A Nordic-Baltic perspective on indications for proton therapy with strategies for identification of proper patients.

The beneficial effects of protons are primarily based on reduction of low to intermediate radiation dose bath to normal tissue surrounding the radiotherapy target volume. Despite promise for reduced long-term toxicity, the percentage of cancer patients treated with proton therapy remains low. This is probably caused by technical improvements in planning and delivery of photon therapy, and by high cost, low availability and lack of high-level evidence on proton therapy. A number of proton treatment facilities are under construction or have recently opened; there are now two operational Scandinavian proton centres and two more are under construction, thereby eliminating the availability hurdle. Even with the advantageous physical properties of protons, there is still substantial ambiguity and no established criteria related to which patients should receive proton therapy. This topic was discussed in a session at the Nordic Collaborative Workshop on Particle Therapy, held in Uppsala 14-15 November 2019. This paper resumes the Nordic-Baltic perspective on proton therapy indications and discusses strategies to identify patients for proton therapy. As for indications, neoplastic entities, target volume localisation, size, internal motion, age, second cancer predisposition, dose escalation and treatment plan comparison based on the as low as reasonably achievable (ALARA) principle or normal tissue complication probability (NTCP) models were discussed. Importantly, the patient selection process should be integrated into the radiotherapy community and emphasis on collaboration across medical specialties, involvement of key decision makers and knowledge dissemination in general are important factors. An active Nordic-Baltic proton therapy organisation would also serve this purpose.

Prognostic factors affecting survival after whole brain radiotherapy in patients with brain metastasized lung cancer.

BACKGROUND: Whole-brain radiotherapy (WBRT) has been the standard of care for multiple NSCLC brain metastases but due to its toxicity and lack of survival benefit, its use in the palliative setting is being questioned. PATIENT AND METHODS: This was a single institution cohort study including brain metastasized lung cancer patients who received WBRT at Karolinska University Hospital. Information about Recursive Partitioning Analysis (RPA) and Graded Prognostic Assessment (GPA) scores, demographics, histopathological results and received oncological therapy were collected. Predictors of overall survival (OS) from the time of received WBRT were identified by Cox regression analyses. OS between GPA and RPA classes were compared by pairwise log rank test. A subgroup OS analysis was performed stratified by RPA class. RESULTS: The cohort consisted of 280 patients. RPA 1 and 2 classes had better OS compared to class 3, patients with GPA <1.5 points had better OS compared to GPA≥ 1.5 points and age >70 years was associated with worse OS (p< .0001 for all comparisons). In RPA class 2 subgroup analysis GPA ≥1.5 points, age ≤70 years and CNS surgery before salvage WBRT were independent positive prognostic factors. CONCLUSIONS: RPA class 3 patients should not receive WBRT, whereas RPA class 1 patients should receive WBRT if clinically indicated. RPA class 2 patients with age ≤70 years and GPA ≥1.5 points should be treated as RPA 1. WBRT should be omitted in RPA 2 patients with age >70. In RPA 2 patients with age ≤70 years and GPA <1.5 points WBRT could be a reasonable option.

Comparison of gastric-cancer radiotherapy performed with volumetric modulated arc therapy or single-field uniform-dose proton therapy.

BACKGROUND: Proton-beam therapy of large abdominal cancers has been questioned due to the large variations in tissue density in the abdomen. The aim of this study was to evaluate the importance of these variations for the dose distributions produced in adjuvant radiotherapy of gastric cancer (GC), implemented with photon-based volumetric modulated arc therapy (VMAT) or with proton-beam single-field uniform-dose (SFUD) method. MATERIAL AND METHODS: Eight GC patients were included in this study. For each patient, a VMAT- and an SFUD-plan were created. The prescription dose was 45 Gy (IsoE) given in 25 fractions. The plans were prepared on the original CT studies and the doses were thereafter recalculated on two modified CT studies (one with extra water filling and the other with expanded abdominal air-cavity volumes). RESULTS: Compared to the original VMAT plans, the SFUD plans resulted in reduced median values for the V18 of the left kidney (26%), the liver mean dose (14.8 Gy (IsoE)) and the maximum dose given to the spinal cord (26.6 Gy (IsoE)). However, the PTV coverage decreased when the SFUD plans were recalculated on CT sets with extra air- (86%) and water-filling (87%). The added water filling only led to minor dosimetric changes for the OARs, but the extra air caused significant increases of the median values of V18 for the right and left kidneys (10% and 12%, respectively) and of V10 for the liver (12%). The density changes influenced the dose distributions in the VMAT plans to a minor extent. CONCLUSIONS: SFUD was found to be superior to VMAT for the plans prepared on the original CT sets. However, SFUD was inferior to VMAT for the modified CT sets.

