J. Praag

Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial

BACKGROUND Most patients with extensive stage small-cell lung cancer (ES-SCLC) who undergo chemotherapy, and prophylactic cranial irradiation, have persistent intrathoracic disease. We assessed thoracic radiotherapy for treatment of this patient group. METHODS We did this phase 3 randomised controlled trial at 42 hospitals: 16 in Netherlands, 22 in the UK, three in Norway, and one in Belgium. We enrolled patients with WHO performance score 0-2 and confirmed ES-SCLC who responded to chemotherapy. They were randomly assigned (1:1) to receive either thoracic radiotherapy (30 Gy in ten fractions) or no thoracic radiotherapy. All underwent prophylactic cranial irradiation. The primary endpoint was overall survival at 1 year in the intention-to-treat population. Secondary endpoints included progression-free survival. This study is registered with the Nederlands Trial Register, number NTR1527. FINDINGS We randomly assigned 498 patients between Feb 18, 2009, and Dec 21, 2012. Three withdrew informed consent, leaving 247 patients in the thoracic radiotherapy group and 248 in the control group. Mean interval between diagnosis and randomisation was 17 weeks. Median follow-up was 24 months. Overall survival at 1 year was not significantly different between groups: 33% (95% CI 27-39) for the thoracic radiotherapy group versus 28% (95% CI 22-34) for the control group (hazard ratio [HR] 0.84, 95% CI 0.69-1.01; p=0.066). However, in a secondary analysis, 2-year overall survival was 13% (95% CI 9-19) versus 3% (95% CI 2-8; p=0.004). Progression was less likely in the thoracic radiotherapy group than in the control group (HR 0.73, 95% CI 0.61-0.87; p=0.001). At 6 months, progression-free survival was 24% (95% CI 19-30) versus 7% (95% CI 4-11; p=0.001). We recorded no severe toxic effects. The most common grade 3 or higher toxic effects were fatigue (11 vs 9) and dyspnoea (three vs four). INTERPRETATION Thoracic radiotherapy in addition to prophylactic cranial irradiation should be considered for all patients with ES-SCLC who respond to chemotherapy. FUNDING Dutch Cancer Society (CKTO), Dutch Lung Cancer Research Group, Cancer Research UK, Manchester Academic Health Science Centre Trials Coordination Unit, and the UK National Cancer Research Network.

Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: Clinical outcome

PURPOSE To report the clinical outcome of treatment using real-time tumor tracking for 70 patients with inoperable stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS Seventy inoperable patients with peripherally located early-stage NSCLC were treated with 45 or 60 Gy in three fractions using CyberKnife. Pathology was available in 51% of patients. Thirty-nine patients had a T1-tumor and 31 had a T2-tumor. Markers were placed using the vascular, percutaneous intra-, or extra-pulmonary approach, depending on the risk of pneumothorax. RESULTS The actuarial 2-year local control rate for patients treated with 60 Gy was 96%, compared to 78% for patients treated with a total dose of 45 Gy (p=0.197). All local recurrences (n=4) occurred in patients with T2-tumors. Overall survival for the whole group at two years was 62% and the cause specific survival was 85%. The median follow-up was 15 months. Grade 3 toxicity occurred in two patients (3%) after marker placement. Treatment-related late grade 3 toxicity occurred in 7 patients (10%). No grade > or = 4 toxicity occurred. CONCLUSION Excellent local control of 96% at 1- and 2-years was achieved using 60 Gy in three fractions for NSCLC patients treated with the real-time tumor tracking. Toxicity was low.

