Summary
Goal: The function of intraoperative radiation remedy (IORT) within the administration of resectable pancreatic most cancers (RPC) stays unclear. So far, the appliance of IORT utilizing a low-energy X-ray supply has not been extensively investigated. Subsequently, this examine was carried out to guage the security and efficacy of IORT utilizing a 50 kV X-ray supply in treating RPC.
Strategies: Sufferers with RPC who underwent radical pancreatectomy and IORT have been enrolled. The first endpoint was time to therapy failure (TTF) survival, whereas the secondary endpoints have been security and total survival (OS).
Outcomes: By November 2023, 35 sufferers with RPC have been handled in keeping with the examine protocol. The median TTF was 11.67 months, whereas the median OS for the cohort was 22.2 months. The native recurrence charge was 20%. The most typical postoperative complication was pancreatic fistula. The incidence of delayed gastric emptying was 20%. Inside 30 days after surgical procedure, one affected person skilled belly ache, one other skilled vomiting, and one died due to belly an infection and a grade C pancreatic fistula. Carcinoembryonic antigen (CEA) and D-dimer ranges considerably correlated with TTF and OS in multivariate analyses. The carbohydrate antigen 19-9 (CA19-9) degree was one other prognostic issue considerably related to OS. Sufferers with low D-dimer and regular CA19-9 ranges confirmed extended OS with an IORT dose ≤ 15 Gy.
Conclusions: This examine helps use of IORT with a 50 kV X-ray supply in treating RPC. IORT utilizing a low-energy X-ray supply was well-tolerated and possible. Moreover, D-dimer, CEA, and CA19-9 ranges could assist determine affected person profiles probably benefitting from IORT.
key phrases
Introduction
Pancreatic most cancers is related to poor scientific outcomes and has a 5-year survival charge under 13%1. Surgical resection stays the first therapy modality; nonetheless, solely 15%–20% of sufferers are eligible for radical surgical procedure at analysis2. Even with adjuvant chemotherapy, the general prognosis stays suboptimal3. Native failure charges are as excessive as 50%–80% in sufferers with resected and domestically superior illness4. One report has indicated that 30% of all sufferers with pancreatic most cancers die from domestically harmful illness5. Reaching larger native management charges is essential for bettering affected person prognosis and high quality of life.
Intraoperative radiation remedy (IORT) entails supply of a single high-dose fraction of radiation throughout surgical procedure6. The goal quantity usually consists of the tumor mattress after gross whole resection or any residual illness if full resection is just not possible. IORT is extra incessantly used for domestically superior pancreatic most cancers7,8 however has additionally proven effectiveness in treating resectable pancreatic most cancers9–13. IORT has been proven to realize 40%–80% decrease locoregional recurrence than noticed with normal therapy14. A meta-analysis has revealed that IORT improves locoregional management and total survival (OS) in sufferers with resectable pancreatic most cancers with out growing postoperative problems or surgery-associated mortality charges15. Nonetheless, some researchers contend that the advantages of IORT are restricted to fastidiously chosen sufferers with non-metastatic illness8,16,17. Regardless of its potential, expertise with IORT in resectable pancreatic most cancers stays restricted, and the results of therapy on time to failure (TTF) survival and OS are unclear.
The two main approaches for IORT in pancreatic most cancers are electron beams and high-dose-rate brachytherapy18. IORT utilizing electron beams poses security issues as a result of sufferers have to be transferred from the working room to a shielded radiation room. In distinction, the miniaturized low-energy X-ray supply utilized in INTRABEAM permits IORT to be administered immediately within the working room. Nonetheless, no clear proof is offered concerning the security of IORT utilizing 50 kV X-rays, and the optimum radiation dose has not been established.
Delivering high-dose-rate brachytherapy to the pancreas is especially difficult, due to the proximity of a number of radiosensitive belly organs. Nonetheless, image-guided IORT and on-line therapy planning considerably enhance the accuracy of those procedures19. Consequently, image-guided IORT performs a vital function within the therapy of pancreatic most cancers.
