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First report on the feasibility of a permanently implantable uni-directional planar low dose rate brachytherapy sheet for patients with resectable or borderline resectable pancreatic cancer

  • Joshua B. Dault
    Correspondence
    Corresponding author. Department of Radiation Oncology, Virginia Commonwealth University Health System, Massey Cancer Center, 401 College Street, Box 980058, Richmond, VA 23298-0058. Tel.: 804-828-7232; fax: 804-828-6042.
    Affiliations
    Department of Radiation Oncology, Virginia Commonwealth University Health System, Massey Cancer Center, Richmond, VA
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  • Dorin Todor
    Affiliations
    Department of Radiation Oncology, Virginia Commonwealth University Health System, Massey Cancer Center, Richmond, VA
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  • Brian J. Kaplan
    Affiliations
    Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University Health System, Massey Cancer Center, Richmond, VA
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  • Jennifer L. Myers
    Affiliations
    Division of Hematology, Department of Internal Medicine, Virginia Commonwealth University Health System, Massey Cancer Center, Oncology, and Palliative Care, Richmond, VA
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  • Emma C. Fields
    Affiliations
    Department of Radiation Oncology, Virginia Commonwealth University Health System, Massey Cancer Center, Richmond, VA
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Published:September 23, 2020DOI:https://doi.org/10.1016/j.brachy.2020.08.010

      Abstract

      Background

      Margin negative resection in pancreatic cancer remains the only curative option but is challenging, especially with the retroperitoneal margin. Intraoperative radiation therapy (IORT) can improve rates of local control but requires specially designed facilities and equipment. This retrospective review describes initial results of a novel implantable mesh of uni-directional low dose rate (LDR) Pd-103 sources (sheet) used to deliver a focal margin-directed high-dose boost in patients with concern for close or positive margins.

      Methods

      Eleven consecutive patients from a single institution with resectable or borderline resectable pancreatic cancer with concern for positive margins were selected for sheet placement and retrospectively reviewed. Procedural outcomes, including the time to implant the device and complications, and clinical outcomes, including survival and patterns of failure, are reported. A dosimetric comparison of the LDR sheet with hypothetical stereotactic body radiotherapy (SBRT) boost is reported.

      Results

      One patient had a resectable disease, and 10 patients had a borderline resectable disease and underwent neoadjuvant treatment. Sheet placement added 15 min to procedural time with no procedural or sheet-related complications. At a median follow up of 13 months, 64% (n = 7) of patients are alive and 55% (n = 6) are disease-free. Compared to a hypothetical SBRT boost, the LDR sheet delivered a negligible dose to kidneys, liver, and spinal cord with a 50% reduction in max dose to the small bowel.

      Conclusion

      This is the first report of the use of an implantable uni-directional LDR brachytherapy sheet in patients with resected pancreatic cancer with concern for margin clearance, with no associated toxicity and favorable clinical outcomes.

