Clinical feasibility of combining intraoperative electron radiation therapy with minimally invasive surgery: a potential for electron-FLASH clinical development.

BACKGROUND: Local cancer therapy by combining real-time surgical exploration and resection with delivery of a single dose of high-energy electron irradiation entails a very precise and effective local therapeutic approach. Integrating the benefits from minimally invasive surgical techniques with the very precise delivery of intraoperative electron irradiation results in an efficient combined modality therapy. METHODS: Patients with locally advanced disease, who are candidates for laparoscopic and/or thoracoscopic surgery, received an integrated multimodal management. Preoperative treatment included induction chemotherapy and/or chemoradiation, followed by laparoscopic surgery and intraoperative electron radiation therapy. RESULTS: In a period of 5 consecutive years, 125 rectal cancer patients were treated, of which 35% underwent a laparoscopic approach. We found no differences in cancer outcomes and tolerance between the open and laparoscopic groups. Two esophageal cancer patients were treated with IOeRT during thoracoscopic resection, with the resection specimens showing intense downstaging effects. Two oligo-recurrent prostatic cancer patients (isolated nodal progression) had a robotic-assisted surgical resection and post-lymphadenectomy electron boost on the vascular and lateral pelvic wall. CONCLUSIONS: Minimally invasive and robotic-assisted surgery is feasible to combine with intraoperative electron radiation therapy and offers a new model explored with electron-FLASH beams.

Role of radiotherapy in the chemotherapy-containing multidisciplinary management of patients with resected pancreatic adenocarcinoma.

BACKGROUND: To analyze prognostic factors associated with long-term outcomes in patients with resected pancreatic cancer treated with chemotherapy (CT) and surgery with or without external beam radiotherapy (EBRT). PATIENTS AND METHODS: From January 1995 to December 2012, 95 patients with adenocarcinoma of the pancreas and locoregional disease [clinical stage IB-IIA (n = 45; 47%), IIB-IIIC (n = 50; 53%)] were treated with curative resection [R0 (n = 52; 55%), R1 (n = 43, 45%)] and CT with (n = 60; 63%) or without (n = 35; 37%) EBRT (45-50.4 Gy). Additionally, 29 patients (48%) also received a pre-anastomosis IOERT boost (applicator diameter size, 7-10 cm; dose, 10-15 Gy; beam energy, 9-18 MeV). RESULTS: With a median follow-up of 17.2 months (range, 1-182), 2-year overall survival (OS), disease-free survival (DFS), and locoregional control were 28, 20, and 53%, respectively. Univariate analyses showed that IIB-IIIC stage (HR, 2.23; p = 0.04), R1 margin resection status (HR, 2.09; p = 0.04), no vascular resection (HR, 0.42; p = 0.02), and not receiving external beam radiotherapy (HR, 2.70; p = 0.004) were associated with locoregional recurrence. In the multivariate analysis, only R1 margin resection status (HR, 2.63; p = 0.009) and not receiving EBRT (HR, 2.91; p = 0.002) retained significance with regard to locoregional recurrence. We observed no difference in toxicity between patients treated with or without EBRT (p = 0.44). Overall treatment mortality was 3%. No long-term treatment-related death occurred. CONCLUSIONS: Although adjuvant CT is still the standard of care for resected pancreatic tumors, OS remains modest owing to the high risk of distant metastases. Locoregional treatment needs to be tested in the context of more efficient systemic therapy.

Post-chemoradiation intraoperative electron-beam radiation therapy boost in resected locally advanced rectal cancer: long-term results focused on topographic pattern of locoregional relapse.

BACKGROUND: Patients with locally advanced rectal cancer (LARC) have a dismal prognosis. We investigated outcomes and risk factors for locoregional recurrence (LRR) in patients treated with preoperative chemoradiotherapy (CRT), surgery and IOERT. METHODS: A total of 335 patients with LARC [⩾cT3 93% and/or cN+ 69%) were studied. In multivariate analyses, risk factors for LRR, IFLR and OFLR were assessed. RESULTS: Median follow-up was 72.6 months (range, 4-205). In multivariate analysis distal margin distance ⩽10 mm [HR 2.46, p = 0.03], R1 resection [HR 5.06, p = 0.02], tumor regression grade 1-2 [HR 2.63, p = 0.05] and tumor grade 3 [HR 7.79, p < 0.001] were associated with an increased risk of LRR. A risk model was generated to determine a prognostic index for individual patients with LARC. CONCLUSIONS: Overall results after multimodality treatment of LARC are promising. Classification of risk factors for LRR has contributed to propose a prognostic index that could allow us to guide risk-adapted tailored treatment.