Lung tumor tracking during stereotactic radiotherapy treatment with the CyberKnife: Marker placement and early results

Lung tumor tracking during stereotactic radiotherapy with the CyberKnife requires the insertion of markers in or close to the tumor. To reduce the risk of pneumothorax, three methods of marker placement were used: 1) intravascular coil placement, 2) percutaneous intrathoracal, and 3) percutaneous extrathoracal placement. We investigated the toxicity of marker placement and the tumor response of the lung tumor tracking treatment. Markers were placed in 20 patients with 22 tumors: 13 patients received a curative treatment, seven a palliative. The median Charlson Comorbidity Score was 4 (range: 1–8). Platinum fiducials and intravascular embolisation coils were used as markers. In total, 78 markers were placed: 34 intrathoracal, 23 intravascular and 21 extrathoracal. The PTV equaled the GTV + 5 mm. A median dose of 45 Gy (range: 30–60 Gy, in 3 fractions) was prescribed to the 70–85% isodose. The response was evaluated with a CTscan performed 6–8 weeks after the last treatment and routinely thereafter. The median follow-up was 4 months (range: 2–11). No severe toxicity due to the marker placement was seen. Pneumothorax was not seen. The local control was 100%. Four tumors in four patients showed a complete response, 15 tumors in 14 patients a partial response, and three tumors in two patients with metastatic disease had stable disease. No severe toxicity of marker placement was seen due to the appropriate choice of one of the three methods. CyberKnife tumor tracking with markers is feasible and resulted in excellent tumor response. Longer follow-up is needed to validate the local control.

Outcome of four-dimensional stereotactic radiotherapy for centrally located lung tumors.

PURPOSE To assess local control, overall survival, and toxicity of four-dimensional, risk-adapted stereotactic body radiotherapy (SBRT) delivered while tracking respiratory motion in patients with primary and metastatic lung cancer located in the central chest. METHODS Fifty-eight central lesions of 56 patients (39 with primary, 17 with metastatic tumors) were treated. Fifteen tumors located near the esophagus were treated with 6 fractions of 8 Gy. Other tumors were treated according to the following dose escalation scheme: 5 fractions of 9 Gy (n = 6), then 5 fractions of 10 Gy (n = 15), and finally 5 fractions of 12 Gy (n = 22). RESULTS Dose constraints for critical structures were generally achieved; in 21 patients the coverage of the PTV was reduced below 95% to protect adjacent organs at risk. At a median follow-up of 23 months, the actuarial 2-years local tumor control was 85% for tumors treated with a BED >100 Gy compared to 60% for tumors treated with a BED ≤ 100 Gy. No grade 4 or 5 toxicity was observed. Acute grade 1-2 esophagitis was observed in 11% of patients. CONCLUSION SBRT of central lung lesions can be safely delivered, with promising early tumor control in patients many of whom have severe comorbid conditions.

High-dose-rate brachytherapy and external-beam radiotherapy for hormone-naïve low- and intermediate-risk prostate cancer: a 7-year experience.

PURPOSE To report clinical outcomes and early and late complications in 264 hormone-naïve patients with low- and intermediate-risk prostate cancer treated with high-dose-rate brachytherapy (HDR-BT) in combination with external-beam radiotherapy (EBRT). METHODS AND MATERIALS Between February 2000 and July 2007, 264 patients underwent HDR-BT in combination with EBRT as a treatment for their low- to intermediate-risk prostate cancer. The HDR-BT was performed using ultrasound-based implantation. The total HDR-BT dose was 18 Gy in 3 fractions within 24 h, with a 6-h minimum interval. The EBRT started 2 weeks after HDR-BT and was delivered in 25 fractions of 1.8 Gy to 45 Gy within 5 weeks. RESULTS After a mean follow-up of 74.5 months, 4 patients (1.5%) showed prostate-specific antigen progression according to the American Society for Radiation Oncology definition and 8 patients (3%) according to the Phoenix definition. A biopsy-proven local recurrence was registered in 1 patient (0.4%), and clinical progression (bone metastases) was documented in 2 patients (0.7%). Seven-year actuarial freedom from biochemical failure was 97%, and 7-year disease-specific survival and overall survival were 100% and 91%, respectively. Toxicities were comparable to other series. CONCLUSIONS Treatment with interstitial HDR-BT plus EBRT shows a low incidence of late complications and a favorable oncologic outcome after 7 years follow-up.

