Radiation-induced cystitis treated with hyperbaric oxygen therapy (RICH-ART): a randomised, controlled, phase 2-3 trial.

BACKGROUND: Late radiation cystitis is an adverse effect of cancer treatment with radiotherapy in the pelvic region. Symptoms of late radiation cystitis can be assessed with the Expanded Prostate Index Composite Score (EPIC). Previous reports indicate that hyperbaric oxygen therapy reduces symptoms from late radiation cystitis, but the evidence is predominantly based on non-randomised and retrospective studies. We aimed to assess whether hyperbaric oxygen therapy would mitigate symptoms of late radiation cystitis. METHODS: We did a randomised, controlled, phase 2-3 trial (RICH-ART [Radiation Induced Cystitis treated with Hyperbaric oxygen-A Randomised controlled Trial]) at five Nordic university hospitals. All patients aged 18-80 years, with pelvic radiotherapy completed at least 6 months previously, a score of less than 80 in the urinary domain of the Expanded Prostate Index Composite Score (EPIC), and referred to participating hyperbaric clinics due to symptoms of late radiation cystitis, were eligible for inclusion. Exclusion criteria were ongoing bleeding requiring blood transfusion exceeding 500 mL in the past 4 weeks, permanent urinary catheter, bladder capacity less than 100 mL, fistula in the urinary bladder, previous treatment with hyperbaric oxygen therapy for late radiation injuries, and contraindications to hyperbaric oxygen therapy. After computer-generated 1:1 randomisation with block sizes of four for each stratification group (sex, time from radiotherapy to inclusion, and previous invasive surgery in the pelvic area), patients received hyperbaric oxygen therapy (30-40 sessions, 100% oxygen, breathed at a pressure of 240-250 kPa, for 80-90 min daily) or standard care with no restrictions for other medications or interventions. No masking was applied. The primary outcome was change in patient-perceived urinary symptoms assessed with EPIC from inclusion to follow-up at visit 4 (6-8 months later), measured as absolute change in EPIC urinary total score. RICH-ART closed enrolment on Dec 31, 2017; the last follow-up data will be compiled in 2023. RICH-ART is registered with ClinicalTrials.gov, number NCT01659723, and with the European Medicines Agency, number EudraCT 2012-001381-15. FINDINGS: Of 223 patients screened between May 9, 2012, and Dec 20, 2017, 87 patients were enrolled and randomly assigned to either hyperbaric oxygen therapy (n=42) or standard care (n=45). After excluding eight patients who withdrew consent directly after randomisation (one in the hyperbaric oxygen therapy group and seven in the standard care group), 79 were included in the intention-to-treat analyses (n=41 in the hyperbaric oxygen therapy group, n=38 in the standard care group). Median time from randomisation to visit 4 was 234 days (IQR 210-262) in the hyperbaric oxygen therapy group and 217 days (195-237) in the standard care group. The difference between change in group mean of EPIC urinary total score at visit 4 was 10·1 points (95% CI 2·2-18·1; p=0·013; 17·8 points [SD 18·4] in the hyperbaric oxygen therapy group vs 7·7 points [15·5] in the standard care group). 17 (41%) of 41 patients in the hyperbaric oxygen therapy group experienced transient grade 1-2 adverse events, related to sight and hearing, during the period of hyperbaric oxygen therapy. INTERPRETATION: Our results suggest that hyperbaric oxygen therapy relieves symptoms of late radiation cystitis. We conclude that hyperbaric oxygen therapy is a safe and well tolerated treatment. FUNDING: The regional research fund of Region Västra Götaland, Sweden, the regional Health Technology Assessment Centre at Sahlgrenska University Hospital, Sweden, and Lions Cancer Research Fund of Western Sweden.