      Keywords

      Introduction

      Pancreatic cancer continues to be a devastating disease with poor long-term survival. Surgery remains the only curative option; however, only 15 to 20 percent of patients initially present with resectable disease (
      • Toesca D.A.S.
      • Koong A.J.
      • Poultsides G.A.
      • et al.
      Management of borderline resectable pancreatic cancer.
      ). Margin negative resection remains the goal as margin positivity results in poorer survival and higher rates of local recurrence (
      • Chandrasegaram M.D.
      • Goldstein D.
      • Simes J.
      • et al.
      Meta-analysis of radical resection rates and margin assessment in pancreatic cancer.
      ,
      • Neoptolemos J.P.
      • Stocken D.D.
      • Dunn J.A.
      • et al.
      Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial.
      ,
      • Campbell F.
      • Smith R.A.
      • Whelan P.
      • et al.
      Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin.
      ,
      • Esposito I.
      • Kleeff J.
      • Bergmann F.
      • et al.
      Most pancreatic cancer resections are R1 resections.
      ,
      • Yeo C.J.
      • Cameron J.L.
      • Lillemoe K.D.
      • et al.
      Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients.
      ,
      • Kato K.
      • Yamada S.
      • Sugimoto H.
      • et al.
      Prognostic factors for survival after extended pancreatectomy for pancreatic head cancer.
      ,
      • Willett C.G.
      • Lewandrowski K.
      • Warshaw A.L.
      • et al.
      Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy.
      ,
      • Ghaneh P.
      • Kleeff J.
      • Halloran C.M.
      • et al.
      The impact of positive resection margins on survival and recurrence following resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma.
      ,
      • Anderson J.D.
      • Wan W.
      • Kaplan B.J.
      • et al.
      Changing paradigm in pancreatic cancer: from adjuvant to neoadjuvant chemoradiation.
      ). While reported rates of margin positivity vary widely given that there is no standardized definition or method of assessing margin status, there is evidence that margins greater than 1 mm provide improved outcomes (
      • Kim K.S.
      • Kwon J.
      • Kim K.
      • et al.
      Impact of resection margin distance on survival of pancreatic cancer: a systematic review and meta-analysis.
      ,
      • Westgaard A.
      • Tafjord S.
      • Farstad I.N.
      • et al.
      Resectable adenocarcinomas in the pancreatic head: the retroperitoneal resection margin is an independent prognostic factor.
      ). Due to the challenging anatomical location, positive posterior or retroperitoneal margins have been shown to be relatively common and a negative prognostic factor (
      • Westgaard A.
      • Tafjord S.
      • Farstad I.N.
      • et al.
      Resectable adenocarcinomas in the pancreatic head: the retroperitoneal resection margin is an independent prognostic factor.
      ,
      • Gnerlich J.L.
      • Luka S.R.
      • Deshpande A.D.
      • et al.
      Microscopic margins and patterns of treatment failure in resected pancreatic adenocarcinoma.
      ).
      In situations where patients are considered borderline resectable at diagnosis, neoadjuvant therapy, including chemotherapy followed by chemoradiation, or increasingly stereotactic body radiotherapy (SBRT), is typically delivered with the goal of converting to resectable disease (
      • Toesca D.A.S.
      • Koong A.J.
      • Poultsides G.A.
      • et al.
      Management of borderline resectable pancreatic cancer.
      ,
      • Roeder F.
      Neoadjuvant radiotherapeutic strategies in pancreatic cancer.
      ). Unfortunately, due to inflammatory changes after treatment, the preoperative imaging is not reliable in determining resectability and many patients still have concern for close or positive retroperitoneal margins given the proximity to major vasculature (
      • Katz M.H.G.
      • Fleming J.B.
      • Bhosale P.
      • et al.
      Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators.
      ,
      • Ferrone C.R.
      • Marchegiani G.
      • Hong T.S.
      • et al.
      Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer.
      ). While dose escalation has been shown to potentially offer improved local control and possibly improved survival, postoperative external beam radiation therapy boost is difficult given the proximity of small bowel with dose-limiting bowel constraints and difficulty in identifying the area at highest risk (
      • Kavanagh B.D.
      • Pan C.C.
      • Dawson L.A.
      • et al.
      Radiation dose–volume effects in the stomach and small bowel.
      ,
      • Krishnan S.
      • Chadha A.S.
      • Suh Y.
      • et al.
      Focal radiation therapy dose escalation improves overall survival in locally advanced pancreatic cancer patients receiving induction chemotherapy and consolidative chemoradiation.
      ).
      Given these concerns, the use of intraoperative radiation therapy (IORT) for a focal radiation boost to the retroperitoneal margin has been investigated with improved rates of local control (
      • Krempien R.
      • Roeder F.
      Intraoperative radiation therapy (IORT) in pancreatic cancer.
      ,
      • Palta M.
      • Willett C.
      • Czito B.
      The role of intraoperative radiation therapy in patients with pancreatic cancer.
      ,
      • Sindelar W.F.
      • Kinsella T.J.
      Studies of intraoperative radiotherapy in carcinoma of the pancreas.
      ). However, traditional IORT requires specially designed and shielded operating suites and an afterloader or accelerator to deliver radiation. The novel device CivaSheet (sheet) is an FDA-cleared product from CivaTech Oncology consisting of a matrix of uni-directional low dose rate (LDR) Pd-103 radiation sources on a bioabsorbable flexible mesh with a gold shield that attenuates dose on one side of the device (Fig. 1) (
      • Cohen G.N.
      • Episcopia K.
      • Lim S.-B.
      • et al.
      Intraoperative implantation of a mesh of directional palladium sources (CivaSheet): dosimetry verification, clinical commissioning, dose specification, and preliminary experience.
      ). The purpose of our study is to demonstrate the feasibility and tolerance of the LDR brachytherapy CivaSheet to deliver a focal high-dose boost, targeted to the area at highest risk in patients with concern for close or positive margins, including those who received neoadjuvant chemoradiation.
      Figure thumbnail gr1
      Fig. 1CivaSheet is an FDA-cleared product from CivaTech Oncology consisting of a matrix of unidirectional Pd-103 radiation sources on a bioabsorbable membrane. Gold shielding discs on one side of sheet produce unidirectional dose distribution. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

      Methods

      Patient selection

      Consecutive patients from a single institution with resectable or borderline resectable pancreatic cancer with preoperative concern for positive margins were selected for consideration of sheet placement. Patient cases were discussed in a multidisciplinary setting to determine resectability. Neoadjuvant treatment with chemotherapy, chemoradiation, and/or SBRT was allowed. Initial staging and restaging scans showed no metastatic disease. Patients who ultimately had sheet placement between January 2017 and November 2019 were included and retrospectively reviewed. One of the included patients was enrolled in the ongoing CivaTech Oncology Phase I/II Protocol “Safety and efficacy of permanently implantable LDR CivaSheet in combination with external beam radiation in the treatment of pancreatic cancer” (NCT02843945). The other 10 patients included in this report were not technically eligible for this protocol due to strict time limitations, no neoadjuvant treatment, or lack of protocol-prescribed neoadjuvant treatment.

