Cytoreductive surgery combined with intraoperative chemo ...

J Hepatobiliary Pancreat Surg (2001) 8:564–570

Cytoreductive surgery combined with intraoperative chemohyperthermia and postoperative radiotherapy in the management of advanced pancreatic adenocarcinoma: feasibility aspects and efficacy Vassilios E. Kouloulias1,2, Konstantina S. Nikita2,3, John R. Kouvaris1, Nikolaos K. Uzunoglu2, Vassilios C. Golematis3, Costas G. Papavasiliou1, and Lambros J. Vlahos1 1

Department of Radiotherapy, Medical School, University of Athens, Aretaieion Hospital, Athens, Greece Institute of Computer and Communication Systems, Department of Electrical and Computer Engineering, National Technical University of Athens, 9 Iroon Polytechniou Street, Zografos 15773, Athens, Greece 3 First Department of Propaedeutic Surgery, Medical School, University of Athens, Hippocration Hospital, Athens, Greece 2

Abstract Background/Purpose. The aim of our study was to evaluate the feasibility and the efficacy of cytoreductive surgery (CS) with intraoperative chemo-hyperthermia in the management of advanced stage IVA (T4N0M0) pancreatic cancer. Methods. From August 1995 through March 1996, seven patients with unresectable adenocarcinoma of the pancreas underwent CS, with preoperative chemotherapy (5-fluorouracil [FU] for 96 h), plus 45-Gy external beam postoperative irradiation with a 6-MeV linear accelerator (1.8 Gy per fraction, 5 days per week). A single session of intraoperative hyperthermia was performed with a waveguide-type applicator operating at 433 MHz, and temperature was measured by inserting a flexiguide needle catheter carrying a thermometry probe with three measuring points into the tumor. The tumor region was heated to 43°C–45°C for up to 60 min, while 5-FU 500 mg was injected simultaneously through the gastroduodenal artery into the splenic artery (intraoperative regional chemotherapy). Results. Postoperative recovery was uneventful for all patients. After the combined treatment, there was a significant decrease in the values of both serum carcinoembryonic antigen (CEA; P ⫽ 0.017, Wilcoxon test) and carbohydrate antigen (CA)19-9 (P ⫽ 0.016; Wilcoxon test), from 7.6 ⫾ 1.5 ng/ml CEA and 869.6 ⫾ 126.9 U/ml CA to 3.5 ⫾ 0.8 ng/ml CEA and 104.7 ⫾ 35.4 U/ml CA19-9. Moreover, there was a significant improvement (P ⫽ 0.016; Wilcoxon test) in Eastern Cooperative Oncology Group performance status, pain score, and body mass index. The median overall survival was 18.5 (SE, 1.8) months. Conclusions. Our preliminary clinical results suggest the tolerability and the considerable potential advantage of using cytoreductive resection with preoperative chemotherapy, intraoperative chemo-hyperthermia, and external beam postoperative radiotherapy for the management of advanced adenocarcinoma of the pancreas.

Offprint requests to: V. Kouloulias Received: May 11, 2001 / Accepted: September 26, 2001

Key words Pancreatic cancer · Cytoreductive surgery · Intraoperative chemo-hyperthermia · Radiotherapy

Introduction Pancreatic cancer is the most common cancer of the major digestive glands. Unfortunately, this cancer is invariably diagnosed when it is advanced because of the lack of specific symptoms or signs. Over the last decade the outlook for adenocarcinoma of the pancreas in terms of curative modalities has remained more or less dismal, in spite of the continuous efforts of surgeons, medical oncologists, and radiotherapists. Approximately 40% of patients with pancreatic carcinoma will be explored and undergo some type of palliative bypass procedure, and only 15% will be resected for cure.1 Palliative surgery does not affect survival and does little to ameliorate the pain and cachexia frequently associated with this disease.2,3 However, surgical reduction of the tumor burden (cytoreduction) in unresectable pancreatic carcinoma has been proposed, aimed at improving the clinical condition and survival of these patients.4,5 Radiotherapy has been widely used in patients with advanced pancreatic carcinoma, showing better local control than other modalities, but with no clear evidence of any impact on survival.6 Even with intraoperative radiotherapy, the results mainly showed relief of pain, without any evidence of tumor regression or benefit in terms of overall survival.7 New agents and new therapeutic modalities have been employed to improve therapy for this disease. Preclinical studies have focused on the anticancer effects of somatostatin analogues, especially in pancreatic carcinomas.8,9 However, regardless of the surgical procedure, the radiation therapy technique, the type of chemotherapy and hormonal therapy, or the combinations thereof, the survival of pancreatic cancer patients remains low, with the