Autologous Platelet-Released Growth Factor and Sexual Dysfunction Amendment: A Pilot Clinical Trial of Successful Improvement Sexual Dysfunction after Pelvic Irradiation

Sexual dysfunction (SDF) is a common sequel to cancer treatment which affects the quality of life in women treated with pelvic radiotherapy. The aim of this study was to evaluate the safety, symptom resolution and objective improvement the injection of autologous platelet released growth factor (APRGF) for treatment of SDF in cited patients. This prospective pilot study enrolled 10 cancer-free patients with SDF who underwent pelvic radiotherapy at least 5 years ago, randomly. Each patient was received 1-2 cc APRGF within four weeks and all patients were re-evaluated at eight weeks and six months. CD34 immuno histochemistry and Masson's trichrome staining were performed on vaginal biopsy section for angiogenesis and fibrosis assay respectively. Sexual satisfaction after the injection of APRFG was clinically difference and the entire patient had sexual satisfaction. In the patient's follow-up, none of them needs to repeat the treatment. Our results declared that APRGF injection was effective and symptoms were disappeared in the entire patients. Significant objective improvements in vaginal diameter (mean before injection, 6.5 cm vs 7.1 cm after injection) (p-value = 0.001) and vaginal flexibility (mean before treatment, 0.72 cm vs 1.85 cm after injection) (P-value = 0.026) were observed. Characteristics of discharge before the injection in 60% of patients were included dry vagina and 40% had mild discharge but after injection 40% of patients had moderate and also 60% had mild and sufficient discharge (P-value= 0.190). Overally, our patients reported better sexual function and showed better vaginal function indexes, after APRFG injection.

Laparoscopic cytoreductive surgery and HIPEC is effective regarding peritoneum tissue paclitaxel distribution.

BACKGROUND: In some patients with peritoneal carcinomatosis, we could perform the cytoreductive surgery and the HIPEC procedure by a complete laparoscopic approach to avoid morbidity. We consider that using laparoscopic approach for performing peritoneal carcinomatosis cytoreductive surgery and HIPEC with closed CO2 recirculation technique is possible and safe, with equal efficacy to conventional methods and hemodynamic complications. OBJECTIVE: Monitoring the effectiveness of the drug distribution in a laparoscopic ctoreductive and HIPEC surgery group with CO2 recirculation respect to a closed and open HIPEC group METHODS: Porcine model that included fifteen mini-pigs. Five pigs were operated with laparoscopic approach performing a pelvic and retroperitoneal lymphadenectomy. They later received a total laparoscopic closed HIPEC with CO2 recirculation (G1). Group 2 (G2): five pigs operated by an open cytoreductive surgery and closed HIPEC technique. Group 3 (G3): five animals in which an open cytoreductive surgery and an open HIPEC technique was performed. Blood and peritoneal determinations were realized after recirculation of the drug, at 60 min using chromatographic analysis. RESULTS: G1-G2: phrenic right peritoneum, p: 0.46. Phrenic left peritoneum, p: 0.46. Pelvic peritoneum, p: 0.17. Serum paclitaxel: p: 0.01. G1-G3: phrenic right peritoneum, p: 0.34. Phrenic left peritoneum, p: 0.34. Pelvic peritoneum, p: 0.17. Serum paclitaxel G1-G3, p: 0.02. CONCLUSIONS: A total laparoscopic approach for ctoreductive surgery and closed HIPEC with CO2 recirculation may be safe and feasible. In our experimental model there was no significant difference in tissue drug distribution respect the conventional techniques and there was a less toxicity because the serum drug concentration was significantly lower with laparoscopic approach respect the other groups.

Magnetic Resonance Imaging of Pelvic Masses: A Compartmental Approach.

Magnetic resonance imaging (MRI) is often "one stop shop" for evaluating female pelvic masses that helps in diagnosis, staging, and restaging of these tumors. A pelvic mass can arise from any tissue present within the pelvis. Although most masses in the female pelvis arise from the reproductive organs, masses may also arise from the gastrointestinal tract, urinary system, adjacent soft tissues, peritoneum, etc. It may not always be possible to determine the site of origin or distinguish these masses based on imaging characteristics. However, familiarity with the clinicopathologic and MRI features of most common pelvic masses helps in narrowing the differential diagnosis. Diagnosis of these masses needs a holistic approach as required for any tumor including clinical history, laboratory data, and imaging characteristics. We focus on MRI characteristics of commonly encountered pelvic masses. A compartmental imaging approach is discussed in this article that helps in identifying and characterizing these masses.

