Outcome of conventional radiotherapy in small centrally located tumours or lymph nodes: minimal toxicity, remarkable survival but challenging loco-regional control.

BACKGROUND: In peripheral lung tumours, stereotactic body radiotherapy (SBRT) is superior to conventional RT. SBRT has also shown high loco-regional control (LC) in centrally located tumours, but there is a high risk of severe toxicity. The STRICTSTARLung trial (NCT05354596) examines if risk-adapted SBRT for central tumours is feasible. In this study, we examined overall survival (OS), Disease-free survival (DSF), LC, and toxicity in patients with central tumours that could have been candidates for SBRT but received conventional RT. MATERIAL AND METHODS: Retrospectively, we evaluated 49 lung cancer patients that between 2008 and 2021 received RT (60-70Gy in 2 Gy fractions) for a solitary tumour or lymph node with a diameter <5cm located <2cm from the bronchial tree, oesophagus, aorta or heart. All tumours were pathologically verified; 30 were primary lung tumours (T1b-T4) and 19 were solitary lymph nodes (T0N1-N2). Chemotherapy was administered as concomitant (29) or sequential (4). OS and LC were analysed using Kaplan Meier. Cox proportional hazards model for OS and disease-free survival (DFS) was performed including tumour volume, histology, sex, T- vs N-site and chemotherapy. Toxicity was scored. RESULTS: In 42 patients, the tumour was located <1 cm to mediastinum. Median follow-up time was 44 months (range: 7-123). The median OS was 51 months. OS at 1-, 3- and 5-year was 88% (SE:5), 59% (SE:7) and 50% (SE:8). Loco-regional recurrences occurred in 16 patients resulting in 1-, and 3-year LC rates of 77% (SE:6) and 64% (SE:8). The majority occurred within 3 years after RT. Only stage showed significant impact on OS and DFS. No patients experienced grade 4-5 toxicity. Seven patients developed grade 3 toxicity (5 oesophageal stenosis, 2 pneumonitis). CONCLUSION: Conventional RT for patients with small central lung tumours or solitary lymph nodes is feasible. Median OS was 51 months, and toxicity was low with no grade 4-5 events.

Repeated deep-inspiration breath-hold CT scans at planning underestimate the actual motion between breath-holds at treatment for lung cancer and lymphoma patients.

PURPOSE/OBJECTIVE: Deep-inspiration breath-hold (DIBH) during radiotherapy may reduce dose to the lungs and heart compared to treatment in free breathing. However, intra-fractional target shifts between several breath-holds may decrease target coverage. We compared target shifts between four DIBHs at the planning-CT session with those measured on CBCT-scans obtained pre- and post-DIBH treatments. MATERIAL/METHODS: Twenty-nine lung cancer and nine lymphoma patients were treated in DIBH. An external gating block was used as surrogate for the DIBH-level with a window of 2 mm. Four DIBH CT-scans were acquired: one for planning (CTDIBH3) and three additional (CTDIBH1,2,4) to assess the intra-DIBH target shifts at scanning by registration to CTDIBH3. During treatment, pre-treatment (CBCTpre) and post-treatment (CBCTpost) scans were acquired. For each pair of CBCTpre/post, the target intra-DIBH shift was determined. For lung cancer, tumour (GTV-Tlung) and lymph nodes (GTV-Nlung) were analysed separately. Group mean (GM), systematic and random errors, and GM for the absolute maximum shifts (GMmax) were calculated for the shifts between CTDIBH1,2,3,4 and between CBCTpre/post. RESULTS: For GTV-Tlung, GMmax was larger at CBCT than CT in all directions. GMmax in cranio-caudal direction was 3.3 mm (CT)and 6.1 mm (CBCT). The standard deviations of the shifts in the left-right and cranio-caudal directions were larger at CBCT than CT. For GTV-Nlung and CTVlymphoma, no difference was found in GMmax or SD. CONCLUSION: Intra-DIBH shifts at planning-CT session are generally smaller than intra-DIBH shifts observed at CBCTpre/post and therefore underestimate the intra-fractional DIBH uncertainty during treatment. Lung tumours show larger intra-fractional variations than lymph nodes and lymphoma targets.