Four-dimensional Stereotactic Radiotherapy for Early Stage Non-Small Cell Lung Cancer: A Comparative Planning Study

In this study we sought to assess the potential of the respiratory tumor tracking system of the CyberKnife to administer 3 fractions of 15 Gy in the treatment of early stage non-small cell lung cancer (NSCLC). The CyberKnife plans were compared to those developed for 3-D conformal radiotherapy (3-D CRT) administering 20 fractions of 3 Gy based on a slow CT. Ten patients with stage I NSCLC, who were previously treated with 3-D CRT, were re-planned with the CyberKnife treatment planning system. In the 3-D CRT plan, the planning target volume (PTV) included the gross tumor volume (GTV)slow and a 15-mm margin, whereas in the CyberKnife plan the margin was 8 mm. The physical doses from both treatment plans were converted to normalized total doses (NTD) using the linear quadratic model with an α/βtumor of 10 Gy and α/βorgans at risk (OAR) of 3 Gy. The average minimal and mean doses administered to the PTV with the CyberKnife and 3-D CRT were 93 and 115.8 Gy and 61 and 66 Gy, respectively (p<0.0001). The mean V20 of the CyberKnife and 3-D CRT plans were 8.2% and 6.8%, respectively (p=0.124). Both plans complied with the OAR constraints. In conclusion, 4-dimensional stereotactic radiotherapy can increase the minimal and mean biological dose with 51% and 75%, in comparison with 3-D CRT without significantly increasing the V20, respectively.

Pemetrexed and cisplatin with concurrent radiotherapy for locally advanced non-small cell and limited disease small cell lung cancer: results from 2 phase I studies.

BACKGROUND The objectives were to determine the maximum tolerated dose (MTD) of pemetrexed and cisplatin with concurrent radiotherapy. Secondary objectives include incidence and nature of acute and late toxicities, tumor response and overall survival. PATIENTS AND METHODS Treatment naïve patients received 1 cycle of cisplatin 80 mg/m(2) in study I (stage III NSCLC), 75 mg/m(2) in study II (LD-SCLC) and pemetrexed 500 mg/m(2) before the phase I part. In study I, patients were treated in cohorts with escalating cisplatin doses (60-80 mg/m(2)), pemetrexed doses (400-500 mg/m(2)) and concurrent escalating radiotherapy doses (66 Gy in 33-27 fractions). In study II, patients were treated with cisplatin 75 mg/m(2) and escalating pemetrexed doses (400-500 mg/m(2)) with concurrent escalating radiotherapy doses (50-62 Gy). RESULTS The trials closed prematurely: study I because of poor accrual, study II because of sponsor decision. Thirteen patients were treated: 4 with NSCLC, 9 with LD-SCLC. No dose-limiting toxicity was observed. There was no grade 4 toxicity, grade 3 hematological toxicity was mild. One patient developed grade 3 acute esophagitis, but was able to complete radiotherapy without delay. Two patients experienced grade 2 late pulmonary toxicity, 1 complete response, 6 partial responses and 1 progressive disease were observed. CONCLUSIONS Although the studies stopped too early to assess MTD, we have demonstrated that the combination of cisplatin and pemetrexed with concurrent radiotherapy up to 66 Gy (33 x 2 Gy) is well tolerated and this new combination shows activity in NSCLC. Pemetrexed is the first 3rd generation cytotoxic found to be tolerable at full dose with concurrent radiotherapy.

Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial

INTRODUCTION In ES-SCLC patients with residual intrathoracic disease after first-line chemotherapy, the addition of thoracic radiotherapy reduces the risk of intrathoracic recurrence, and improves 2-year survival. To identify patient subgroups for future trials investigating higher dose (extra)thoracic radiotherapy, we investigated the prognostic importance of number and sites of metastases in patients included in the CREST trial. MATERIALS/ METHODS Additional data on sites and numbers of metastases were collected from individual records of 260 patients from the top 9 recruiting centers in the randomized CREST trial (53% of 495 study patients), which compared thoracic radiotherapy (TRT) to no TRT in ES-SCLC patients after any response to chemotherapy. All patients received prophylactic cranial irradiation. RESULTS The clinical characteristics and outcomes of the 260 patients analyzed here did not differ significantly from that of the other 235 patients included in the CREST trial, except that fewer patients had a WHO=0 performance status (24% vs 45%), and a higher proportion had WHO=2 (15% vs 5%; p<0.0001). No distant metastases were recorded in 5%, 39% had metastases confined to one organ, 34% to two, and 22% to three or more organ sites. Metastases were present in the liver (47%), bone (40%), lung (28%), extrathoracic (non-supraclavicular) lymph nodes (19%), supraclavicular nodes (18%), adrenals (17%) and other sites (12%). The OS (p=0.02) and PFS (p=0.04) were significantly better in patients with 2 or fewer metastases, with OS significantly worse if liver (p=0.03) and/or bone metastases (p=0.04) were present. DISCUSSION This analysis of patients recruited from the top 9 accruing centers in the CREST trial suggests that future studies evaluating more intensive thoracic and extra-thoracic radiotherapy in ES-SCLC should focus on patients with fewer than 3 distant metastases.

