Berit Wennberg

Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy.

PURPOSE The impact of stereotactic body radiotherapy (SBRT) on 3-year progression-free survival of medically inoperable patients with stage I non-small-cell lung cancer (NSCLC) was analyzed in a prospective phase II study. PATIENTS AND METHODS Fifty-seven patients with T1NOMO (70%) and T2N0M0 (30%) were included between August 2003 and September 2005 at seven different centers in Sweden, Norway, and Denmark and observed up to 36 months. SBRT was delivered with 15 Gy times three at the 67% isodose of the planning target volume. RESULTS Progression-free survival at 3 years was 52%. Overall- and cancer-specific survival at 1, 2, and 3 years was 86%, 65%, 60%, and 93%, 88%, 88%, respectively. There was no statistically significant difference in survival between patients with T1 or T2 tumors. At a median follow-up of 35 months (range, 4 to 47 months), 27 patients (47%) were deceased, seven as a result of lung cancer and 20 as a result of concurrent disease. Kaplan-Meier estimated local control at 3 years was 92%. Local relapse was observed in four patients (7%). Regional relapse was observed in three patients (5%). Nine patients (16%) developed distant metastases. The estimated risk of all failure (local, regional, or distant metastases) was increased in patients with T2 (41%) compared with those with T1 (18%) tumors (P = .027). CONCLUSION With a 3-year local tumor control rate higher than 90% with limited toxicity, SBRT emerges as state-of-the-art treatment for medically inoperable stage I NSCLC and may even challenge surgery in operable instances.

Stereotactic body radiotherapy for medically inoperable patients with stage I non-small cell lung cancer – A first report of toxicity related to COPD/CVD in a non-randomized prospective phase II study

BACKGROUND AND AIMS In a retrospective study using stereotactic body radiotherapy (SBRT) in medically inoperable patients with stage I NSCLC we previously reported a local control rate of 88% utilizing a median dose of 15Gyx3. This report records the toxicity encountered in a prospective phase II trial, and its relation to coexisting chronic obstructive pulmonary disease (COPD) and cardio vascular disease (CVD). MATERIAL AND METHODS Sixty patients were entered in the study between August 2003 and September 2005. Fifty-seven patients (T1 65%, T2 35%) with a median age of 75 years (59-87 years) were evaluable. The baseline mean FEV1% was 64% and median Karnofsky index was 80. A total dose of 45Gy was delivered in three fractions at the 67% isodose of the PTV. Clinical, pulmonary and radiological evaluations were made at 6 weeks, 3, 6, 9, 12, 18, and 36 months post-SBRT. Toxicity was graded according to CTC v2.0 and performance status was graded according to the Karnofsky scale. RESULTS At a median follow-up of 23 months, 2 patients had relapsed locally. No grade 4 or 5 toxicity was reported. Grade 3 toxicity was seen in 12 patients (21%). There was no significant decline of FEV1% during follow-up. Low grade pneumonitis developed to the same extent in the CVD 3/17 (18%) and COPD 7/40 (18%) groups. The incidence of fibrosis was 9/17 (53%) and pleural effusions was 8/17 (47%) in the CVD group compared with 13/40 (33%) and 5/40 (13%) in the COPD group. CONCLUSION SBRT for stage I NSCLC patients who are medically inoperable because of COPD and CVD results in a favourable local control rate with a low incidence of grade 3 and no grade 4 or 5 toxicity.

Early response of lung in breast cancer irradiation: radiologic density changes measured by CT and symptomatic radiation pneumonitis☆