V.E. Kouloulias et al.: CS with IO chemo-hyperthermia and postoperative RT for advanced pancreatic carcinoma

major problem that of the local control of disease.10 Local intraoperative hyperthermia (IOHT) has already been used, with promising results, without systemic toxicity.11–13 In the present approach, we chose 5-fluorouracil (5FU) in combination with IOHT; the synergistic role of this antimetabolite with hyperthermia has already been reported.14 The aim of this study was to evaluate the feasibility and the efficacy of cytoreductive surgery (CS) with intraoperative chemo-hyperthermia in the management of advanced-stage (IVA) pancreatic cancer.

Methods Patients and methods From August 1995 through March 1996, seven patients with unresectable adenocarcinoma of the pancreas received preoperative chemotherapy with 5-FU, and surgery plus IOHT, combined with intraoperative chemotherapy, at the Hippocration Hospital, First Department of Propaedeutic Surgery of the Medical School of the University of Athens. Preoperative chemotherapy was administered with an intravenous injection of 5-FU 1g for 96h, starting 96 h before surgery. As adjuvant treatment, the patients received 45-Gy external beam postoperative irradiation, with a 6-MeV linear accelerator (1.8 Gy per fraction, 25 fractions, 5 days per week), at the Radiotherapy Department of Areteion University Hospital. Radiotherapy was administered with three fields per session (two lateral and one anterior, with the patient in the supine position), encompassing the pancreatic area (plus a 2-cm safety margin) and the regional lymph-nodes. The patient’s ages ranged from 62 to 71 years (median, 65 years) and the male-tofemale ratio was 2 :5. The sizes of the tumors ranged from 2 cm ⫻ 2.5cm ⫻ 2.5cm to 5cm ⫻ 4cm ⫻ 3.5cm. In all patients, the primary malignant neoplasm was adenocarcinoma of the head, body, or tail of pancreas, moderately or poorly differentiated, and the patients were admitted for primary treatment. All of our patients met the following criteria: Eastern Cooperative Oncology Group (ECOG) status, less than 4; WBC, 3500/µl or more, platelets, 100000/µl or more; hemoglobulin, 9.5 g/dl or more, total bilirubin, 2.0mg/dl or less; aspartate transaminase and alanine aminotransferase, less than the upper limit of normal; and serum creatinine concentration, 1.5 mg/dl or less. All patients gave written informed consent before entering the study. Intraoperative chemo-hyperthemia procedure At laparotomy, the resectability of the tumors was further assessed, and peritoneal surfaces, liver, and re-

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gional lymph nodes were examined for evidence of tumor. It was found that some of the tumors had invaded the great vessels (i.e., superior mesenteric artery or portal vein) or neighboring organs, such as the duodenum, bile duct, and peripancreatic tissues (mesenteric fat, mesocolon, greater and lesser omentum) and could not be totally excised. These tumors were carefully debulked with a thin diathermic incisor, and limited resection of the pancreatic parenchyma and macroscopic reduction (as much as possible) of the gross tumor mass invading the surrounding tissues was performed. Our aim was to reduce the tumor burden in the patient’s body as much as possible. One patient had a tumor (2cm ⫻ 2.5cm ⫻ 2.5cm) located in the pancreatic head, infiltrating the superior mesenteric and the posterior inferior pancreaticoduodenal arteries. This patient underwent CS with resection of the tumorous tissues, carried out selectively, with careful preparation of the artery trunk and of the duodenal walls. Direct microwave hyperthermia was applied to surgically exposed residual tissue, with the tumor residual mass and excision margins constituting the region of interest (ROI). The ROI was isolated carefully, i.e., the stomach and transverse colon were carefully retracted to protect them from thermal injury. Intraoperative hyperthermia was performed with direct-contact waveguide applicators. Applicators operating at 433MHz used for treating superficial tumors15 were appropriately modified to achieve conformity with the surgical opening and the size of the regions to be treated. The waveguide applicator to be used was covered with sterilized nylon, and its radiating aperture was placed in direct contact with the surface of the region to be heated. During each hyperthermia session, special care was taken, due to the presence of important vessels (i.e., superior mesenteric and splenic arteries) in the ROI. Temperature was measured during the entire hyperthermia session with a 15-gauge flexiguide catheter carrying a thermocouple probe inserted into the ROI. The thermocouple probe, with three measuring points along its axis at 0.8-cm intervals, was used to measure temperature at three points along the applicator axis, corresponding to 1 cm, 1.8cm, and 2.6 cm depths from the surface of the ROI. The target tumor temperature was in the region of 43°C–45°C for up to 60 min. Adjustments in emitted microwave power were made during treatment to maintain the monitored temperature within therapeutic limits. According to the literature, parameters associated with local control include average minimal intratumoral temperature.16 For this reason, we decided to convert monitored temperatures to average minimum (Tmin) values. Details of the hyperthermic treatment for each patient are given in Table 1. The chemotherapy drug (5-FU, 500mg) was diluted in 100 ml of normal saline and then infused for a period

