MR-based follow-up after brachytherapy and proton beam therapy in uveal melanoma.

PURPOSE: MRI is increasingly used in the diagnosis and therapy planning of uveal melanoma (UM). In this prospective cohort study, we assessed the radiological characteristics, in terms of anatomical and functional imaging, of UM after ruthenium-106 plaque brachytherapy or proton beam therapy (PBT) and compared them to conventional ultrasound. METHODS: Twenty-six UM patients were evaluated before and 3, 6 and 12 months after brachytherapy (n = 13) or PBT (n = 13). Tumour prominences were compared between ultrasound and MRI. On diffusion-weighted imaging, the apparent diffusion value (ADC), and on perfusion-weighted imaging (PWI), the time-intensity curves (TIC), relative peak intensity and outflow percentages were determined. Values were compared between treatments and with baseline. RESULTS: Pre-treatment prominences were comparable between MRI and ultrasound (mean absolute difference 0.51 mm, p = 0.46), but larger differences were observed post-treatment (e.g. 3 months: 0.9 mm (p = 0.02)). Pre-treatment PWI metrics were comparable between treatment groups. After treatment, brachytherapy patients showed favourable changes on PWI (e.g. 67% outflow reduction at 3 months, p < 0.01). After PBT, significant perfusion changes were observed at a later timepoint (e.g. 38% outflow reduction at 6 months, p = 0.01). No consistent ADC changes were observed after either treatment, e.g. a 0.11 × 10-3mm2/s increase 12 months after treatment (p = 0.15). CONCLUSION: MR-based follow-up is valuable for PBT-treated patients as favourable perfusion changes, including a reduction in outflow, can be detected before a reduction in size is apparent on ultrasound. For brachytherapy, a follow-up MRI is of less value as already 3 months post-treatment a significant size reduction can be measured on ultrasound.

Inter-Observer Variability in MR-Based Target Volume Delineation of Uveal Melanoma.

Purpose: Several efforts are being undertaken toward MRI-based treatment planning for ocular proton therapy for uveal melanoma (UM). The interobserver variability of the gross target volume (GTV) on magnetic resonance imaging (MRI) is one of the important parameters to design safety margins for a reliable treatment. Therefore, this study assessed the interobserver variation in GTV delineation of UM on MRI. Methods and Materials: Six observers delineated the GTV in 10 different patients using the Big Brother contouring software. Patients were scanned at 3T MRI with a surface coil, and tumors were delineated separately on contrast enhanced 3DT1 (T1gd) and 3DT2-weighted scans with an isotropic acquisition resolution of 0.8 mm. Volume difference and overall local variation (median standard deviation of the distance between the delineated contours and the median contour) were analyzed for each GTV. Additionally, the local variation was analyzed for 4 interfaces: sclera, vitreous, retinal detachment, and tumor-choroid interface. Results: The average GTV was significantly larger on T1gd (0.57cm3) compared with T2 (0.51cm3, P = .01). A not significant higher interobserver variation was found on T1gd (0.41 mm) compared with T2 (0.35 mm). The largest variations were found at the tumor-choroid interface due to peritumoral enhancement (T1gd, 0.62 mm; T2, 0.52 mm). As a result, a larger part of this tumor-choroid interface appeared to be included on T1gd-based GTVs compared with T2, explaining the smaller volumes on T2. Conclusions: The interobserver variation of 0.4 mm on MRI are low with respect to the voxel size of 0.8 mm, enabling small treatment margins. We recommend delineation based on the T1gd-weighted scans, as choroidal tumor extensions might be missed.

Comparison of Magnetic Resonance Imaging-Based and Conventional Measurements for Proton Beam Therapy of Uveal Melanoma.