PURPOSE To quantify radiologic changes in the lung with CT after radiotherapy (RT) for breast cancer (BC) and to study their association with treatment techniques and symptomatic radiation pneumonitis (RP). METHODS AND MATERIALS CT scans of the lungs were performed before and 4 months after RT in 121 BC patients treated with four different RT techniques. The changes in mean density (MDCs) were analyzed at two lung levels (i.e., the central and apical CT slice). The central CT slice was also analyzed with respect to the MDCs in the anterior third and anterior half of the ipsilateral lung area. In mastectomized patients who received chest wall RT with an en-face electron beam, the maximal depths for a range of isodose curves were measured. The occurrence of mild/moderate symptomatic RP was assessed prospectively 1, 4, and 7 months after RT. Data on covariates with potential confounding effect on RT-induced lung toxicity were also collected prospectively. RESULTS In the entire study population, an association between the MDCs in the anterior third of the central CT slice and treatment technique (p <0.001) and symptomatic RP (p <0.001) was found. Among patients with chest wall treatment consisting of an en-face electron beam, the MDCs of the anterior third of the central CT slice correlated with the 35% isodose curve (16-30 Gy) (p = 0.046) and age (p <0.001). No association between post-RT lung density changes and pre-RT chemotherapy, concurrent tamoxifen intake, or smoking habits was found. Among patients treated with locoregional RT, an association was found between the MDCs in the anterior third of the central CT slice and the incidence of RP. MDCs in the apical CT slice, however, were not associated with RP. CONCLUSION The results imply that short-term post-RT lung density changes and symptomatic RP were associated with RT techniques, total doses as low as 16-30 Gy, and increasing age. Structural changes in the central part of lung appeared to be more important for the development of RP than changes in the apex.

Pulmonary complications following different radiotherapy techniques for breast cancer, and the association to irradiated lung volume and dose

AbstractPurpose. This study investigates the incidence of short-term pulmonary complications following radiotherapy (RT) for breast cancer (BC) with different treatment techniques/incidentally irradiated lung volumes and the importance of confounding factors on RT-induced pulmonary complications. Patients and methods. Prospectively, 475 patients with BC were followed for pulmonary complications 1, 4 and 7 months post-RT. Mean lung dose volume histograms (MDVH) were constructed and compared for the different RT-techniques. Among a subset of the mastectomized patients treated with loco-regional (LR-) RT, who had undergone complete three-dimensional (3-D) dose planning (n= 43), MDVH for asymptomatic patients was compared with MDVH for patients experiencing both radiological and clinical pulmonary side-effects. Results. Moderate pulmonary complications, that is requiring treatment with corticosteroids, were rare following local RT ( < 1%), but were diagnosed among 11% of the patients treated with LR-RT. A correlation between increasing irradiated lung volumes at the > 20 Gy-level (V20), based on MDVH for the RT-techniques, and pulmonary complications was found (P < 0.001). Furthermore, increasing age and reduced pre-RT functional level were independently associated with a higher rate of pulmonary complications (P = 0.005 and P = 0.018). Among the subgroup of mastectomized patients treated with LR-RT, who had undergone complete 3-D dose planning, a difference in mean V20 was found between patients experiencing both clinical and radiological pulmonary side-effects compared to patients experiencing neither of the two side-effects (P = 0.007). Conclusion. Moderate pulmonary complications following local RT for BC are rare. The incidence of short-term moderate pulmonary complications in LR-RT is, however, clinically significant and to define quality assurance guidelines for these RT-techniques, 3-D RT planning can be used.

SBRT of lung tumours: Monte Carlo simulation with PENELOPE of dose distributions including respiratory motion and comparison with different treatment planning systems.

The purpose of this work was to simulate with the Monte Carlo (MC) code PENELOPE the dose distribution in lung tumours including breathing motion in stereotactic body radiation therapy (SBRT). Two phantoms were modelled to simulate a pentagonal cross section with chestwall (unit density), lung (density 0.3 g cm(-3)) and two spherical tumours (unit density) of diameters respectively of 2 cm and 5 cm. The phase-space files (PSF) of four different SBRT field sizes of 6 MV from a Varian accelerator were calculated and used as beam sources to obtain both dose profiles and dose-volume histograms (DVHs) in different volumes of interest. Dose distributions were simulated for five beams impinging on the phantom. The simulations were conducted both for the static case and including the influence of respiratory motion. To reproduce the effect of breathing motion different simulations were performed keeping the beam fixed and displacing the phantom geometry in chosen positions in the cranial and caudal and left-right directions. The final result was obtained by combining the different position with two motion patterns. The MC results were compared with those obtained with three commercial treatment planning systems (TPSs), two based on the pencil beam (PB) algorithm, the TMS-HELAX (Nucletron, Sweden) and Eclipse (Varian Medical System, Palo Alto, CA), and one based on the collapsed cone algorithm (CC), Pinnacle(3) (Philips). Some calculations were also carried out with the analytical anisotropic algorithm (AAA) in the Eclipse system. All calculations with the TPSs were performed without simulated breathing motion, according to clinical practice. In order to compare all the TPSs and MC an absolute dose calibration in Gy/MU was performed. The analysis shows that the dose (Gy/MU) in the central part of the gross tumour volume (GTV) is calculated for both tumour sizes with an accuracy of 2-3% with PB and CC algorithms, compared to MC. At the periphery of the GTV the TPSs overestimate the dose up to 10%, while in the lung tissue close to the GTV PB algorithms overestimate the dose and the CC underestimates it. When clinically relevant breathing motions are included in the MC simulations, the static calculations with the TPSs still give a relatively accurate estimate of the dose in the GTV. On the other hand, the dose at the periphery of the GTV is overestimated, compared to the static case.

