Ingmar Lax

Stereotactic High Dose Fraction Radiation Therapy of Extracranial Tumors Using An Accelerator: Clinical experience of the first thirty-one patients

A stereotactic body frame with a fixation device has been developed for stereotactic radiation therapy of extracranial targets, a precision localization and positioning system in analogy with the stereotactic head frames used for intracranial targets. Results of the first 42 treated tumors in 31 patients are presented. Most of the patients had solitary tumors in liver, lung or retroperitoneal space. Clinical target volumes ranged from 2 to 622 cm3 (mean 78 cm3) and minimum doses to the planning target volumes (PTV) of 7.7-30 Gy/fraction (mean 14.2 Gy) were given on 1-4 occasions to a total minimum dose to the PTVs of 7.7-45 Gy (mean 30.2 Gy) to the periphery of the PTV and total mean doses to the PTVs of 8-66 Gy (mean 41 Gy). The central part of the tumor was usually given about 50% higher dose compared to that of the periphery of the PTV by a planned inhomogeneous dose distribution. Some of the patients received stereotactic radiation therapy concomitantly to more than one target, in others new metastases were also treated which appeared during the follow-up period. We observed a local rate of no progressive disease of 80% during a follow-up period of 1.5-38 months. Fifty percent of the tumors decreased in size or disappeared.

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 RADIOTHERAPY OF MALIGNANCIES IN THE ABDOMEN Methodological aspects

A method for stereotactic high-dose radiotherapy of malignancies in the abdomen has been developed. A stereotactic frame for the body has been developed and a method for fixation of the patient in the frame is described. The reproducibility in the stereotactic system of tumours in the liver and the lung was found to be within 5-8 mm for 90% of the patient set-ups. The diaphragmatic movements were reduced to 5-10 mm, by applying a pressure on the abdomen. An analytical method is used to calculate dose distributions for a continuum of beams in an isocentric treatment technique. The advantage of a heterogeneous target dose is demonstrated and proposed for the present application. A non-coplanar treatment technique, using eight individually shaped beams is proposed and has been used for patient treatments. The dose distribution for a patient with a metastasis in the liver is shown as well as dose volume histograms for the target and the liver.

Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer

One concern with adjuvant radiation therapy for early breast cancer is the potential risk of increasing intercurrent mortality due to radiation-induced damage of the myocardium. The paper presents an analysis of long-term survival among 960 patients with primary breast cancer included in a randomized trial of pre- or postoperative radiation therapy (45 Gy/5 weeks) versus surgery alone. All patients were treated with a modified radical mastectomy. The mean follow-up was 16 years (range: 13-19 years). During the entire follow-up period there was an overall survival difference in favor of the irradiated patients that was of borderline significance (p = 0.09). There was no increase in intercurrent mortality due to any cause. However, when the results were analyzed according to estimated doses of radiation to the myocardium, the subset of patients who received the highest doses, that is, those treated with tangential 60Co fields for left-sided tumors, were found to have a significantly increased risk of death due to ischemic heart disease compared to the surgical controls (relative hazard: 3.2, p less than 0.05). No such increase was observed among the patients who received less radiation to the myocardium, that is, whose chest wall and internal mammary nodes were treated with electrons or those with right-sided tumors, irrespective of the treatment technique. It is concluded that cardiovascular mortality associated with radiation therapy for early breast cancer is correlated with the biological dose of radiation to the heart and the irradiated volume. All of the following factors are thus important: laterality of the tumor, portal arrangements, radiation energy, fractionation, and total dose. The study illustrates that an increased cardiovascular mortality can be avoided by the use of appropriate techniques and avoidance of excessive treatment.

The role of radiotherapy in treatment of stage I non-small cell lung cancer

Most information on results with radiotherapy (RT) for stage I non-small cell lung cancer (NSCLC) is based on retrospective studies on RT-treated inoperable NSCLC cases. Thus, the role of RT for stage I NSCLC, as a curative modality, has not yet been established. A literature search for studies on stage I non-small cell lung carcinoma (NSCLC) treated by RT alone resulted in 18 papers published between 1988 and 2000. The majority of stage I patients received RT treatment because they were medically inoperable. The main contraindications for surgery were grave impairment of pulmonary function and serious cardiovascular disease. Local recurrence was the most common reason for treatment failure (median value 40%) but varied highly between the studies, ranging from 6.4 to 70%. In contrast with local recurrence, regional failure was not a major problem (0-3.2%). Generally, smaller tumour size, low T-stage and increased dose had a favourable impact on local control and increased local control was followed by increased survival. No serious treatment complications were recorded in the majority of these studies. Overall treatment results were, however, disappointing. The median survival in these studies ranged from 18 to 33 months. The 3- and 5-year overall survival was 34+/-9 and 21+/-8% (mean value+/-1 S.E.), respectively. The cause-specific survival at 3 and 5 years was 39+/-10 and 25+/-9% (mean value+/-1 S.E.), respectively. Dose escalation, in a setting with conformal RT using involved field or stereotactic RT, should be the focus of developmental therapeutic strategies with inoperable stage I NSCLC to improve local control and survival.