Nutritional Supplement Based on Zinc, Prebiotics, Probiotics and Vitamins to Prevent Radiation-related Gastrointestinal Disorders.

AIM: The present phase II study aimed to evaluate the tolerance and safety of Dixentil, a nutritional supplement based on zinc with the addition of prebiotics (galacto-oligosaccharides), tyndalized probiotics (Lactobacillus acidophilus and L. casei) and vitamins B1, B2 and B6, and nicotinamide), given as prophylaxis to patients undergoing pelvic radiotherapy and its efficacy in the prevention and reduction of radiation-related gastrointestinal disorders. PATIENTS AND METHODS: Forty consecutive patients who were candidates for pelvic radiotherapy received Dixentil before starting and during radiotherapy. The primary end-point was to evaluate the safety and tolerance of Dixentil. Secondary end-points were incidence and severity of radiation-induced diarrhea and number of patients who discontinued radiotherapy because of diarrhea. RESULTS: Radiation-induced enteritis occurred in 17 patients, grade I and grade II diarrhea was documented in 14 and 3 patients respectively; no grade III or IV diarrhea was observed. Radiotherapy was discontinued due to treatment-induced enteritis only in two patients for 6 days. CONCLUSION: Use of Dixentil is an easy, safe, and feasible approach to protect patients against the risk of radiation-induced diarrhea.

Neuroblastoma: treatment outcome after incomplete resection of primary tumors.

PURPOSE: For International Neuroblastoma Staging System (INSS) stages III or IV neuroblastoma (intermediate or high risk), complete excision of the primary tumor is not always feasible. Most current studies on the treatment outcome of these patients have reported on the complete excision status. The aim of this study is to review the treatment outcome after the incomplete resection. METHODS: The medical records of 37 patients that underwent incomplete resection between January 1986 and December 2005 were reviewed retrospectively. Incomplete resection was assessed by review of the operative notes and postoperative computerized tomography. Age, gender, tumor location, INSS stage, N-myc gene copy number, pre- and postoperative therapy, and treatment outcome were reviewed. The treatment outcome was evaluated according to the postoperative treatment protocol in the high-risk group. RESULTS: Intermediate-risk patients were treated with conventional chemotherapy, isotretinoin (ITT) and interleukin-2 (IL-2). High-risk patients were treated with peripheral blood stem cell transplantation (PBSCT), ITT, and IL-2 (N = 11). Before the introduction of PBSCT, the high-risk patients were also treated with the conventional chemotherapy (N = 19). Intermediate-risk patients (N = 5) currently have no evidence of disease (NED). For the high-risk patients (N = 32), 19 patients were treated with chemotherapy alone; 15 patients died of their disease while four patients currently have an NED status. Eight of 11 patients that underwent PBSCT are currently alive. CONCLUSIONS: For intermediate risk, conventional chemotherapy appears to be acceptable treatment. However, for high-risk patients, every effort should be made to control residual disease including the use of myeloablative chemotherapy, differentiating agents and immune-modulating agents.

Complaint-adaptive power density optimization as a tool for HTP-guided steering in deep hyperthermia treatment of pelvic tumors.

For an efficient clinical use of HTP (hyperthermia treatment planning), optimization methods are needed. In this study, a complaint-adaptive PD (power density) optimization as a tool for HTP-guided steering in deep hyperthermia of pelvic tumors is developed and tested. PD distribution in patients is predicted using FE-models. Two goal functions, Opt1 and Opt2, are applied to optimize PD distributions. Optimization consists of three steps: initial optimization, adaptive optimization after a first complaint and increasing the weight of a region after recurring complaints. Opt1 initially considers only target PD whereas Opt2 also takes into account hot spots. After patient complaints though, both limit PD in a region. Opt1 and Opt2 are evaluated in a phantom test, using patient models and during hyperthermia treatment. The phantom test and a sensitivity study in ten patient models, show that HTP-guided steering is most effective in peripheral complaint regions. Clinical evaluation in two groups of five patients shows that time between complaints is longer using Opt2 (p = 0.007). However, this does not lead to significantly different temperatures (T50s of 40.3 (Opt1) versus 40.1 degrees C (Opt2) (p = 0.898)). HTP-guided steering is feasible in terms of PD reduction in complaint regions and in time consumption. Opt2 is preferable in future use, because of better complaint reduction and control.