OBJECTIVE: Conventionally, ocular proton therapy (PT) is planned using measurements obtained by an ophthalmologist using ultrasound, fundoscopy, biometry, and intraoperative assessments. Owing to the recent advances in magnetic resonance imaging (MRI) of uveal melanoma (UM), it is possible to acquire high-resolution 3-dimensional images of the eye, providing the opportunity to incorporate MRI in ocular PT planning. In this study, we described how these measurements can be obtained using MRI, compared the MRI-based measurements with conventional ophthalmic measurements, and identified potential pitfalls for both modalities. DESIGN: Cross-sectional study. SUBJECTS: Data from 23 consecutive patients with UM treated with PT were retrospectively evaluated. METHODS: Magnetic resonance imaging-based measurements of axial length, tumor height and basal diameter, and marker-tumor distances were compared with the conventional ophthalmic measurements, and discrepancies were evaluated in a multidisciplinary setting. MAIN OUTCOME MEASURES: Tumor prominence and basal diameters on MRI and ultrasound, axial length on MRI and biometry, tumor-marker distances on MRI and measured intraoperatively. RESULTS: The mean absolute differences of the tumor height and basal diameter measurements between ultrasound and MRI were 0.57 mm and 1.44 mm, respectively. Larger absolute differences in height and basal diameter were observed when the full tumor extent was not visible on ultrasound (0.92 mm and 1.67 mm, respectively) compared with when the full tumor extent was visible (0.44 mm and 1.15 mm, respectively). When the full tumor was not visible on ultrasound, MRI was considered more reliable. Tumor-marker distances measured using MRI and intraoperative techniques differed < 1 mm in 55% of the markers. For anteriorly located and mushroom-shaped tumors (25% of the markers), MRI provided more accurate measurements. In flat UM (15% of the markers), however, it was difficult to delineate the tumor on MRI. The mean absolute difference in axial length between optical biometry and MRI was 0.50 mm. The presence of the tumor was found to influence optical biometry in 15 of 22 patients; the remaining patients showed a better agreement (0.30 mm). Magnetic resonance imaging-based biometry was considered more reliable in patients with UM. CONCLUSIONS: Magnetic resonance imaging allowed for the 3-dimensional assessment of the tumor and surrounding tissue. In specific patients, it provided a more reliable measurement of axial length, tumor dimensions, and marker-tumor distances and could contribute to a more accurate treatment planning. Nevertheless, a combined evaluation remains advised, especially for flat UM.

The European Particle Therapy Network (EPTN) consensus on the follow-up of adult patients with brain and skull base tumours treated with photon or proton irradiation.

PURPOSE: Treatment-related toxicity after irradiation of brain tumours has been underreported in the literature. Furthermore, there is considerable heterogeneity on how and when toxicity is evaluated. The aim of this European Particle Network (EPTN) collaborative project is to develop recommendations for uniform follow-up and toxicity scoring of adult brain tumour patients treated with radiotherapy. METHODS: A Delphi method-based consensus was reached among 24 international radiation-oncology experts in the field of neuro-oncology concerning the toxicity endpoints, evaluation methods and time points. RESULTS: In this paper, we present a basic framework for consistent toxicity scoring and follow-up, using multiple levels of recommendation. Level I includes all recommendations that are considered minimum of care, whereas level II and III are optional evaluations in the advanced clinical or research setting, respectively. Per outcome domain, the clinical endpoints and evaluation methods per level are listed. Where relevant, the organ at risk threshold doses for recommended referral to specific organ specialists are defined. CONCLUSION: These consensus-based recommendations for follow-up will enable the collection of uniform toxicity data of brain tumour patients treated with radiotherapy. With adoptation of this standard, collaboration will be facilitated and we can further propel the research field of radiation-induced toxicities relevant for these patients. An online tool to implement this guideline in clinical practice is provided at www.cancerdata.org.

Update of the EPTN atlas for CT- and MR-based contouring in Neuro-Oncology.