Multidisciplinary therapy for patients with locally oligo-recurrent pelvic malignancies.

PURPOSE: To analyze prognostic factors and long-term outcomes in patients with locally recurrent pelvic cancer (LRPC) treated with a multidisciplinary approach. METHODS AND MATERIALS: From January 1995 to December 2011, 81 patients [rectal (47 %); gynecologic (39 %); retroperitoneal sarcoma (14 %)] underwent extended surgery [multiorgan (58 %), bone (35 %), vascular (9 %), soft tissue (63 %)] and intraoperative electron beam radiation therapy (IOERT) to treat recurrent tumors in the pelvic region. Thirty-five patients (43 %) received external beam radiotherapy (EBRT). Survival was estimated using the Kaplan-Meier method, and risk factors were identified using univariate and multivariate analysis. RESULTS: Median follow-up was 39 months (6-189 months); the 1- 3- and 5-year rates of locoregional control (LRC) were 83, 53, and 41 %, respectively. Univariate Cox proportional hazard analysis revealed worse LRC in patients who did not receive integrated EBRT as rescue treatment of pelvic recurrence (p = 0.003) or underwent non-radical resection (p = 0.01). In the multivariate analysis EBRT, non-radical resection, and tumor fragmentation retained significance (p = 0.002, p = 0.004, and p = 0.05, respectively). CONCLUSIONS: Radical resection, absence of tumor fragmentation and addition of EBRT for rescue are associated with improved LRC in patients with LRPC. Our results suggest that this group can benefit from EBRT combined with extended surgical resection and IOERT.

How to expand the safe limits in hepatic resections?

The size of the remnant liver after an extended hepatectomy is currently the main limiting factor for performing curative hepatic surgery in patients with tumors and liver metastasis. The current guidelines for extended hepatectomies require that the future remnant liver volume needs to be higher than 20% of the original liver in healthy organs, of 30% in livers with steatosis or exposed to chemotherapy, and of 40% in patients with cirrhosis in order to prevent the "small-for-size" syndrome, characterized by the development of liver dysfunction with ascites, coagulopathy and cholestasis. Observations from the use of small liver grafts in liver transplantation and an increased surgical experience has improved our understanding of the mechanisms responsible for the development of liver dysfunction after extended hepatectomies. Increasing the size of the future liver remnant, the introduction of the "small-for-flow" concept with the perioperative monitoring and modulation of portal blood flow and pressure, and the exploration of the potential effects of regeneration preconditioning, are all promising strategies that could expand the indications and increase the safety of liver surgery.

Chemoradiation for resected pancreatic adenocarcinoma with or without intraoperative radiation therapy boost: Long-term outcomes.

BACKGROUND/OBJECTIVES: To analyze prognostic factors associated with long-term outcomes in patients with pancreatic cancer treated with chemoradiation therapy (CRT) and surgery with or without intraoperative electron beam radiotherapy (IOERT). PATIENTS AND METHODS: From January 1995 to December 2012, 60 patients with adenocarcinoma of the pancreas and locoregional disease (clinical stage IB [n = 13; 22%], IIA [n = 16; 27%], IIB [n = 22; 36%], IIIC [n = 9; 15%]) were treated with CRT (45-50.4 Gy before surgery [n = 19; 32%] and after surgery [n = 41; 68%]) and curative resection (R0 [n = 34; 57%], R1 [n = 26, 43%]). Twenty-nine patients (48%) also received a pre-anastomosis IOERT boost (applicator diameter size, 7-10 cm; dose, 10-15 Gy; beam energy, 9-18 MeV). RESULTS: With a median follow-up of 15.9 months (range, 1-182), 5-year overall survival (OS), disease-free survival (DFS), and locoregional control were 20%, 13%, and 58%, respectively. Univariate analyses showed that R1 margin resection status (HR, 3.17; p = 0.04), not receiving IOERT (HR, 7.33; p = 0.01), and postoperative CRT (HR, 5.12; p = 0.04) were associated with a higher risk of locoregional recurrence. In the multivariate analysis, only margin resection status (HR, 3.0; p = 0.05) and not receiving IOERT (HR, 6.75; p = 0.01) retained significance with regard to locoregional recurrence. Postoperative mortality and perioperative complications were 3% (n = 2) and 43% (n = 26). CONCLUSIONS: Although local control is good in the radiation-boosted area, OS remains modest owing to high risk of distant metastases. Intensified locoregional treatment needs to be tested in the context of more efficient systemic therapy.