Thorough design and pre-trial quality assurance (QA) decrease dosimetric impact of delineation and dose planning variability in the STRICTLUNG and STARLUNG trials for stereotactic body radiotherapy (SBRT) of central and ultra-central lung tumours.

INTRODUCTION: SBRT of central lung tumours implies significant risk of toxicity. We are initiating two phase II trials prescribing 56 Gy/eight fractions to PTV, allowing for dose escalation of GTV. We prioritize organs at risk (OAR) constraints over target coverage, making the treatment plans very sensitive to OAR delineation variations. The aim of this study is to quantify the dosimetric impact of contouring variations and to provide a thorough description of pre-trial quality assurance to be used in upcoming trials to provide consistent clinical care. MATERIALS AND METHODS: Delineation: Seven physicians delineated OAR in three rounds, with evaluations in-between. For each patient case, seven treatment plans, repeatedly using each of the OAR structure sets from the seven physicians, were made and compared to evaluate the dosimetric effect of delineation variability. Treatment planning: Treatment plans for seven cases were made at six departments in two rounds, with discussion in-between. RESULTS: OAR delineation variation between centres resulted in high variabilities in OAR dose for simulated plans and led to potential overdosage of the lobar bronchus (constraint: D0.03cc < 45 Gy), with maximum doses ranging between 58 Gy (first round), and 50 Gy (third round). For mediastinal tissue, the constraint (D0.03cc < 45 Gy) was violated for the majority of the delineations in all three rounds, with maximum doses of 84 Gy (first round), and 72 Gy (third round).For the treatment planning study, the range of the standard deviation for GTV mean dose was 12.8-18.5 Gy (first round) and 2.8-3.5 Gy (second round). CONCLUSIONS: Even small variations in OAR delineation led to high OAR overdosage. The study demonstrates the importance of having extensive QA procedures in place before initiating clinical trials on dose escalation in SBRT.

Optimal beam angle selection and knowledge-based planning significantly reduces radiotherapy dose to organs at risk for lung cancer patients.

BACKGROUND: Lung cancer patients struggle with high toxicity rates. This study investigates if IMRT plans with individually set beam angles or uni-lateral VMAT plans results in dose reduction to OARs. We investigate if introduction of a RapidPlan model leads to reduced dose to OARs. Finally, the model is validated prospectively. MATERIAL AND METHODS: Seventy-four consecutive lung cancer patients treated with IMRT were included. For all patients, new IMRT plans were made by an experienced dose planner re-tuning beam angles aiming for minimized dose to the lungs and heart. Additionally, VMAT plans were made. The IMRT plans were selected as input for a RapidPlan model, which was used to generate 74 new IMRT plans. The new IMRT plans were used as input for a second RapidPlan model. This model was clinically implemented and used for generation of clinical treatment plans. Dosimetric parameters were compared using a Wilcoxon signed rank test or a 1-sided student's t-test. p < .05 was considered significant. RESULTS: IMRT plans significantly reduced mean doses to lungs (MLD) and heart (MHD) by 1.6 Gy and 1.7 Gy in mean compared to VMAT plans. MLD was significantly (p < .001) reduced from 10.8 Gy to 9.4 Gy by using the second RapidPlan model. MHD was significantly (p < .001) reduced from 4.9 Gy to 3.9 Gy. The model was validated in prospectively collected treatment plans showing significantly lower MLD after the implementation of the second RapidPlan model. CONCLUSION: Introduction of RapidPlan and beam angles selected based on the target and OARs position reduces dose to OARs.

Local failure after radical radiotherapy of non-small cell lung cancer in relation to the planning FDG-PET/CT.