In a current examine, IORT was administered with a cell 50kV X-ray supply (Intrabeam 600, Carl Zeiss, Germany). Picture-guided IORT was facilitated by intraoperative cone beam computed tomography (CBCT). The first goal of the current examine was to guage the native management, long-term survival, security, and feasibility of IORT in sufferers with pancreatic most cancers present process surgical resection. Moreover, this examine was aimed toward investigating the correlation between affected person traits and survival outcomes, and figuring out efficient strategies for figuring out which sufferers may profit from IORT.
Supplies and strategies
Examine inhabitants and scientific information
The data of sufferers with pancreatic most cancers handled with IORT with a 50 kV X-ray supply and present process distal pancreatectomy with en bloc splenectomy have been reviewed. The aim of this scientific trial was to guage the efficacy and security of IORT utilizing a low-energy X-ray supply. Sufferers have been stratified by IORT dose (≤ 15 Gy vs. > 15 Gy). At our establishment, sufferers with pancreatic most cancers underwent distal pancreatectomy, and an IORT dose of 15 Gy with a 50 kV X-ray supply is our routine scientific follow. Subsequently, we selected 15 Gy because the cut-off for stratification. The Institutional Overview Board of Tianjin Medical College Most cancers Institute & Hospital authorized the examine (protocol quantity: E20230004). Written knowledgeable consent was obtained from all contributors.
Sufferers who have been recognized with pancreatic most cancers at Tianjin Medical College Most cancers Institute & Hospital between February 2021 and November 2023, and who supplied knowledgeable consent, have been enrolled on this examine. Information have been collected from blood checks carried out 1 week earlier than surgical procedure and earlier than the initiation of adjuvant chemotherapy.
Key eligibility standards included the next: (1) age ≥ 18 years; (2) resectable or borderline resectable pancreatic most cancers, as outlined by Nationwide Complete Most cancers Community pointers20, and confirmed by way of CT, endoscopic ultrasound, or different imaging modalities; (3) good Jap Cooperative Oncology Group efficiency standing (0–1); (4) tumor location within the pancreatic physique or tail, making distal pancreatectomy with en bloc splenectomy technically possible; (5) candidacy for IORT; (6) enough organ operate to tolerate surgical procedure and IORT.
Key exclusion standards included the next: (1) presence of extreme comorbidities, similar to coronary heart failure, renal failure, liver failure, bleeding peptic ulcer, intestinal paralysis, intestinal obstruction, or uncontrolled diabetes; (2) tumors situated within the pancreatic head or neck; (3) proof of illness not localized to the pancreas; (4) present enrolment in one other investigational drug or machine trial clinically interfering with this examine; (5) incapability to adjust to the examine necessities or follow-up schedule; (6) girls with childbearing potential or sexually lively fertile males whose companions have been girls of childbearing potential who have been unwilling or unable to make use of acceptable contraception strategies all through the examine; (7) historical past of lively most cancers, together with concurrent a number of cancers or heterogeneous a number of cancers with a disease-free interval
After the resection section, intraoperative radiotherapy pictures have been collected and reconstructed in 3 dimensions with CBCT (Cios Spin 3D, Siemens Healthineers, Germany). The three-dimensional (3D) pictures have been then imported into specialised planning software program for intraoperative radiotherapy (PUNENG IORT therapy planning system, China) to precisely calculate and consider the goal radiation dose. A cell 50kV X-ray supply was used for IORT. The goal quantity included the tumor mattress, the celiac and superior mesenteric arteries, the mesenteric root, and any extra areas thought of to be in danger by the surgeon and radiation oncologist. The radiation dose pointers beneficial 10–20 Gy to the resection mattress21. Age, bodily situation, web site of irradiation, and dose limiting elements of the organ in danger have been elements influencing dose choice. The present INTRABEAM therapy planning mannequin makes use of a way for calculating delivered doses in keeping with the 1-dimensional match of a look-up desk of depth dose charges measured in water alongside the central axis of the X-ray supply. On the idea of the dose charge and the penetration depth, the INTRABEAM 600 calculates the whole publicity time. Sufferers acquired adjuvant chemotherapy 4–12 weeks after surgical procedure.