Postchemoradiation laparoscopic resection and intraoperative electron-beam radiation boost in locally advanced rectal cancer: long-term outcomes.

BACKGROUND: In selected patients with rectal cancer, laparoscopic surgery is as safe as open surgery, with similar resection margins and completeness of resection. In addition, recovery is faster after laparoscopic surgery. We analyzed long-term outcomes in a group of patients with locally advanced rectal cancer (LARC) treated with preoperative therapy followed by laparoscopic surgery and intraoperative electron-beam radiotherapy (IOERT). METHODS AND MATERIALS: From June 2005 to December 2010, 125 LARC patients were treated with 2 induction courses of FOLFOX-4 (oxaliplatin 85 mg/m(2)/d1, intravenous leucovorin at 200 mg/m(2)/d1-2, and an intravenous bolus of 5-fluorouracil 400 mg/m(2)/d1-2) and preoperative chemoradiation (4,500-5,040 cGy) followed by total mesorectal excision (laparoscopic, 35 %; open surgery, 65 %) and a presacral boost with IOERT. RESULTS: Patients in the laparoscopic surgery group lost less blood (median 200 vs 350 mL, p < 0.01) and had a shorter hospital stay (7 vs 11 days; p = 0.02) than those in the open surgery group. Laparoscopic procedures were shorter than open surgery procedures (270 vs 302 min; p = 0.67). Postoperative morbidity (32 vs 44 %; p = 0.65), RTOG grade ≥3 acute toxicity (25 vs 25 %; p = 0.97), and RTOG grade ≥3 chronic toxicity (7 vs 9 %; p = 0.48) were similar in the laparoscopy and open surgery groups. The median follow-up time for the entire cohort of patients was 59.5 months (range 7.8-90); no significant differences were observed between the groups in locoregional control (HR 0.91, p = 0.89), disease-free survival (HR 0.80, p = 0.65), and overall survival (HR 0.67, p = 0.52). CONCLUSIONS: Postchemoradiation laparoscopically assisted IOERT is feasible, with an acceptable risk of postoperative complications, shorter hospital stay, and similar long-term outcomes when compared to the open surgery approach.

Prognostic impact of external beam radiation therapy in patients treated with and without extended surgery and intraoperative electrons for locally recurrent rectal cancer: 16-year experience in a single institution.

PURPOSE: To analyze prognostic factors associated with survival in patients after intraoperative electrons containing resective surgical rescue of locally recurrent rectal cancer (LRRC). METHODS AND MATERIALS: From January 1995 to December 2011, 60 patients with LRRC underwent extended surgery (n=38: multiorgan [43%], bone [28%], soft tissue [38%]) or nonextended (n=22) surgical resection, including a component of intraoperative electron-beam radiation therapy (IOERT) to the pelvic recurrence tumor bed. Twenty-eight (47%) of these patients also received external beam radiation therapy (EBRT) (range, 30.6-50.4 Gy). Survival outcomes were estimated by the Kaplan-Meier method, and risk factors were identified by univariate and multivariate analyses. RESULTS: The median follow-up time was 36 months (range, 2-189 months), and the 1-year, 3-year, and 5-year rates for locoregional control (LRC) and overall survival (OS) were 86%, 52%, and 44%; and 78%, 53%, 43%, respectively. On multivariate analysis, R1 resection, EBRT at the time of pelvic rerecurrence, no tumor fragmentation, and non-lymph node metastasis retained significance with regard to LRR. R1 resection and no tumor fragmentation showed a significant association with OS after adjustment for other covariates. CONCLUSIONS: EBRT treatment integrated for rescue, resection radicality, and not involved fragmented resection specimens are associated with improved LRC in patients with locally recurrent rectal cancer. Additionally, tumor fragmentation could be compensated by EBRT. Present results suggest that a significant group of patients with LRRC may benefit from EBRT treatment integrated with extended surgery and IOERT.