BACKGROUND AND PURPOSE: To update the digital online atlas for organs at risk (OARs) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging with new OARs. MATERIALS AND METHODS: In this planned update of the neurological contouring atlas published in 2018, ten new clinically relevant OARs were included, after thorough discussion between experienced neuro-radiation oncologists (RTOs) representing 30 European radiotherapy-oncology institutes. Inclusion was based on daily practice and research requirements. Consensus was reached for the delineation after critical review. Contouring was performed on registered CT with intravenous (IV) contrast (soft tissue & bone window setting) and 3 Tesla (T) MRI (T1 with gadolinium & T2 FLAIR) images of one patient (1 mm slices). For illustration purposes, delineation on a 7 T MRI without IV contrast from a healthy volunteer was added. OARs were delineated by three experienced RTOs and a neuroradiologist based on the relevant literature. RESULTS: The presented update of the neurological contouring atlas was reviewed and approved by 28 experts in the field. The atlas is available online and includes in total 25 OARs relevant to neuro-oncology, contoured on CT and MRI T1 and FLAIR (3 T & 7 T). Three-dimensional (3D) rendered films are also available online. CONCLUSION: In order to further decrease inter- and intra-observer OAR delineation variability in the field of neuro-oncology, we propose the use of this contouring atlas in photon and particle therapy, in clinical practice and in the research setting. The updated atlas is freely available on www.cancerdata.org.

The ROCOCO performance scoring system translates dosimetric differences into clinically relevant endpoints: Comparing IMPT to VMAT in an example pilocytic astrocytoma dataset.

BACKGROUND AND PURPOSE: Proton therapy is expected to outperform photon-based treatment regarding organs at risk (OAR) sparing but to date there is no method to practically measure clinical benefit. Here, we introduce the novel ROCOCO Performance Scoring System (RPSS) translating dose differences into clinically relevant endpoints and apply this to a treatment plan comparison of volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) in 20 pilocytic astrocytoma patients. MATERIAL AND METHODS: The RPSS was developed on the basis of expert-based weighting factors and toxicity scores per OAR. The imaging datasets of 20 pilocytic astrocytoma patients having undergone radiotherapy were included in this in silico dosimetric comparison trial as proof of principle. For each of these patients, treatment plans to a total dose of 54 Gy (RBE) were generated for VMAT and IMPT and these were compared regarding radiation dose to the clinical target volume (CTV) and OARs. The RPSS was calculated for each treatment plan comparing VMAT and IMPT. RESULTS: In 40 analysed treatment plans, the average and low dose volumes to various OARs were significantly reduced when using IMPT compared to VMAT (p < 0.05). Using the RPSS, a significant difference between both treatment modalities was found, with 85% of the patients having a lower RPSS in favour of the IMPT plan. CONCLUSION: There are dosimetric differences between IMPT and VMAT in pilocytic astrocytoma patients. In absence of clinically validated NTCP models we introduce the RPSS model in order to objectively compare treatment modalities by translating dosimetric differences in potential clinical differences.

Proton therapy for selected low grade glioma patients in the Netherlands.

Proton therapy offers an attractive alternative to conventional photon-based radiotherapy in low grade glioma patients, delivering radiotherapy with equivalent efficacy to the tumour with less radiation exposure to the brain. In the Netherlands, patients with favourable prognosis based on tumour and patient characteristics can be offered proton therapy. Radiation-induced neurocognitive function decline is a major concern in these long surviving patients. Although level 1 evidence of superior clinical outcome with proton therapy is lacking, the Dutch National Health Care Institute concluded that there is scientific evidence to assume that proton therapy can have clinical benefit by reducing radiation-induced brain damage. Based on this decision, proton therapy is standard insured care for selected low grade glioma patients. Patients with other intracranial tumours can also qualify for proton therapy, based on the same criteria. In this paper, the evidence and considerations that led to this decision are summarised. Additionally, the eligibility criteria for proton therapy and the steps taken to obtain high-quality data on treatment outcome are discussed.

[A woman with lumps in her breast]. / Een vrouw met knobbeltjes in de borst.

A 61-year-old woman was examined for multiple lumps and an ulcer in her breast, 23 years after breast-conserving therapy for breast cancer, including surgery, chemotherapy and radiation therapy. Clinical examination and imaging showed extensive calcifications as a late effect of irradiation, which was confirmed by the pathologist after surgery.

Secondary cytoreductive surgery and peri-operative intraperitoneal chemotherapy for peritoneal recurrence of colorectal and appendiceal peritoneal carcinomatosis following prior primary cytoreduction.

