Theoretical evaluation of the impact of diverse treatment conditions by calculation of the tumor control probability (TCP) of simulated cervical cancer Hyperthermia-Radiotherapy (HT-RT) treatments in-silico.

INTRODUCTION: Hyperthermia (HT) induces various cellular biological processes, such as repair impairment and direct HT cell killing. In this context, in-silico biophysical models that translate deviations in the treatment conditions into clinical outcome variations may be used to study the extent of such processes and their influence on combined hyperthermia plus radiotherapy (HT + RT) treatments under varying conditions. METHODS: An extended linear-quadratic model calibrated for SiHa and HeLa cell lines (cervical cancer) was used to theoretically study the impact of varying HT treatment conditions on radiosensitization and direct HT cell killing effect. Simulated patients were generated to compute the Tumor Control Probability (TCP) under different HT conditions (number of HT sessions, temperature and time interval), which were randomly selected within margins based on reported patient data. RESULTS: Under the studied conditions, model-based simulations suggested a treatment improvement with a total CEM43 thermal dose of approximately 10 min. Additionally, for a given thermal dose, TCP increased with the number of HT sessions. Furthermore, in the simulations, we showed that the TCP dependence on the temperature/time interval is more correlated with the mean value than with the minimum/maximum value and that comparing the treatment outcome with the mean temperature can be an excellent strategy for studying the time interval effect. CONCLUSION: The use of thermoradiobiological models allows us to theoretically study the impact of varying thermal conditions on HT + RT treatment outcomes. This approach can be used to optimize HT treatments, design clinical trials, and interpret patient data.

Radiotherapy combined with deep regional hyperthermia in elderly and frail patients with muscle-invasive bladder cancer: quality analysis of hyperthermia and impact on clinical results.

Purpose: Radiotherapy (RT) in combination with deep regional hyperthermia (HT) after transurethral removal of bladder tumor (TURBT) can be offered to elderly and frail patients with muscle-invasive bladder cancer (MIBC).Methods: In total, 21 patients (mean age 84 years) with unifocal or multifocal MIBC received radiation to a dose of 48-50 Gy/16-20 fractions with weekly HT. The primary endpoint was the variation in temperature metrics, thermal dose expressed as cumulative equivalent minutes at 43 °C when the measured temperature is T90 (CEM43T90) and net power applied in target volume per each HT session. Secondary endpoints were three-year overall survival (OS), disease-free survival (DFS), local progression-free survival (LPFS) and toxicity.Results: The temperature metrics, CEM43T90, mean and maximum net power applied did not differ significantly among the HT sessions of the 21 patients. With a median follow-up of 65 months, 52% (95% CI 32-72%) of patients had died 3 years after treatment. The three-year DFS and LPFS rates were 62% (95%CI 41-79%) and 81% (95%CI 60-92%), respectively. The three-year bladder preservation rate was 100%. Three out of four patients with local failure received a thermal dose CEM43T90 below a median of 2.4 min. The rates of acute and late grade-3 toxicities were 10% and 14%, respectively.Conclusion: The reproducibility of HT parameters between sessions was high. A moderately high CEM43T90 (> 2.4 min) for each HT session seems to be preferable for local control. RT combined with HT is a promising organ-preservation therapy for elderly and frail MIBC patients.

Real World Analysis of Quality of Life and Toxicity in Cancer Patients Treated with Hyperthermia Combined with Radio(chemo)therapy.

Hyperthermia (HT) in combination with radio(chemo)therapy (RCT) is a well-established cancer treatment strategy. This report analyses the quality of life (QoL), toxicity and survival outcomes in patients with different tumor entities who received HT in combination with RCT. The primary endpoint of this study was the assessment of QoL scale items 3 and 12 months after treatment in patients who were treated with palliative intent and curative intent, respectively. The secondary endpoints of this study were acute toxicities, 1-year overall survival (OS), and local progression-free survival (LPFS). Patients treated with curative intent experienced significant improvement in emotional functioning (EF), social functioning (SF), financial difficulties (FI) and insomnia (SL) 12 months after treatment. Patients had significantly improved FI and pain (PA) three months after palliative treatment. Acute toxicity of grade 3 or more was 26% during treatment and 4% after three months. The 1-year OS rates were 90% (95% CI: 79-96%) and 44% (95% CI: 31-59%) for patients treated with curative and palliative RCT combined with HT, respectively. Moreover, the 1-year LPFS rates were 94% (95% CI: 84-98%) for patients treated with curative intent and 64% (95% CI: 50-77%) for palliative patients. In summary, combined RCT and HT stabilized or improved QoL scale items for both curative and palliative indications.