Postchemoradiation resected locally advanced esophageal and gastroesophageal junction carcinoma: long-term outcome with or without intraoperative radiotherapy.

BACKGROUND: To report feasibility, tolerance, anatomical topography of locoregional recurrence (LRR), and long-term outcome for esophageal and esophagogastric (EG) cancer patients treated with preoperative chemoradiation (CRT) and surgery with or without a radiation boost of intraoperative electron beam radiotherapy (IOERT). METHODS: From January 1995 to December 2010, 53 patients with primary esophageal (n = 26; 44 %) or EG carcinoma (n = 30; 56 %), and disease confined to locoregional area [clinical stage: IIb (n = 30; 57 %), IIIa (n = 14; 26 %), IIIb (n = 6; 11 %), IIIc (n = 3; 6 %)], were treated with preoperative CRT, curative (R0) resection with an extended (two-field) lymph node dissection in all cases. Thirty-seven patients also received a preanastomotic reconstruction IOERT boost (applicator diameter size 6-9 cm, dose 10-15 Gy, beam energy 6-15 MeV) over the tumor bed in the mediastinum and upper abdominal lymph node area. RESULTS: With a median follow-up time of 27.9 months (range, 0.2-148), LRR rate was 15 % (n = 8). Five-year overall survival (OS) and disease-free survival was 48 and 36 %, respectively. Univariate log-rank analyses showed that receiving IOERT was associated with lower risk of LRR (p = 0.004). On multivariate analysis, only the IOERT group retained significance in relation to LRR (odds ratio, 0.08; 95 % confidence interval, 0.01-0.48; p = 0.01). Postoperative mortality and perioperative complications were 11 % (n = 6) and 30 % (n = 16). CONCLUSIONS: Local control is high in the radiation-boosted area, but OS remains modest, given the high risk of distant metastases. Intensified locoregional treatment needs to be tested in the context of more efficient concurrent, neo-, and adjuvant systemic therapy.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignant disease.

Peritoneal Malignant Disease (PMD) is the presence of tumoral tissue on the peritoneal surface from primary tumors or tumors from other locations (e.g. digestive or gynecologic). It is a regional disease with poor prognosis when treated with repeated "debulking" and traditional systemic chemotherapy. Cytoreduction plus hyperthermic intraperitoneal chemotherapy (HIPEC) is a combined multimodal regional procedure aimed at reducing the macroscopic tumoral mass as much as possible and treating with chemotherapy the microscopic disease that is out of the scope of the surgeon. This combined treatment may change the natural history of PMD, it is translated into a higher overall survival and cancer-free survival and it offers the option of cure in selected cases. The high-complexity procedure is also associated with complications and mortality, but in similar rates as other major oncologic procedures.

Is gum chewing useful for ileus after elective colorectal surgery? A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: The evaluation of the usefulness of gum chewing for postoperative ileus has given inconclusive results. We evaluated the efficacy of gum chewing in the treatment of ileus after elective colorectal surgery. MATERIALS AND METHODS: We performed a meta-analysis of randomized clinical trials comparing the effect of gum chewing+standard treatment vs. standard treatment on ileus after colorectal surgery. MEDLINE, EMBASE, the Cochrane Controlled Trial Register, and the Cochrane Database of Systematic Reviews were searched until August 2008. Primary outcomes were time to first flatus, time to first passage of feces, and length of hospital stay. The mean difference (MD) in hours was calculated with the random effects model to assess the effect of gum chewing on the outcomes. RESULTS: Six trials including 244 patients were analyzed. Time to first flatus was significantly reduced with gum chewing+standard treatment compared to standard treatment alone (MD -14 h, 95% confidence interval [95%CI] -23.5 to -4.6). Time to first passage of feces was significantly reduced (MD -25 h, 95%CI -42.3 to -7.7), but the length of hospital stay was only marginally reduced (MD -26.2 h, 95%CI -57.5 to 5.2) with gum chewing. CONCLUSION: In patients with ileus after colonic surgery, gum chewing in addition to standard treatment significantly reduces the time to first flatus and the time to first passage of feces when compared to standard treatment alone. There is also a trend to reduce the length of hospital stay. Gum chewing should be added to the standard treatment of these patients.