PURPOSE: Primary cytoreductive surgery (CRS) and peri-operative intraperitoneal chemotherapy (PIC) is the only curative option for patients with colorectal cancer peritoneal carcinomatosis (PC). A significant proportion of patients develop peritoneal recurrence. Outcomes of patients undergoing secondary CRS and PIC for recurrent PC were examined. METHODS: All patients undergoing second procedures with curative intent for recurrent appendiceal or colorectal cancer PC in three centers were included. Patients with recurrent pseudomyxoma peritonei (PMP) were excluded. Morbidity and mortality, overall survival, and disease-free survival were primary outcome parameters. RESULTS: The study included 18 patients (13 colorectal and 5 appendiceal cancer). At primary CRS, mean Peritoneal Cancer Index (PCI) was 9.1. In 13 patients complete resection was achieved. Median time to recurrence was 14 months (range: 1-33). At secondary CRS, mean PCI was 6.3 and CRS was complete in 13 patients. There was no 30-day mortality and 1- and 2-year survival were 74% and 50%, respectively. In 14 patients a recurrence after the second procedure was diagnosed. CONCLUSIONS: A secondary CRS for recurrent colorectal or appendiceal cancer PC is safe and feasible, however, relapse is frequent. Further investigations are required to critically assess the efficacy of a secondary procedure and to define optimal patient selection criteria in the era of effective modern chemotherapy.

Addition of biological therapies to palliative chemotherapy prolongs survival in patients with peritoneal carcinomatosis of colorectal origin.

OBJECTIVES: Combination chemotherapy regimens have shown promising results in patients with metastatic colorectal cancer. However, only very few studies have studied the effect of palliative chemotherapy in peritoneal carcinomatosis (PC) and no data are present incorporating biological therapies in the treatment of PC in colorectal cancer. METHODS: By means of merging with the regional Eindhoven Cancer Registry, all consecutive patients diagnosed with synchronous PC of colorectal origin since the year 2000 treated with palliative chemotherapy in our hospital were included. Data on chemotherapeutic agents used were collected retrospectively. The effect of biological therapies on survival was investigated. RESULTS: Fifty consecutive patients were included. Chemotherapeutic treatment consisted mainly of 5-fluorouracil-based chemotherapy with oxaliplatin. In 22 patients biological therapies were added. Overall survival was 12.5 months [95% confidence interval (CI), 9.2-15.5]. In patients receiving chemotherapy in combination with a biological therapy, overall survival was significantly prolonged as compared with those treated without (18.2 months, 95% CI, 9.5-27.0 vs. 10.1 mo, 95% CI, 6.2-14.1, respectively; P=0.001). Prolongation of survival of patients receiving biological therapies in first-line treatment was even more pronounced, being 22.4 months (95% CI, 15.0-29.5). Similar effects were observed on progression-free survival. CONCLUSIONS: Systemic chemotherapy, once regarded as futile in patients suffering from PC, resulted in an overall survival of 12 months in this unselected group of PC-patients. Addition of biological therapies in the first line of treatment prolonged overall survival to 22.4 months. Although the results of this small study should be interpreted with caution, this promising finding warrants further research.

Peritoneal carcinomatosis of colorectal origin: Incidence, prognosis and treatment options.

Peritoneal carcinomatosis (PC) is one manifestation of metastatic colorectal cancer (CRC). Tumor growth on intestinal surfaces and associated fluid accumulation eventually result in bowel obstruction and incapacitating levels of ascites, which profoundly affect the quality of life for affected patients. PC appears resistant to traditional 5-fluorouracil-based chemotherapy, and surgery was formerly reserved for palliative purposes only. In the absence of effective treatment, the historical prognosis for these patients was extremely poor, with an invariably fatal outcome. These poor outcomes likely explain why PC secondary to CRC has received little attention from oncologic researchers. Thus, data are lacking regarding incidence, clinical disease course, and accurate treatment evaluation for patients with PC. Recently, population-based studies have revealed that PC occurs relatively frequently among patients with CRC. Risk factors for developing PC have been identified: right-sided tumor, advanced T-stage, advanced N-stage, poor differentiation grade, and younger age at diagnosis. During the past decade, both chemotherapeutical and surgical treatments have achieved promising results in these patients. A chance for long-term survival or even cure may now be offered to selected patients by combining radical surgical resection with intraperitoneal instillation of heated chemotherapy. This combined procedure has become known as hyperthermic intraperitoneal chemotherapy. This editorial outlines recent advancements in the medical and surgical treatment of PC and reviews the most recent information on incidence and prognosis of this disease. Given recent progress, treatment should now be considered in every patient presenting with PC.

