CRT, and the lack of an association between initial resectability and survival supports this belief. Although many of these cases will manifest disease progression either on restaging CT or at surgical exploration, a significant minority will be rendered resectable by neoadjuvant CRT and will have an opportunity for long-term survival. We specifically do not use the term downstage, because the shrinkage or sterilization of the primary tumor may not affect its propensity for metastasis but may merely improve its technical resectability.

At MDACC, a grading system for pancreatic cancer histological response to CRT was modified from one developed for other malignancies.^14–16 This system is based on the percentage of tumor cell destruction. Most patients in their series (60%) had <50% tumor destruction. A trend toward improved survival was seen in patients with >50% tumor destruction as compared with patients who had <50% destruction.¹⁶ Rather than estimating tumor destruction, we estimated the extent of the tumor mass occupied by residual viable tumor cells, as opposed to fibrosis or necrotic tumor cells. This subtle difference may be important for pancreatic cancers, in which significant fibrosis may be present both before and after CRT.

Residual tumor load was found to be an independent negative prognostic factor, and patients with only moderate or smaller residual tumor loads had an apparent survival advantage of >1 year compared with patients who had large residual tumor loads. Complete histological responses were uncommon; they occurred in only four patients (6%), and this precluded any meaningful statistical analysis of this specific subgroup. However, it is clear that patients with a complete response of their primary tumor can still harbor distant metastatic disease, because two of the four complete responders experienced recurrence. This is disappointing but not surprising, because currently used systemic therapies (5-fluorouracil and gemcitabine) are not very effective against metastatic disease.¹⁸ The high rate of distant progression (20%) on restaging CT after preoperative CRT underscores this fact.¹¹ The predominant role of chemotherapy in neoadjuvant protocols is as a radiation sensitizer for the primary tumor and regional lymph nodes.

We hoped to further refine the evaluation of histological response by specifically considering the degree of tumor fibrosis and tumor necrosis. Such a large percentage of specimens had extensive fibrosis (74%) that this was not found to be a useful variable. Furthermore, the significance of this factor may have been obscured by the impossibility of distinguishing between baseline and CRT-induced fibrosis. Tumor necrosis was, surprisingly, a strong and independent negative prognostic factor; patients without necrosis had a greater than 2-fold longer median survival than patients with necrosis. The best explanation for these findings may be that tumor necrosis in response to CRT is a surrogate marker for rapid tumor cell division and aggressive biology, similar to tumor differentiation. Another possibility is that—if necrosis precedes fibrosis—necrosis may be a marker for a relatively early or incomplete treatment effect, whereas the absence of necrosis may simply reflect the completion of the necrosis phase of this dynamic process.

We attempted to learn more about the nature of tumor cells that survive neoadjuvant CRT by examining expression of two relevant proteins: p53 and EGFR. p53 is a tumor suppressor that is critical for radiation sensitivity. Loss of wild-type p53 and the resultant overexpression of mutant p53 is common in pancreatic cancers and has been associated with radiation resistance and, inconsistently, with worse prognosis.^19–21 p53 overexpression was present in more than half of the treated, resected tumors in this series and was significantly more prevalent in specimens with large residual tumor loads. p53 overexpression was not, however, associated with worse prognosis. EGFR is a receptor tyrosine kinase that is an important regulator of cell growth and differentiation. Overexpression of EGFR is also common in pancreatic cancers and correlates with a worse clinical outcome.²²²³ Overexpression of EGFR was present in only two specimens. These findings raise more questions than they answer. Are p53-overexpressing cells more resistant to radiation? Are EGFR-over-expressing cells easier to kill, or is the prevalence of EGFR overexpression actually lower than expected in this selected population? The ability to compare pre-CRT tumor with post-CRT tumor might clarify these issues, but pre-CRT tumor tissue is not routinely available for immunohistochemical analysis, because histological diagnosis is usually made by fine-needle aspiration. The concept of using pre-CRT tumor to prospectively identify who will or will not respond to neoadjuvant CRT is intriguing, but the analysis of post-CRT specimens may be equally important to better focus our efforts on killing the cells that survive CRT.

To really affect this disease, better systemic therapies are needed to eradicate microscopic distant disease and improve radiosensitivity. Information gained from the analysis of tumor tissue before and after CRT may eventually help to identify new agents or select appropriate agents. Meanwhile, we believe that there are strong theoretical advantages to the neoadjuvant approach over the standard approach of surgery followed by adjuvant therapy. The presence of a positive association between a histological response to neoadjuvant CRT and survival—no matter how strong—cannot be considered proof that neo-adjuvant CRT is beneficial. A histological response to neoadjuvant CRT—as measured by residual tumor load—may simply be a marker for favorable tumor biology. However, in addition to providing additional prognostic information, the histological response may serve as a surrogate marker for treatment efficacy, which will be helpful in the evaluation of new therapeutic strategies.

Received for publication March 31, 2004. Accepted for publication November 15, 2004.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by White, R. R. Articles by Tyler, D. S. Search for Related Content PubMed PubMed Citation Articles by White, R. R. Articles by Tyler, D. S.