Observe-up and toxicity analysis
All sufferers have been adopted up in keeping with the institutional protocol, which comprised evaluations each 3 months for the primary 2 years after therapy, adopted by evaluations each 6 months for a further 3 years. Routine restaging occurred each 6 months with a computed tomography (CT) scan of the stomach and pelvis. Carbohydrate antigen 19-9 (CA 19-9) ranges have been measured, and follow-up CT scans (chest, stomach, and pelvis) with distinction have been carried out each 3–6 months for the primary 2 years after surgical resection. Surgical problems have been assessed with the Clavien–Dindo classification.
Statistical evaluation
Statistical evaluation was carried out in SPSS (model 19.0) statistical software program. The first endpoint was TTF survival, whereas secondary endpoints included security and OS. TTF was outlined because the interval from surgical procedure to the primary radiologic proof of recurrent illness at any web site or to the date of the final imagiological examination if no illness recurrence was noticed. OS was measured from the time of surgical procedure to the affected person’s loss of life, no matter trigger, or to the date of censoring. The Kaplan-Meier methodology was used to estimate the likelihood of TTF and OS. Potential associations have been evaluated by way of univariate and multivariate analyses with the Cox proportional hazards mannequin with a significance threshold of P χ2 take a look at or Fisher’s actual take a look at. Receiver working attribute curves have been calculated, and the Youden index was estimated to find out the optimum cut-off worth for elements with out reference values. The cut-off values for D-dimer, CEA, and CA19-9 have been on the higher restrict of regular in our hospital.
Outcomes
From February 2021 to November 2023, 37 sufferers with RPC have been enrolled. Two sufferers have been excluded from the evaluation due to intraoperative findings of distant metastasis. The final follow-up occurred on November 4, 2024. A complete of 31 sufferers accomplished at the least 1 yr of follow-up. The variety of sufferers adopted up for greater than 2 years was 15 (42.9%). The median follow-up length for all the affected person cohort was 23.2 months (vary: 2.8–44.3 months). Two sufferers have been misplaced to follow-up, and 13 sufferers have been alive on the time of research. Table 1 shows the affected person and illness traits.
Affected person and illness traits
The median age of all sufferers was 67 years (vary: 52–76 years). All contributors underwent R0 resection. An applicator with an acceptable diameter (2.0, 3.0, 4.0, or 5.0 cm) was chosen in keeping with the scale of the goal quantity and was connected over the probe of the X-ray supply. The median applicator diameter was 3.0 cm. 4 sufferers didn’t bear adjuvant chemotherapy: 2 declined chemotherapy, 1 was misplaced to follow-up, and one other died within the hospital due to belly an infection and grade C pancreatic fistula. At current, solely 2 stage III sufferers have been recruited; subsequently, no subgroup evaluation was carried out for staging. The predefined subgroups of sufferers in keeping with IORT dose confirmed no important variations in TTF and OS. All variables listed in Table 1 have been included within the univariate analyses.
TTF survival
Of the 35 sufferers analyzed, 7 skilled native recurrence, thus leading to a locoregional recurrence charge of 20%; 23 had distant metastases; and 5 confirmed each native recurrence and distant metastases. The median time to native failure was 9.8 months (vary: 1.1–38.1 months). The median TTF was 11.67 months (vary: 1.1–40.0 months). The median TTF was 11.667 months within the IORT dose ≤ 15 Gy group (n = 28) and seven.6 months within the IORT dose > 15 Gy group (n = 7, P = 0.53). The median TTF for phases I (n = 9), II (n = 24), and III (n = 2) was 20.867 months, 9.2 months and a pair of.1 months, respectively (P = 0.216).
Univariate analyses revealed a considerably elevated threat of recurrence amongst sufferers with elevated preoperative CEA (P = 0.036) (Figure 1A) and D-dimer (P = 0.005) ranges (Table 2 and Figure 1B). Among the many 24 sufferers within the CEA n = 10). The opposite 6 (24%) native recurrent occasions occurred within the 25 contributors with excessive D-dimer ranges. CEA and D-dimer ranges considerably correlated with TTF in multivariate analyses (Table 3).
Kaplan-Meier survival curves displaying time to failure (TTF) survival in keeping with CEA (A) D-dimer (B).