The last four columns (right side) represent details of intraoperative hyperthermic treatment (Tmin, average minimum temperature), response to treatment (PR, partial response; SD, stable disease), hepatic metastases-free survival (HMFS), and overall survival (OS) CEA, Carcinoembryonic antigen; CA19-9, carbohydrate antrgen 19-9; BT, status before treatment; PT, status posttreatment; BMI, body mass index a Pain was scored by multiplying the severity of pain (0, no pain; 1, mild; 2, strong; 3, severe) by the frequency of pain (0, never; 1, less than once per day; 2, more than once per day; 3, constant) b ECOG status denotes Eastern Cooperative Oncology Group performance status for patients with cancer (grades 0 through 4) c SH scale, Scott-Huskisson visual analogue pain scale

6 22 34 13 17 8 15 SD PR PR PR PR SD SD 21.5 22.7 23.1 21.1 22.7 21.3 22.6 Male Female Female Female Female Male Female

65 64 63 71 62 68 67

Body-tail Body-tail Head Body Body Tail Tail

9.7 9.5 8.1 6.2 7.3 5.9 6.7

5.1 3.8 3.2 2.9 3.4 3 3.2

980 1010 847 950 898 697 705

170 77 64 124 113 86 99

6 4 4 2 2 4 2

2 0 0 0 0 1 1

3 2 2 2 2 2 2

1 0 0 0 0 1 1

6 3 3 4 4 4 4

2 0 0 0 0 1 1

19.7 19.1 18.7 16.3 17.2 16.2 19.4

42.4 43.4 43.8 43.1 43.3 42.9 43.1

HMFS (months) Response Tmin (°C) PT BT PT BT PT BT PT BT PT BT PT BT Sex

SH scalec

BMI Tumor site Age (years)

ECOG, statusb Pain scorea CA19-9 (U/ml) CEA (ng/ml)

Table 1. Patient characteristics, pain score, performance status, Scott-Huskisson visual analogue pain scale, and body mass index

7 27 35 14 19 9 18


OS (months)

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of 60min during the intraoperative heating. The drug was infused regionally according to tumor location: i.e., through the gastroduodenal entery into the splenic artery for tumors located in the pancreatic body or tail; and into the gastroduodenal artery, no further than the junction of common hepatic and gastroduodenal arteries, for tumors located in the pancreatic head. It is important to note that no change was observed in the patients’ general condition (e.g., pulse rate, blood pressure) during the intraoperative chemo-hypenthermia. Postoperatively, all patients received Sandostatin (octreotide acetate; Novartis), 0.1mg every 6h for 3 days. Postoperative external beam irradiation was administered after the combined surgery and chemohyperthermia, at a median time interval of 33 days. During surgery, specific clips were used to outline the margins of the tumor as an aid for the planning of the subsequent external beam radiation treatment. Endpoints and follow-up Pain was scored in two ways: first, according to the Scott-Huskisson (SH) scale, which is a zero-to-ten visual-analogue scale;17 and second, by multiplying the severity of pain (0, no pain; 1, mild; 2, strong; 3, severe) by the frequency of pain (0, never; 1, less than once per day; 2, more than once per day; 3, constant). The patients’ performance status was evaluated according to the ECOG scale. The body mass index (BMI) was assessed using the formula: BMI ⫽ weight/height2 (kg/m2). The time at the beginning of preoperative chemotherapy was taken as baseline for the measurements for pain-score values, ECOG, status and BMI, while a second measurement for these variables was performed 2 months after the completion of the combined treatment. Serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were also evaluated at diagnosis and 3 months after the end of the combined treatment (last session of radiotherapy). The main endpoint was overall survival (OS), measured from the time of the histologic diagnosis. Hepatic metastases-free survival (HMFS) was also recorded from the time of the histologic diagnosis until the time of radiologic appearance of liver metastases. Follow-up was continuous, with an examination every month after surgery for 6 months, and after this time point every 3 months until death, based on clinical examination and computed tomography (CT) scans. Postoperatively, at a time ranging from 7 to 12 days, a CT scan of the upper abdomen was performed to measure the residual tumor mass after CS; this examination was taken as a baseline measurement for CT scan assessments. At this time point, the residual tumor mass ranged from 0.5cm ⫻ 0.7cm ⫻ 1 cm to 1cm ⫻ 1 cm ⫻ 1cm. Tumor volume response was assessed by reviewing baseline CT scans