Contouring practices and artefact management within a synthetic CT-based radiotherapy workflow for the central nervous system.

BACKGROUND: The incorporation of magnetic resonance (MR) imaging in radiotherapy (RT) workflows improves contouring precision, yet it introduces geometrical uncertainties when registered with computed tomography (CT) scans. Synthetic CT (sCT) images could minimize these uncertainties and streamline the RT workflow. This study aims to compare the contouring capabilities of sCT images with conventional CT-based/MR-assisted RT workflows, with an emphasis on managing artefacts caused by surgical fixation devices (SFDs). METHODS: The study comprised a commissioning cohort of 100 patients with cranial tumors treated using a conventional CT-based/MR-assisted RT workflow and a validation cohort of 30 patients with grade IV glioblastomas treated using an MR-only workflow. A CE-marked artificial-intelligence-based sCT product was utilized. The delineation accuracy comparison was performed using dice similarity coefficient (DSC) and average Hausdorff distance (AHD). Artefacts within the commissioning cohort were visually inspected, classified and an estimation of thickness was derived using Hausdorff distance (HD). For the validation cohort, boolean operators were used to extract artefact volumes adjacent to the target and contrasted to the planning treatment volume. RESULTS: The combination of high DSC (0.94) and low AHD (0.04 mm) indicates equal target delineation capacity between sCT images and conventional CT scans. However, the results for organs at risk delineation were less consistent, likely because of voxel size differences between sCT images and CT scans and absence of standardized delineation routines. Artefacts observed in sCT images appeared as enhancements of cranial bone. When close to the target, they could affect its definition. Therefore, in the validation cohort the clinical target volume (CTV) was expanded towards the bone by 3.5 mm, as estimated by HD analysis. Subsequent analysis on cone-beam CT scans showed that the CTV adjustment was enough to provide acceptable target coverage. CONCLUSION: The tested sCT product performed on par with conventional CT in terms of contouring capability. Additionally, this study provides both the first comprehensive classification of metal artefacts on a sCT product and a novel method to assess the clinical impact of artefacts caused by SFDs on target delineation. This methodology encourages similar analysis for other sCT products.

"High-risk" tumors of the lip treated with external beam radiotherapy and high-dose-rate brachytherapy: Long-term outcome.

BACKGROUND: Radiotherapy is a well-established treatment for lip cancer, with external radiotherapy (EBRT) or brachytherapy (BT). METHODS: This study evaluated outcome, tumor control, and aesthetics, for 101 patients with carcinoma of the lip, not suitable for surgery, treated with combined EBRT and BT. RESULTS: Squamous cell carcinoma was seen in 78 patients, basal cell carcinoma in 15, and other histologies in 8 patients. Tumors were advanced: 73% in category T2-T4. Local control at 3 and 5 years was 89%. Local failure appeared in 4/56 patients (7%) with primary RT compared to 7/45 (16%) in those with prior surgery, regional recurrence in 5 patients. Toxicity was mild. Cosmetic outcome, 87 patients evaluated, was bad for 9/40 patients with upfront surgery compared to 1/47 for primary RT patients (p = 0.003). Seven patients died from lip cancer (7%), three with originally N+ disease (43%). CONCLUSIONS: Combined EBRT and BT could be considered for lip tumors not candidates for surgery.

On the stability of Leksell Vantage stereotactic head frame fixation in Gamma Knife radiosurgery: a study based on cone-beam computed tomography imaging and the High Definition Motion Management system.

