Does coronary artery calcium score have an impact on overall survival for locally advanced non-small cell lung cancer treated with definitive radiotherapy.

BACKGROUND AND PURPOSE: Coronary artery calcium score (CACs) is an excellent marker for survival in non-cancer patients, but its role in locally advanced non-small cell lung cancer (LA-NSCLC) patients remains uncertain. In this study, we hypothesize that CACs is a prognostic marker for survival in a competing risk analysis in LA-NSCLC patients treated with definitive radiotherapy. MATERIALS AND METHODS: We included 644 patients with LA-NSCLC treated in 2014-2015 in Denmark. Baseline patient characteristics were derived from the Danish Lung Cancer Registry. Radiotherapy planning CT scans were used for manual CACs measurements, and the patients were divided into four groups, CACs 0, 1-99, 100-399, and ≥400. A multivariable Cox model utilizing bootstrapping for cross-validation modeled overall survival (OS). RESULTS: The median follow-up time was seven years, and the median OS was 26 months (95% CI 24-29). Within each CAC group 0, 1-99, 100-399, and ≥400 were 172, 182, 143, and 147 patients, respectively. In the univariable analysis, the survival decreased with increasing CACs. However, after adjustment for age, PS, radiotherapy dose, and logarithmic GTV, CACs did not have a statistically significant impact on OS with hazard ratios of 1.04 (95% CI 0.85-1.28), 1.11 (95%CI 0.89-1.43), and 1.16 (95%CI 0.92-1.47) for CACs 1-99, CACs 100-399 and ≥400, respectively. Elevated CACs was observed in 73 % of the patients suggesting a high risk of cardiac comorbidity before radiotherapy. CONCLUSION: CACs did not add prognostic information to our population's classical risk factors, such as tumor volume, performance status, and age; the lung cancer has the highest priority despite the risk of baseline cardiac comorbidity.

Prospectively scored pulmonary toxicities in non-small cell lung cancer: Results from a randomized phase II dose escalation trial.

PURPOSE: Prospectively scored radiation pneumonitis (RP) observed in a national, randomized phase II dose-escalation trial for patients with locally advanced non-small cell lung cancer (NSCLC) was investigated. METHODS: Patients with stage IIB-IIIB histologically proven NSCLC were treated with concomitant chemo-radiotherapy (oral Vinorelbine 3times/week) at 60 Gy/30fx (A-59pts) and 66 Gy/33fx (B-58pts) from 2009 to 2013 at five Danish RT centers. Grade 2 RP (CTCAEv3.0) was investigated with univariate analysis for association with clinical and dosimetric parameters, including dyspnea and cough at baseline and during RT. Multivariable logistic regression and Cox regression with regularization were used to find a multivariable model for RP ≥ G2. RESULTS: Despite a tendency of higher mean lung dose in the high-dose arm (median[range] A = 14.9 Gy[5.8,23.1], B = 17.5 Gy[8.6,24.8], p = 0.075), pulmonary toxicities were not significantly different (RP ≥ G2 41%(A) and 52%(B), p = 0.231). A Kaplan Meier analysis of the time to RP ≥ G2 between the two arms did not reach statistical significance (p = 0.180). Statistically significant risk factors for RP ≥ G2 were GTV size (OR = 2.091/100 cm3, p = 0.002), infection at baseline or during RT (OR = 8.087, p = 0.026), dyspnea at baseline (OR = 2.184, p = 0.044) and increase of cough during RT (OR = 2.787, p = 0.008). In the multivariable logistic regression and the Cox regression analysis, the deviances of the most predictive models were within one standard deviation of the null model. CONCLUSION: No statistical difference between the high- and low dose arm was found in the risk of developing RP. The univariate analysis identified target volume, infection, dyspnea at baseline, and increase of cough during RT as risk factors for RP. The number of patients was too small to establish a statistically sound multivariable model.

A randomized phase II trial of concurrent chemoradiation with two doses of radiotherapy, 60Gy and 66Gy, concomitant with a fixed dose of oral vinorelbine in locally advanced NSCLC.

