Early experience with intraoperative radiotherapy in patients with resected pancreatic adenocarcinoma

The American Journal of Surgery 195 (2008) 308 –312

The Midwest Surgical Association

Early experience with intraoperative radiotherapy in patients with resected pancreatic adenocarcinoma Craig Messick, M.D.a, Jeffrey M. Hardacre, M.D.a,*, Michael F. McGee, M.D.a, Christopher T. Siegel, M.D., Ph.D.a, Thomas A. Stellato, M.D.a, Juan R. Sanabria, M.D.a, Timothy J. Kinsella, M.D.b, James A. Schulak, M.D.a a

Department of Surgery, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH 44106-5047, USA b Department of Radiation Oncology, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA Manuscript received December 13, 2007; revised manuscript December 13, 2007

Abstract Background: The use of intraoperative radiotherapy (IORT) in patients with resected pancreatic adenocarcinoma has not been clearly defined. Methods: The medical records of our first 22 patients receiving IORT for resected pancreatic adenocarcinoma (2001 to 2006) were reviewed and compared with the records of 27 consecutive patients not receiving IORT for resected pancreatic adenocarcinoma (2004 to 2006). Results: There were no 30-day mortalities in either group, and complication rates were similar. Local recurrence occurred in 18% in the IORT group (median 14 months) and 12% in the no-IORT group (median 7 months). Distant recurrence occurred in 47% in the IORT group (median 11 months) and 32% in the no-IORT group (median 6.5 months). Median overall, stage-specific, and location-specific survival did not differ between the groups. Conclusions: Although limited in size and follow-up, our experience showed that complications, recurrence, and survival were not affected by IORT, but time to recurrence may be longer with IORT. © 2008 Elsevier Inc. All rights reserved. Keywords: Intraoperative radiotherapy; Pancreatic cancer

Pancreatic cancer is the fourth leading cause of cancer death in the United States, with approximately 37,000 deaths annually [1]. Despite advances in the surgical management and adjuvant treatment of patients with pancreatic cancer, median and long-term survival rates have not significantly improved during the last 30 years [2– 4]. In an attempt to improve outcomes in the multimodality management of patients with resected pancreatic cancer, intraoperative radiotherapy (IORT) has been employed by a number of institutions. The rationale for the use of IORT is that the high dose of radiotherapy focused on the resection bed will minimize complications associated with externalbeam radiation therapy (EBRT), improve local control, and ultimately improve survival. To date, reported experiences * Corresponding author. Tel.: ⫹1-216-844-7047; fax: ⫹1-216-8442888. E-mail address: [email protected] 0002-9610/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjsurg.2007.12.024

with IORT suggest that its use is not associated with increased overall survival [5– 8]; however, some reports suggest an improvement in local control [9 –13]. The goal of this study was to review our initial experience with IORT in patients with resected pancreatic cancer. Methods The institutional review board of the University Hospitals Case Medical Center approved this study. The medical records of our first 22 patients receiving IORT for resected pancreatic adenocarcinoma (2001 to 2006) were reviewed. The use of IORT was based on surgeon preference in consultation with radiation oncology specialists. Comparisons were made with the records of 27 consecutive patients who underwent resection without IORT (2004 to 2006). IORT was administered in a dedicated operating room using a mobile linear accelerator (Mobetron; Intraop Medical, Sunnyvale, California). Treatment was delivered after re-

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309

Table 3 Adjuvant treatment

Table 1 Operative data Operative data

No IORT

IORT

P

Adjuvant treatment

NO IORT

IORT

Whipple (%) Distal (%) Total (%) Estimated blood loss in mL (mean ⫾ SEM) Median units transfused Operative time in min (mean ⫾ SEM)

18/27 (67) 3/27 (11) 6/27 (22)

13/22 (59) 7/22 (32) 2/22 (9)

NS NS NS

696 ⫾ 99 0 405 ⫾ 24

1159 ⫾ 203 0 474 ⫾ 27

.049 NS .06

Chemotherapy (%) EBRT 5-Fluorouracil Gemcitabine Docetaxel Erlotinib Oxaliplatin Median IORT dose (cGy) Median EBRT dose (cGy)

16/25 (64) 16/25 (64) 13/16 (82) 12/16 (75) 1/16 (6) 3/16 (19) 1/16 (6) None 6300