A patterns of care analysis of hyperthermia in combination with radio(chemo)therapy or chemotherapy in European clinical centers.

PURPOSE: The combination of hyperthermia (HT) with radio(chemo)therapy or chemotherapy (CT) is an established treatment strategy for specific indications. Its application in routine clinical practice in Europe depends on regulatory and local conditions. We conducted a survey among European clinical centers to determine current practice of HT. METHODS: A questionnaire with 22 questions was sent to 24 European HT centers. The questions were divided into two main categories. The first category assessed how many patients are treated with HT in combination with radio(chemo)therapy or CT for specific indications per year. The second category addressed which hyperthermia parameters are recorded. Analysis was performed using descriptive methods. RESULTS: The response rate was 71% (17/24) and 16 centers were included in this evaluation. Annually, these 16 centers treat approximately 637 patients using HT in combination with radio(chemo)therapy or CT. On average, 34% (range: 3-100%) of patients are treated in clinical study protocols. Temperature readings and the time interval between HT and radio(chemo)therapy or CT are recorded in 13 (81%) and 9 (56%) centers, respectively. The thermal dose quality parameter "cumulative equivalent minutes at 43 °C" (CEM43°C) is only evaluated in five (31%) centers for each HT session. With regard to treatment sequence, 8 (50%) centers administer HT before radio(chemo)therapy and the other 8 in the reverse order. CONCLUSION: There is a significant heterogeneity among European HT centers as to the indications treated and the recording of thermometric parameters. More evidence from clinical studies is necessary to achieve standardization of HT practice.

Tetramodal therapy with transurethral resection followed by chemoradiation in combination with hyperthermia for muscle-invasive bladder cancer: early results of a multicenter phase IIB study.

BACKGROUND: Transurethral resection of bladder tumor (TUR-BT) followed by chemoradiation (CRT) is a valid treatment option for patients with muscle-invasive bladder cancer (MIBC). This study aimed to investigate the efficacy of a tetramodal approach with additional regional hyperthermia (RHT). METHODS: Patients with stages T2-4 MIBC were recruited at two institutions. Treatment consisted of TUR-BT followed by radiotherapy at doses of 57-58.2 Gy with concurrent weekly platinum-based chemotherapy and weekly deep RHT (41-43 °C, 60 min) within two hours of radiotherapy. The primary endpoint was a complete response six weeks after the end of treatment. Further endpoints were cystectomy-free rate, progression-free survival (PFS), local recurrence-free survival (LRFS), overall survival (OS) and toxicity. Quality of life (QoL) was assessed at follow-up using the EORTC-QLQ-C30 and QLQ-BM30 questionnaires. Due to slow accrual, an interim analysis was performed after the first stage of the two-stage design. RESULTS: Altogether 27 patients were included in the first stage, of these 21 patients with a median age of 73 years were assessable. The complete response rate of evaluable patients six weeks after therapy was 93%. The 2-year cystectomy-free rate, PFS, LRFS and OS rates were 95%, 76%, 81% and 86%, respectively. Tetramodal treatment was well tolerated with acute and late G3-4 toxicities of 10% and 13%, respectively, and a tendency to improve symptom-related quality of life (QoL) one year after therapy. CONCLUSION: Tetramodal therapy of T2-T4 MIBC is promising with excellent local response, moderate toxicity and good QoL. This study deserves continuation into the second stage.

Present Practice of Radiative Deep Hyperthermia in Combination with Radiotherapy in Switzerland.