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and CT scans done after the end of the combined treatment, and measuring the tumor volume. A radiologic response was defined as partial when there was a 50% or more decrease in tumor volume for a minimum of 4 weeks, with no evidence of new lesions, or a decrease of more than 25% in the lesions already noted. Stable disease was defined as a decrease of less than 25% in the tumor volume. Progressive disease was defined as an increase in the tumor volume by 25% or more, or the development of any new lesions. Toxicity was assessed using WHO toxicity criteria. Statistical analysis Differences between measured variables, before and after the combined treatment i.e., serum CEA, serum CA19-9, ECOG performance status, Scott-Huskisson visual-analogue pain scale, pain-score values, and BMI, were evaluated using the Wilcoxon test.18 The value of the thermal parameter, Tmin, was correlated with OS using the Spearman correlation coefficient.18 Survival was assessed using the Kaplan-Meier method. All analyses were performed using the Statistical Packet for Social Sciences (SPSS version 6.0; SPSS, Chicago, IL, USA).

Results During the operation, the surgical stage for all patients was evaluated as stage IVA (T4N0M0, according to the International Union Against Cancer [UICC] classification). In the perioperative period, no change in hepatic enzymes was observed, and glucose and amylase levels remained within normal limits. Glucose and amylase levels also remained within normal limits throughout the multimodal treatment period. No toxicity was recorded related to any of the treatment modalities. The median length of postoperative hospital stay after CS was 18 days (range, 16–20 days). Four of the seven patients had a partial response, and the remaining three had stable disease. No progressive disease (PD) was noted, and the median OS was 18.5 (SE, 1.8) months, while the median HMFS was 15.3 (SE, 1.7) months. OS and HMFS in terms of Kaplan-Meier distribution are shown in Fig. 1. All patients died of hepatic metastases (1–5 months after the diagnosis of metastases); however, none of them presented with obstruction. There was a significant correlation of OS with Tmin (Spearman-rho ⫽ 0.98; P ⬍ 0.001). After the combined treatment, there was a significant decrease in the values of both serum CEA (P ⫽ 0.017; Wilcoxon test) and CA19-9 (P ⫽ 0.016; Wilcoxon test), from 7.6 ⫽ 1.5 ng/ml CEA and 869.6 ⫾ 126.9U/ml CA19-9 to 3.5 ⫾ 0.8 ng/ml CEA and 104.7 ⫾ 35.4U/ml CA19-9. After the com-

Fig. 1. Overall survival (OS); continuous line and hepatic metastases-free survival (HMFS); dotted line distribution, calculated according to the Kaplan-Meier method. The median OS was 18.5 months (SE, 1.8), while the median HMFS was 15.3 months (SE, 1.7)

bined treatment, there was a significant reduction (P ⫽ 0.016; Wilcoxon test) in the Scott-Huskisson visual analogue pain scale score from 4 (⫾1) to 0.57 (⫾0.78). Moreover, after the combined treatment, there was a significant improvement (P ⫽ 0.016; Wilcoxon test) in the pain score (3.4 ⫾ 1.5 to 0.6 ⫾ 0.8) and ECOG performance status (2.1 ⫾ 0.4 to 0.4 ⫾ 0.5). There was also a significant improvement (P ⫽ 0.016; Wilcoxon test) in the mean BMI value, from 18.08 (⫾1.49) to 22.14 (⫾0.81). Patient characteristics and measured parameters for each patient are shown in Table 1.