[Tailgut cysts]. / Hamartomas quísticos retrorrectales.

Retrorectal cystic hamartomas (tailgut cysts) are rare congenital lesions thought to arise from remnants of the embryonic postanal gut. They predominantly occur as asymptomatic retrorectal multicystic masses in women. The treatment of choice is by complete surgical excision. The most important complications of these cysts are infection with a secondary fistula and malignant degeneration. The differential diagnosis includes a wide variety of conditions that occur in the retrorectal space. In this article, 3 cases showing different surgical technical aspects of treatment are presented. In addition, the aetiopathogenic features and histopathological appearance, clinical presentation and complications, imaging features and differential diagnosis of tailgut cysts are described.

[Intraoperative therapeutic intensification techniques in locally advanced abdominal sarcomas]. / Intensificación terapéutica intraoperatoria en el tratamiento de los sarcomas abdominales localmente avanzados.

INTRODUCTION: Sarcomas are rare tumors that develop from mesenchymal cells. Their management is difficult due to their changing histology, location, and behavior. In this article, we discuss the use of two intraoperative therapeutic intensification techniques, intraoperative radiotherapy (IORT) and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC), in the treatment of locally advanced abdominal sarcomas and peritoneal sarcomatosis. MATERIAL AND METHODS: We analyzed a series of 20 consecutive patients diagnosed with advanced abdominal sarcoma and 5 patients with a diagnosis of peritoneal sarcomatosis who were evaluated and treated in our department from December 1996 to October 2005. In advanced abdominal sarcoma, we performed complete or maximal resection followed by IORT. In peritoneal sarcomatosis we performed massive cytoreduction followed by HIIC. RESULTS: The survival rate in advanced abdominal sarcomas without sarcomatosis was 65% at 26 months. Among the 5 patients diagnosed with peritoneal sarcomatosis, 3 were alive, and 2 were without recurrence at 20 months of follow-up. CONCLUSIONS: IORT associated with radical surgery seems to improve local control and survival in advanced abdominal sarcomas. Maximal cytoreduction plus HIIC used as treatment of peritoneal sarcomatosis is a feasible technique that offers a therapeutic option with curative intent.

[E = m x c2/4 men and an aneurysm]. / E = m x c2/4 hombres y un aneurisma.

As a contribution to International Physics Year (2005), we performed a historical study of Einstein's final years and the diseases that required surgical treatment. Because of the particular circumstances of the age, two of the most famous surgeons of the time, Rudolph Nissen and Frank Glenn, as well as the well-known radiologist, Gustav Bucky, came together with Albert Einstein over the abdominal aortic aneurysm that ended his life in April 1955. We discuss little known or hitherto unpublished data and anecdotes about the physicist's final surgical disease.

Neoadjuvant chemoradiation with tegafur in cancer of the pancreas: initial analysis of clinical tolerance and outcome.

The early institutional experience in the neoadjuvant treatment of potentially resectable pancreatic carcinoma using oral Tegafur as radioenhancing agent is analyzed. Fifteen patients (10 male and 5 female, mean age of 61 years) were treated over a 30-month period. Tegafur dose was 1,200 mg/d along the external radiotherapy period (45-55 consecutive days). Preoperative radiotherapy achieved a total dose of 45 to 50 Gy (1.8 Gy/d). Intraoperative electron boost (10-15 Gy) was delivered at the time of surgery. Hematologic tolerance showed a significant decrease of neutrophil and platelet counts from the outset to the end of the neoadjuvant period (p = 0.001 and p = 0.004, respectively). Five grade III vomiting episodes (33%) were also registered. In 9 patients (60%), surgical resection was performed after chemoradiation. Three complete pathologic responses (pT0 specimens) were identified; in seven cases, the resection achieved tumor-free surgical margins of the specimen. With a median follow-up of 21 months, median survival time was 17 months, with actuarial rates of 45% at 1 year and 24% at 3 years. Median survival for the resected patients was 23 months, and for the unresected patients median survival was 8 months (p = 0.02). The overall median survival in completely resected patients was 28 months, with a 71% survival rate at 1 and 3 years. It is concluded that the treatment scheme described is feasible and acceptably tolerated. The use of oral Tegafur seems to induce results similar to those of other therapeutic protocols using intravenous radioenhancing chemotherapy.