      Sheet placement and prescription

      Prior to surgery, the multidisciplinary team reviewed imaging, and if there was the potential for close or positive margin resection, referral for LDR brachytherapy sheet placement was made.
      The prescribed sheet dose was 37.8 Gy in seven patients, 50.4 Gy in two patients, 30.8 Gy in one patient, and 45 Gy in one patient. Patient 1, who was not enrolled on the above-mentioned protocol and did not receive neoadjuvant chemoradiation, received a prescribed sheet dose of 45 Gy. Patient 6, who was on institutional protocol with investigational systemic agents, received a sheet prescribed to 30.8 Gy after neoadjuvant treatment. While only Patient 2 was enrolled on the above-mentioned Phase I dose-escalation protocol, seven patients in our sample received a prescribed sheet dose of 37.8 Gy, which represented the second dose level on the protocol. Subsequent dose escalation per the above-mentioned protocol leads to manufacturer-recommended doses of 50.4 Gy, which was prescribed to Patients 10 and 11 although they were also not on protocol.
      The sheet comes in two sizes, a small (5 × 10 cm, containing 72 sources) and a large (5 × 15 cm, containing 108 sources). At the time of the placement, the physician can customize the sheet by trimming the necessary surface out of the standard size. The air kerma strength for the implant day is ordered based on a nomogram that correlates the prescription dose (at either D90 or D95 level), the depth for the prescription, and total air kerma strength (
      • Rivard M.J.
      A directional 103Pd brachytherapy device: dosimetric characterization and practical aspects for clinical use.
      ). Calibration of sources was performed using individual sources from the same batch (at least 10% of the ordered number of sources), and a manufactured provided jig, with typical differences of approximately 2% between the manufacturer and site measurements. The dose is typically prescribed to 5 mm depth and in this study was between 30.8 and 50.4 Gy. While the prescription is, in fact, a minimum peripheral dose, a large inhomogeneous dose is delivered throughout the tumor bed (Fig. 2). The sheets are designed with bioabsorbable material intended to degrade beyond the useful life of the Pd-103 seeds. After degradation, the seeds may move locally but are not intended to be extracted.
      Figure thumbnail gr2
      Fig. 2LDR brachytherapy sheet dosimetric characteristics. Dose is 30.8 to 45 Gy prescribed to 5 mm depth. (Image used by permission from CivaTech Oncology).
      For each implant, the sheet was placed during surgery by the same surgical oncologist with guidance from the same radiation oncologist at the site of concern for a close or positive margin to cover the area at risk plus an additional 1 cm margin. Sheets were cut to size as needed, pulled tight to avoid folding and the potential for hot spots, and secured with fibrin glue applied as a thin layer to the sheet surface or with a combination of corner sutures along with fibrin glue to the sheet surface, per the surgeon’s discretion (Fig. 3). Postoperatively, patients had a CT scan around 1 week later (Fig. 4). The tumor bed and organs at risk were contoured. The delivered dose to the target and organs at risk was calculated using BrachyVision (Varian Medical Systems, Inc) treatment planning software using a TG43 formalism but the full anisotropic source definition (
      • Rivard M.J.
      A directional 103Pd brachytherapy device: dosimetric characterization and practical aspects for clinical use.
      ). An additional 10% of the total number of sources ordered was received as individual CivaDot sources from the same batch as the sterilized CivaSheet sources; these sources were calibrated to confirm the implanted air kerma strength. For qualitative comparison, a hypothetical SBRT boost plan was created using Eclipse treatment planning software (Varian Medical Systems, Inc) for the purpose of dose comparison to the same target volume and organs at risk using the postimplant CT obtained for sheet dosimetry. The free-breathing CT used for implant evaluation was also used for SBRT planning. The GTV/CTV was defined by the surface of the sheet expanded 5 mm unidirectionally. A PTV was created by expanding the CTV isotropically by 5 mm. Organs at risk were contoured, including stomach, duodenum, liver, kidney, small bowel, and spinal cord. Planning constraints were similar to the ones published in previous SBRT studies (
      • Chuong M.D.
      • Springett G.M.
      • Weber J.
      • et al.
      Induction gemcitabine-based chemotherapy and neoadjuvant stereotactic body radiation therapy achieve high margin-negative resection rates for borderline resectable pancreatic cancer.
      ,
      • Hanna G.G.
      • Murray L.
      • Patel R.
      • et al.
      UK consensus on normal tissue dose constraints for stereotactic radiotherapy.
      ). No constraint was placed for the region of vessel abutment/encasement. CT density corrections were made to the artifact from the sheet to tissue equivalence. A dose of 30 Gy in five fractions was prescribed in this hypothetical plan consistent with our institution’s typical practice and to be consistent with sheet dosing levels.
      Figure thumbnail gr3
      Fig. 3Placement of LDR brachytherapy sheet intraoperatively. (Left) Gold shielding is placed anteriorly as sources are directed toward the retroperitoneal margin. (Right) Fibrin glue is often used to secure the sheet. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
      Figure thumbnail gr4
      Fig. 4Postoperative CT scan at 1 week with LDR sheet sources and organs at risk contoured (Patient 9).