OBJECTIVE: The authors' objective was to investigate the stability of the newly introduced Vantage stereotactic frame fixation in single-fraction Gamma Knife radiosurgery. METHODS: A total of 255 patients were included in this work and treated with the Vantage frame and Leksell Gamma Knife (LGK) Icon equipped with cone-beam computed tomography (CBCT) imaging. After the frame was mounted on the patient's head, a CT scan was acquired. After the patient was positioned on the couch of LGK, CBCT was acquired to verify the target position before treatment delivery. A second CBCT examination was acquired after treatment delivery to assess intrafractional motion. During treatment delivery, the High Definition Motion Management (HDMM) system was enabled to track a marker on the nose tip of the patient as a surrogate of intracranial motion. The stability of the Vantage frame was deconstructed into two parts: 1) motion between CT and the first CBCT prior to treatment delivery (CT-CBCT1), and 2) motion between CBCT procedures during treatment delivery (CBCT1-CBCT2). Transformation between CT and CBCT1 was given by Leksell GammaPlan, whereas transformation between CBCT1 and CBCT2 required mathematical processing of the transformation and coregistration matrices in the source files. RESULTS: The average CT-CBCT1 displacement vector was 0.31 mm, with a range as great as 1.09 mm, and 89% and 97% of cases were within 0.5 mm and 0.7 mm, respectively. The CBCT1-CBCT2 displacement vectors averaged at 0.09 mm, with 97% of cases being within 0.2 mm. Spatial shift in the posterior direction was evident, with 94% of cases demonstrating this trend and averaging 0.05 mm. This was attributed to increased pressure on the posterior fixation pins. The HDMM displacement vectors presented larger values with an average of 0.4 mm and a range as great as 1.6 mm, and 98% of cases were within 1.0 mm. The correlation between CBCT1-CBCT2 and HDMM displacements was weak, which was attributed to the high stability of the Vantage frame and consequently small target displacements coupled with the sensitivity of HDMM to face mimics. CONCLUSIONS: This work demonstrated that the Vantage frame possess the same degree of submillimeter stability as the well-established Leksell Coordinate Frame G (G-frame). Displacements between CT and CBCT1 were 3 times higher than between CBCT1 and CBCT2. A suggested HDMM threshold of 1.2 mm ensures a target accuracy within 0.2 mm in Vantage frame treatments.

Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden.

INTRODUCTION: The use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life. METHODS AND ANALYSIS: PRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints. ETHICS AND DISSEMINATION: To implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05190172).

Investigation of Relation of Radiation Therapy Quality With Toxicity and Survival in LAP07 Phase 3 Trial for Locally Advanced Pancreatic Carcinoma.

PURPOSE: The LAP07 multicenter randomized study assessed whether chemoradiation therapy increases overall survival versus continuation chemotherapy in patients whose locally advanced pancreatic cancer was controlled after 4 months of induction chemotherapy. This analysis investigated whether failure to adhere to radiation therapy (RT) guidelines influenced survival and toxicity. METHODS AND MATERIALS: This is a planned analysis of secondary objectives in the framework of a randomized international phase 3 trial. The protocol included detailed written RT guidelines. All participating institutions undertook an initial benchmark case to check adherence to protocol guidelines. Centers with major deviation were not allowed to include patients until they achieved a significant improvement and rigorously followed the guidelines. On-trial RT quality assurance consisted of a central review of treatment plan with dose-volume histograms for each patient. Adherence to guidelines was graded as per protocol (PP), minor deviation (MiD), or major deviation (MaD). RESULTS: Fifty-seven benchmark cases were evaluated, 26% were classified as PP, 60% were MiD, and 14% were MaD. Among the 442 included patients, 133 patients were randomized in the chemoradiation therapy arm, and 117 patients were assessable for RT quality analysis. RT quality was graded as PP in 38.5% of patients, MiD in 43.6% of patients, and MaD in 17.9% of patients. The most frequent protocol violations were dose distribution heterogeneities. Median overall survival was 17 months with PP and MiD versus 13.4 months with MaD (hazard ratio [HR], 1.63; 95% confidence interval [CI], 0.99-2.71; P = .055). There was no difference in terms of progression-free survival (HR, 1.09; 95% CI, 0.66-1.8; P = .72). Patients with MaD had more nausea than patients treated PP or with MiD (P = .0045). CONCLUSIONS: MaD was associated with a trend for worst survival. There was no difference in terms of progression-free survival. Because of the low rate of major deviations, their effects on the LAP07 trial results may be negligeable.