Toxicity and quality of life after high-dose-rate brachytherapy as monotherapy for low- and intermediate-risk prostate cancer.

BACKGROUND AND PURPOSE The use of HDR brachytherapy (HDR-BT) as monotherapy for prostate cancer (PC) is increasing worldwide with good tumour control rates and acceptable toxicity. We report our results on toxicity and quality of life (QoL) after HDR-BT monotherapy for PC patients. MATERIALS AND METHODS 166 low- and intermediate-risk localized PC patients were treated with HDR-BT to a total dose of 38Gy in four fractions. Genitourinary (GU) and gastrointestinal (GI) toxicities were prospectively assessed using EORTC-RTOG questionnaires and physicians charts. QoL was evaluated using EORTC QLQ-PR25 questionnaires. RESULTS Three months after treatment, acute GU and GI toxicities were reported in 10.8% and 7.2%. Acute toxicity resolved within two months in the majority of patients (61%). Late grade ⩾ 2 GU and GI toxicity were reported in 19.7% and 3.3% of patients 12 months after HDR-BT. Mean QLQ-PR25 scores showed clinically relevant changes from baseline for urinary symptoms and sexual functioning. With a mean follow-up of 35 months, biochemical failure was observed in 2.4%. Overall survival at 60 months was 93.6% and cancer-specific survival was 100%. CONCLUSIONS HDR-BT monotherapy for localized PC showed excellent clinical outcome and acceptable acute and late toxicity. Urinary symptoms and sexual function QoL decreased after treatment.

Prophylactic Cranial Irradiation Versus Observation in Radically Treated Stage III Non–Small-Cell Lung Cancer: A Randomized Phase III NVALT-11/DLCRG-02 Study

Purpose The purpose of the current study was to investigate whether prophylactic cranial irradiation (PCI) reduces the incidence of symptomatic brain metastases in patients with stage III non-small-cell lung cancer (NSCLC) treated with curative intention. Patients and Methods Patients with stage III NSCLC-staged with a contrast-enhanced brain computed tomography or magnetic resonance imaging-were randomly assigned to either observation or PCI after concurrent/sequential chemoradiotherapy with or without surgery. The primary end point-development of symptomatic brain metastases at 24 months-was defined as one or a combination of key symptoms that suggest brain metastases-signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures, and focal neurologic symptoms-and magnetic resonance imaging or computed tomography demonstrating the existence of brain metastasis. Adverse effects, survival, quality of life, quality-adjusted survival, and health care costs were secondary end points. Results Between 2009 and 2015, 175 patients were randomly assigned: 87 received PCI and 88 underwent observation only. Median follow-up was 48.5 months (95% CI, 39 to 54 months). Six (7.0%) of 86 patients in the PCI group and 24 (27.2%) of 88 patients in the control group had symptomatic brain metastases ( P = .001). PCI significantly increased the time to develop symptomatic brain metastases (hazard ratio, 0.23; [95% CI, 0.09 to 0.56]; P = .0012). Median time to develop brain metastases was not reached in either arm. Overall survival was not significantly different between both arms. Grade 1 and 2 memory impairment (26 of 86 v seven of 88 patients) and cognitive disturbance (16 of 86 v three of 88 patients) were significantly increased in the PCI arm. Quality of life was only decreased 3 months post-PCI and was similar to the observation arm thereafter. Conclusion PCI significantly decreased the proportion of patients who developed symptomatic brain metastases with an increase of low-grade toxicity.