Univariate evaluation of associations of affected person, tumor, therapy, and pathologic traits with survival
Multivariate evaluation of associations of affected person, tumor, therapy, and pathologic traits with survival
Age, gender, receipt of neoadjuvant and adjuvant therapy, surgical procedure sort, TNM stage, chemotherapy regimens, IORT dose, and CA19-9 weren’t considerably related to TTF. Sufferers with regular serum CEA ranges had a considerably longer median TTF than these with elevated CEA ranges (16.90 vs. 6.75 months). The median TTF was 27.0 months within the D-dimer
Subgroup evaluation
Within the group with IORT dose ≤ 15 Gy, solely D-dimer degree was related to TTF. Sufferers with D-dimer vs. 8.967 months, 95% CI 8.066-9.868, P = 0.001). No important prognostic elements have been recognized within the IORT dose > 15 Gy group.
OS
Among the many 20 deceased sufferers, 18 (90%) died due to most cancers development, whereas 1 (5%) died due to treatment-associated toxicity, and one other (5%) died due to SARS-CoV-2 an infection. The median OS time for all the cohort was 22.2 months. The median OS was 21.7 months within the IORT dose ≤ 15 Gy group and 22.2 months within the IORT dose > 15 Gy group (P = 0.984).
Univariate analyses indicated that stage II/III, and better D-dimer ranges and preoperative CEA and CA19-9 ranges have been related to poorer OS (Table 2 and Figure 2). Moreover, multivariate evaluation revealed that D-dimer ranges and preoperative CEA and CA19-9 ranges have been impartial prognostic elements for OS (Table 3).
Kaplan-Meier survival curves displaying total survival (OS) in keeping with D-dimer (A), CEA (B), and CA19-9 (C).
The mortality charges within the high and low D-dimer teams have been 30% (3/10) and 68% (17/25), respectively. Furthermore, 11 of 24 sufferers with CEA vs. 11.9 months). The median OS was not reached within the CA19-9
Subgroup evaluation
Within the group receiving an IORT dose ≤ 15 Gy, univariate analyses revealed a considerably better threat of loss of life amongst sufferers with elevated D-dimer (P = 0.026), CA19-9 (P = 0.005), and CEA (P = 0.033) ranges. Within the multivariate evaluation, D-dimer (HR, 0.153; 95% CI 0.036–0.655, P = 0.011) and CA19-9 (HR, 0.164; 95% CI 0.042–0.637, P = 0.009) ranges have been independently related to OS. The median OS was not reached within the D-dimer vs. 14.733 months). Sufferers with low D-dimer and regular CA19-9 ranges confirmed extended OS. No important prognostic elements have been recognized within the group receiving an IORT dose > 15 Gy group.
Postoperative problems
Pancreatic fistula was the commonest complication (n = 33, 94.2%), amongst which 30 instances have been labeled as grade A. A complete of 27 sufferers (81.8%) within the IORT dose ≤ 15 Gy group and 6 sufferers (18.2%) within the IORT dose > 15 Gy group skilled pancreatic fistula (P = 0.365). Two sufferers receiving 12 Gy skilled grade B pancreatic fistula. The 1 affected person with a grade C pancreatic fistula acquired a dose of IORT of 20 Gy. Different postoperative problems included delayed gastric emptying and intra-abdominal abscess (Table 4). A complete of 6 of 28 sufferers skilled delayed gastric emptying within the group receiving an IORT dose ≤ 15 Gy. The variety of delayed gastric emptying occasions was 1 among the many different 7 sufferers receiving an IORT dose > 15 Gy. Most of those problems have been managed conservatively. Nonetheless, one affected person who acquired a 20 Gy dose died within the hospital, due to a number of organ failure, belly an infection, and a grade C pancreatic fistula. The typical size of hospital keep was 18.69 days. Moreover, one affected person was readmitted with belly ache, and one other skilled delayed gastric emptying inside 30 days after surgical procedure (Table 4).
Postoperative problems
Dialogue
This examine assessed the efficacy and security of intraoperative radiation remedy in 35 sufferers with pancreatic most cancers who underwent radical distal pancreatectomy with en bloc splenectomy. Relating to therapy efficacy, the median TTF was 11.67 months, and the OS for all the cohort was 22.2 months. The locoregional recurrence charge was 20%. Most postoperative problems have been manageable.