Intraoperative versus early postoperative intraperitoneal chemotherapy after cytoreduction for colorectal peritoneal carcinomatosis: an experimental study.

BACKGROUND: Perioperative intraperitoneal chemotherapy is used as an adjunct to cytoreductive surgery (CS) for peritoneal carcinomatosis (PC) in order to prolong survival. Worldwide, hyperthermic intraperitoneal chemotherapy (HIPEC), early postoperative intraperitoneal chemotherapy (EPIC), and combinations of the two are used. It remains unclear which regimen is most beneficial. METHODS: The rat colon carcinoma cell line CC-531 was injected into the peritoneal cavity of 80 WAG/Rij rats to induce PC. Animals were randomized into four treatment groups (n = 20): CS only, CS followed by HIPEC (mitomycin 35 mg/m(2) at 41.5°C), CS followed by EPIC during 5 days (i.p. injection of mitomycin on day 1 and 5-fluorouracil on days 2-5), and CS followed by HIPEC plus EPIC. Primary outcome was survival. RESULTS: In rats treated with CS only, median survival was 53 days (95% confidence interval (CI) 49-57 days). In rats treated with CS followed by HIPEC, survival was significantly (P = 0.001) increased (median survival 94 days, 95% CI 51-137 days). In the group treated with EPIC after CS, 12 out of 20 rats were still alive at the end of the experiment (P < 0.001 as compared with CS only). In the group receiving both treatments, 11 rats died of toxicity, and therefore this group was not included in the survival analysis. CONCLUSIONS: Both EPIC and HIPEC were effective in prolonging survival. The beneficial effect of EPIC on survival seemed to be more pronounced than that of HIPEC. Further research is indicated to evaluate and compare the possible benefits and adverse effects associated with both treatments.

Outcomes of elderly patients undergoing cytoreductive surgery and perioperative intraperitoneal chemotherapy for colorectal cancer peritoneal carcinomatosis.

BACKGROUND: The combined treatment of cytoreductive surgery (CRS) and perioperative chemotherapy (PIC) for colorectal peritoneal carcinomatosis (PC) is a rigorous surgical treatment most suited for fit and young patients. With technical maturity and improved perioperative care, we examined the outcomes of elderly patients undergoing CRS and PIC for colorectal PC. METHODS: All consecutive patients treated in two tertiary centers for PC of colorectal cancer who were 70 years of age or older at the time of surgery were included. Data on patient characteristics, concomitant diseases, operation details, perioperative course, and follow-up were retrieved from medical charts. Primary outcomes were perioperative morbidity and mortality. Secondary outcomes were disease-free and overall survival. RESULTS: Twenty-four patients (11 male) were included in this study (mean age 73.5 years). In eight patients major complications occurred. In six patients the postoperative course was complicated by minor adverse events. There was no perioperative mortality. Median overall survival was 35 months with a 6, 12, and 18 months survival rate of 94%, 83%, and 68%, respectively. CONCLUSIONS: CRS and PIC for colorectal PC may be safely performed with acceptable morbidity in selected elderly patients. When considering patients for surgery, performance status, and the disease extent should be used as eligibility criteria rather than age.

Hyperthermia and intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis: an experimental study.