[A case of effective regimen of tegafur and uracil (UFT)/leucovorin (LV) plus irinotecan (CPT-11) for advanced rectal carcinoma with severe pelvic infiltration to be performed curative resection].

A 72-year-old man was admitted to our hospital, complaining of severe diarrhea. Computed tomography, barium enema and colonoscopy revealed a cysto-rectal fistula and massive invasion to middle rectum and retroperitoneal space from the main tumor in the upper rectum. Because of obstruction of passage of stool, sigmoid colostomy was performed. Oral UFT/LV+CPT-11 were undertaken after surgery for 4 cycles to remarkably reduce the tumor both clinically and on an outpatient basis. During this period, no side effect was detected, and a performance status (PS) of 0 has been maintained. As the result, radical resection was performed 5 months after the first operation. The histological effect was judged to be grade 2. Furthermore, no recurrence was recognized after 16 months postoperatively. Therefore, oral administration of UFT/LV+CPT-11 was considered as effective neoadjuvant chemotherapy for advanced rectal carcinoma, and this also could be a promising regimen to maintain the quality of life (QOL) for patients in ambulatory therapy.

Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma.

PURPOSE: The purpose of this single-center phase II study was to determine the activity of pemetrexed administered as second-line therapy in patients with advanced urothelial carcinoma. METHODS: Patients with advanced urothelial carcinoma that had relapsed after receiving perioperative chemotherapy, or progressed on first-line chemotherapy for metastatic disease, were eligible for enrollment. Patients received pemetrexed 500 mg/m(2) every 21 days along with folic acid and vitamin B12 supplementation. RESULTS: A total of 13 patients were enrolled. An objective response was achieved in 1/12 evaluable patients for an overall response rate of 8% (90% upper limit 29%). This level of activity did not meet criteria for expansion based on the pre-defined optimal 2-stage Simon design and the trial was concluded. Treatment was generally well tolerated, however, 2/13 patients developed febrile neutropenia. Non-hematologic grade > or = 3 toxicity was rare. CONCLUSIONS: Pemetrexed as second-line therapy in advanced urothelial carcinoma is associated with modest activity. The role of this novel antifolate in chemotherapy-naïve patients warrants further investigation.

[Thermal dosimetric study on hyperthermia combined with radiotherapy for deep seated pelvic malignancies].

OBJECTIVE: To ascertain a clinically meaningful thermal dose unit-temperature equivalent minute (TEM) 42.5 degrees C and the relationship between TEM 42.5 degrees C and tumor response rate. METHODS: From August 1998 to December 2002, 49 patients with recurrent or metastatic malignancies in the pelvis were treated with hyperthermia combined with conventional radiotherapy. Direct thermometry with high resistance lead needle was used whenever possible to measure the temperature by inserting Teflon catheter into the tumor. TEM 42.5 degrees C was used as the thermal dose unit and the relationship between TEM 42.5 degrees C and tumor response rate was monitored. RESULTS: There was a positive correlation between response rate TEM 42.5 degrees C and the radiation dose. The tumor volume and number of heat treatment showed no influence on response. CONCLUSION: Both univariate analysis and multivariate logistic regression analysis indicate that there is a positive correlation between the response rate, TEM 42.5 degrees C and the radiation dose. TEM 42.5 degrees C may act as a useful thermal dose unit in the combination of hyperthermia and radiotherapy. To lower the incidence of complications in thermometry, direct thermometry with high resistance lead needle can be used to measure the temperature by inserting Teflon catheter into the deep-seated malignancies.

Radiofrequency ablation in the treatment of pelvic recurrence of rectal cancer.