Pancreatic most cancers stays among the many most difficult malignancies to deal with, regardless of developments in surgical procedure, chemotherapy, and radiation remedy, and the general 5-year survival charge has not considerably improved1. Native failure charges vary from 50% to 80% in sufferers with resected and domestically superior illness4. Cardillo et al.22 have demonstrated that uncontrolled locoregional illness is the main reason for hospitalization amongst sufferers with pancreatic most cancers. IORT has emerged as a protected and efficient process that enhances native management with out growing morbidity or mortality dangers9,14,15,23. A meta-analysis encompassing 15 research in 834 sufferers has demonstrated that IORT considerably will increase locoregional management and OS in sufferers with resectable pancreatic most cancers, with out growing postoperative complication charges or operation-related mortality15. Nonetheless, some reviews have steered that IORT may result in extreme postoperative problems with out bettering OS24–27. In our examine, solely 7 sufferers skilled locoregional recurrence. The median TTF and OS have been 11.67 months and 22.2 months, respectively, thus indicating a decrease locoregional recurrence charge than reported in historic information. Recruitment for this examine is ongoing, and long-term follow-up information aren’t but obtainable. As a result of most reported experiences have come from single establishments and have concerned restricted numbers of sufferers, the true function of IORT within the scientific administration of pancreatic most cancers stays unclear.
Chen et al.13, in a examine of the long-term outcomes of intraoperative electron beam radiation remedy in China, noticed that delayed gastric emptying was the commonest postoperative complication (7.7%), with pancreatic fistula noticed in 8 sufferers (3.2%) and biliary fistula noticed in 3 sufferers (1.2%); furthermore, gastrointestinal hemorrhage was noticed in 7 sufferers (2.8%)28. In our examine, pancreatic fistula was the predominant complication (grade A: 85.7%, grade B: 5.7%, grade C: 2.9%). No cases of biliary fistula and gastrointestinal hemorrhage have been noticed. The IORT dose was not considerably related to postoperative problems. Our findings steered that IORT could be safely built-in into the administration of resectable pancreatic most cancers, and demonstrates acceptable morbidity and mortality charges.
The identification of sufferers who may profit from IORT stays a vital space of investigation. CT imaging traits and serum CA19-9 ranges have been proposed for stratification of sufferers with domestically superior pancreatic most cancers present process IORT in keeping with development threat28. In a examine by Kazuhiko et al.29 exploring IORT with or with out exterior beam radiotherapy for resected pancreatic most cancers, elements similar to chemotherapy use, diploma of resection, CA19-9 degree, and pathological node stage have been discovered to considerably affect OS. Equally, within the present examine, CA 19-9 ranges, CEA ranges, and D-dimer ranges have been recognized as impartial prognostic elements for OS. Sufferers with regular serum CA19-9 ranges had a considerably longer median OS than these with elevated CA19-9 ranges (14.733 months vs. not obtainable) (P = 0.009). Given the restricted pattern dimension within the present examine, a nomogram for stratifying sufferers with resectable pancreatic most cancers into low- and high-risk teams after IORT was not constructed. CEA is a broadly used marker for predicting pancreatic most cancers prognosis30–33. Sato et al.32 have demonstrated that top serum CEA serves as an indicator of quick survival after pancreaticoduodenectomy for pancreatic most cancers. In settlement with earlier analysis findings, CEA was considerably larger in people with shorter survival in our examine. D-dimer ranges, indicative of cancer-related hypercoagulation and metastatic potential, have been additionally related to poor survival outcomes34. A meta-analysis has indicated the affiliation between larger preoperative D-dimer ranges and superior tumor stage, bigger tumor dimension, in addition to distant metastases35. Within the current examine, the median OS of sufferers with excessive and low D-dimer ranges was 15.067 months and never reached, respectively (P = 0.016). Irritation, acknowledged for its function in tumourigenesis and metastasis36, has been extensively studied in pancreatic most cancers. A examine together with sufferers with pancreatic most cancers with liver metastases has reported that the prognostic dietary index, the neutrophil-to-lymphocyte ratio (NLR), CA19-9, CEA, gender, and chemotherapy are considerably related to OS33. Elements such because the NLR, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, neutrophil-platelet rating, systemic irritation response index, ratio of NLR to pAlb, systemic immune irritation index, systemic irritation rating, fibrinogen-NLR rating, and ratio of NLR to albumin don’t have any prognostic worth concerning OS.