Randomized phase II study of sequential docetaxel and irinotecan with 5-fluorouracil/folinic acid (leucovorin) in patients with advanced gastric cancer: the GATAC trial.

BACKGROUND: The optimal chemotherapy in patients with advanced gastric carcinoma (GC) is yet to be determined. We compared sequential administration of docetaxel and irinotecan, both in combination with infused 5-fluorouracil/leucovorin (5-Fu/Lv), and randomly assigned patients to start with either of the two. METHODS: Patients with previously untreated locally advanced or metastatic GC and with measurable lesions (response evaluation criteria in solid tumors; RECIST) were randomly assigned to start with docetaxel 45 mg/m(2) (arm T) or irinotecan 180 mg/m(2) (arm C) with bolus/44-h infusion of 5-Fu/Lv (day 1 every 2 weeks). After four courses, there was a prescheduled crossover to the alternative regimen for four additional courses. RESULTS: Eighty-one patients were randomized and 78 started treatment. Complete and partial responses were seen in 31 (40%) patients after 8 weeks and in 32 (41%) after 16 weeks, with similar results in both study arms. The median overall survival (OS) was 11.5 and 10.6 months in arms T and C, respectively (P = 0.3). The two schedules were feasible and did not differ in the overall rate of severe adverse events (SAEs). CONCLUSION: This is the first randomized comparison of two of the newer cytostatic drugs in GC therapy. No differences favoring either arm T or arm C were found with respect to response rate, OS, or toxicity. The median OS of 11 months indicates that sequential administration of the two combinations is effective and is similar to triple combinations. Thus, comparable efficacy to platinum combinations appears to be obtained with newer, less toxic regimens when given sequentially.

An in silico planning study comparing doses and estimated risk of toxicity in 3D-CRT, IMRT and proton beam therapy of patients with thymic tumours.

PURPOSE: To compare the dose distributions produced in patients (pts) treated for thymic tumours with spot-scanning proton beam therapy (PBT) implemented with single-field uniform dose (SFUD), intensity-modulated radiation therapy (IMRT) and three-dimensional conformal photon-beam based radiotherapy (3D-CRT). METHODS: Twelve pts, treated with 3D-CRT, were included. Alternative IMRT and SFUD plans were constructed. The IMRT plans were created using a setup with beams incident from 5 to 6 different angles. For the SFUD plans, a field-specific planning target volume (PTV) was created for each patient and a clinical target volume (CTV)-based robust optimization was performed. A robustness evaluation was performed for the CTV for all SFUD plans. A dosimetric evaluation was conducted for the doses to the CTV and organs at risk (OARs) for all plans. The normal tissue complication probability (NTCP), for different endpoints, was calculated using the Lyman-Kutcher-Burman (LKB)-model and compared between plans. RESULTS: SFUD was associated with significantly lower mean doses to the oesophagus, the heart, the left anterior descending coronary artery (LAD), lungs and breasts compared to 3D-CRT and IMRT. The maximum dose given to the spinal cord was significantly lower with SFUD. The risks for pneumonitis, esophagitis and myelopathy were significantly reduced in the SFUD plans. CONCLUSIONS: The present study showed dosimetric advantages of using scanned-beam PBT for the treatment of thymic tumours, as compared to 3D-CRT and IMRT, especially in regard to lower doses to the oesophagus and lungs. The risk of toxicity was reduced with SFUD.

Estimation of the risk for radiation-induced liver disease following photon- or proton-beam radiosurgery of liver metastases.

