As displayed in , the median age at diagnosis was 67 with a range from 45–82 for the 18 patients involved in this retrospective analysis. All patients began with an ECOG Performance Status ≤ 1 prior to starting therapy. Twelve of the patients were male and 6 were female. Seventy-two percent of the masses (n=13) involved the pancreatic head, 11.1% (n=2) were located in the body, and 16.7% (n=3) involved the body/tail. A pretreatment CT was performed in all 18 patients, while 14 of the patients underwent an EUS as well. Mean mass size by CT was 3.4 cm (n=17) and 3.3 cm by EUS (n=14). The median number of administered cycles of GTX was 3 in our retrospective analysis. Thirteen patients received 3 cycles, one was given 4 cycles, and four received 2 cycles. Median time from the date of diagnosis to start of chemotherapy was 18 days. The median IMRT dose was 5000cGy. Thirteen patients received 5000cGy, three were given 4500cGy, and one received 5200cGy. One patient did not receive IMRT because of disease progression while receiving induction chemotherapy, thus only 17 patients finished the complete neoadjuvant regimen.
Characteristics of the 18 Borderline Resectable Pancreatic Cancer Patients
Sites of vascular abutment that defined the diagnosis of borderline resectable disease are illustrated in . Abutment could be assessed in 15 of the 18 patients by CT and in 10 of the 14 patients who had an EUS. The majority of the borderline resectable cases consisted of portal vein (PV) and superior mesenteric vein (SMV) abutment. Utilizing CT, 22% of the cases displayed abutment with the PV, 28% with the SMV, and 17% with the PV/SMV confluence. EUS suggested that 29% of the cases had abutment with the PV, 21% with the SMV, and 14% with the PV/SMV confluence. Three patients were not found to have vessel abutment by the initial CT and EUS, but abutment was seen when taken for immediate resection. Surgery was aborted in these 3 cases and they were then diagnosed as having borderline resectable disease.
Tumor Vascular Abutment by CT vs. EUS
Pretreatment CA19-9 levels and PET SUV are displayed in . The median CA 19-9 level (n=18) prior to treatment was 483. The median pretreatment max SUV for the 15 patients who had a PET scan was 5.7.
Biochemical and Imaging Characteristics before and after Neoadjuvant Therapy
Response to Neoadjuvant Therapy
CA 19-9, CT mass size, and PET SUV significantly decreased after neoadjuvant therapy (). Sixteen patients had both pre and post-therapy CA 19-9 levels checked. Median CA 19-9 decreased from 483 to 50 (p<0.01), representing a median 83% decrease. Eight out of the 16 patients had a >85% decrease in CA 19-9 levels. Fourteen patients had both pre and post-therapy PET scans. Median PET max SUV decreased from 5.7 to 1.6 (p<0.001). Seven of the 14 patients (50%) had a 100% decrease in PET SUV. Graphical representations of the significant change in CA 19-9 levels and PET SUV after neoadjuvant therapy are illustrated in and for each patient who had pre and post CA 19-9 levels and PET scans. Median CT mass size decreased from 3.35 to 2.70cm after neoadjuvant therapy (p=0.002).
Percent change in CA 19-9 level after neoadjuvant therapy for each of the 16 patients who had pre and post CA 19-9 levels drawn. Eight patients had >85% decrease in their CA 19-9 levels.
Percent change in PET SUV after neoadjuvant therapy for each of the 14 patients who had pre and post PET scans performed. Seven patients had a complete loss of PET avidity.