15/17 (88) 13/17 (76) 14/15 (93) 9/15 (60) 1/15 (7) 2/15 (13) None 1200 6300

section but before reconstruction and excluded the pancreatic remnant. The median dose delivered was 1200 cGy (range 1000 to 1200). Postsurgical adjuvant chemotherapy and/or radiotherapy were administered based on patient and oncologist preference. Clinical, pathologic, and outcome data were gathered and analyzed. Local (resection bed) and distant (liver, peritoneum, or other site) recurrences were identified by a change in serial cross-sectional imaging or by biopsy. Statistical analysis was performed using the chi-square test for categoric variables and Student t test for continuous variables. Survival analysis was performed using Kaplan-Meier method, and differences were determined by log-rank test [14]. Significance was defined as P ⬍ .05. Results Mean age of the 27 patients in the no-IORT group was 71 years, and that of the 22 patients in the IORT group was 63 years (P ⫽ .012). Fifty-two percent of the patients in the no-IORT group were female, whereas 41% in the IORT group were female (P ⫽ not significant [NS]). Surgical data are listed in Table 1. There were no differences in type of resections performed between groups. Estimated blood loss was significantly greater in the IORT group, and surgical time tended to be longer in the IORT group. There were no 30-day deaths in either group. Thirtyseven percent of patients in the no-IORT group and 50% of patients in the IORT group suffered at least 1 complication (P ⫽ NS). There were no significant differences in delayed gastric emptying (4.2 % vs 6.7%; P ⫽ NS), wound infection (22% vs 4.5%; P ⫽ .06), or pancreatic fistula (4.8% vs 10%, P ⫽ NS) in the no-IORT versus the IORT group. Median length of stay did not differ between groups (8 vs 8.5 days; P ⫽ NS). Table 2 Pathology Pathology

No IORT

IORT

P

Tumor size in cm (mean ⫾ SEM) Poorly differentiated (%) Margin positive (%) Node positive (%) Nodes harvested (mean ⫾ SEM) Positive nodes (mean ⫾ SEM) Stage 2b (%)

5.3 ⫾ .7 12/24 (50) 20/27 (74) 21/27 (78) 24 ⫾ 3 6⫾2 20/27 (74)

5.2 ⫾ .5 5/21 (24) 16/22 (73) 21/22 (95) 28 ⫾ 3 6⫾1 21/22 (95)

NS .06 NS .06 NS NS .03

Pathology data are listed in Table 2. Mean tumor size in both groups was ⬎5 cm. Tumors in the no-IORT group tended to be more poorly differentiated than those in the IORT group. The node-positivity rate tended to be higher in the IORT group. Tumors in a significantly greater percentage of patients in the IORT group were stage 2b. Data regarding adjuvant treatment are listed in Table 3. A similar number of patients in both groups received adjuvant chemotherapy and adjuvant EBRT. Furthermore, patients in both groups received similar types of adjuvant chemotherapy. Recurrence and survival data are listed in Table 4. There were no differences in the rates of local or distant recurrence between those patients who did and did not receive IORT. However, the time to both local and distant recurrence tended to be longer in the IORT group. There were no differences in median overall, stage-specific, or locationspecific survival (Table 4 and Fig. 1). Comments IORT was introduced by Beck [15] in 1907 but was popularized in the early 1970s when Abe in began using the therapy in Japan for select patients with advanced intraabdominal malignancy [16]. The goal of IORT is to deliver a high dose of radiation therapy to a localized target, sparing surrounding normal tissue from the risk of incurring the side effects of radiation. It is hoped that IORT will improve local tumor control and translate into improved patient survival.

Table 4 Recurrence and survival Recurrence and survival

No IORT

IORT

Available for follow-up Median follow-up in mo (range) Local recurrence (%) Time to local recurrence in mo (median) Distant recurrence (%) Time to distant recurrence in mo (median) Median overall survival (mo) Median stage 2b survival (mo) Whipple median survival (mo) Distal median survival (mo)

25 13.3 (3–36) 3/25 (12)

17 10.1 (1–36) 3/17 (18)

1.5–8 (7) 8/25 (32)

6–24 (14) 8/17 (47)

1.5–13 (6.5) 20 19.7 20 15.3

6–24 (11) 13 13 13 18

P

NS NS NS NS

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C. Messick et al. / The American Journal of Surgery 195 (2008) 308 –312

A 1.0 0.9 0.8 Proportion Surviving

0.7 0.6

No IORT

0.5 0.4 0.3 0.2

IORT

0.1 0.0 0

5

10

15

20

25

30

35

Survival (months)

B 1.0 0.9 0.8 Proportion Surviving

0.7 0.6 0.5

No IORT

0.4 0.3

IORT

0.2 0.1 0.0 0

5

10

15

20

25

30

35

Survival (months)

Fig. 1. (A) Overall survival. (B) Stage-specific (2b) survival.