BACKGROUND: Moderate hyperthermia is a potent and evidence-based radiosensitizer. Several indications are reimbursed for the combination of deep hyperthermia with radiotherapy (dHT+RT). We evaluated the current practice of dHT+RT in Switzerland. METHODS: All indications presented to the national hyperthermia tumor board for dHT between January 2017 and June 2021 were evaluated and treatment schedules were analyzed using descriptive statistics. RESULTS: Of 183 patients presented at the hyperthermia tumor board, 71.6% were accepted and 54.1% (99/183) finally received dHT. The most commonly reimbursed dHT indications were "local recurrence and compression" (20%), rectal (14.7%) and bladder (13.7%) cancer, respectively. For 25.3% of patients, an individual request for insurance cover was necessary. 47.4% of patients were treated with curative intent; 36.8% were in-house patients and 63.2% were referred from other hospitals. CONCLUSIONS: Approximately two thirds of patients were referred for dHT+RT from external hospitals, indicating a general demand for dHT in Switzerland. The patterns of care were diverse with respect to treatment indication. To the best of our knowledge, this study shows for the first time the pattern of care in a national cohort treated with dHT+RT. This insight will serve as the basis for a national strategy to evaluate and expand the evidence for dHT.

Clinical Evidence for Thermometric Parameters to Guide Hyperthermia Treatment.

Hyperthermia (HT) is a cancer treatment modality which targets malignant tissues by heating to 40-43 °C. In addition to its direct antitumor effects, HT potently sensitizes the tumor to radiotherapy (RT) and chemotherapy (CT), thereby enabling complete eradication of some tumor entities as shown in randomized clinical trials. Despite the proven efficacy of HT in combination with classic cancer treatments, there are limited international standards for the delivery of HT in the clinical setting. Consequently, there is a large variability in reported data on thermometric parameters, including the temperature obtained from multiple reference points, heating duration, thermal dose, time interval, and sequence between HT and other treatment modalities. Evidence from some clinical trials indicates that thermal dose, which correlates with heating time and temperature achieved, could be used as a predictive marker for treatment efficacy in future studies. Similarly, other thermometric parameters when chosen optimally are associated with increased antitumor efficacy. This review summarizes the existing clinical evidence for the prognostic and predictive role of the most important thermometric parameters to guide the combined treatment of RT and CT with HT. In conclusion, we call for the standardization of thermometric parameters and stress the importance for their validation in future prospective clinical studies.

Quantification of thermal dose in moderate clinical hyperthermia with radiotherapy: a relook using temperature-time area under the curve (AUC).

BACKGROUND: Thermal dose in clinical hyperthermia reported as cumulative equivalent minutes (CEM) at 43 °C (CEM43) and its variants are based on direct thermal cytotoxicity assuming Arrhenius 'break' at 43 °C. An alternative method centered on the actual time-temperature plot during each hyperthermia session and its prognostic feasibility is explored. METHODS AND MATERIALS: Patients with bladder cancer treated with weekly deep hyperthermia followed by radiotherapy were evaluated. From intravesical temperature (T) recordings obtained every 10 secs, the area under the curve (AUC) was computed for each session for T > 37 °C (AUC > 37 °C) and T ≥ 39 °C (AUC ≥ 39 °C). These along with CEM43, CEM43(>37 °C), CEM43(≥39 °C), Tmean, Tmin and Tmax were evaluated for bladder tumor control. RESULTS: Seventy-four hyperthermia sessions were delivered in 18 patients (median: 4 sessions/patient). Two patients failed in the bladder. For both individual and summated hyperthermia sessions, the Tmean, CEM43, CEM43(>37 °C), CEM43(≥39 °C), AUC > 37 °C and AUC ≥ 39 °C were significantly lower in patients who had a local relapse. Individual AUC ≥ 39 °C for patients with/without local bladder failure were 105.9 ± 58.3 °C-min and 177.9 ± 58.0 °C-min, respectively (p = 0.01). Corresponding summated AUC ≥ 39 °C were 423.7 ± 27.8 °C-min vs. 734.1 ± 194.6 °C-min (p < 0.001), respectively. The median AUC ≥ 39 °C for each hyperthermia session in patients with bladder tumor control was 190 °C-min. CONCLUSION: AUC ≥ 39 °C for each hyperthermia session represents the cumulative time-temperature distribution at clinically defined moderate hyperthermia in the range of 39 °C to 45 °C. It is a simple, mathematically computable parameter without any prior assumptions and appears to predict treatment outcome as evident from this study. However, its predictive ability as a thermal dose parameter merits further evaluation in a larger patient cohort.