      Outcomes/Statistics

      Patients were followed with routine surveillance imaging every 3 months. Procedural outcomes evaluated included surgical data such as procedural time, time to implant the device, procedural complications related to sheet placement, length of hospital stay, and postoperative complications. Clinical outcomes assessed were disease-free survival (DFS), overall survival (OS), and patterns of failure. DFS was defined as the interval that the patient was disease-free from the time of surgery to the time of death, disease recurrence, or last follow-up. OS was defined as interval that the patient was alive from the time of surgery to the time of death or last follow-up. Toxicity related to sheet placement was recorded as described by providers. Dosimetric data was collected for neoadjuvant treatment, and a comparison of a hypothetical SBRT boost plan to the LDR brachytherapy sheet boost plan was created based on a representative patient.

      Results

      Patient characteristics

      From March 2017 to November 2019, 11 patients received the LDR sheets during surgery. Patient characteristics are listed in Table 1. The median age was 63 years (range 51 to 75 years), and seven patients were female. One patient had surgery and sheet placement as initial therapy, followed by adjuvant gemcitabine for two cycles. Seven patients received neoadjuvant chemotherapy with four × six cycles of FOLFINIROX, followed by neoadjuvant chemoradiation prior to surgery and sheet placement. Three of these patients (Patients 6, 10, and 11) were treated on an institutional clinical trial with concurrent radiation and gemcitabine, sorafenib, and vorinostat, with Patient 11 also receiving adjuvant chemotherapy with four additional cycles of FOLFIRINOX. Patient 5 underwent total neoadjuvant treatment prior to surgery with an additional six cycles of FOLFIRINOX after an initial six cycles of FOLFIRINOX and chemoradiation. Neoadjuvant chemoradiation consisted of 3-D conformal or intensity-modulated radiation therapy prescribed to a dose of 50.4 Gy in 28 fractions to the gross tumor plus a 1 cm margin with concurrent gemcitabine, except in Patient 10 where 5-FU-based chemoradiation to 50.4 Gy using intensity-modulated radiation therapy was delivered to the gross tumor with an unknown margin, as full records from the outside facility are not available. Alternatively, three patients (Patients 7, 8, and 9) received neoadjuvant treatment with SBRT and chemotherapy with four × six cycles of FOLFIRINOX or FOLFOX, except that Patient 9 received only one cycle of FOLFIRINOX due to intolerance and was switched to gemcitabine and Abraxane, but also tolerated only one cycle. In all these cases, neoadjuvant SBRT was prescribed to 30 Gy in five fractions to the gross tumor plus a 5 mm margin. Patient 8 received total neoadjuvant treatment with additional two cycles of gemcitabine, and Abraxane was given prior to SBRT, while Patient 7 received another two cycles of FOLFIRINOX adjuvantly after neoadjuvant treatment, surgery, and sheet placement.
      Table 1Patient characteristics
      IDAgeSexInitial diseaseNeoadjuvant treatmentAdjuvant treatment
      170MResectableNone2 cycles gemcitabine
      251FBorderline4 cycles FOLFIRINOX

      Gemcitabine-based 3D chemoRT to 50.4 Gy
      None
      372FBorderline5 cycles FOLFIRINOX

      Gemcitabine-based 3D chemoRT to 50.4 Gy
      None
      461MBorderline6 cycles FOLFIRINOX

      Gemcitabine-based 3D chemoRT to 50.4 Gy
      None
      563MBorderline6 cycles FOLFIRINOX

      5-FU based IMRT chemoRT to 50.4 Gy
      Chemoradiation delivered at an outside facility.


      6 cycles FOLFIRINOX
      None
      675FBorderline4 cycles FOFIRINOX

      Institutional protocol 3D chemoRT with gemcitabine, sorafenib, and vorinostat

      50.4 Gy
      None
      764FBorderline2 cycles FOLFOX ×2 then 4 cycles FOLFIRINOX

      SBRT to 30 Gy in 5 fractions
      2 cycles FOLFIRINOX
      860FBorderline4 cycles FOLFIRINOX
      Oxaliplatin dropped from cycle four.


      2 cycles Gemcitabine and Abraxane

      SBRT to 30 Gy in 5 fractions
      None
      960FBorderline1 cycle FOLFIRINOX

      1 cycle Gemcitabine and Abraxane

      SBRT to 30 Gy in 5 fractions
      None
      1063MBorderline4 cycles FOFIRINOX

      Institutional protocol IMRT chemoRT with gemcitabine, sorafenib, and vorinostat

      50.4 Gy
      None
      1171FBorderline4 cycles FOFIRINOX

      Institutional protocol 3D chemoRT with gemcitabine, sorafenib, and vorinostat

      50.4 Gy
      4 cycles FOLFIRINOX
      ChemoRT–concurrent chemotherapy and radiation therapy.
      a Chemoradiation delivered at an outside facility.
      b Oxaliplatin dropped from cycle four.

