Rene Vernhout

Management of Lung Nodules Detected by Volume CT Scanning

BACKGROUND The use of multidetector computed tomography (CT) in lung-cancer screening trials involving subjects with an increased risk of lung cancer has highlighted the problem for the clinician of deciding on the best course of action when noncalcified pulmonary nodules are detected by CT. METHODS A total of 7557 participants underwent CT screening in years 1, 2, and 4 of a randomized trial of lung-cancer screening. We used software to evaluate a noncalcified nodule according to its volume or volume-doubling time. Growth was defined as an increase in volume of at least 25% between two scans. The first-round screening test was considered to be negative if the volume of a nodule was less than 50 mm(3), if it was 50 to 500 mm(3) but had not grown by the time of the 3-month follow-up CT, or if, in the case of those that had grown, the volume-doubling time was 400 days or more. RESULTS In the first and second rounds of screening, 2.6% and 1.8% of the participants, respectively, had a positive test result. In round one, the sensitivity of the screen was 94.6% (95% confidence interval [CI], 86.5 to 98.0) and the negative predictive value 99.9% (95% CI, 99.9 to 100.0). In the 7361 subjects with a negative screening result in round one, 20 lung cancers were detected after 2 years of follow-up. CONCLUSIONS Among subjects at high risk for lung cancer who were screened in three rounds of CT scanning and in whom noncalcified pulmonary nodules were evaluated according to volume and volume-doubling time, the chances of finding lung cancer 1 and 2 years after a negative first-round test were 1 in 1000 and 3 in 1000, respectively. (Current Controlled Trials number, ISRCTN63545820.)

Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial

BACKGROUND Treatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma. METHODS The BELOB trial was an open-label, three-group, multicentre phase 2 study undertaken in 14 hospitals in the Netherlands. Adult patients (≥18 years of age) with a first recurrence of a glioblastoma after temozolomide chemoradiotherapy were randomly allocated by a web-based program to treatment with oral lomustine 110 mg/m(2) once every 6 weeks, intravenous bevacizumab 10 mg/kg once every 2 weeks, or combination treatment with lomustine 110 mg/m(2) every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Randomisation of patients was stratified with a minimisation procedure, in which the stratification factors were centre, Eastern Cooperative Oncology Group performance status, and age. The primary outcome was overall survival at 9 months, analysed by intention to treat. A safety analysis was planned after the first ten patients completed two cycles of 6 weeks in the combination treatment group. This trial is registered with the Nederlands Trial Register (www.trialregister.nl, number NTR1929). FINDINGS Between Dec 11, 2009, and Nov 10, 2011, 153 patients were enrolled. The preplanned safety analysis was done after eight patients had been treated, because of haematological adverse events (three patients had grade 3 thrombocytopenia and two had grade 4 thrombocytopenia) which reduced bevacizumab dose intensity; the lomustine dose in the combination treatment group was thereafter reduced to 90 mg/m(2). Thus, in addition to the eight patients who were randomly assigned to receive bevacizumab plus lomustine 110 mg/m(2), 51 patients were assigned to receive bevacizumab alone, 47 to receive lomustine alone, and 47 to receive bevacizumab plus lomustine 90 mg/m(2). Of these patients, 50 in the bevacizumab alone group, 46 in the lomustine alone group, and 44 in the bevacizumab and lomustine 90 mg/m(2) group were eligible for analyses. 9-month overall survival was 43% (95% CI 29-57) in the lomustine group, 38% (25-51) in the bevacizumab group, 59% (43-72) in the bevacizumab and lomustine 90 mg/m(2) group, 87% (39-98) in the bevacizumab and lomustine 110 mg/m(2) group, and 63% (49-75) for the combined bevacizumab and lomustine groups. After the reduction in lomustine dose in the combination group, the combined treatment was well tolerated. The most frequent grade 3 or worse toxicities were hypertension (13 [26%] of 50 patients in the bevacizumab group, three [7%] of 46 in the lomustine group, and 11 [25%] of 44 in the bevacizumab and lomustine 90 mg/m(2) group), fatigue (two [4%], four [9%], and eight [18%]), and infections (three [6%], two [4%], and five [11%]). At the time of this analysis, 144/148 (97%) of patients had died and three (2%) were still on treatment. INTERPRETATION The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment. FUNDING Roche Nederland and KWF Kankerbestrijding.