The aim was to assess the response to the treatment using thermal radiofrequency ablation in patients with pelvic recurrent rectal cancer. The location of the lesions as well as the placement of the percutaneous probe were guided by computed tomography. All ablations were performed with a RITA Medical Systems Starburst XL (nine-array, 5-cm) thermal ablation catheter and the Model 1500 generator (RITA Medical Systems, Inc.). The radiofrequency ablation treatment was performed in two patients with pelvic recurrent rectal cancer with poor response to chemoradiotherapy with no indication of new surgical treatment and suffering strong pain in the sacrum area. The serum carcinoembryonic antigen had a sharp reduction in a sixty-day period. The post-procedure tomography analysis showed the center of the tumor with necrosis and a ring of edema around it. Both patients had no complaints about the procedure, and they needed to take mild analgesics only on the first day right after the procedure for pain. In the follow-up one patient developed an abscess and needed to be readmitted but without recurrent pelvic pain. An effective response was shown by tumor necrosis and total relief of pain of the sacrum area.

Massive pelvic hemangioma in a patient with blue rubber bleb nevus syndrome.

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder characterized by gastrointestinal and cutaneous hemangiomas. Patients typically present with gastrointestinal bleeding and anemia. Management of gastrointestinal bleeding may be challenging, since these lesions may be diffusely distributed throughout the gastrointestinal tract. The most common location is the small bowel, and recurrence is common. We describe a patient with BRBNS and lower gastrointestinal bleeding resulting from a large pelvic hemangioma eroding into the rectal wall.

[The role of intraperitoneal chemotherapy after curative excision of primary abdominopelvic sarcoma]. / Place de la chimiothérapie intrapéritonéale après exérèse curative des sarcomes abdomino-pelviens primitifs.

Local recurrence and prognosis of abdominopelvic sarcomas depend on complete resection of the primary malignancy. Peritoneal seeding of the tumor can be assessed by the size of the tumor and the number of abdominopelvic regions involved by sarcoma. Under these conditions, we analyzed 14 consecutive patients with primary sarcoma. Complete resection of the tumor was performed in 9 patients with peritoneal involvement less than or equal to 3 abdomino-pelvic regions and complete resection combined with perioperative intraperitoneal chemotherapy was performed for the last 5 patient with involvement of more than 3 abdomino-pelvic regions. Results shows that the median survival was 28 months and the survival for very large tumors treated with perioperative intraperitoneal chemotherapy was similar to survival for smaller tumors treated by resection only. These results suggest the efficacy of chemotherapy on the site of resection and argue in favour of the use of regional chemotherapy in an attempt to achieve long-term disease-free survival for primary sarcoma.

Three-dimensional monitoring of small temperature changes for therapeutic hyperthermia using MR.

Radiofrequency hyperthermia of deep-seated pelvic tumors requires noninvasive monitoring of temperature distributions in patients. Methods of MR thermography were reported to be a promising tool in solving this problem. However, to be truly useful for monitoring hyperthermia treatments, MR thermography should be able to cover the entire pelvis in acquisition times no longer than for a breath-hold (< or = 15 seconds) and to resolve small temperature differences (< 1 degrees C). Three methods exploiting the temperature dependence of spin-lattice relaxation time (T1), of self-diffusion coefficient (D), and of chemical shift of proton resonance frequency (PRF) were applied in phantom experiments; the pulse sequences were the T1-weighted gradient echo, the pulsed diffusion gradient spin echo made faster through the keyhole technique, and the gradient echo with the phase reconstruction, respectively. The high planar resolution was compromised, and instead, coarse and more isotropic voxels were used. Experiments were performed in two consecutive steps, thus imitating a possible scenario for monitoring hyperthermia. In the first step, calibration curves were recorded, which were then used in the second step to obtain maps of temperature changes. The results show a clear superiority of the PRF method, followed by the D and the T1 methods. The uncertainty of temperature changes predicted both from calibration curves and from maps was less than 1 degrees C only with the PRF and the D-based methods.

Clinical experience using 8 MHz radiofrequency capacitive hyperthermia in combination with radiotherapy: results of a phase I/II study.