      Procedural outcomes

      At diagnosis, Patient 1 had a resectable disease and the remaining 10 patients had a borderline resectable disease as determined by multidisciplinary discussion and consensus guidelines (
      • Al-Hawary M.M.
      • Francis I.R.
      • Chari S.T.
      • et al.
      Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the society of abdominal radiology and the American pancreatic association.
      ). Procedural and sheet details are listed in Table 2. Surgical techniques included one laparoscopic, five laparoscopic converted to open, and five open laparotomies. Seven were pancreaticoduodenectomies, two of which included portal vein/superior mesenteric vein reconstruction, and four were distal pancreatectomies, one of which included reconstruction of the celiac and hepatic arteries and vein grafting. The mean procedure time was 7 h 38 min (range 4 h 50 min–11 h 46 min), out of which sheet placement added an average of 15 min. Most sheets were secured with fibrin glue and/or vicryl sutures. The prescribed physical dose was 37.8 Gy in seven patients, 50.4 Gy in two patients, 30.8 Gy in one patient, and 45 Gy in one patient, as described above. The median number of sources placed was 54 (range 30–108), and the median air kerma strength of the sheet was 49.6U (range 25.8U–126.36U). The mean distance to the retroperitoneal margin was 3.8 mm (range 0.3 mm–20 mm), with Patient 4 having complete pathologic response at the time of surgery and Patient 11 with a negative margin, but the distance was not reported. Postoperatively, three patients required one night in the ICU, and the mean length of hospitalization was 7 days (range 4 to 10 days). There were no immediate postoperative complications attributable to the sheet placement. CT simulation 1 week postoperatively confirmed placement and was used to reconstruct the sources and evaluate dose. There were no cases of postoperative mortality up to 90 days. There was one case of presumed bowel air leak in a patient with local recurrence found on the same imaging, but no instance of biliary or pancreatic anastomotic leak.
      Table 2Procedural details
      IDProcedure techniqueProcedure typeProcedure time (hours)Sources implantedTotal air kerma strength (U)Sheet dose (Gy)Pathologic stageRP margin distance (mm)
      1Laparoscopic to openDistal pancreatectomy6:41108126.3645.0pT3N01
      2LaparotomyPancreaticoduodenectomy with partial PV/SMV resection and autologous vein patch8:497261.737.8ypT3N04
      3LaparotomyPancreaticoduodenectomy6:08454037.8ypT3N11.5
      4LaparoscopicDistal pancreatectomy5:016054.4237.8yPT0N0NA
      5Laparoscopic to openDistal Pancreatectomy with reconstruction of the celiac and hepatic arteries and vein interposition graft11:467258.3237.8ypT2Nx0.3
      6Laparoscopic to openDistal pancreatectomy and splenectomy4:504229.430.8ypT1cN02
      7LaparotomyPancreaticoduodenectomy with partial portal vein/SMV resection and reconstruction7:203025.837.8ypT1aN11
      8LaparotomyPancreaticoduodenectomy with portal vein resection and reconstruction10:595443.7437.8ypT1cN020
      9LaparotomyPancreaticoduodenectomy8:215444.6637.8ypT3bN21
      10Laparoscopic to openPancreaticoduodenectomy8:137887.450.4ypT3N03
      11Laparoscopic to openPancreaticoduodenectomy5:594249.650.4ypT1aN0Negative but not reported
      Median7:385449.637.84.3

      Clinical outcomes

      Clinical outcomes are listed in Table 3. At a median follow up of 13 months (range 3–34 months) from surgery, 64% (N = 7) of patients are alive, and 55% (N = 6) are disease free. Patient 1, who had a resectable disease and received no neoadjuvant treatment with two cycles of adjuvant gemcitabine, died related to a rare pulmonary complication of gemcitabine with no evidence of disease at 5 months. Patient 6 developed local recurrence alone at 5 months posttreatment, which appeared to originate several centimeters medial to the sheet but grew toward and adjacent to the sheet and died at 17 months. Patients 2 and 9 developed concurrent local and distant recurrence. Patient 9 had ypN2 disease with nodal, omental, and local recurrence, who also was found to have an intraabdominal air leak either related to surgery or tumor, diagnosed at 3 months posttreatment and who died at 6 months, whose imaging was performed outside and was not available for review to determine the location of the local recurrence related to the sheet. Patient 2 had local recurrence in the resection bed 5.5 cm medial to the sheet and distant recurrence with peritoneal and omental implants diagnosed at 6 months posttreatment and died at 13 months. Patient 3, who has the longest follow up of 34 months, developed local recurrence at 22 months posttreatment in the resection bed located 1.8 cm anterior to the sheet and is alive with disease. The remaining six patients are alive without disease from 3 to 29 months posttreatment (median 14 months), including Patient 4, who had pathologic complete response who is alive at 29 months with no disease. During the followup, there have been no reported toxicities directly related to sheet placement.
      Table 3Clinical outcomes
      IDHospital stay (days)Months follow-upDisease status
      1105Dead at 5 months without disease
      2513Local and distant recurrence at 6 months