INTRODUCTION: In order to test the best performing radiation dose with a convenient chemotherapy schedule of an oral formulation of radio-sensitizing vinorelbine in inoperable locally advanced non-small cell lung cancer (NSCLC), we performed a randomized phase II trial based on a "pick the winner" design. METHODS: After 2 cycles of neoadjuvant chemotherapy, 117 patients with NSCLC stage IIB-IIIB in performance status 0-1 were randomized to radiotherapy 60Gy/30 fractions or 66Gy/33 fractions concurrent with a fixed dose of oral vinorelbine 50mg administered 3 times weekly. The primary endpoint was local progression free interval. A scheduled FDG-PET-CT-scan was performed 9months after randomization. The study was registered at ClinicalTrials.gov (NCT 00887783). RESULTS: Both arms were well tolerated. The local progression free interval at 9months was 54% in the 60Gy arm and 59% in the 66Gy arm (log rank test p=0.55). There was no statistically significant difference in overall survival. The median survival was 23.3 and 23.7months in the 60 and 66Gy arm, respectively. No significant difference in toxicity was observed. CONCLUSION: Both 60 and 66Gy administered concomitant with oral vinorelbine showed similar local control and overall survival, and was well tolerated. The pick the winner design choose 66Gy as the winning arm.

Accuracy of 18F-FDG PET-CT in triaging lung cancer patients with suspected brain metastases for MRI.

OBJECTIVE: Brain metastases are common in lung cancer. Whole-body 2-deoxy-2-[fluorine-18]fluoro-D-glucose ([F]FDG) PET/computed tomography (CT) is used for general staging, but MRI is the best modality for characterizing brain abnormalities. We aimed to determine whether PET/CT is suitable for selecting patients for MRI on the suspicion of brain metastases. MATERIALS AND METHODS: F-FDG PET/CT (from the vertex to mid-thigh) was performed in 1108 consecutive patients suspected of lung cancer. The final diagnoses were extracted from medical records as lung cancer, with or without brain metastases, other kinds of cancers, or no cancer. The sensitivity, specificity, and positive predictive value for detecting brain metastases were calculated. Interobserver variation was tested in a subset of 88 PET/CT scans. RESULTS: Of the 1108 referred patients, 596 had lung cancer. Sixty-six had brain metastases. One PET/CT was false positive. Thirty-one scans were true positive among the 43 patients who were diagnosed with brain metastases 1 month before to 3 months after PET/CT (metastasis prevalence, 7.3%). Twelve PET/CT scans were false negative. Sensitivity, specificity, and positive predictive values were 72, 100, and 97%, respectively. Interobserver agreement between two experienced observers was high (κ=0.83), whereas agreement between the experienced and the inexperienced observer was poor. CONCLUSION: The sensitivity of brain PET/CT for detecting brain metastases in lung cancer was above 70%, and the specificity was very high. Thus, PET/CT may be suitable for selecting patients for MRI in diagnostic centers that do not perform routine MRI in the pretherapeutic staging workup. The agreement among experienced readers was very high.

New dose constraint reduces radiation-induced fatal pneumonitis in locally advanced non-small cell lung cancer patients treated with intensity-modulated radiotherapy.

BACKGROUND: Intensity-modulated radiotherapy (IMRT) in locally advanced non-small cell lung cancer (NSCLC) allows treatment of patients with large tumour volumes, but radiation pneumonitis (RP) remains a dose limiting complication. The incidence of severe RP using three-dimensional (3D) conformal radiotherapy, was previously reported to be 17%, with 2% lethal RP. The aim of this study was to monitor the incidence of RP following the introduction of IMRT. MATERIAL AND METHODS: IMRT was delivered using 4-8 beam arrangements and introduced in three phases. In phase I, 12 patients were treated using only one dose constraint (V20), in which the total lung volume receiving 20 Gy was limited to 40%. In phase II, 25 patients were treated with an additional dose constraint of mean lung dose (MLD) ≤ 20 Gy. In phase III, 50 patients were treated with an extra dose constraint (V5) in which the total lung volume receiving a dose of 5 Gy was ≤ 60%. RP was prospectively documented. The results of phase I & II (IMRT-1) were compared to those in phase III (IMRT-2). RESULTS: The median follow-up time was 17 months. The introduction of IMRT was associated with an increase in the incidence of RP in Phase I&II (IMRT-1) to 41%, six of 37 (16%) had grade 5 RP (IMRT-1). Introducing the dose constraint V5, led to a significant reduction in the lung volume receiving doses ≤ 20 Gy from 51 ± 2% to 41 ± 1% (p < 0.0001). Introducing V5 constraint did not decrease the incidence of severe (grade ≥ 3) RP, but significantly decreased the lethal pneumonitis to 4% (two of 50 patients), p = 0.05. CONCLUSION: Introducing IMRT resulted in an increase in the incidence of severe and fatal RP, however a new dose constraint to the volume of lung receiving low doses reduced the incidence of lethal pneumonitis.