For pancreatic cancer, IORT was initially used in the treatment of patients with unresectable disease at the time of exploration and, ultimately, biliary and/or duodenal bypass. Tepper et al obtained a mean survival of 9 months with IORT in patients with unresectable pancreatic cancer [17]. Schuricht et al published 1- and 2-year survival rates of 60% and 17%, respectively, in this setting [18]. Willett et al showed median survival of 13 months and 3-year survival of 7% [4]. IORT has also been used in the setting of patients with resected pancreatic cancer [2,5–11,19 –21]. The treatment is delivered after resection but before reconstruction, and the pancreatic remnant is usually excluded because there have been reports of serious anastomotic complications when the pancreatic remnant is radiated [22,23]. Included in the radiation field is the retroperitoneal, or uncinate, margin along the superior mesenteric artery because that margin is the most difficult to clear surgically [2,12,13]. Existing literature regarding the use of IORT for patients with resected pancreatic cancer reports median survival rates of 14 to 19 months. Pisters et al [19] reported median survival of 19 months in patients who received neoadjuvant chemoradiation therapy before resection and IORT. Reni et al [10] showed improved median survival with IORT at 18.5 months compared with 13 months in their no-IORT group. Schwarz et al [20] published median survival of 14

months in patients receiving IORT. Local and distant recurrence rates in these and other studies vary from 12% to 50% and 42% to 94%, respectively, with the use of IORT [10,11, 19,20]. None of these data are from randomized, controlled studies. Our institution started using IORT in patients with resected pancreatic cancer in 2001. It has not been used routinely, but rather selectively, at the discretion of the surgeon and the radiation oncologist. The three busiest surgeons (43 of 49 cases in this study) used IORT in 88%, 30%, and 0%, respectively, of their cases. This may explain the discrepancy between the IORT and no-IORT groups in terms of patient age. IORT patients were younger, and this therapy may have been employed when the surgeon wanted to be more aggressive or was more worried about surgical margins based on preoperative imaging. The idea that surgery may be more difficult based on preoperative imaging and thus IORT chosen may also explain why the patients in the IORT group had greater blood loss than those in the no-ORT group. Understandably, surgical times tended to be longer in the IORT group by just ⬎1 hour. Despite longer operations and greater blood loss, there were no differences in transfusion requirement, length of stay, mortality, or morbidity between the IORT and noIORT groups. It is not clear why there tended to be a greater wound infection rate in the no-IORT group. In a series of randomized clinical trials at the National Cancer Institute that studied IORT in patients with pancreatic cancer, gastric cancer, and retroperitoneal sarcoma, there were no differences in acute (⬍30 days) or late complications, with the exception of peripheral neuropathy in patients receiving an IORT dose ⬎1500 cGy [24,25]. The patients in both groups in our study had advanced tumors. The mean tumor size was just ⬎5 cm in each group. The patients in the no-IORT group had tumors that tended to be more poorly differentiated than those in the IORT group, but the patients in the no-IORT group tended to have a lower node-positivity rate. Adequate resections were performed in both groups, with 24 nodes harvested in the no-IORT group and 28 harvested in the IORT group. Data are emerging showing that at least 6 nodes, and some studies suggest at least 10 nodes, should be harvested in pancreaticoduodenectomy specimens for appropriate staging [26,27]. Margin-positivity rates were the same in both groups at 73% to 74%, but they were higher than in most published series, where rates range from 19% to 51% [2,3,28]. This may explained by our pathologists calling a margin positive if the is tumor was ⱕ1 mm from an inked margin. Further, our pathologists not only comment on bile duct, duodenal and gastric, pancreatic neck, portal and superior mesenteric vein, and retroperitoneal margins, they also comment on anterior and posterior radial margins. If any of these margins are positive by the definition described previously, the resection is considered margin positive. If the anterior and posterior radial margins were excluded and presence of tumor at the inked margin required to call the margin positive, our margin positivity rates would have been 41% in the IORT group and 33% in the no-IORT group. Other than IORT, the use of adjuvant treatment was similar in both groups. In general, most patients received

C. Messick et al. / The American Journal of Surgery 195 (2008) 308 –312

adjuvant 5-fluorouracil-based chemotherapy with high-dose EBRT based on previous studies [2,29,30]. Gemcitabine was administered at the discretion of the medical oncologists. In general, early in the study period, it was administered after a documented recurrence, but later it was administered after the completion of the 5-fluoruracil-based chemoradiotherapy. Other agents were used at the discretion of the medical oncologist and generally after the development of metastatic disease. Recurrence rates in our study compare favorably to those in the literature, both with and without the use of IORT. With IORT, local recurrence rates of 12% to 50% have been published, and without IORT, local recurrence rates of 40% to 56% have been documented. Distant recurrence with IORT varies from 60% to 90%, and without IORT, the range is 42% to 67% [2,10,11,20,21,30]. Our local recurrence rate was 18% in the IORT group and 12% in the no-IORT group. Distant recurrence was documented in 47% of patients in the IORT group and 32% patients in the no-IORT group. Although the rates of local and distant recurrence between the IORT and no-IORT groups were not different, time to recurrence tended to be longer in the IORT group, possibly suggesting a benefit of the therapy. Median overall, stage- (2b), and location-specific survival did not differ between the IORT and no-IORT groups. Our survival data are comparable with those in the literature, where median survival between 14 and 19 months is documented [2–11,17–21,28,30]. Although not statistically significant, median overall and stage-specific survival differences between the IORT (13 months) and no-IORT (20 months) groups seem clinically significant. Our study was limited by a number of factors. Its small sample size limits its statistical utility. Further, it was retrospective in nature and hampered by the various types of bias introduced by such studies, particularly selection bias. Nonetheless, our data demonstrate that IORT may be used safely in the treatment of patients with resected pancreatic cancer. Furthermore, we believe that with the development of better systemic agents to treat micrometastases, IORT could play a key role, along with sound surgical techniques, to obtain local control and improve patient outcomes. However, randomized studies that control for surgical technique and postsurgical adjuvant therapy are clearly needed to determine whether the use of IORT in patients with pancreatic cancer is warranted.