      Dead from disease at 13 months
      3534Alive with local recurrence at 22 months
      4429Alive with no disease
      5722Alive with no disease
      6517Local recurrence at 5 months

      Dead from disease at 17 months
      7916Alive with no disease
      8812Alive with no disease
      973Local and distant recurrence at 3 months

      Dead from disease at 6 months
      1084Alive with no disease
      1193Alive with no disease
      Median713

      Dosimetric comparisons

      The dose-volume histograms from the initial radiation treatment plans for those patients who received neoadjuvant chemoradiation showed the small bowel volume receiving 45 Gy (V45), was a median of 69.9 ccs (range 15.7–194.5 ccs) and the median maximum bowel dose was 53.4 Gy (range 53.1–54.1 Gy) (Fig. 5). Patient 10, who received neoadjuvant treatment at an outside facility using the intensity-modulated radiation therapy, did not have full records available to assess bowel doses. Per Quantec and current pancreatic protocols, the V45 Gy for small bowel should be < 195 cc with a max of ≤58 Gy to prevent small bowel obstruction, fistula, and perforation. With these fixed constraints, only an additional 5–10 Gy boost would be possible with standard fractionation EBRT, compared with approximately 38–50.4 Gy that could be delivered more conformally with the LDR brachytherapy sheet. Although SBRT provides the most conformal external beam treatment approach allowing the most sparing to nearby organs at risk, the application of SBRT as a boost after resection is limited without demonstrated safety. However, to facilitate a comparison between these highly conformal modalities, a hypothetical SBRT boost plan was created using a representative patient (Fig. 6). Table 4 shows representative doses received by organs at risk comparing the LDR sheet with SBRT, demonstrating almost no dose given to kidneys, liver, stomach, and spinal cord and a 50% reduction in max dose and virtually no low dose to the small bowel using the sheet while delivering dramatic dose escalation within the target beyond what is possible with SBRT, given the dose inhomogeneity of the sheet.
      Figure thumbnail gr5
      Fig. 5Representative neoadjuvant 3-D conformal radiation plan (top) and dose volume histogram (bottom) showing small bowel max and dose to other organs at risk for Patient 2.
      Figure thumbnail gr6
      Fig. 6Visual comparison of an LDR brachytherapy sheet boost plan (left) and a hypothetical SBRT tumor bed boost plan (right) for Patient 9.
      Table 4Dosimetric comparison using representative LDR brachytherapy sheet plan and hypothetical SBRT plan
      StructureLDR sheetHypothetical SBRT plan
      Prescription37.8 Gy30 Gy (6 Gy × 5 fractions)
      CTV D90%38.8 Gy34.5 Gy
      CTV V100%5.4 mL6 mL
      Small Bowel (0.035 cc)7.2 Gy20.0 Gy
      Small Bowel (V5Gy)0.4 mL103.3 mL
      Kidneys (mean)0.7 Gy5.1 Gy
      Liver (mean)0.1 Gy1.0 Gy
      Stomach (mean)0 Gy1.6 Gy
      Spinal Cord (max)0.3 Gy6.4 Gy