OBJECTIVES: Local recurrence (rec) in lung cancer is associated with poor survival. This study examined whether the pattern of failure is associated with the most PET avid volume in the planning-FDG-PET/CT scan (p-PET/CT). METHODS: 162 consecutive inoperable NSCLC patients (pts) receiving radiotherapy between January 2012 and April 2014 were reviewed. Radiotherapy was delivered in 2 Gy/fraction (5f/week) to a total dose of 60-66 Gy. Pts were followed with CT scans every third month. Patients with local rec as first event were analyzed. For the primary tumor (T) the overlap-fraction (OF) between 50% of SUVpeak on p-PET/CT and the volume of T-rec was calculated: OF = (SUVp50∩T-rec)/min(SUVp50, T-rec). Similarly for the GTV on the p-CT: OF = (GTV∩T-rec)/min(GTV, T-rec). OF was based on a rigid registration between p-PET/CT and rec-CT with PET guided delineation of T- rec. For lymph nodes (LN), the correlation between the location of treated-LN and the location of recurrence-LN was evaluated. RESULTS: 67 patients developed local rec. 51 pts had rec in T-site, 45 pts in LN-site. Due to anatomical changes, reliable registration between p-CT and rec-CT was only obtained in 26 pts with T-rec. The median OFSUVp50 was 52, 8% [range 26; 100%] and the median OFGTV was 80.5% [19.7; 100%]. Eleven pts had higher OFSUVp50 than OFGTV. LN-rec predominantly occurred in the station 2R (32%), 4R (46%), 7 (46%) and right hilum (36%). Pts with malignant LNs in station 4R or 7 on p-CT had a high risk of rec in these stations; 4R (55%) and 7 (83%). CONCLUSIONS: This study indicates that the most PET active volume on p-PET-CT is a driver for rec at T-site. LN-recurrences predominantly appear in station 2R, 4R, 7 and right hilum. Additional confirmatory studies regarding lymph node mapping and selective lymph node irradiation is needed.

Reliability of dose volume constraint inference from clinical data.

Dose volume histogram points (DVHPs) frequently serve as dose constraints in radiotherapy treatment planning. An experiment was designed to investigate the reliability of DVHP inference from clinical data for multiple cohort sizes and complication incidence rates. The experimental background was radiation pneumonitis in non-small cell lung cancer and the DVHP inference method was based on logistic regression. From 102 NSCLC real-life dose distributions and a postulated DVHP model, an 'ideal' cohort was generated where the most predictive model was equal to the postulated model. A bootstrap and a Cohort Replication Monte Carlo (CoRepMC) approach were applied to create 1000 equally sized populations each. The cohorts were then analyzed to establish inference frequency distributions. This was applied to nine scenarios for cohort sizes of 102 (1), 500 (2) to 2000 (3) patients (by sampling with replacement) and three postulated DVHP models. The Bootstrap was repeated for a 'non-ideal' cohort, where the most predictive model did not coincide with the postulated model. The Bootstrap produced chaotic results for all models of cohort size 1 for both the ideal and non-ideal cohorts. For cohort size 2 and 3, the distributions for all populations were more concentrated around the postulated DVHP. For the CoRepMC, the inference frequency increased with cohort size and incidence rate. Correct inference rates >[Formula: see text] were only achieved by cohorts with more than 500 patients. Both Bootstrap and CoRepMC indicate that inference of the correct or approximate DVHP for typical cohort sizes is highly uncertain. CoRepMC results were less spurious than Bootstrap results, demonstrating the large influence that randomness in dose-response has on the statistical analysis.

Prophylactic cranial irradiation in patients with small cell lung cancer. A retrospective study of recurrence, survival and morbidity.