PURPOSE: Since 1985, the University of Minnesota Hospital and Clinic has investigated the efficacy and safety of 8 MHz radiofrequency (RF) capacitive hyperthermia using the Thermotron RF-8. This study reports the thermometric and clinical results of 119 patients treated with RF hyperthermia in combination with radiotherapy (RT). METHODS AND MATERIALS: Of 119 patients, 69 received high-dose RT and 50 patients received low-dose RT because of previous irradiation to the treatment site. The most common anatomic sites treated were within the pelvic cavity or head and neck area. Thirty-three percent and 24% of tumors treated were > 7 cm and > 10 cm in largest diameter, respectively. Forty percent of the patients had deep-seated tumors (depth > 6 cm). Hyperthermia was given as soon as possible after RT twice weekly, allowing at least 72 h between treatments. The objective was to raise intratumoral temperatures to 42-43 degrees C or above for 30-50 min while keeping normal tissue temperatures below 40-41 degrees C. RESULTS: Of 119 patients, 40% achieved a Tmax tumor temperature of > 42 degrees C and 40% achieved 40-42 degrees C Tmax. Higher Tmax) tumor temperatures were observed as tumor size increased. Tumors > 10 cm in largest diameter had a Tmax of 42.2 degrees C. Tumor depth was not a significant factor for the tumor temperatures achieved. Of 119 patients, 11% achieved complete response and 38% achieved partial response. Of the no-response patients, 34% had symptomatic palliation and 15% had stable disease for at least 12 months after treatment. We were able to treat tumors of patients with subcutaneous fat as thick as 3 cm by precooling the fat for 20 min with 10-15 degrees C saline-filled boluses prior to the initiation of heating. During treatment, 60% of patients complained of varying degrees of pain and 19% had pain that was a factor in limiting treatment. Vital signs were relatively stable and not a factor in limiting treatment. CONCLUSION: The Thermotron RF-8 is a useful hyperthermia device that can raise tumor temperatures to a therapeutic level (i.e., 42 degrees C) in a significant proportion of patients with superficial, subsurface, and deep-seated tumors, with minimal adverse effects, complications, and systemic stress. Further clinical studies using improved thermometry systems are warranted.

Endoscopic ultrasonography in the assessment of colonic wall invasion by adjacent diseases.

For assessing the direct invasion of the colonic wall by pelvic or abdominal tumors, endoscopic ultrasonography was performed prospectively in patients who were suspected of having colonic wall invasion by barium enema. Three patients with ovarian cancer, two with endometriosis, and one with pancreatic cancer were included in this study. Preoperative endoscopic ultrasonography (EUS) revealed the relationship between the tumor and the colon in all cases. A surgical procedure was performed in all patients: resection of the tumor and a portion of the invaded colon (4) and removal of the tumor (only adhesion) (2). A correct preoperative diagnosis of the depth of tumor invasion was obtained in five of the six (83%) cases. In patients with pelvic or abdominal tumors, preoperative EUS may be useful for evaluating the presence and the degree of invasion of the colonic wall by the tumor.

[CT-guided Tru Cut biopsy of solid pelvic space-occupying lesions. The indications, technic and results]. / CT-gesteuerte Tru-Cut-Biopsie soldier pelviner Raumforderungen. Indikationen, Technik und Ergebnisse.

Solid lesions in different localisations of the pelvis were biopsied with a large-bore Tru-Cut cannula (G 14) in 88 patients under computed tomographic guidance. Special techniques for safe access to pelvic lesions are described. Indications for biopsy were suspected extraluminal tumour recurrence (n = 49), masses outside the pelvic organs in the absence of a known pelvic primary (n = 21) and in the presence of a known pelvic primary (n = 10). In 8 cases, lesions situated within pelvic organs were punctured. Without any repeat biopsy, accuracy reached 96.6%, sensitivity was 95.2% and specificity was 100%. In comparison to the results of FNA reported in the literature diagnostic accuracy can be improved upon by using large-bore biopsy. No complications occurred.

Clinical investigations on blood perfusion in human malignancies of the pelvis and abdomen: significance for tumor therapy.

Blood flow of deep pelvic and abdominal tumors was investigated with the thermal clearance method, dynamic CT and dynamic MRI. There are good correlations between the measurement values obtained by these methods. A low flow was observed in rectal cancer and soft tissue sarcoma in contrast to pancreatic cancer and hypernephroma. The temperature increase induced by regional hyperthermia was dependent on the individual tumor blood flow. Dynamic CT can be used pretherapeutically and predict the quality of a heat treatment, which is important with regard to concepts consisting in radiotherapy or chemotherapy plus hyperthermia.