Evaluation of factors associated with loco-regional failure and survival in limited disease small cell lung cancer patients treated with chemoradiotherapy.

BACKGROUND: Loco-regional failure (LRF) remains a significant problem in limited disease small cell lung cancer (LD-SCLC) patients treated with definitive chemoradiotherapy. Dose-escalation may be a way forward to reduce the failure rate. However, the risk of toxicity rises with increasing doses. Knowledge on factors associated with LRF could aid the selection of patients for more aggressive treatment. Therefore, the aim of this study is to evaluate factors correlated with LRF in a cohort of LD-SCLC patients treated with definitive chemoradiotherapy. Moreover, factors associated with improved survival were investigated. MATERIAL AND METHODS: We included 147 consecutive LD-SCLC patients treated from 2007 to 2013. Radiotherapy was delivered as either 45 Gy in 1.5-Gy fractions twice daily or 46-50 Gy in 2-Gy fractions once daily. Chemotherapy was etoposide combined with either carboplatin or cisplatin given mainly concomitantly with radiotherapy. Pattern of first failure and survival were evaluated retrospectively. Cumulative LRF (CLRF) and overall survival (OS) were calculated by the Kaplan-Meier method. The impact of covariates on LRF and OS was evaluated by using Cox proportional hazards model. RESULTS: With a median follow-up time of 42.2 months, 37 patients experienced LRF as first failure. Isolated LRF was seen in 16 patients, but no isolated regional failure was seen. The CLRF rate was 22% at 1-year and 43% at 3-years. N3-stage was an independent prognostic factor correlated with LRF development (p = 0.043). Median OS was 24.1 months (95% CI 19-29 months) and a three-year survival of 34%. Prognostic factors associated with improved OS were staging including a positron emission tomography (PET) scan (p = 0.004) and receiving prophylactic cranial irradiation (PCI) (p = 0.006). CONCLUSION: N3-stage was an independent prognostic factor for LRF. Receiving a pretreatment PET scan and receiving PCI were prognostic factors for improved OS. Reduction in LRF may be achieved with dose-escalation in patients with N3-stage. This can be evaluated in prospective dose-escalation trials.

Clinical outcome of image-guided adaptive radiotherapy in the treatment of lung cancer patients.

BACKGROUND: Adaptive strategy with daily online tumour match is a treatment option when treating locally advanced lung cancer patients with curative intended radiotherapy (RT). MATERIAL AND METHODS: Fifty-two consecutive lung cancer patients treated with soft tissue match, adaptive RT and small planning target volumes (PTV) margins were analysed. A control group of 52 consecutive patients treated with bone match, no adaptive strategy and larger margins was included. Patients were followed with computed tomography (CT) scans every third month. CT-images showing loco-regional recurrences were identified. The recurrence gross tumour volume was delineated and registered with the original radiation treatment plan to identify site of failure. All patients were toxicity-scored using CTCAE 4.03 grading scale. Data were analysed using the Kaplan-Meier analysis. RESULTS: The median follow-up time was 16 months (3-35). Within a year, 35% of the patients in the adaptive group (ART-group) and 53% in the control group (No-ART-group) experienced loco-regional failure, showing improved loco-regional control in the ART group (p = 0.05). One patient in the ART-group and four patients in the No-ART-group showed marginal failure. Median overall progression-free survival time for the ART-group was 10 months (95% CI 8-12), and 8 months (95% CI 6-9) for the No-ART-group. Severe pneumonitis (grade 3-5) decreased from 22% in the No-ART-group to 18% in the ART-group (non-significant, p = 0.6). No significant difference in severe dysphagia was found between the two groups. CONCLUSION: In the first small cohort of patients investigated, implementation of soft-tissue tumour match and adaptive strategies for locally advanced lung cancer patients increased the loco-regional control rate without increasing treatment-related toxicity.