Discussion Pancreatic adenocarcinoma continues to be regarded as a neoplasm that rarely yields to palliative efforts, much less to curative ones, regardless of the modality of treatment.10,19 Radiotherapy, as an adjuvant treatment modality alone or in combination with chemotherapy, has already been used in many clinical trials, but with limited effectiveness.6 The potential role of hyperthermia in conjunction with radiotherapy in the treatment of cancer is known.20 Under these circumstances, a place for intraoperative hyperthermia as part of a multimodality treatment appears promising.11,21 Ashayeri et al.12 reported a mean survival of 15.8 months in patients with unresectable pancreatic adenocarcinoma who were treated with simultaneous intraoperative radiotherapy and IOHT. Shibamoto et al.21 reported that, because no effective method for delivering external regional hyper-

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thermia has yet been established, IOHT seems to be the best method of heating a pancreatic tumor adequately. All reports concerning IOHT can be summarized in terms of two major conclusions: significant pain relief and a slight benefit in survival.11,12,21 In our present series, we used hyperthermia intraoperatively, as a phase I trial, and found that it was possible to heat pancreatic tumors effectively without causing any damage to neighboring normal tissues; this was in contrast with devices that have been used to heat deep-seated tumors, which produced severe burns of subcutaneous fat.21 Moreover, we found a significant correlation between survival and the thermal parameter Tmin. This observation is in agreement with the reports of other authors who have noted the role of thermal parameters as prognostic factors for local control of the disease.16 Our present study should be regarded as a combination phase I/II study that evaluated the clinically tolerable toxicity and the possible clinical benefit of IOHT when used in combination with 5-FU. The synergistic effect of hyperthermia with 5-FU has already been reported in detail.14 The main technique for intraoperative chemotherapy used in our study was similar to the intraarterial procedure reported by Cantore et al.22 Although definitive conclusions are premature, our results, in terms of no progressive disease and no obstruction recorded during follow-up, suggest the advantage of combining IOHT and chemotherapy in patients with unresectable pancreatic adenocarcinoma. Several studies with radiotherapy (without IOHT) in patients with unresectable pancreatic adenocarcinoma have reported median survival times of around 9 months after diagnosis.23–25 Even with accelerated radiotherapy, a median OS time of 9 months seems to be the upper limit for unresectable pancreatic carcinoma,26 in contrast to intraoperative radiotherapy, for which the median OS seems to be slightly better.27 The effectiveness of IOHT in pancreatic cancer was preliminarily reported in 1993 by Ashayeri et al.12 Postoperative survival averaged 15.8 months, which is similar to our results. Recently, Matsui et al.28 also reported significant improvements in clinical and laboratory findings and local control after the administration of interstitial IOHT in unresectable pancreatic cancer. The median overall survival of 18.5 months in our series shows a considerable clinical benefit of this multimodality treatment, which needs to be confirmed in more patients. Along with such clinical benefit, it is also necessary to improve the patients’ quality of life by means of pain relief, improvement of performance status, and better nutrition (as reflected by an increase in BMI). There is also a potential benefit related to palliative cytoreductive resection. Several groups have reported the advantages of performing CS, in terms of improvements in quality of life and in survival, in patients with