      Discussion

      This is the first report on the use of a novel permanently implanted uni-directional Pd-103 LDR brachytherapy sheet in pancreatic cancer. Our experience provides some promising clinical results in a small sample of 11 patients, as seven are alive, six of whom are without the disease, at a median followup of 13 months. Of the six patients alive without disease, three had retroperitoneal margins of 3 mm or less (0.3 mm, 1 mm, and 3 mm), and another patient having a negative margin without a specific distance reported. Three of the four patients who developed local recurrence had ypT3 disease. In two of these cases, recurrences were outside of the target volume of the sheet, and in one case, the outside imaging was not available to assess the location of early recurrence but occurred along with nodal and omental recurrence in a patient with ypN2 disease, and no further systemic therapy. In the one case of recurrence with ypT1 disease, the recurrence appeared to begin well medial to the sheet at 5 months but grew to be adjacent to the sheet. The device is well tolerated, with no reported toxicity attributable to the sheet, minimal increase in procedural time, relative ease of implantation, and no increase in the length of hospital stay.
      In spite of high rates of regional or distant metastatic pancreatic cancer at presentation, local control is important, as about one-third of patients die from complications of local disease (
      • Iacobuzio-Donahue C.A.
      • Fu B.
      • Yachida S.
      • et al.
      DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer.
      ). Novel genetic markers may help identify patients at higher risk of locally destructive disease, as intact Smad4/Dpc4 portends to higher rates of local disease with lower rates of metastatic disease (
      • Iacobuzio-Donahue C.A.
      • Fu B.
      • Yachida S.
      • et al.
      DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer.
      ,
      • Crane C.H.
      • Varadhachary G.R.
      • Yordy J.S.
      • et al.
      Phase II trial of cetuximab, gemcitabine, and Oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of smad4(dpc4) immunostaining with pattern of disease progression.
      ). Local control is negatively impacted by the difficulty in obtaining margin negative resection, especially in the retroperitoneum in the region of the superior mesenteric and celiac arteries. Margin positivity, and specifically positive retroperitoneal margins, are negative prognostic factors with survival outcomes rivaling unresectable disease (
      • Chandrasegaram M.D.
      • Goldstein D.
      • Simes J.
      • et al.
      Meta-analysis of radical resection rates and margin assessment in pancreatic cancer.
      ,
      • Neoptolemos J.P.
      • Stocken D.D.
      • Dunn J.A.
      • et al.
      Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial.
      ,
      • Campbell F.
      • Smith R.A.
      • Whelan P.
      • et al.
      Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin.
      ,
      • Esposito I.
      • Kleeff J.
      • Bergmann F.
      • et al.
      Most pancreatic cancer resections are R1 resections.
      ,
      • Yeo C.J.
      • Cameron J.L.
      • Lillemoe K.D.
      • et al.
      Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients.
      ,
      • Kato K.
      • Yamada S.
      • Sugimoto H.
      • et al.
      Prognostic factors for survival after extended pancreatectomy for pancreatic head cancer.
      ,
      • Willett C.G.
      • Lewandrowski K.
      • Warshaw A.L.
      • et al.
      Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy.
      ,
      • Ghaneh P.
      • Kleeff J.
      • Halloran C.M.
      • et al.
      The impact of positive resection margins on survival and recurrence following resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma.
      ,
      • Kim K.S.
      • Kwon J.
      • Kim K.
      • et al.
      Impact of resection margin distance on survival of pancreatic cancer: a systematic review and meta-analysis.
      ,
      • Westgaard A.
      • Tafjord S.
      • Farstad I.N.
      • et al.
      Resectable adenocarcinomas in the pancreatic head: the retroperitoneal resection margin is an independent prognostic factor.
      ,
      • Gnerlich J.L.
      • Luka S.R.
      • Deshpande A.D.
      • et al.
      Microscopic margins and patterns of treatment failure in resected pancreatic adenocarcinoma.
      ). Given historically reported high rates of local failure and the importance of margin clearance, a few reports of dose escalation with EBRT and SBRT have shown the potential for improved local control and possibly survival (
      • Krishnan S.
      • Chadha A.S.
      • Suh Y.
      • et al.
      Focal radiation therapy dose escalation improves overall survival in locally advanced pancreatic cancer patients receiving induction chemotherapy and consolidative chemoradiation.
      ,
      • Ben-Josef E.
      • Schipper M.
      • Francis I.R.
      • et al.
      A phase I/II trial of intensity-modulated radiation (IMRT) dose escalation with concurrent fixed- dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer.
      ,
      • Ma S.J.
      • Prezzano K.M.
      • Hermann G.M.
      • et al.
      Dose escalation of radiation therapy with or without induction chemotherapy for unresectable locally advanced pancreatic cancer.
      ,
      • Zaorsky N.G.
      • Lehrer E.J.
      • Handorf E.
      • et al.
      Dose escalation in stereotactic body radiation therapy for pancreatic cancer: a meta-analysis.
      ). However, external beam dose escalation has the potential to increase toxicity given the relatively sensitive nature of the gastrointestinal organs, especially the small bowel, as maximum and volumetric dose constraints to minimize this risk narrow the therapeutic window for dose escalation significantly (
      • Kavanagh B.D.
      • Pan C.C.
      • Dawson L.A.
      • et al.
      Radiation dose–volume effects in the stomach and small bowel.
      ).
      Thus, IORT has been proposed as a method to widen the therapeutic window by preferentially sparing the nearby organs at risk while providing focal dose escalation (
      • Krempien R.
      • Roeder F.
      Intraoperative radiation therapy (IORT) in pancreatic cancer.
      ). The use of IORT in resectable disease has been reported in the literature, mainly with retrospective single or multiinstitution studies. These reports consistently show improved rates of local control that most often do not translate into improved overall survival.19 A small prospective randomized controlled trial conducted by the National Cancer Institute enrolled 24 patients randomized to EBRT with or without IORT, which showed improved local control and median survival (18 months vs 12 months, p = 0.01) (
      • Sindelar W.F.
      • Kinsella T.J.