Early results and volumetric analysis after spot-scanning proton therapy with concomitant hyperthermia in large inoperable sacral chordomas.

OBJECTIVE: Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). METHODS:: Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. RESULTS:: Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture. CONCLUSION: Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. ADVANCES IN KNOWLEDGE:: This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.

A Pilot Study of Radiotherapy and Local Hyperthermia in Elderly Patients With Muscle-Invasive Bladder Cancers Unfit for Definitive Surgery or Chemoradiotherapy.

Purpose: To present the outcomes of a pilot study with hyperthermia (HT) and radiotherapy (RT) in elderly patients of muscle-invasive bladder cancers (MIBC) unfit for surgery or chemoradiotherapy (CTRT). Methods: Sixteen elderly patients with unifocal or multifocal MIBCs received a total dose of 48 Gy/16 fractions/4 weeks or 50 Gy/20 fractions/4 weeks, respectively. HT with a radiofrequency HT unit was delivered once weekly for 60 min before RT and a mean temperature of 41.3°C was attained (maximum temperature 41.1-43.5°C). Local control was assessed using RECIST criteria at 3-monthly intervals by cystoscopy with or without biopsy. Results: The median age, KPS and age-adjusted Charlson comorbidity index were 81 years, 70 and 5, respectively. At median follow-up of 18.5 months (range: 4-65), bladder preservation was 100% with satisfactory function. 11/16 patients (68.7%) had no local and/or distant failure, while isolated local, distant and combined local and distant failures were evident in 2, 2, and 1 patient, respectively. Two local failures were salvaged by TUR-BT resulting in a local control rate of 93.7%. The 5-year cause-specific (CS) local disease free survival (LDFS), disease free survival (DFS), and overall survival (OS) were 64.3, 51.6, and 67.5%, respectively while 5-year non-cause-specific (NCS)-LDFS, NCS-DFS, and NCS-OS were 26.5, 23.2, and 38%, respectively. None of the patients had acute or late grade 3/4 gastrointestinal or genitourinary toxicities. Conclusions: The outcomes from this pilot study indicate that thermoradiotherapy is a feasible therapeutic modality in elderly MIBC patients unfit for surgery or CTRT. HTRT is well-tolerated, allows bladder preservation and function, achieves long-term satisfactory locoregional control and is devoid of significant treatment-related morbidity. This therapeutic approach deserves further evaluation in randomized studies.

Quality assurance guidelines for superficial hyperthermia clinical trials : II. Technical requirements for heating devices.

Quality assurance (QA) guidelines are essential to provide uniform execution of clinical trials with uniform quality hyperthermia treatments. This document outlines the requirements for appropriate QA of all current superficial heating equipment including electromagnetic (radiative and capacitive), ultrasound, and infrared heating techniques. Detailed instructions are provided how to characterize and document the performance of these hyperthermia applicators in order to apply reproducible hyperthermia treatments of uniform high quality. Earlier documents used specific absorption rate (SAR) to define and characterize applicator performance. In these QA guidelines, temperature rise is the leading parameter for characterization of applicator performance. The intention of this approach is that characterization can be achieved with affordable equipment and easy-to-implement procedures. These characteristics are essential to establish for each individual applicator the specific maximum size and depth of tumors that can be heated adequately. The guidelines in this document are supplemented with a second set of guidelines focusing on the clinical application. Both sets of guidelines were developed by the European Society for Hyperthermic Oncology (ESHO) Technical Committee with participation of senior Society of Thermal Medicine (STM) members and members of the Atzelsberg Circle.

Quality assurance guidelines for superficial hyperthermia clinical trials: I. Clinical requirements.