OBJECTIVE: Hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C can improve survival if used as an adjunct to cytoreductive surgery (CS) for treatment of peritoneal carcinomatosis (PC). It remains unclear if both hyperthermia and chemotherapy are essential for the reported survival benefit. METHODS: Eighty WAG/Rij rats were inoculated intraperitoneally with the rat colon carcinoma cell line CC-531. Animals were randomly assigned to 1 of the 4 treatment groups (n = 20): CS only, CS followed by HIPEC (mitomycin 35 mg/m(2) at 41°C), CS followed by intraperitoneal mitomycin perfusion at 37°C, CS followed by intraperitoneal saline perfusion at 41°C. Survival was the primary outcome with a maximum follow up of 126 days. RESULTS: Median survival was 62 days in rats treated with CS only and 57 days in rats treated with CS followed by hyperthermic saline perfusion. Rats receiving HIPEC had a median survival of 121 days (P = 0.022 when compared with CS only). In the group treated with chemotherapy at 37°C, 13 of 20 animals were still alive at the end of the experiment so median survival was not reached. (CS vs. IPEC: P = 0.002, hazard ratio 0.36, 95% CI 0.19-0.69) Rats treated with hyperthermic saline perfusion did not have an increased survival as compared with CS only. CONCLUSIONS: The effectiveness of intraoperative intraperitoneal perfusion after CS is highly dependent on the presence of chemotherapeutic agents in the perfusate but not on hyperthermia. The need to include hyperthermia in the adjuvant intraoperative treatment after CS for PC should be further investigated.

C-reactive protein concentration is associated with prognosis in patients suffering from peritoneal carcinomatosis of colorectal origin.

PURPOSE: Only a limited number of patients with peritoneal carcinomatosis (PC) of colorectal origin benefit from palliative chemotherapy. Identification of prognostic factors may aid in patient selection. The plasma concentration of C-reactive protein (CRP) is increasingly recognized as prognostic factor in a variety of malignancies. However, its value in peritoneal PC of colorectal origin is currently unknown. The aim of the present study was to investigate the association of plasma CRP concentrations with survival in patients suffering from PC of colorectal origin who receive palliative chemotherapy. METHODS: Fifty patients with colorectal PC were identified from the Eindhoven Cancer Registry. Relevant data were retrieved from their clinical records. The most discriminatory CRP concentration was identified and patients were stratified accordingly, resulting in a group with low and a group with high CRP concentrations. Further comparisons were made between these groups. RESULTS: A CRP concentration <35 mg/L was associated with a better prognosis (median survival 22.4 months) than a CRP concentration ≥35 mg/L (7.9 months) (p = 0.0002). CRP concentrations were inversely related to albumin concentrations which could predict survival at a cut-off value of 35 g/L (median survival 7.2 vs. 12.9 months, p = 0.01). High CRP concentrations were related to a decreased resectability rate of the primary tumor. CONCLUSION: Elevated CRP plasma concentrations are associated with decreased survival in patients with colorectal PC. This reflects the importance of inflammation in cancer survival. Further research is warranted to assess the clinical applicability of the current findings.

Results of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy after early failure of adjuvant systemic chemotherapy.

BACKGROUND AND OBJECTIVES: Failure to respond to systemic chemotherapy is considered an exclusion criterion by some institutions for treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). However, it is unknown if these patients benefit from HIPEC treatment. This study aimed to report on outcomes of HIPEC in patients who failed to respond to adjuvant systemic chemotherapy. METHODS: Patients were selected from a prospective database containing data on all patients who underwent HIPEC, using the following criteria: (1) Metachronous peritoneal carcinomatosis (PC) from colorectal origin, (2) adjuvant chemotherapy after primary tumor resection, (3) development of PC or local recurrence within 18 months after start of chemotherapy. Treatment and survival data were retrospectively collected. RESULTS: Twenty-one patients (29% male, mean age 57 years) were included. Median time to recurrence of disease was 9 months (range 2-15) after first chemotherapy administration. Median survival was 28 months (range 3-100). One- and 2-year survival were 71% and 43%, respectively. CONCLUSIONS: Patients who initially failed to respond to systemic adjuvant treatment showed a survival after HIPEC similar to results reported in literature in patients with unknown responsiveness. Failure to respond to previous adjuvant systemic treatment should therefore not be considered an exclusion criterion for HIPEC treatment.