BACKGROUND: Radiotherapy of liver metastases is commonly being performed with photon-beam based stereotactic body radiation therapy (SBRT). The high risk for radiation-induced liver disease (RILD) is a limiting factor in these treatments. The use of proton-beam based SBRT could potentially improve the sparing of the healthy part of the liver. The aim of this study was to use estimations of normal tissue complication probability (NTCP) to identify liver-metastases patients that could benefit from being treated with intensity-modulated proton therapy (IMPT), based on the reduction of the risk for RILD. METHODS: Ten liver metastases patients, previously treated with photon-beam based SBRT, were retrospectively planned with IMPT. A CTV-based robust optimisation (accounting for setup and range uncertainties), combined with a PTV-based conventional optimisation, was performed. A robustness criterion was defined for the CTV (V95% > 98% for at least 10 of the 12 simulated scenarios). The NTCP was estimated for different endpoints using the Lyman-Kutcher-Burman model. The ΔNTCP (NTCPIMPT - NTCPSBRT) for RILD was registered for each patient. The patients for which the NTCP (RILD) < 5% were also identified. A generic relative biological effectiveness of 1.1 was assumed for the proton beams. RESULTS: For all patients, the objectives set for the PTV and the robustness criterion set for the CTV were fulfilled with the IMPT plans. An improved sparing of the healthy part of the liver, right kidney, lungs, spinal cord and the skin was achieved with the IMPT plans, compared to the SBRT plans. Mean liver doses larger than the threshold value of 32 Gy led to NTCP values for RILD exceeding 5% (7 patients with SBRT and 3 patients with the IMPT plans). ΔNTCP values (RILD) ranging between - 98% and - 17% (7 patients) and between 0 and 2% (3 patients), were calculated. CONCLUSIONS: In this study, liver metastases patients that could benefit from being treated with IMPT, based on the NTCP reductions, were identified. The clinical implementation of such a model-based approach to select liver metastases patients to proton therapy needs to be made with caution while considering the uncertainties involved in the NTCP estimations.

Estimation of Risk of Normal-tissue Toxicity Following Gastric Cancer Radiotherapy with Photon- or Scanned Proton-beams.

BACKGROUND/AIM: Gastric cancer (GC) radiotherapy involves irradiation of large tumour volumes located in the proximities of critical structures. The advantageous dose distributions produced by scanned-proton beams could reduce the irradiated volumes of the organs at risk (OARs). However, treatment-induced side-effects may still appear. The aim of this study was to estimate the normal tissue complication probability (NTCP) following proton therapy of GC, compared to photon radiotherapy. PATIENTS AND METHODS: Eight GC patients, previously treated with volumetric-modulated arc therapy (VMAT), were retrospectively planned with scanned proton beams carried out with the single-field uniform-dose (SFUD) method. A beam-specific planning target volume was used for spot positioning and a clinical target volume (CTV) based robust optimisation was performed considering setup- and range-uncertainties. The dosimetric and NTCP values obtained with the VMAT and SFUD plans were compared. RESULTS: With SFUD, lower or similar dose-volume values were obtained for OARs, compared to VMAT. NTCP values of 0% were determined with the VMAT and SFUD plans for all OARs (p>0.05), except for the left kidney (p<0.05), for which lower toxicity was estimated with SFUD. CONCLUSION: The NTCP reduction, determined for the left kidney with SFUD, can be of clinical relevance for preserving renal function after radiotherapy of GC.

Comparative study of the calculated risk of radiation-induced cancer after photon- and proton-beam based radiosurgery of liver metastases.

INTRODUCTION: The potential of proton therapy to improve the sparing of the healthy tissue has been demonstrated in several studies. However, even small doses delivered to the organs at risk (OAR) may induce long-term detriments after radiotherapy. In this study, we investigated the possibility to reduce the risk of radiation-induced secondary cancers with intensity modulated proton therapy (IMPT), when used for radiosurgery of liver metastases. MATERIAL AND METHODS: Ten patients, previously treated for liver metastases with photon-beam based stereotactic body radiation therapy (SBRT) were retrospectively planned for radiosurgery with IMPT. A treatment plan comparison was then performed in terms of calculated risk of radiation-induced secondary cancer. The risks were estimated using two distinct models (Dasu et al., 2005; Schneider et al., 2005, 2009). The plans were compared pairwise with a two-sided Wilcoxon signed-rank test with a significance level of 0.05. RESULTS: Reduced risks for induction of fatal and other types of cancers were estimated for the IMPT plans (p<0.05) with the Dasu et al. MODEL: Using the Schneider et al. model, lower risks for carcinoma-induction with IMPT were estimated for the skin, lungs, healthy part of the liver, esophagus and the remaining part of the body (p<0.05). The risk of observing sarcomas in the bone was also reduced with IMPT (p<0.05). CONCLUSION: The findings of this study indicate that the risks of radiation-induced secondary cancers after radiosurgery of liver metastases may be reduced, if IMPT is used instead of photon-beam based SBRT.