Factors important for efficacy of stereotactic body radiotherapy of medically inoperable stage I lung cancer. A retrospective analysis of patients treated in the Nordic countries

We reviewed results of SBRT treatment of 138 patients with medically inoperable stage I NSCLC treated during 1996–2003 at five different centres in Sweden and Denmark. Mean age was 74 years (range 56–90) with 69 men and 72 women. SBRT was delivered using a 3D conformal multifield technique and a stereotactic body frame. Doses delivered were 30–48 Gy (65% isodose at the periphery of planning target volume, PTV) in 2–4 fractions. Equivalent dose in 2 Gy fractions (EQD2) was in the range of 50–100 Gy. Mean gross tumour volume (GTV) was 39 cm3 (2–436), and planning target volume was 101 cm3 (11–719). Overall response rate (CR, PR) was 61% (84/138). SD was noted in 36% (50/138). During a median follow-up period of 33 months (1–107), 16 (12%) local failures occurred, ten of which also included distant metastases. Local failure was associated with tumour size, target definition and central or pleura proximity. Distant metastases occurred in 25% (35/138) of the patients. Ninety-one (65%) patients died during follow-up of which 55 patients (60%) died of other causes than lung cancer. Three- and 5-year overall survival was 52 and 26% respectively. Lung cancer specific 3- and 5-year overall survival was 66 and 40% respectively. Fifty nine percent (83/138) of the patients had no side effects. Fourteen patients experienced grade 3–4 toxicity according to radiation therapy oncology group (RTOG). EQD2 (> v.s.<55.6 Gy) showed a statistically significant benefit survival for the higher doses. SBRT for stage I NSCLC results in favourable local control not inferior to fractionated RT and with acceptable toxicity.

Radiation pneumonitis after breast cancer irradiation: analysis of the complication probability using the relative seriality model

BACKGROUND Toxicity of the respiratory system is quite common after radiotherapy of thoracic tumors; breast cancer patients represent one of the groups for which there is also a long expected survival. The quantification of lung tissue response to irradiation is important in designing treatments associated with a minimum of complications and maximum tumor control. METHODS The study population consisted of 68 patients who received irradiation for breast cancer at Stage II. Radiation pneumonitis was retrospectively assessed on the basis of clinical symptoms and radiological findings. For each patient, a measure of the exposure (i.e., the lung dose-volume histogram [DVH]) and a measure of the outcome was available. Based on these data, a maximum likelihood fitting to the relative seriality model was performed. The uncertainties of the model parameters were calculated and their impact on the dose-response curve was studied. The optimum parameter set was then applied to 5 other patient groups treated for breast cancer, and the normal tissue complication probability (NTCP) was calculated. Each group was individuated by the radiotherapy treatment technique used; the dose distribution in the lung was described by a mean DVH and the incidence of radiation pneumonitis in each group was known. Lung radiosensitivity was assumed to be homogeneous through all of the calculations. RESULTS The relative seriality model could describe the dataset. The volume effect was found to be relevant in the description of radiation pneumonitis. Age was found to be associated with increased risk of radiation pneumonitis. Two distinct dose-response curves were obtained by splitting the group according to age. The impact of the parameter uncertainties on the dose-response curve was quite large. The parameter set determined could be used predictively on 3 of the 5 patient groups. CONCLUSION The complication data could be modeled with the relative seriality model. However, further independent datasets, classified according to the same endpoint, must be analyzed before introducing NTCP modeling in clinical practice.

Evaluation of irradiated heart volumes in stage I breast cancer patients treated with postoperative adjuvant radiotherapy.