Quality assurance guidelines are essential to provide uniform execution of clinical trials and treatment in the application of hyperthermia. This document provides definitions for a good hyperthermia treatment and identifies the clinical conditions where a certain hyperthermia system can or cannot adequately heat the tumour volume. It also provides brief description of the characteristics and performance of the current electromagnetic (radiative and capacitive), ultrasound and infra-red heating techniques. This information helps to select the appropriate heating technique for the specific tumour location and size, and appropriate settings of the water bolus and thermometry. Finally, requirements of staff training and documentation are provided. The guidelines in this document focus on the clinical application and are complemented with a second, more technical quality assurance document providing instructions and procedure to determine essential parameters that describe heating properties of the applicator for superficial hyperthermia. Both sets of guidelines were developed by the ESHO Technical Committee with participation of senior STM members and members of the Atzelsberg Circle.

Radiotherapy infrastructure and human resources in Switzerland : Present status and projected computations for 2020.

PURPOSE: The purpose of this study was to evaluate the present status of radiotherapy infrastructure and human resources in Switzerland and compute projections for 2020. MATERIALS AND METHODS: The European Society of Therapeutic Radiation Oncology "Quantification of Radiation Therapy Infrastructure and Staffing" guidelines (ESTRO-QUARTS) and those of the International Atomic Energy Agency (IAEA) were applied to estimate the requirements for teleradiotherapy (TRT) units, radiation oncologists (RO), medical physicists (MP) and radiotherapy technologists (RTT). The databases used for computation of the present gap and additional requirements are (a) Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) for cancer incidence (b) the Directory of Radiotherapy Centres (DIRAC) of the IAEA for existing TRT units (c) human resources from the recent ESTRO "Health Economics in Radiation Oncology" (HERO) survey and (d) radiotherapy utilization (RTU) rates for each tumour site, published by the Ingham Institute for Applied Medical Research (IIAMR). RESULTS: In 2015, 30,999 of 45,903 cancer patients would have required radiotherapy. By 2020, this will have increased to 34,041 of 50,427 cancer patients. Switzerland presently has an adequate number of TRTs, but a deficit of 57 ROs, 14 MPs and 36 RTTs. By 2020, an additional 7 TRTs, 72 ROs, 22 MPs and 66 RTTs will be required. In addition, a realistic dynamic model for calculation of staff requirements due to anticipated changes in future radiotherapy practices has been proposed. This model could be tailor-made and individualized for any radiotherapy centre. CONCLUSION: A 9.8 % increase in radiotherapy requirements is expected for cancer patients over the next 5 years. The present study should assist the stakeholders and health planners in designing an appropriate strategy for meeting future radiotherapy needs for Switzerland.

Is hyperthermia combined with radiotherapy adequate in elderly patients with muscle-invasive bladder cancers? Thermo-radiobiological implications from an audit of initial results.

PURPOSE: The aim of this study was to evaluate the outcomes of loco-regional hyperthermia (HT) with radiotherapy (RT) and/or chemotherapy (CT) in elderly patients with muscle-invasive bladder cancers (MIBC). MATERIAL AND METHODS: Twenty consecutive MIBC patients were treated with HTRT (n = 8) or HTCTRT (n = 12) following transurethral resection of their bladder tumours. Weekly HT was administered prior to RT to a mean temperature of 40.6-42.7 °C for 60 min. A mean RT dose of 54.6 Gy (SD ± 4.2) was delivered. Single-agent cisplatin (n = 2) or carboplatin (n = 10) was used in HTCTRT patients. RESULTS: The median age was 81 years. HTRT patients received a mean RT dose of 51.0 Gy compared to 57.1 Gy with HTCTRT (p < 0.001) in a shorter overall treatment time (OTT) (30.8 ± 6.9 versus 43.9 ± 4.0 days, p < 0.001). All HTRT patients had long-term local disease control, while 41.6% of HTCTRT recurred during follow-up. None of the HTRT patients experienced grade III/IV acute and late toxicities, while these were evident in two and one HTCTRT patients respectively. Taken together, the 3-year bladder preservation, local disease-free survival, cause-specific survival and overall survival were 86.6%, 60.7%, 55% and 39.5% respectively. Even though the mean biological effective dose (BED) for both groups was similar (57.8 Gy15), the thermo-radiobiological BED estimated from HT-induced reduction of α/ß was significantly higher for HTRT patients (91 ± 4.4 versus 85.8 ± 4.3 Gy3, p = 0.018). CONCLUSIONS: Thermal radiosensitisation with consequent reduction in α/ß results in a higher thermo-radiobiological BED with a relatively higher RT dose/fraction and shorter OTT. This translates into a favourable outcome in elderly MIBC patients. Any benefit of CT in these patients needs further investigation.