displays the surgical outcomes after neoadjuvant therapy. Seventeen out of the 18 patients from the database finished neoadjuvant therapy. One patient progressed while receiving induction chemotherapy, so neoadjuvant therapy was not completed. Following a discussion at our GI Tumor Board, 14 out of the 17 patients (82%) who completed neoadjuvant therapy met radiologic evidence for resectability based on NCCN guidelines and were subsequently brought to surgery. Of these 14 patients who went to surgery, pancreatic mass resections were performed in 9 cases (64%). Two of the cases involved reconstruction of the PV/SMV. Pancreatic disease could not be resected in 5 patients at exploration due to unexpected encasement of the SMA/SMV in 2 cases, encasement of the SMA/SMV/PV in 1 case, mesenteric disease and SMV encasement in 1 case, and peritoneal metastases in another case that were not found on the post-neoadjuvant scans. From the 9 patients who were able to undergo resections, an R0 resection was achieved in 8 of these cases (89%). Overall, 8 out of the 17 patients (47%) who finished our neoadjuvant protocol achieved an R0 resection. By ITT analysis, 8 of 18 borderline resectable patients underwent a successful Whipple procedure with negative margins. The common bile duct, proximal gastric, pancreatic, retroperitoneal, and duodenal margins were examined for each resection. Of the 8 R0 resection specimens, the pathologist noted that 7 displayed minimally residual disease that was consistent with significant treatment effect. The other specimen did not reveal any carcinoma and was completely fibrotic. The median time from the initiation of neoadjuvant therapy to the date of surgery was 5.82 months.
Surgical Outcomes for Patients who Finished Neoadjuvant Therapy
Survival analysis is not complete as 6 out of the 18 patients are still alive. Three of these 6 patients are without evidence of disease. Of the initial 18 patients, one patient progressed to develop liver metastases during induction chemotherapy and could not finish neoadjuvant therapy. Nine other patients progressed after neoadjuvant therapy. However, only 3 of these patients progressed after resection. Progression involved development of liver metastases (n=1), peritoneal metastases (n=1), lung metastases (n=2), malignant ascites/growth of tumor (n=1), increased lymphadenopathy/growth of tumor (n=1), vascular encasement (n=1), and significantly worsening CA 19-9 levels/symptoms (n=2). Kaplan-Meier curves for progression-free survival and overall survival are illustrated in . Median progression-free survival was 10.48 months (95% CI: 6.01–14.55) and median overall survival was 15.64 months (95% CI: 14.49–23.92); however, 6 patients are still alive. Median follow-up time for the 6 patients who are still alive was 13.27 months.
Kaplan-Meier curves for progression-free survival and overall survival for the 18 borderline resectable pancreatic cancer patients. Median OS was 15.64 mo and the median PFS was 10.48 mo. Six patients are still alive (censored).
Toxicities and Complications
The toxicities related to neoadjuvant therapy did not prevent any of the patients from completing treatment or cause any subsequent surgical morbidity. Significant temporary toxicities related to treatment consisted of hand-foot syndrome (n=7), mucositis (n=8), abdominal pain (n=1), diarrhea (n=3), febrile neutropenia (n=1), and thrombocytopenia (n=3). Post-operative complications included a pulmonary embolism (n=1), wound infection (n=1), seizures (n=1), and acute renal failure (n=1). There were no deaths from neoadjuvant therapy or surgery. All patients who were admitted for surgery were discharged home.
Correlation between Diagnostic Modalities
The mean mass size determined by CT did not differ when compared to that measured by EUS. Primary tumor size as measured by EUS was significantly correlated with the size measured by CT scan. The Concordance correlation coefficient was 0.85 for patients who had both CT and EUS (n=13, 95% CI: 0.596–0.950), consistent with statistical agreement. As shown in , CT and EUS agreed upon the extent of vascular involvement in 12 out of the 14 patients (86%) who had both pretreatment CT and EUS assessments (p=0.02 Chi-square test). Statistical reproducibility was demonstrated by a Kappa index of 0.59 (95% CI: 0.1–1.0).
Vessel Abutment Agreement by CT and EUS for Patients who had Both Studies
When investigating for a possible association between CA 19-9 and CT mass size, the Pearson correlation coefficient (r) was found to be −0.084. Therefore, CA19-9 was not correlated with tumor size as measured by CT scan (p = 0.75). Less than 1% of the variability in CA19-9 could be explained by the variability in size by CT scan as indicated by r2 = 0.0071.
When evaluating for a possible association between PET SUV and CT mass size, the Pearson correlation coefficient (r) was found to be 0.38. Thus, SUV max was not significantly correlated with tumor size as measured by CT scan (p = 0.18). Only 15% of the variability in SUV max could be explained by the variability in size by CT scan as indicated by r2 = 0.1475.