noncurable disease.4,5 Taschieri et al.29 also concluded that the indications for resection in unresectable pancreatic cancer should be widened to include CS. In the present study, the main objective of palliative CS was to reduce the tumor load in patients with stage IVA pancreatic cancer. That is, extensive CS was not performed, but CS was carried out during exploration of the pancreatic tumor and peripancreatic tissues. With regard to palliation, all of our patients, had significant pretreatment symptoms, and all showed substantial or complete relief of symptoms during the follow-up period, as indicated by the significant improvement in ECOG status, pain score values, and BMI. This significant palliation effect should not be underestimated. However, two main questions may a rise from our present approach: was CS necessary in such palliative treatment, and, if it was might it be likely to cause hepatic metastases because of dissemination? According to Gouma et al.,30 palliative surgical treatment is generally indicated only for patients with a life expectancy of more than 6 months; our data are in accordance with this suggestion, because all of our patients had a survival time of more than 6 months. In another study, Nakagohri et al.31 examined the role of inferior head resection of the pancreas versus conventional pancreatoduodenectomy for intraductal papillary mucinous tumors and reported that six of seven patients were still alive without recurrent disease after a median follow-up of 3 years. According to Kayahara et al.,32 palliative surgical resection prolongs the average survival for patients with carcinoma of the body and tail of the pancreas, even in patients with peritoneal dissemination. According to Pederzoli et al.,4 when the malignancy is not completely resectable due to vessel involvement or extensive liver metastases, surgical reduction of the tumor burden (cytoreduction) is feasible, aimed at improving the clinical condition and survival of these patients. These data support the role of palliative cytoreduction in patients with pancreatic cancer; moreover, reduction of the cancerous load may be the only hope for patients with a dismal prognosis.4,5,29 The hypothesis that the risk of dissemination is higher with CS than with conventional surgery cannot be rejected, however. All of our patients died of liver metastases. However, only two patients presented with secondary liver lesions 6 and 8 months after the multimodality treatment, while the remainder were free of hepatic metastases for more than 1 year. Although it is difficult to assess the incidence of liver metastases after CS, a few such cases have already been reported; however, whether the metastases were related to the CS or the systemic disease is a question that has to be raised.4,31 Nevertheless, the risk of dissemination is not minimal, even for radical pancreatic resection.33 Moreover, the role of radiotherapy in minimizing the risk of disseminated microscopic disease is well known;


in our study, all patients underwent postoperative radiotherapy with safety margins of 2 cm around the target volume (the remaining pancreatic parenchyma, the residual mass, and the regional lymph nodes). CT scans showed no metastases to the peritoneum or to regional lymph nodes (superior and inferior to the pancreatic head and body, anterior and posterior pancreaticoduodenal, pyloric, and proximal mesenteric, common bile duct, and proximal mesenteric and splenic), perhaps due to the local sterilization effect of the postoperative irradiation. Our opinion is that, although CS is not an evidence-based procedure, at present, it is not clear that it leads to dissemination, and surgeons should not be discouraged from performing CS, especially as a salvage treatment option; the final decision is the surgeon’s and depends on his or her evaluation at laparotomy and experience. However, patients should receive intraarterial postoperative chemotherapy for the prevention of liver metastases. Beger et al.34 reported a decrease of 17% in the occurrence of liver metastases after postoperative celiac artery infusion compared with patients who did not receive adjuvant intraarterial chemotherapy. Combined resection of the vessels in pancreatic cancer has recently been the focus of renewed interest, mainly because of low morbidity and mortality, and improvements in surgical and diagnostic techniques.35,36 Launois et al.37 and Bottger38 have recently reported significantly better results after portal vein resection. However we did not perform combined resection of the vessels, mainly because neither intravascular ultrasonography nor superior mesenteric arterial portography was carried out to diagnose portal vein tumor invasion. As an argument in favor of our approach, we note that van Geenen et al.,39 using only perioperative evaluation, reported that 59% of their patients had microscopically tumor-positive resection margins after portal or superior mesenteric vein resection. We would also like to comment that, although three radiology experts checked the follow-up CT scans, it was difficult to judge the response to the treatment, in terms of measurable tumor size after CS using CT scans. The main problem was always that, postoperatively, the anatomical region of the pancreas appeared fuzzy on the CT scans. Although the criteria for treatment effectiveness that we used were in agreement with the Southwest Oncology Group (SWOG) criteria, it seems that an alternative evaluation of CA19-9 levels, according to the criteria of Cantore et al.,22 would be more convenient. In accordance with the these latter criteria, all patients showed a partial response, because the CA19-9 values decreased by more than 50%. Our patient population was small, and there was no definitive evidence to indicate that this multimodality treatment was superior to other types of combined

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therapy, suggesting the need for further investigation in a randomized trial to confirm that this treatment has a positive impact on survival. However, the entire procedure was rather costly and complicated, because the administration of IOHT was time-consuming, and many medical personnel (surgeons, anesthesiologists, radiotherapists, and biomedical engineers) were required. Improved programs of IOHT, with sufficient and accurate control of the applied thermal dose, together with the development of more effective combinations of chemotherapeutic agents, may further enhance the effectiveness of such combined treatment in pancreatic cancer. Future studies should also focus on the concurrent administration of intraoperative radiotherapy and hyperthermia. In the present study, only IOHT was performed in the multimodality treatment, because intraoperative radiotherapy is unavailable in our department. The results presented here should serve as a stimulus and a basis for the continued study of multimodality therapy in the treatment of unresectable adenocarcinoma of the pancreas.

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