BACKGROUND: Prophylactic cerebral irradiation (PCI) is a standard treatment for all small cell lung cancer (SCLC) patients with response to chemotherapy. The aims of this study were: to evaluate patients undergoing PCI with regard to cerebral recurrence rate, site of recurrence, and overall survival (OS) and to investigate the influence of steroid dose on acute toxicity. MATERIALS AND METHODS: From 2007 to 2010 a total of 118 consecutive patients underwent PCI (25 Gray in 10 fractions). In total, 114/118 received full PCI dose, all 118 were included in the study. Data were analyzed retrospectively with regard to disease stage, treatment, date of PCI, steroid dose during PCI, toxicity, time to recurrence, site of recurrence and time of death. The median follow up time was 16.6 months (range 3-54 months). RESULTS: Of the 118 patients undergoing PCI, 74 had limited disease (LD-SCLC) and 44 had extensive disease (ED-SCLC). The median age was 65 years (range 46-80 years). The median overall survival of all patients from the time of diagnosis was 16.0 months (CI 95% 13.0-19.0), in LD-SCLC it was 24.0 months (CI 95% 19.6-28.3), and in ED-SCLC it was 12.0 months (CI 95% 9.6-14.4). Twenty-one patients (17.8%) were diagnosed with cerebral recurrence. Five of these presented with metastatic disease within the limbic system. Of these five patients, four had miliary cerebral disease and one had non-oligometastatic disease. The time from PCI to cerebral recurrence ranged from 4 to 27 months. Prednisolone administration varied from 0 to 100 mg/day. Forty-eight patients were not treated with steroids, 64.6% of these patients reported acute toxicity. Of the 36 patients receiving 50 mg prednisolone, only 22.2% had side effects. The most common symptoms during PCI were nausea and headache. CONCLUSIONS: Twenty-one patients out of 118 developed brain metastases after PCI: five of the twenty-one had metastases located in the limbic system. The study showed that prophylactic steroid use might reduce acute toxicity to PCI. Survival data and recurrence rates are comparable to other clinical studies.

The role of pelvic lymph node dissection as a predictive and prognostic factor in bladder cancer.

The aim of this study was to evaluate the value of pelvic lymph node dissection (PLND) performed as a separate procedure in a consecutive Danish bladder cancer cohort and also to analyse if the number of lymph nodes excised had an impact on outcome. From 1992 to 1998, 339 cystectomy candidates were retrospectively reviewed. Based on a preoperative PLND, 248 patients (10% N+) underwent radical cystectomy and 91 (87% N+) underwent radio- or chemotherapy. The median follow-up was 6.3 years. PLND was able to separate N+ from N0 patients with a false-negative rate of 3% compared with the following cystectomy. Lymph node-positive patients treated with cystectomy (n=24) all died from their bladder cancer. Therefore, accurate pathological N classification before the treatment decision seems worthwhile. The median number of lymph nodes excised was six and the number of lymph nodes had an independent prognostic impact on survival. This underlines the need for guidelines for surgical lymphadenectomy and the pathological assessment of lymph nodes in bladder cancer.

Intense inflammation in bladder carcinoma is associated with angiogenesis and indicates good prognosis.

The aim of this study was to investigate the prognostic influence of microvessel density using the hot spot method in 107 patients diagnosed with transitional cell carcinoma of the bladder. In each case, inflammation was found in the invasive carcinoma, therefore we classified the degree of inflammation as minimal, moderate or intense. Microvessel density was then reevaluated in each tumour in areas corresponding to these three categories. Median microvessel density irrespective of degree of inflammation was 71. Areas of minimal, moderate and intense inflammation were found in 48, 92 and 32 tumours. Microvessel density increased significantly with increasing degree of inflammation. Disease-specific survival was improved if areas of intense inflammation were present in the carcinoma (P=0.004). High microvessel density, irrespective of the degree of inflammation, was associated with a significantly better disease-specific survival (P=0.01). Multivariate analysis using death of disease as endpoint demonstrated an independent prognostic value of N-classification (N0, hazard ratio (HR)=1 vs N1, HR=2.89 (range, 1.52-5.52) vs N2, HR=3.61 (range, 1.84-7.08)), and intense inflammation, HR=0.48 (range, 0.24-0.96). Malignancy grade, T classification and microvessel density were not independent significant markers of poor outcome. In conclusion, inflammation was significantly correlated to microvessel density, and areas of intense inflammation were an independent marker of good prognosis.