A examine together with 30 sufferers with pancreatic most cancers has revealed elevated ranges of cytokines related to the PI3K/SMAD pathway in peritoneal fluid after IORT37. Moreover, peritoneal fluid from IORT-treated sufferers inhibits the expansion, migration, and invasiveness of pancreatic most cancers cells. These findings counsel that IORT exerts anti-tumor results by activating immune responses. Combining IORT with novel therapeutic brokers, similar to immune checkpoint inhibitors, in scientific trials is likely to be a promising technique to reinforce outcomes for sufferers with pancreatic most cancers.
Prior to now, IORT has relied totally on visible and guide steering with out the usage of 3D therapy planning or correction for tissue heterogeneity. This strategy has restricted the precision of dose software and the correct documentation of dose distribution inside tissues. Combining intraoperative CBCT with preoperative CT scans has enabled exact dose calculations whereas making certain correct positioning of the radiation supply/applicator19. Roeder et al.38 have demonstrated the appliance of image-guided IORT within the abdominopelvic area, by incorporating real-time intraoperative dose calculations primarily based on particular person affected person anatomy. Nonetheless, their examine centered on a single affected person with locoregionally recurrent rectal most cancers after neoadjuvant re-chemoradiation38. In our examine, solely 2 sufferers acquired image-guided IORT. Nonetheless, future remedies will incorporate this expertise extra extensively.
A number of examine limitations have to be acknowledged. First, the single-arm examine design precludes definitive conclusions from being drawn concerning the potential superiority of including IORT to surgical procedure versus surgical procedure alone, by way of problems or therapy outcomes. Potential randomized managed trials are required. Due to the growing numbers of laparoscopic operations, the security of surrounding organs can’t be absolutely ensured, and laparoscopic intraoperative radiotherapy has not but been carried out. The sluggish enrollment has affected examine progress and the effectivity of information assortment. To make sure a scientific and efficient examine, the analysis workforce determined to research the present information for well timed analysis of the analysis progress and therapy results, to allow changes or determine whether or not to proceed the examine. The findings can even require validation by way of additional follow-up, due to the restricted participant cohort. Moreover, the protocol didn’t specify postoperative adjuvant chemotherapy.
Conclusions
In abstract, our findings counsel that IORT could be safely built-in into the administration of resectable pancreatic most cancers, and is appropriate by way of morbidity and mortality. Sufferers with decrease ranges of CEA, CA19-9, and D-dimer may expertise extended survival.
Battle of curiosity assertion
No potential conflicts of curiosity are disclosed.
Creator contributions
Conceived and designed the evaluation: Xingyun Chen, Shuo Li, Chuntao Gao, Wei Wang, Rui Liu, Jihui Hao.
Collected the information: Xingyun Chen, Shuo Li, Haorui Li, Yuxiao Liu.
Contributed information or evaluation instruments: Xingyun Chen, Shuo Li.
Carried out the evaluation: Xingyun Chen, Shuo Li.
Wrote the paper: Xingyun Chen, Shuo Li.
Information availability assertion
The info generated on this examine can be found upon request from the corresponding writer.
Acknowledgments
We thank Weidong Ma, Jian Wang, Tiansuo Zhao, Xiuchao Wang, Music Gao, Yuexiang Liang, Hongwei Wang, and Wei Li on the Tianjin Medical College Most cancers Institute & Hospital for recruitment and operation. We thank Jing Zhang, Daguang Zhang, and Jing Wang on the Division of Radiation Oncology, Tianjin Medical College Most cancers Institute & Hospital, for IORT technical assist. We recognize the belief and efforts of the contributors within the scientific trial.
- Obtained July 25, 2024.
- Accepted November 25, 2024.
- Copyright: © 2025, The Authors