Pemetrexed Maintenance Therapy in Patients with Malignant Pleural Mesothelioma

Purpose: To investigate the toxicity and effectiveness of pemetrexed maintenance therapy (PMT) in patients with malignant pleural mesothelioma (MPM). Patients and Methods: Eligible were patients with histologically proven advanced MPM, WHO PS 0-2 and adequate hematological, renal and hepatic function in whom during 6 courses of pemetrexed containing induction therapy no disease progression was observed. PMT, 500 mg/m2 intravenously on day 1 every 3 weeks, was continued until disease progression, unacceptable toxicity, or if continuation was considered to be not in the patient’s best interest. Written informed consent was obtained from all patients. Results: Of the 27 patients who received induction therapy, 13 were treated with PMT. The median number of PMT courses was 4 (range = 2 to 14). No grade 4 toxicity was observed. Grade 3 neutropenia, leucopenia and anemia occurred 15%, 8% and 8%, respectively. The only non-hematological grade 3 toxicity during PMT was fatigue (15%). During PMT creatinine clearance decreased from 88 (±21) ml/min to 77 (±26) ml/min (p < 0.05). The reason to stop PMT was disease progression (69%), toxicity (23%) and in patient’s best interest (8%). During PMT 23% of the patients with stable disease after induction therapy achieved a partial response. Time to progression and overall survival were 3.4 and 6.0 months versus 8.5 and 17.9 months, respectively (p < 0.0001). Conclusions: PMT in MPM patients is non-toxic, well tolerated and although promising effects on TTP and OS are demonstrated, the effectiveness of PMT should be further explored in a prospective randomized clinical trial.

The role of conventional bronchoscopy in the workup of suspicious CT scan screen-detected pulmonary nodules.

BACKGROUND Up to 50% of the participants in CT scan lung cancer screening trials have at least one pulmonary nodule. To date, the role of conventional bronchoscopy in the workup of suspicious screen-detected pulmonary nodules is unknown. If a bronchoscopic evaluation could be eliminated, the cost-effectiveness of a screening program could be enhanced and the potential harms of bronchoscopy avoided. METHODS All consecutive participants with a positive result on a CT scan lung cancer screening between April 2004 and December 2008 were enrolled. The diagnostic sensitivity and negative predictive value were calculated at the level of the suspicious nodules. In 95% of the nodules, the gold standard for the outcome of the bronchoscopy was based on surgical resection specimens. RESULTS A total of 318 suspicious lesions were evaluated by bronchoscopy in 308 participants. The mean ± SD diameter of the nodules was 14.6 ± 8.7 mm, whereas only 2.8% of nodules were > 30 mm in diameter. The sensitivity of bronchoscopy was 13.5% (95% CI, 9.0%-19.6%); the specificity, 100%; the positive predictive value, 100%; and the negative predictive value, 47.6% (95% CI, 41.8%-53.5%). Of all cancers detected, 1% were detected by bronchoscopy only and were retrospectively invisible on both low-dose CT scan and CT scan with IV contrast. CONCLUSION Conventional white-light bronchoscopy should not be routinely recommended for patients with positive test results in a lung cancer screening program.

Towards a close computed tomography monitoring approach for screen detected subsolid pulmonary nodules

Pulmonary subsolid nodules (SSNs) have a high likelihood of malignancy, but are often indolent. A conservative treatment approach may therefore be suitable. The aim of the current study was to evaluate whether close follow-up of SSNs with computed tomography may be a safe approach. The study population consisted of participants of the Dutch-Belgian lung cancer screening trial (Nederlands Leuvens Longkanker Screenings Onderzoek; NELSON). All SSNs detected during the trial were included in this analysis. Retrospectively, all persistent SSNs and SSNs that were resected after first detection were segmented using dedicated software, and maximum diameter, volume and mass were measured. Mass doubling time (MDT) was calculated. In total 7135 volunteers were included in the current analysis. 264 (3.3%) SSNs in 234 participants were detected during the trial. 147 (63%) of these SSNs in 126 participants disappeared at follow-up, leaving 117 persistent or directly resected SSNs in 108 (1.5%) participants available for analysis. The median follow-up time was 95 months (range 20–110 months). 33 (28%) SSNs were resected and 28 of those were (pre-) invasive. None of the non-resected SSNs progressed into a clinically relevant malignancy. Persistent SSNs rarely developed into clinically manifest malignancies unexpectedly. Close follow-up with computed tomography may be a safe option to monitor changes. Persistent subsolid pulmonary nodules may be safely monitored with follow-up computed tomography http://ow.ly/CqWN1

The Role of the (18)F-Fluorodeoxyglucose-Positron Emission Tomography Scan in the Nederlands Leuvens Longkanker Screenings Onderzoek Lung Cancer Screening Trial