PURPOSE To quantify the proportion of heart volumes that received at least 25 Gy with tangential photon fields in patients with left-sided stage I (T1 NOMO) breast cancer treated with breast-conserving surgery. METHODS AND MATERIALS The dose planning of 100 consecutive patients was reviewed. All were irradiated with tangential photon fields that covered the left breast only. A three-dimensional computed tomographic (CT)-based dose planning was made for each patient. The prescribed dose to the tumor was 50 Gy. For each patient, the proportion of the heart included in the 50% isodose was determined from the cumulative dose-volume histogram (DVH). The same volume determination was made for the left-sided breast cancer patients treated with tangential fields during the first Stockholm Breast Cancer Trial. RESULTS The mean irradiated heart volume that received at least 25 Gy was 5.7% (SD = 4.5%) for the whole group and 11.9% (SD = 3.7%) in those with the highest volumes. The mean irradiated heart volume included in the 50% isodose for patients in the Stockholm Trial was 25% (SD = 11.9%). CONCLUSION In this study, the majority of patients with left-sided T1NOMO breast cancer did not receive irradiation to substantial heart volumes. However, in 6% of all studied patients, the proportion of irradiated heart volume was close to the irradiated heart volumes with one of the treatment techniques used in the Stockholm Trial for patients with left-sided tumors. That technique has been associated with significantly increased cardiac mortality during long-term follow-up evaluation in a previous study. The CT-based three-dimensional treatment-planning system (TMS) represents a valuable tool in identifying such patients; thus, treatment may be conformed to reduce the irradiated heart volume.

Risk for hemorrhage during the 2-year latency period following gamma knife radiosurgery for arteriovenous malformations

PURPOSE Radiosurgery does not immediately obliterate an arteriovenous malformation (AVM), and the risk for hemorrhage still persists until the AVM is occluded. There is controversy about whether this risk is altered after as compared to before radiosurgery. The aim of this paper is to study this topic further and to suggest a model to predict the risk for posttreatment hemorrhage. METHODS AND MATERIALS The incidence of hemorrhages within the first 24 months following Gamma Knife radiosurgery was studied retrospectively among 1593 AVM patients, and was related to patient, AVM, and treatment parameters. RESULTS Fifty-six patients experienced a hemorrhage in the latency period, representing an average annual incidence of 1.8%. The incidence of posttreatment hemorrhage was related to the patients age, AVM volume, minimum dose, and average dose delivered to the AVM nidus. Based on these observations, an equation was defined that could quantify the probability for a posttreatment hemorrhage to occur. CONCLUSION A model that can predict the probability for a hemorrhage within the first 24 months after radiosurgery is presented. The risk is higher for larger AVMs and for older patients, and it is lower when higher doses of radiation are used.

Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma

The treatment options in renal cancer are few and the response rates are low. It is also a cancer form that has a diverse biology-the vast majority of cases progress rapidly but in a small fraction of patients the progression occurs slowly and in rare cases spontaneous regression are known to occur [1]. These have been reported in virtually all types of human cancer, although the greatest numbers of cases are reported in neuroblastoma, renal cell carcinoma, melanoma and lymphomas/leukemias. Spontaneous regression of cancer is an interesting phenomenon and elucidating the mechanisms by which it occurs offers the hope that more effective methods of treating and preventing cancer could be developed. In renal cell carcinomas spontaneous regression predominate in males by a ratio of 3:1. In over 90% of cases, pulmonary metastases are the site of regression. Regression of other sites such as skin, liver, intestine, bone and nodal areas have also been reported [2]. Most frequently spontaneous regression occurs after nephrectomy but the phenomenon has been reported in the absence of surgery or after vascular embolisation, radiofrequency ablation and radiotherapy [1]. Stereotactic radiotherapy (SRT) has been used in our center for almost 15 years for treating inoperable primary tumors of renal cell carcinoma and metastatic lesions in various malignant diseases [3 6]. In 28 renal cell carcinoma patients with treated and untreated metastatic lesions, we have four cases where non-irradiated metastases have regressed temporarily or seemingly permanently after treatment with SRT of either the primary tumor or other metastatic lesions. The frequency of such responses observed in our patient cohort is comparable to the response rates for conventional treatments like interferon and interleukin-2 and is strikingly high compared to the literature, where spontaneous regression of metastasis in renal cell cancer is reported to occur in 0.3 7% of cases [1]. The findings are in agreement with data indicating that local radiation treatment may induce systemic effects, a phenomenon referred to in the literature as the ‘‘abscopal effect’’ [7 12]. The phenomenon has been reported in various tumor forms but mainly as singular events [7,9,10,13,14]. The term ‘‘abscopal effect’’ caused by radiotherapy was first coined by R. H. Mole in 1953 (abscopal /distant target). This was originally defined as an action at a distance from the irradiated volume but within the same organism [15]. Recently the definition of the abscopal effect has been broadened to include other forms of local therapy that have systemic effects, i.e., a distant bystander effect [16,17]. The following cases illustrate both the possible induction of an anti-tumoral response against untreated metastases after SRTas well as the efficacy of this therapeutic option in slowly progressing renal