Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer.

BACKGROUND: The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS: We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS: Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS: In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).

Toxicity at three years with and without irradiation of the internal mammary and medial supraclavicular lymph node chain in stage I to III breast cancer (EORTC trial 22922/10925).

INTRODUCTION: The EORTC 22922/10925 trial investigated the potential survival benefit and toxicity of elective irradiation of the internal mammary and medial supraclavicular (IM-MS) nodes Accrual completed in January 2004 and first results are expected in 2012. We present the toxicity reported until year 3 after treatment. PATIENTS AND METHODS: At each visit, toxicity was reported but severity was not graded routinely. Toxicity rates and performance status (PS) changes at three years were compared by chi(2) tests and logistic regression models in all the 3,866 of 4,004 patients eligible to the trial who received the allocated treatment. RESULTS: Only lung (fibrosis; dyspnoea; pneumonitis; any lung toxicities) (4.3% vs. 1.3%; p < 0.0001) but not cardiac toxicity (0.3% vs. 0.4%; p = 0.55) significantly increased with IM-MS treatment. No significant worsening of the PS was observed (p = 0.79), suggesting that treatment-related toxicity does not impair patient's daily activities. CONCLUSIONS: IM-MS irradiation seems well tolerated and does not significantly impair WHO PS at three years. A follow-up period of at least 10 years is needed to determine whether cardiac toxicity is increased after radiotherapy.

Short-term outcome of primary operated early breast cancer by hormone and HER-2 receptors.

INTRODUCTION: Prognostic subgroup classification of operable breast cancers using cDNA clustering of breast cancer-related genes resembles the classification based on the combined immunohistochemical (IHC) expression of the hormone and HER-2 receptors. We here report the short-term disease-free interval (DFI) of operable breast cancers by their joint hormone receptor/HER-2 phenotype. PATIENTS AND METHODS: Short-term follow-up (FU) of a prospective cohort of 1,958 breast-cancer patients primary operated at our institution between 2000 and 2005. Receptors were evaluated using IHC. Steroid receptors were considered positive for any nuclear staining; HER-2 for strong (3+) membrane staining or positive fluorescence in situ hybridization (FISH). Kaplan-Meier (KM) DFI curves were calculated for any relapse defined as a local, regional, contralateral, or distant breast cancer event for the six predefined breast cancer subgroups: ER + PR + HER-2 - (PPN), ER + PR - HER-2 - (PNN), ER + PR + HER-2 + (PPP), ER - PR - HER-2 - (NNN), ER - PR - HER-2 + (NNP), and ER + PR - HER-2 + (PNP). P-values were calculated for comparison of the six different survival curves using two possible adaptations for multiple testing. A multivariate model for the receptors predicting DFI did incorporate local and systemic adjuvant therapy. RESULTS: Median patient age was 57 years (ranges 26-96) and median FU was 3.35 years. Overall, DFI at median FU was 91%; 94% for PPN, 89% for PNN, 86% for NNN, 81% for PPP, 80% for PNP, and 76% for NNP cases. Some receptor subgroups had a significantly better DFI than others based on multiple testing, especially when the PPN group was compared against the four most frequent subtypes. The multivariate model with local and systemic adjuvant therapy confirmed the prognostic value of ER, PR, and HER-2 for short-term DFI. CONCLUSION: It is possible to distinguish short-term prognostic breast cancer subgroups only on the basis of ER, PR, and HER-2 even when stratified for local and systemic adjuvant therapy. While gene expression profiles based on microarray data of over hundreds of genes will probably teach us much about breast cancer biology, heterogeneity, and prognosis, we emphasize the important short-term prognostic value of currently used IHC markers for ER, PR, and HER-2.

Axillary lymph node status of operable breast cancers by combined steroid receptor and HER-2 status: triple positive tumours are more likely lymph node positive.

AIMS: To examine the frequency of axillary lymph node (ALN) invasion of operable breast cancers by their combined oestrogen receptor (ER), progesterone receptor (PR) and HER-2 status. METHODS: 2227 recently operated cases in one centre were retrieved from the Multidisciplinary Breast Centre database and stratified according to their combined immunohistochemical (IHC) expression of ER/PR/HER-2 status. An equivocal HER-2 status was further analysed by Fluorescence in situ Hybridisation (FISH). The following 6 groups were considered: ER(-)PR(-)HER-2(-) (NNN; triple negative), ER(-)PR(-)HER-2(+) (NNP), ER(+)PR(-)HER-2(-) (PNN), ER(+)PR(-)HER-2(+) (PNP), ER(+)PR(+)HER-2(- )(PPN), ER(+)PR(+)HER-2(+) (PPP; triple positive). For ALN, the following variables were tested in uni- and multivariate models: age at diagnosis (years), tumour size (mm), tumour grade, ER, PR, HER-2 and the combined steroid receptor and HER-2 status. Likelihood ratio chi(2)-tests were used for univariate analysis and logistic regression for multivariate analysis. RESULTS: Triple positive tumours had a higher likelihood of being ALN positive than others (56.2% versus 35.7%; P<0.0001). Univariate logistic regression also withheld age, size, grade and HER-2 as predictors of ALN involvement. Final multivariate logistic regression revealed age, size, grade and PPP versus non-PPP to be independent predictors of ALN involvement; the odds ratio (OR) and 95% CI for PPP versus non-PPP tumours was 2.169 (1.490-3.156). CONCLUSION: Our data provide insight into the natural history of triple positive breast carcinomas. Such tumours are more likely ALN positive than those with another steroid receptor and HER-2 status. How these findings correlate with breast cancer prognosis remains to be investigated.