Development of radiation pneumopathy and generalised radiological changes after radiotherapy are independent negative prognostic factors for survival in non-small cell lung cancer patients.

BACKGROUND AND PURPOSE: To investigate the risk factors for radiation pneumopathy (RP) and survival rate of non-small cell lung cancer patients with RP and generalised interstitial lung changes (gen-ILC). MATERIAL AND METHODS: A total of 147 consecutive patients receiving curative radiotherapy were analysed. RP was graded according to Common Terminology Criteria for Adverse Events v. 3. Computed tomography images were assessed for the presence of gen-ILC after radiotherapy. Univariate and multivariate analyses were performed to identify significant factors. RESULTS: Median follow-up was 16.2 months (range 1.4-58.6). Radiological changes after radiotherapy were confined to high dose irradiation volume in 111 patients, while 31 patients developed gen-ILC. Dosimetric parameters and level of C-reactive protein before radiotherapy were significantly associated with severe RP. Development of gen-ILC (p=0.008), as well as severe RP (p=0.03) had significant negative impact on patients' survival. These two factors remained significant in the multivariate analysis. CONCLUSIONS: Severe radiation pneumopathy and generalised radiographic changes were significant independent prognostic factors for survival. More studies on pathophysiology of radiation induced damage are necessary to fully understand the mechanisms behind it.

Matrix metalloproteinase-9 measured in urine from bladder cancer patients is an independent prognostic marker of poor survival.

INTRODUCTION: Matrix metalloproteinase 9 (MMP-9) is an endopeptidase involved in various cellular processes, such as tumour development and metastatic spread. In biological samples, MMP-9 can occur as pro-MMP-9 and active MMP-9, or these factors complexed with the inhibitor TIMP-1. An assay, which can measure active and total MMP-9 in biological samples, has been used on the urine from bladder cancer patients and demonstrated a significant correlation between MMP-9 and clinical parameters. The prognostic value of these measurements has never been investigated. Using this assay we have investigated the prognostic influence of total and active MMP-9 in urine from bladder cancer patients. MATERIAL AND METHODS: Fresh voided urines from 188 consecutive patients diagnosed with bladder cancer were collected and frozen at diagnosis. After 15 years follow-up 13 patients were still alive, and 175 patients had died. MMP-9 was measured with an immunocapture activity assay. RESULTS: Median MMP-9(total) was 173.7 units/10 g creatinine (range 0-34 792), and median MMP-9(active) was 14 units/10g creatinine (range, 0-294 757). The two factors were correlated (Spearman´s rho 0.74, p<0.0001). High MMP-9(total) and MMP-9(active) were significantly correlated with large tumour size and poor malignancy grade. Increasing tertiles of MMP-9(total) and MMP-9(active) were associated with poor overall survival (p<0.0001 and p=0.003, respectively). A Cox multivariate analysis using death as endpoint identified high tertiles of MMP-9(total) as independent prognostic markers with a relative risk 2.25 (95% confidence interval, 1.53-3.30). CONCLUSION: MMP-9 measured in urine from bladder cancer patients was a strong independent prognostic marker of poor survival. This is the first time high levels of MMP-9 measured in urine from bladder cancer patients have been linked to poor prognosis. This may reflect MMP-9 playing a role in tumour invasion and metastasis. It may be possible to non-invasively measure tumour response to therapy and identify possible tumour recurrence in an early phase.

Late neurological complications after irradiation of malignant tumors of the testis.