Pulmonary function following adjuvant chemotherapy and radiotherapy for breast cancer and the issue of three-dimensional treatment planning

BACKGROUND AND PURPOSE The frequency and grade of pulmonary complications following adjuvant radiotherapy for breast cancer are still debated. This study focuses on loss of pulmonary function. MATERIALS AND METHODS We have measured the reduction of pulmonary function 5 months following radiotherapy in 144 node-positive stage II breast cancer patients by using pulmonary function tests. RESULTS No deterioration of pulmonary function was detected among the patients who were treated with local radiotherapy. On the contrary, there was a mean increase in diffusion capacity by 7% (P = 0.004) following radiotherapy, which most likely was explained by the adjuvant chemotherapy administered prior to the baseline pulmonary function tests. Patients undergoing loco-regional radiotherapy showed a mean reduction in diffusion capacity by 5% (P < 0.001) and in vital capacity by 3% (P = 0.001). The subset of patients (9%) who were diagnosed with severe pulmonary complications needing cortisone treatment had significantly larger mean paired differences in vital capacity (-0.446 L, -15% (equivalent to 15 years of normal ageing or the loss of 3/4 of a lung lobe)) compared to the patients who were asymptomatic (-0.084 L) (P < 0.05). When the effects of potential confounding factors and different radiotherapy techniques were tested on the reduction of pulmonary function by stepwise multiple regression analysis, a significant correlation was found only to locoregional radiotherapy including the lower internal mammary lymph nodes. CONCLUSIONS We conclude that a clinically important reduction of pulmonary function is seen in the subset of patients who are diagnosed with severe pulmonary complication following loco-regional radiotherapy for breast cancer. The results of this study warrant further studies based on individual lung dose volume histograms.

Dose distributions in SBRT of lung tumors: Comparison between two different treatment planning algorithms and Monte-Carlo simulation including breathing motions

In stereotactic body radiotherapy (SBRT) of lung tumors, dosimetric problems arise from: 1) the limited accuracy in the dose calculation algorithms in treatment planning systems, and 2) the motions with the respiration of the tumor during treatment. Longitudinal dose distributions have been calculated with Monte Carlo simulation (MC), a pencil beam algorithm (PB) and a collapsed cone algorithm (CC) for two spherical lung tumors (2 cm and 5 cm diameter) in lung tissue, in a phantom situation. Respiratory motions were included by a convolution method, which was validated. In the static situation, the PB significantly overestimates the dose, relative to MC, while the CC gives a relatively accurate estimate. Four different respiratory motion patterns were included in the dose calculation with the MC. A “narrowing” of the longitudinal dose profile of up to 20 mm (at about 90% dose level) is seen relative the static dose profile calculated with the PB.

A Descriptive Study of Pulmonary Complications After Postoperative Radiation Therapy in Node-Positive Stage II Breast Cancer

This study was conducted to assess the frequencies of symptomatic pulmonary complications following adjuvant postoperative radiotherapy using different treatment techniques in patients with Stage II node-positive breast cancer. During 1991-1993, 177 patients were referred to the Radiotherapy Department of Stockholm Söder Hospital; 144 after modified radical mastectomy and 33 after partial mastectomy. The records of these patients were studied retrospectively for clinically diagnosed radiotherapy-induced lung complications 1-7 months after treatment. Thirty-three of 138 patients (24%) irradiated after modified radical mastectomy developed pulmonary complications and 20 (14%) of these were diagnosed as severe, i.e. needing medical treatment with corticosteroids. No statistically significant difference could be found between the different electron energies used for treating the chest wall and the frequency of respiratory side-effects. Eighteen of 33 patients completed the prescribed treatment after partial mastectomy. Nine of these 18 patients (50%) developed pulmonary complications and 4 (22%) developed severe reactions. Fifteen patients received alternative treatments. With the techniques used after partial mastectomy the median central lung distance was 32 mm among the patients who experienced respiratory side-effects compared with 25 mm among the patients who were not affected (p = 0.03). This study identifies acute/subacute pulmonary side-effects as a clinically significant problem. Prospective follow-up with lung function tests, identification of risk factors, and individual lung dose volume histograms is warranted to assess the long-term implications.