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Discussion Kevin Staveley O’Carroll, M.D. (Happy Valley, PA): Most of the studies looking at IORT to date are small and retrospective and have a bias associated with nonrandomization like yours. For that reason, we have had difficulty sorting out the benefits of IORT. Certainly, your study shows that IORT can be used safely. I would like to ask you a couple questions about a number of interesting things in your data. What is your interpretation of your 75% R-1 resection rate? Craig Messick, M.D.: Our pathologists consider margin-positive patients to include those with invasive cancer ⱕ1 mm of the inked margin. In addition to commenting on the standard surgical margins in patients with resected pancreatic cancer, ie, the gastric and duodenal, common bile duct, pancreatic, neck, uncinate, and portal vein margins, our pathologists also comment on the anterior and posterior radial margins, which potentially may have affected our margin-positivity rate. Kevin Staveley O’Carroll, M.D.: Your pathologists are diligent, and they take the time to count many nodes as well. I was impressed with the amount of nodes that were taken with these specimens. Were many of these procedures extended lymphadenectomies? Craig Messick, M.D.: All of the patients underwent standard lymphadenectomy. No aggressive dissection was attempted. Data from Johns Hopkins and the Mayo Clinic show that aggressive or extensive lymphadenectomy has no impact on overall survival, so we performed standard resection. Kevin Staveley O’Carroll, M.D.: When we use radiation neoadjuvantly, I am more inclined to do a vein resection, and many of my colleagues tell me the same thing. Were many vein resections done in this study with IORT? Craig Messick, M.D.: Fewer than 5 patients underwent vein resection in the IORT group. We experienced no complications with vein resection in that subset of patients. Some large animal studies have looked statistically at animals that received vein resection or alteration followed by radiation therapy. The animal studies showed that they could tolerate doses up to 30 cGy. Gerard V. Aranha, M.D. (Maywood, IL): Dr. Messick, I thought IORT was nearly extinct, and now I see that your

group is making a valid effort to resuscitate this modality of treatment. Given that 50% of patients in your no-IORT group had differentiated carcinoma, would that explain why the patients in your IORT group fared better? Craig Messick, M.D.: It is difficult for me to say whether or not the percentage of patients who had poorly differentiated tumors actually made a difference in survival. In looking back at all the contributing variables that these patients had, I do not think that the data regarding the degree of advanced or pathologic disease has much with to do with patient outcome. Tumor size in these patients was very large. Mean blood loss and surgical time were also contributing factors. I do not know if what we currently have to treat pancreatic cancer patients is enough to prolong their survival. It is a grim disease at diagnosis, and the median survival rate is 14 to 19 months. I do not think that histologic grade of the pancreatic cancer has that much of an impact. A diagnosis of adenocarcinoma in and of itself is a morbid diagnosis. Norman C. Estes, M.D. (Peoria, IL): How much of a dose can you give intraoperatively? I have done this at 2 institutions. We used to take patients down the hall in Indiana. We had a dedicated room in Kansas, and at both institutions, we have pretty well stopped administering IORT. Part of the problem was the amount of dose you can give. A technique is now being developed whereby a single dose delivers 500 cGy. It is what I call a “long run for a short slide.” Craig Messick, M.D.: In reviewing the literature, in terms of what normal tissue can tolerate, 500 cGy is on the lower side of what can be administered. Increasing the intraoperative dosage could potentially make a difference, but no studies with higher doses showed any difference in overall mortality. Local recurrence rates are about the same. We were trying to use a lower dose, to minimize any side effects from the radiation therapy, but administer the same amount of radiation in terms of local control in these patients. I definitely agree that we could have probably have gone up on the dosage. As we push forward with this and draw the line in terms of whether or not IORT is warranted, at higher doses it could potentially provide a benefit in this patient population.