To identify and describe late neurological complications in a Danish testis cancer cohort treated by radiotherapy. Clinical retrospective material of 94 consecutive patients with malignant testicular tumours treated at Aarhus County Hospital from 1964 to 1973. The irradiated dose in the paraaortic field varied from 27 to 55 Gy given 5 or 6 days a week, from the back and front alternately. The biological equivalent dose of the spinal cord was calculated using the linear-quadratic model. Median follow-up was 25 years, range 7 to 33 years. Seven patients were identified with late neurological complications after irradiation. One developed symptoms 9 months after treatment, but in the six other cases we found a latency period between 10 and 20 years from radiotherapy until the initial neurological symptoms began. The clinical picture in all seven patients was dominated by muscle atrophy, flaccid paresis in the lower limbs and absence of sphincter disturbances or sensory symptoms. High spinal cord dose was related to increased risk of neurological damage. During follow-up 19 patients developed another primary cancer in the radiation field; nine patients were diagnosed with severe arteriosclerosis and 13 patients with long-term gastrointestinal morbidity. Seven patients were identified with late neurological complications, and a clear dose-incidence relationship was shown. The latency period, from irradiation to the initial neurological symptoms began, ranged from 9 months to 20 years with progression of symptoms beyond 25 years. Furthermore many patients in the cohort suffered from solid tumours in the radiation field, severe arteriosclerosis and long-term gastrointestinal morbidity.

Early and late treatment-related morbidity following radical cystectomy.

OBJECTIVE: To evaluate treatment-related morbidity following cystectomy in a cohort of consecutive bladder cancer patients. The impact of age, comorbid condition, previous pelvic radiotherapy and type of urinary diversion was analysed. MATERIAL AND METHODS: Between 1992 and 1998 the treatment-related early (<30 days after cystectomy) and late morbidity was recorded in 268 consecutive bladder cancer patients (median age 65 years) undergoing cystectomy and the following types of urinary diversion: ileal conduit, n = 195; orthotopic neobladder, n = 36; continent reservoir, n = 33; and ureterocutaneous diversion, n = 4. Twenty-four patients had received previous pelvic radiotherapy and 79 had pre-existing morbidity. The median follow-up period was 5.4 years. RESULTS: The postoperative mortality rate was 2%. Age >70 years and pre-existing morbidity (especially cardiovascular disease) significantly increased the mortality rate. No relationship was found between early complication (57%) and re-exploration rates (17%) and either age, previous radiotherapy, pre-existing morbidity or type of urinary diversion. Patients undergoing orthotopic neobladder or continent reservoir had a significantly increased risk of calculus formation as well as cystectomy-related surgical procedures compared to patients undergoing ileal conduit. Age had a significant impact on vitamin B12 deficiency and renal deterioration, whereas previous pelvic irradiation significantly increased the probability of ureteroenteric stricture and lost renal function. Age and urinary diversion had no impact on hernia, ureteroenteric stricture or pyelonephritis. CONCLUSION: The risk of treatment-related morbidity was high and careful patient selection before cystectomy seems important. The lack of standard criteria regarding how to report morbidity makes comparison with other studies difficult.

Prognostic factors, pattern of recurrence and survival in a Danish bladder cancer cohort treated with radical cystectomy.

A cohort of 248 consecutive patients with bladder cancer undergoing radical cystectomy between 1992 and 98 was retrospectively followed from diagnosis until death. Prognostic factors, pattern of recurrence and survival were analysed. Pathological T and N, angiolymphatic and perineural invasion had an independent prognostic influence on survival. Patients without muscle-invasive tumour (Ta, T1) had a good prognosis, whereas patients with primarily superficial tumour progressing to muscle-invasive tumour had a significantly poorer outcome. Forty-six percent of these patients developed recurrences in the follow-up period, with a median time from recurrence to death of 5 months. The 5-year disease-specific survival for all 248 patients was 57%. Patients with pT4b or N + all died within 3 years. Patients with positive lymph nodes or T4b were not curable with cystectomy alone. Patients with advanced T or with perineural/vessel invasion are in need of improved treatment options. Patients with superficial tumours at high risk of progression should be offered early cystectomy.