Reduction of radiation pneumonitis by V20-constraints in breast cancer

IntroductionAdjuvant local-regional radiotherapy (LRRT) is routinely recommended for breast cancer patients. It is well known being related to pulmonary side-effects. We studied post-RT radiological changes on X-ray and CT, and correlated the findings with Quality of Life (QoL), common dosimetric factors and co-variates. The results were compared with a previously reported cohort of 137 irradiated women.Methods88 women underwent chest X-ray and CT pre-and 4-5 months after 3-D planned LRRT, minimizing the dose to the ipsilateral lung to V20 < 30%. The lung field was divided into 3 regions and the development of post-RT density changes were graded (0-3). Patients with radiological changes were compared with non-responders. Clinical symptoms were registered and data on patient and treatment related co-variates were gathered prospectively. The ipsilateral lung dosimetric factors V13, V20, V30 and mean dose were calculated and QoL was assessed before and 4 months after RT.ResultsThe use of dose-volume constraints significally reduced moderate-severe radiological changes on chest X-ray compared with our earlier study (Chi square trend test: p < 0.001). Symptomatic pneumonitis was also rare in the present study. No agreement was found between CT and chest X-ray as diagnostic tools for post-RT pneumonitis. V13 correlated independently with radiological changes on CT (logistic regression: p = 0.04; ROC area: 0.7). The Co-variates smoking habits, age, chemotherapy, endocrine or trastuzumab therapy did not influence the outcome on multivariate analysis. QoL changes in physical function, i.e. fatigue, dyspnoea were not detected but there was a trend for a worse recovery after chemotherapy in patients with high V13 (Spearman Rank Correlation: p < 0.05).ConclusionsThe use of dose-volume constraints significantly reduced post-RT radiological changes on chest X-ray in LRRT for BC. The lung changes on CT were also generally limited when we used this strategy and was not always picked up on chest X-ray. Variation in V13 alone was correlated with occurrence of lung changes on CT.

NTCP modelling of lung toxicity after SBRT comparing the universal survival curve and the linear quadratic model for fractionation correction

Abstract Background. In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of lung toxicity is found. The aim of this study is to compare the LQ model and the universal survival curve (USC) to calculate biologically equivalent doses in SBRT to see if this will improve knowledge on this relationship. Material and methods. Toxicity data on radiation pneumonitis grade 2 or more (RP2+) from 57 patients were used, 10.5% were diagnosed with RP2+. The lung DVHs were corrected for fractionation (LQ and USC) and analysed with the Lyman- Kutcher-Burman (LKB) model. In the LQ-correction α/β = 3 Gy was used and the USC parameters used were: α/β = 3 Gy, D0 = 1.0 Gy, = 10, α = 0.206 Gy−1 and dT = 5.8 Gy. In order to understand the relative contribution of different dose levels to the calculated NTCP the concept of fractional NTCP was used. This might give an insight to the questions of whether “high doses to small volumes” or “low doses to large volumes” are most important for lung toxicity. Results and Discussion. NTCP analysis with the LKB-model using parameters m = 0.4, D50 = 30 Gy resulted for the volume dependence parameter (n) with LQ correction n = 0.87 and with USC correction n = 0.71. Using parameters m = 0.3, D50 = 20 Gy n = 0.93 with LQ correction and n = 0.83 with USC correction. In SBRT of lung tumours, NTCP modelling of lung toxicity comparing models (LQ,USC) for fractionation correction, shows that low dose contribute less and high dose more to the NTCP when using the USC-model. Comparing NTCP modelling of SBRT data and data from breast cancer, lung cancer and whole lung irradiation implies that the response of the lung is treatment specific. More data are however needed in order to have a more reliable modelling.