Intraoperative ultrasound-guided iodine-125 seed implantation for unresectable pancreatic carcinoma

The incidence of pancreatic carcinoma has increased in recent decades, yet the treatment outcome for this disease remains unsatisfactory. Despite the introduction of new therapeutic techniques combined with aggressive modalities, such as external beam radiotherapy (EBRT) and chemotherapy, the prognosis of pancreatic carcinoma remained to be very poor, with a mortality rate of more than 90% [1]. Only 15% to 20% of patients with pancreatic carcinoma are suitable for resection, and even with resection, long term survival still remains poor [2, 3]. Most of pancreatic carcinoma was diagnosed in the locally advanced or metastatic stage, and the median survival rate was approximately 6 months with palliative treatment. Biliary and gastric bypass have been used for palliation in unresectable pancreatic carcinomas and median survival in these patients was often 5–6 months [4, 5].

More recently, EBRT and chemotherapy have been standard adjuvants for locally advanced pancreatic carcinoma. EBRT alone has failed to control disease progression and yields a median survival of 5.5–7 months [6, 7], while the addition of chemotherapy to EBRT increased the median survival to 9–10 months [8–10]. The introduction of intraoperative electron beam radiotherapy, combined with EBRT and chemotherapy, has also failed to significantly improve long-term results, with recent studies reporting median survival rates of 7–16 months [11–14].

Despite the availability of many treatments, there was currently no consensus regarding the optimal therapeutic modality for unresectable pancreatic carcinomas. Therefore, it is necessary to investigate new techniques that may improve the prognosis. In this study we investigated the efficacy and feasibility of ¹²⁵I seed implantation guided by intraoperative ultrasound in managing unresectable pancreatic carcinoma.

The treatment of unresectable pancreatic cancer continues to be a major challenge. More than half of patients have a locally or regionally confined tumor requiring local treatment. Stereotactic radiotherapy (SRT) allows an escalation of radiation doses to be applied to a small target volume within a small margin. SRT is administered in one or a few fractions with the goal of sparing the surrounding normal tissue by using multiple non-coplanar field arrangements for the administration. In a phase II study on the use of SRT in the treatment of locally advanced pancreatic carcinoma by Huyer et al, the median survival time was only 5.7 months, and the one-year survival rate was 5% [17]. These data associate SRT with a poor outcome, unacceptable toxicity, and questionable palliative effects, making SRT unadvisable for patients with advanced pancreatic carcinoma. In contrast, interstitial permanent implantation of radioactive seeds into the tumor site provides the advantage of delivering a high dose of irradiation to the tumor (range 140–160 Gy) which drops off sharply outside the local implanted field. ¹²⁵I seeds with a half-life of approximately 59.4 days were selected as the radioactive source for permanent implantation in this study, allowing approximately 95% of the needed dose to be delivered within a year [18].

Implantation of radioactive isotopes for the treatment of pancreatic carcinoma has been used for the past several decades. For example, Handly et al. reported the use of radium needle implantation in 7 patients for the treatment of pancreatic carcinoma in 1934 [19]. Of those, one patient survived up to two years. Hilaris, who was a pioneer in the development of ¹²⁵I seeds for implantation for the treatment of pancreatic carcinoma, published a study of 98 patients receiving seed implants that responded with a median survival of 7 months [20], with 1 patient surviving for five years. Pain control was achieved in 65% of patients and lasted between 5 and 47 months (with a median of 6 months).

In a review study by Morrow et al., no difference in survival between patients treated with interstitial brachytherapy and patients treated by surgical resection at the same institution were observed [21]. The median survival time was 7 months, and at least one patient survived up to five years. Pain control was achieved in 65% of the patients [22]. Syed et al. reported 18 patients treated with biliary bypass surgery, ¹²⁵I interstitial brachytherapy, and EBRT [23]. Ten patients with the interstitial brachytherapy were "sandwiched" between two courses of EBRT. Typically, patients received 30 Gy EBRT following biopsy and bypass surgery, then 2 weeks later an additional interstitial brachytherapy of 100–150 Gy, and then an additional 15–20 Gy EBRT was administered 3–4 weeks after interstitial implantation. The results showed a 13 month median survival time in 12 patients with head and body pancreatic carcinoma. ¹²⁵I seed implantation has been attempted in patients with locally advanced pancreatic carcinoma, and no difference in overall survival was found compared with the use of other techniques [24, 25].

In this study, the interstitial needle position and distribution were determined using ultrasound supervision and with the intent to spare at least 1 cm from nearby or normal tissues including the internal pancreatic duct and small blood vessels. The placement of an omental fat pad over the implanted volume was also used to protect the gastric and transverse colon mucosa from irradiation. Our results indicate that the local control of disease was achieved in 78.6% of all patients. 87.5% (7/8) of all patients experienced complete and partial pain relief and shown satisfactory palliative effect. The overall 1-, 2- and 3-year survival rates were 33.9%, 16.9% and 7.8%, respectively with the median survival of 10 months. The survival rate and survival times were found to be the most advantageous for some selected stage II/III patients in this study.

Permanent interstitial administration of radioactive seeds appears to offer consistent and improved local control, although a major drawback is the high rate of perioperative morbidity and mortality. The significant causes of high morbidity of ¹²⁵I seed intraoperative implantation were due to the needles penetrated into pancreatic duct, small blood vessels in the pancreas and/or organ at risk resulting in fistula and abscess formation. The major long-term complication from the combined effects of multimodality treatments has been gastrointestinal bleeding and obstruction [26]. The high incidence of complications maybe related to that the seeds were implanted nearby normal tissues such as gastric, colon and jejunum. The second reason may be the activity of seeds was high. The third reason maybe the doses of seeds beyond the tolerance of normal pancreas tissue. In earlier studies, perioperative mortality was 16% – 25% from acute pancreatitis, fistulization, and abscess formation [23]. Side effects reported in the Hilaris et al., study included 1 patient developing a post-operative mortality, another patient suffered from a pancreatic fistula, 4 patients developed biliary fistula, 4 developed abscesses, 4 developed gastrointestinal bleeding, 6 developed obstruction of the gastrointestinal tract, 5 patients developed sepsis, and 4 patients developed deep venous thrombophlebitis [20]. In comparison, the study by Syed et al. included 8 patients with a poorer prognosis, 2 patients with prolonged wound drainage, 3 patients developed insulin-dependent diabetes, and 2 patients developed other interstitial complications [23]. For this study, perioperative mortality was considerably less than that observed in earlier studies, one patient suffered from chylous fistula, one patient suffered from pancreatitis and one suffered from gastritis, seven patients suffered from low fever, there were no grade III and grade IV toxicity and complications, and less than most series of surgically-treated pancreatic cancer patients published in the literature [22, 27].

In conclusion, ¹²⁵I seed implantation with intraoperative ultrasound guidance provides a satisfactory distribution of seeds in tumor mass, minimizes radiation to surrounding organs due to the sharp dose fall-off outside the implanted volume, and generates no damage. We hypothesize that a further improvement in median survival of patients with unresectable pancreatic carcinoma may be obtained with the combined aggressive use of EBRT, systemic chemotherapy.