Dosimetric Comparison of Plans for Photon- or Proton-Beam Based Radiosurgery of Liver Metastases.

PURPOSE: Radiosurgery treatment of liver metastases with photon beams has been an established method for more than a decade. One method commonly used is the stereotactic body radiation therapy (SBRT) technique. The aim of this study was to investigate the potential sparing of the organs at risk (OARs) that the use of intensity-modulated proton therapy (IMPT), instead of SBRT, could enable. PATIENTS AND METHODS: A comparative treatment-planning study of photon-beam and proton-beam based liver-cancer radiosurgery was performed. Ten patients diagnosed with liver metastasis and previously treated with SBRT at the Karolinska University Hospital were included in the study. New IMPT plans were prepared for all patients, while the original plans were set as reference plans. The IMPT planning was performed with the objective of achieving the same target dose coverage as with the SBRT plans. Pairwise dosimetric comparisons of the treatment plans were then performed for the OARs. A 2-sided Wilcoxon signed-rank test with significance level of 5% was carried out. RESULTS: Improved sparing of the OARs was made possible with the IMPT plans. There was a significant decrease of the mean doses delivered to the following risk organs: the nontargeted part of the liver (P = .002), the esophagus (P = .002), the right kidney (P = .008), the spinal cord (P = .004), and the lungs (P = .002). The volume of the liver receiving less than 15 Gy was significantly increased with the IMPT plans (P = .004). CONCLUSION: The IMPT-based radiosurgery plans provided similar target coverage and significant dose reductions for the OARs compared with the photon-beam based SBRT plans. Further studies including detailed information about varying tissue heterogeneities in the beam path, due to organ motion, are required to evaluate more accurately whether IMPT is preferable for the radiosurgical treatment of liver metastases.

Interobserver variation of clinical target volume delineation in gastric cancer.

PURPOSE: To evaluate interobserver variability in clinical target volume (CTV) delineation in gastric cancer performed with the help of a delineation guide. PATIENTS AND METHODS: Ten radiotherapy centers that participate in the CRITICS Phase III trial were provided with a delineation atlas, preoperative CT scans, a postoperative planning CT scan, and clinical information for a gastric cancer case and were asked to construct a CTV and create a dosimetric plan according to departmental policy. RESULTS: The volumes of the CTVs and planning target volumes (PTVs) differed greatly, with a mean (SD) CTV volume of 392 (176) cm(3) (range, 240-821 cm(3)) and PTV volume of 915 (312) cm(3) (range, 634-1677 cm(3)). The overlapping volume was 376 cm(3) for the CTV and 890 cm(3) for the PTV. The greatest differences in the CTV were seen at the cranial and caudal parts. After planning, dose coverage of the overlapping PTV volume showed less variability than the CTV. CONCLUSION: In this series of 10 plans, variability of the CTV in postoperative chemoradiotherapy for gastric cancer is large. Strict and clear delineation guidelines should be provided, especially in Phase III multicenter studies. Adaptations of these guidelines should be evaluated in clinical studies.

Advances in the treatment of patients with gastric adenocarcinoma.