Proton Irradiation with Hyperthermia in Unresectable Soft Tissue Sarcoma.

PURPOSE: Unresectable soft tissue sarcomas (STSs) do not usually exhibit significant tumor downstaging with preoperative radiotherapy and/or chemotherapy due to their limited radiosensitivity/chemosensitivity. Limb amputations for tumors of the extremities inevitably lead to considerable loss of function and impairment in quality of life. Local hyperthermia at 39°C to 43°C and proton irradiation combine thermoradiobiological and physical dose distribution advantages, possibly mimicking those of a 12C ion therapy. We report the first 2 patients treated with this unique approach of proton thermoradiotherapy. MATERIALS AND METHODS: Both patients had an unresectable STS of the left lower leg (1 grade 2 myxoid fibrosarcoma, 1 grade 3 undifferentiated pleomorphic sarcoma). Both patients had declined the above-knee amputation that had been advised due to their involvement of the neurovascular bundles. They were, therefore recruited to the Hyperthermia and Proton Therapy in Unresectable Soft Tissue Sarcoma (HYPROSAR) study protocol (ClinicalTrials.gov NCT01904565). Local hyperthermia was delivered using radiofrequency waves at 100 Mhz once a week after proton therapy. Proton irradiation was undertaken to a dose of 70 to 72 Gy (relative biological effectiveness) delivered at 2.0 Gy (relative biological effectiveness)/ fraction daily for 7 weeks. RESULTS: Patients tolerated the treatment well with no significant acute or late morbidity. Both primary tumors showed a near complete response on serial magnetic resonance imaging. At a follow-up of 5 and 14 months, the patients were able to carry out indoor and outdoor activities with normal limb function. CONCLUSION: This is the first report of proton beam irradiation combined with hyperthermia for cancer therapy. Our first experience in 2 consecutive patients with unresectable STSs shows that the approach is safe, feasible, and effective, achieving functional limb preservation with near total tumor control.

Hyperthermia and reirradiation for locoregional recurrences in preirradiated breast cancers: a single institutional experience.

QUESTIONS UNDER STUDY: The aim of this retrospective analysis was to evaluate the safety and efficacy of local hyperthermia (HT) and reirradiation (ReRT) in the management of preirradiated locoregional recurrent breast cancers at Kantonsspital Aarau, Switzerland. METHODS: Twenty-four previously irradiated patients who had developed locoregional recurrences in the chest wall or breast, with or without regional lymph node involvement, were reirradiated to a mean dose of 36.8 Gy (range 20-50 Gy) delivered at a mean dose per fraction of 2.33 Gy (range 1.8-4.0 Gy). All patients received local HT at 41 to 43 °C, once or twice a week prior to radiotherapy. Online thermometry was carried out during the hyperthermia sessions. RESULTS: An overall objective response rate of 91.7% (22/24) with a complete response in 66.7% (16/24) of patients and partial response in 25% (6/24) of patients was observed. Post-thermoradiotherapy follow-up ranged from 1 to 38 months (median 10 months). The 3-year actuarial local control rate was 59.7%. More patients who attained complete response had sustained locoregional control until their death or last follow-up when compared with those who were partial or non-responders (median local disease-free survival for complete responders not reached; for partial and non-responders 4 months; p <0.001). Post-retreatment median overall survival for all 24 patients was 10 months. Grade III/IV acute toxicity was seen in only one patient and no patient had any significant late morbidity. CONCLUSIONS: ReRT and HT is an effective and a safe modality to treat locoregional recurrences in previously irradiated breast cancers. The approach can lead to sustainable long-term palliation with minimal morbidity.