Background: In computed tomography lung cancer screening programs, up to 30% of all resections are futile. Objective: To investigate whether a preoperative positron emission tomography (PET) after a conclusive or inconclusive nonsurgical workup will reduce the resection rate for benign disease in test-positive participants of a lung cancer screening program. Methods: (18)F-Fluorodeoxyglucose-PET scans were made in 220 test positives. Nodules were classified as positive, indeterminate, or negative based on visual comparison with background activity. Gold standard for a positive PET was the presence of cancer in the resection specimen or the detection of cancer during more than 2 years follow-up. Sensitivity, specificity, positive predictive value, and negative predictive value (NPV) were calculated at participant level and 95% confidence intervals (CIs) constructed. Results: The sensitivity of PET to detect cancer was 84.2% (95% CI: 77.6–90.7%), the specificity 75.2% (95% CI: 67.1–83.3), the positive predictive value 78.9% (95% CI: 71.8–86.0), and the NPV 81.2% (95% CI: 73.6–88.8). The resection rate for benign disease was 23%, but 26% of them had a diagnosis with clinical consequences. A preoperative PET after an inconclusive nonsurgical workup reduced the resection rate for benign lesions by 11 to 15%, at the expense of missing 12 to 18% lung cancer cases. A preoperative PET after a conclusive nonsurgical workup reduced the resection rate by 78% at the expense of missing 3% lung cancer cases. Conclusion: A preoperative PET scan in participants with an inconclusive nonsurgical workup is not recommended because of the very low NPV, but after a conclusive nonsurgical workup, the resection rate for benign disease can be decreased by 72%.

External beam radiation therapy to prevent anastomotic intimal hyperplasia in prosthetic arteriovenous fistulas: results of a randomized trial

External beam irradiation has a documented effect on intimal hyperplasia reduction. However, it did not result in less reinterventions or stenoses after radiation treatment of the venous anastomosis in polytetrafluoroethylene dialysis access.

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.

No Benefit for Consensus Double Reading at Baseline Screening for Lung Cancer with the Use of Semiautomated Volumetry Software

PURPOSE To retrospectively evaluate the performance of consensus double reading compared with single reading at baseline screening of a lung cancer computed tomography (CT) screening trial. MATERIALS AND METHODS The study was approved by the Dutch Minister of Health and ethical committees. Written informed consent was obtained from all participants. The benefit of consensus double reading was expressed by the percentage change in cancer detection rate, recall rate, number of additional nodules detected, and change in sensitivity and specificity in 7557 participants. The reference standard was a retrospective analysis of the serial CT scans performed in participants diagnosed with lung cancer during a 2-year period after baseline. Semiautomated volumetric software was used for nodule evaluation. McNemar tests were performed to test statistical significance. In addition, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated and 95% confidence intervals (CIs) constructed. RESULTS Seventy-four cases of lung cancer were qualified as detectable at baseline. Compared with single reading, consensus double reading did not increase the cancer detection rate (2.7%; 95% CI: -1.0%, 6.4%; P = .50) or change the recall rate (20.6% vs 20.8%, P = .28), but led to the detection of 19.0% (1635 of 8623; 95% CI: 18.0%, 19.9%, P < .01) more nodules. The sensitivity, specificity, PPV, and NPV were 95.9% (71 of 74), 80.2% (6001 of 7483), 4.6% (71 of 1553) and 99.9% (6001 of 6004) for single reading and 98.6% (73 of 74), 80.0% (1497 of 7483), 4.6% (73 of 1570), and 99.9% (5986 of 5987) for consensus double reading, respectively. CONCLUSION There is no statistically significant benefit for consensus double reading at baseline screening for lung cancer with the use of a nodule management strategy based solely on semiautomated volumetry.

A Phase II Study of Induction Therapy with Carboplatin and Gemcitabine among Patients with Locally Advanced Non-small Cell Lung Cancer

Introduction: The objectives of this trial were to evaluate the activity and safety of gemcitabine carboplatin as induction therapy in patients with locally advanced non-small cell lung cancer Methods: Patients received two cycles of gemcitabine (1250 mg/m2 on day 1 and 8), plus carboplatin (area under the curve = 5 on day 1), after which response was established. Patients received a third course only in the case of an objective response (OR). Non-responding patients were directly irradiated. Toxicity was assessed according to the NCI-CTC version 2, radiation toxicity was assessed according to RTOG criteria. Response evaluation was performed according to RECIST criteria. Results: We identified 42 patients, of whom 37 were eligible. Of these, 51% (95% CI, 34%-68%) achieved an OR, all partial responses. No disease progression on therapy was established. Toxicity was mostly hematological: 35% trombocytopenia grade 3 and 4, and 40% neutropenia grade 3 and 4. No severe bleeding or hospitalization because of febrile neutropenia occurred. Conclusions: Gemcitabine and carboplatin administered according to a 3-week schedule is an active and safe induction regimen. Pending the results of a phase III study, we believe that it is a reasonable alternative among patients for whom cisplatin-based chemotherapy is contraindicated.