      Studies of intraoperative radiotherapy in carcinoma of the pancreas.
      ). Other retrospective reports have shown improved rates of local control by around 30% with no increase in perioperative morbidity or complications, with Reni et al. also reporting improved median overall survival and Calvo et al. reporting that all included patients that survived 5 years or more received IORT and maintained local control (
      • Zerbi A.
      • Fossati V.
      • Parolini D.
      • et al.
      Intraoperative radiation therapy adjuvant to resection in the treatment of pancreatic cancer.
      ,
      • Alfieri S.
      • Morganti A.G.
      • Giorgio A.D.
      • et al.
      Improved survival and local control after intraoperative radiation therapy and postoperative radiotherapy: a multivariate analysis of 46 patients undergoing surgery for pancreatic head cancer.
      ,
      • Reni M.
      • Panucci M.G.
      • Ferreri A.J.M.
      • et al.
      Effect on local control and survival of electron beam intraoperative irradiation for resectable pancreatic adenocarcinoma.
      ,
      • Showalter T.N.
      • Rao A.S.
      • Rani Anne P.
      • et al.
      Does intraoperative radiation therapy improve local tumor control in patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma? A propensity score analysis.
      ,
      • Calvo F.A.
      • Sole C.V.
      • Atahualpa F.
      • et al.
      Chemoradiation for resected pancreatic adenocarcinoma with or without intraoperative radiation therapy boost: long-term outcomes.
      ). While most of these reports preceded more modern dose-escalated neoadjuvant chemotherapy with chemoradiation, a recent report by Keane et al. on borderline resectable patients who underwent neoadjuvant chemoradiation found a nonsignificant increase in median overall survival (35.1 months vs 24.5 months) but no difference in local progression (31.6% vs 27.2% with IORT, p = 0.76) in spite of increased rates of close/positive margins (
      • Keane F.K.
      • Wo J.Y.
      • Ferrone C.R.
      • et al.
      Intraoperative radiotherapy in the era of intensive neoadjuvant chemotherapy and chemoradiotherapy for pancreatic adenocarcinoma.
      ). With the use of SBRT for neoadjuvant treatment of pancreatic cancer on the rise, a recent meta-analysis by Zaorsky et al. found that dose escalation comparing calculated biologically equivalent doses (BED) did not show a significant improvement in local control nor increased toxicity at higher BED across various fractionation schemes (
      • Zaorsky N.G.
      • Lehrer E.J.
      • Handorf E.
      • et al.
      Dose escalation in stereotactic body radiation therapy for pancreatic cancer: a meta-analysis.
      ). Thus, IORT provides benefits of improving local control while likely not increasing toxicity, but requires significant investment in the program in the form of facilities and equipment, limiting wide acceptance.
      CivaSheet is a form of IORT developed to capture the benefits of IORT while providing several advantages over traditional IORT. First, the boost dose using the sheet can be dramatically increased to the immediately adjacent targeted tissue while the dose to nearby organs at risk, especially the small bowel, is a fraction of the prescribed dose given the unidirectional nature of the sheet. So the use of the sheet is possible regardless of the neoadjuvant radiation therapy technique utilized. Second, the sheet is adaptable to specific patients, and can be custom ordered, sized, and positioned intraoperatively for optimal target coverage. Third, implementing a CivaSheet program is relatively simple and requires no investment in specialized equipment, including afterloaders or accelerators, or shielded operating suites (
      • Cohen G.N.
      • Episcopia K.
      • Lim S.-B.
      • et al.
      Intraoperative implantation of a mesh of directional palladium sources (CivaSheet): dosimetry verification, clinical commissioning, dose specification, and preliminary experience.
      ). Further, placement of the sheet requires only standard operating techniques, although the proper orientation is important but relatively simple, given the visible gold shielding (
      • Rivard M.J.
      A directional 103Pd brachytherapy device: dosimetric characterization and practical aspects for clinical use.
      ). Last, the sources are visible on postoperative CT imaging, providing an opportunity for in vivo dosimetry calculations (
      • Cohen G.N.
      • Episcopia K.
      • Lim S.-B.
      • et al.
      Intraoperative implantation of a mesh of directional palladium sources (CivaSheet): dosimetry verification, clinical commissioning, dose specification, and preliminary experience.
      ).
      While our results are encouraging, there are several limitations, including that this is a small retrospective series of only 11 patients, which significantly impacts generalizability. However, these patients represent several varying neoadjuvant management options for resectable/borderline resectable pancreatic cancer and show that the addition of the LDR brachytherapy sheet can be integrated into several different treatment paradigms. Further, this series has a relatively short followup that can lead to overstating favorable outcomes. For example, the patient with the longest followup of 34 months developed local recurrence at 22 months. To better clarify the safety and efficacy of the sheet, a prospective multiinstitutional Phase1/2 trial (NCT02843945) is ongoing, as mentioned previously.
      There is an opportunity to better define patient selection criteria for this implantable sheet. In our series, a multidisciplinary approach was utilized, and the same surgical oncologist and radiation oncologist participated in decisions about resectability and concern for margin status. However, our data show that one patient had a 20 mm retroperitoneal margin, one patient had a small scattered focus of residual disease after neoadjuvant treatment resulting in margin status not being reported, and one patient had a pathologic complete response as noted on the surgical pathology. Therefore, if possible, more robust criteria could be developed to better select patients that would most benefit.

      Conclusion

      This is the first study to report the safety and feasibility of the implantable, uni-directional, LDR brachytherapy CivaSheet in patients with pancreatic cancer with a concern for close or positive margins at the time of curative surgery. This novel, unidirectional, Pd-103 sheet provides a unique and relatively straight-forward solution for delivering a focal radiotherapy boost without increased toxicity and will hopefully continue to show favorable results that translate into improved rates of local control, and ultimately overall survival.

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