Despite a decline in its incidence in the Western world, gastric cancer (GC) remains the fourth most frequent cancer diagnosis worldwide and is, after lung cancer, the second leading cause of death from a malignant disease globally. Based on the published literature, treatment guidelines and reports from international meetings, we here review the current treatment options for GC and discuss insights and perspectives from the latest clinical studies. The management of GC in the early stages of the disease is based on an optimal surgical resection of the primary tumor and the regional lymph nodes. However, less than one third of patients have a resectable disease at diagnosis and among those operated, more than half are not cured by surgery alone, due to a high rate of relapse. Thus, for the majority of patients, systemic cytotoxic therapy, and sometimes radiotherapy, is a treatment option both as an adjunct to surgery and in the palliative setting. Adjuvant chemotherapy offers only a marginal benefit and has not become a standard of care in the West. In North America, adjuvant chemoradiation is broadly used, shown to significantly improve overall survival, albeit with the cost of high toxicity. Furthermore, a recently reported study from the United Kingdom demonstrated a significant disease-free and survival benefit by the use of perioperative combination chemotherapy. Several chemotherapeutic agents have been tested as a palliative therapy in advanced GC including 5- fluorouracil (5-FU), oral pyrimidines, platinum derivatives, anthracyclines, taxanes and camptothecans. It is now accepted that chemotherapy is better than best supportive care only and that 5-FU based combinations are more effective than monotherapy. However, the response rates have generally been moderate and there is no consensus on the optimal combination of cytotoxic agents and the potential role of more recently developed "targeted therapies".

Efficacy of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma.

Presently, no effective systemic therapy is available for patients with advanced hepatocellular carcinoma (aHCC). We sought to determine whether systemic treatment with pegylated liposomal doxorubicin (PLD) would yield a response rate of 20% in chemotherapy naïve patients with aHCC. The study was designed according to the phase II Gehan two-step procedure with a precision of 10%. Enrollment criteria included histological diagnosis and radiological documentation of unresectable/metastatic HCC, WHO PS 0-2, relatively normal organ function, life expectancy greater than three months, lack of cardiomyopathy and active cardiac disease NYHA > or = II. PLD (40 mg/m(2) IV 1h-infusion) was administered on d1 q 4 wk and response to treatment was evaluated radiologically every 3rd cycle (WHO-criteria). Secondary endpoints included overall (OS) and progression free survival (PFS) and registration of toxicity. The median number of administered PLD cycles was 3. The best radiological response among the first 14 patients was 1 PR, 5 SD, 3 PD, and 6 NE due to progressive disease clinically (Step 1). The 15th patient did not respond to the PLD-therapy and the study was closed for accrual as the pre-planned analysis could be executed (Step 2). A response rate > or = 20% could be ruled out. The median PFS and OS survival was 82 days and 130 days, respectively. Adverse events were generally mild in the subgroup of patients without signs of moderate hepatic failure at base line. Patients with WHO PS 2, liver tumour involvement >50%, bilirubin > or = 34 micromol/L, albumin <33 g/L, and/or Child Pugh B were unlikely to survive >90 days. PLD can be delivered safely in patients with aHCC and no signs of moderate hepatic failure. The therapy resulted, however, in few responses or cases of disease stabilization and has thus very limited activity in aHCC. Future studies on systemic chemotherapy should focus on patients without moderate hepatic failure, with WHO PS <2, and with liver tumour involvement <50%.

Capecitabine as third line therapy in patients with advanced colorectal cancer.

This study sought to determine whether third line therapy with capecitabine (cap.) could provide any clinical benefit in patients with advanced colorectal cancer who have progressed on 5-Fu combination therapy with both irinotecan and oxaliplatin. Twenty patients who were pretreated with and had progressed on irinotecan+Nordic FLv (5-Fu/leukovorin) and oxaliplatin+c.i. 5-Fu/leukovorin were studied. Cap. was administered at 1000-1250 mg/m2 bid d1-14 q 3 w. Time to progression (TTP) (either radiological or clinical) and overall survival (OS) were estimated with the Kaplan-Meier actuarial method. The median number of administered cap. courses was four. No radiological or biochemical responses were observed. Three patients were classified as having stable disease at three months. Two of these patients had, however, minor radiological progression and a =100% increase in CEA compared to base line. Seventeen patients were classified as having progressive disease during the first three months period. Median TTP and OS were 2.8 months and 6.1 months, respectively. A response rate of =15% for third line cap. in metastatic CRC can be ruled out. Median PFS was limited in the study population. This observation and the few cases with SD at three months, lead us to believe that little or no clinical benefit can be expected from single drug cap. in patients with irinotecan- and oxaliplatin-combination resistant advanced colorectal cancer.