Impact of the boost dose of 10 Gy versus 26 Gy in patients with early stage breast cancer after a microscopically incomplete lumpectomy: 10-year results of the randomised EORTC boost trial.

PURPOSE: To assess the impact of the boost dose in patients with involved surgical margins. PATIENTS AND METHODS: In the EORTC "boost versus no boost" trial, 251 patients with a microscopically incomplete tumour excision were randomised to receive either a low boost dose of 10 Gy (126 patients) or a high boost dose of 26 Gy (125 patients). Overall survival and the cumulative incidence of local recurrence as first event were compared by Logrank and Gray test, respectively (2-sided alpha=0.05), with a median follow-up of 11.3 years. The planned sample size was 660 patients, but only 251 were recruited. RESULTS: The median age at randomisation was 54 years. Thirty-seven patient initially relapsed locally. At 10 years, the cumulative incidence of local recurrence was 17.5% (95% CI: 10.4-24.6%) versus 10.8% (95% CI: 5.2-16.4%) for the low and high boost dose groups, respectively (HR=0.83, 95% CI: 0.43-1.57, Gray p>0.1). Overall, 64 patients have died (25.5%), 47 of them of breast cancer, without a difference in duration of survival between the two groups (HR=0.97, 95% CI=0.59-1.5, p>0.1). Severe fibrosis was palpated in the breast in 1% versus 5% and in the boost area in 3% versus 13% in the low and high boost dose groups, respectively. CONCLUSIONS: There was no statistically significant difference in local control or survival between the high boost dose of 26 Gy and the low boost dose of 10 Gy in patients with microscopically incomplete excision of early breast cancer. Fibrosis, however, was noted significantly more frequently in cases treated with the high boost dose.

Quality assurance in breast cancer: EORTC experiences in the phase III trial on irradiation of the internal mammary nodes.

The EORTC 22922/10925 trial randomly compares irradiation or no irradiation of the internal mammary and medio supraclavicular (IM-MS) nodes for stage I-III breast cancer. We report on the characteristics of 4004 participating patients, aspects of quality assurance and compliance to protocol treatment. The actual population has intermediate-risk disease: 51.8% stage II, 56% positive axillary nodes. The allocated treatment was not followed in 3.2% in the IM-MS irradiation arm versus 2% in the no IM-MS irradiation arm. In the IM-MS arm, there were major deviations for dose in 0.8%, surgery-to-radiotherapy time interval in 3.9% and in overall treatment time in 0.9% cases. Major deviations were found in 7.9% patients in the IM-MS group and in 2% patients in the no IM-MS group. In the final trial analysis, a sensitivity analysis should evaluate the subgroup of patients receiving an optimal treatment to verify the robustness of the results and the true impact of IM-MS irradiation.

Malignancies of the nasal cavity and paranasal sinuses: long-term outcome with conventional or three-dimensional conformal radiotherapy.

PURPOSE: To evaluate the long-term clinical outcome and toxicity of conventional and three-dimensional conformal radiotherapy for malignancies of the nasal cavity and paranasal sinuses. METHODS AND MATERIALS: Between January 1976 and February 2003, 127 patients with histologically proven cancer of the paranasal sinuses (n = 119) or nasal cavity (n = 8) were treated with preoperative (n = 61), postoperative (n = 51), or primary (n = 15) radiotherapy, using conventional (n = 74) or three-dimensional conformal (n = 53) techniques. No elective neck irradiation of the cervical lymph nodes was performed in N0 patients. RESULTS: Median follow-up was 5.6 years (range, 3-307 months) for all patients, and 7.3 years (range, 47-307 months) for patients still alive at the close-out date. The actuarial 5-year local control, overall survival, and disease-free survival rates were 53%, 54%, and 37%, respectively. Only 6 (5%) of all 127 patients and 4 (3%) of 122 originally N0 patients developed a regional failure in the neck. Distant metastasis occurred in 20% of patients. Both primary tumor extent and lymph node involvement were the most important prognostic factors, together with squamous cell carcinoma histology. CONCLUSION: Local failure remains the dominant cause of poor outcome for patients with sinonasal cancer, despite aggressive local treatment with combined surgery and radiotherapy in operable patients. Distant metastasis and certainly regional relapse were much less common sites of failure. Overall survival remains poor, suggesting the need for more efficacious local and possibly systemic therapy.

Post-operative intensity-modulated radiotherapy for malignancies of the nasal cavity and paranasal sinuses.

PURPOSE: To evaluate the clinical outcome and toxicity of post-operative intensity-modulated radiotherapy (IMRT) for malignancies of the nasal cavity and paranasal sinuses. METHODS AND MATERIALS: Twenty-five patients with histological proven cancer of the paranasal sinuses (n=21) or nasal cavity (n=4) were post-operatively treated with IMRT at the Leuven department to a total dose of 60 Gy (n=15) or 66 Gy (n=10). Both acute and chronic toxicity were prospectively scored in all patients. RESULTS: Median follow-up was 27 months (range: 12-47 months) among surviving patients. The actuarial 2-year local control (LC), overall survival (OS) and disease-free survival (DFS) rates were 81%, 88% and 77%, respectively. One patient developed isolated distant metastasis, while none of the patients developed regional failure. No grade 3 or 4 toxicity was reported, either acute or chronic. No radiation-induced blindness or brain necrosis was reported to date, although longer follow-up has to be awaited for definitive results. CONCLUSION: Post-operative IMRT for sinonasal cancer resulted in similar local control and survival rates as conventional or 3D-conformal radiotherapy techniques, and was associated with little acute toxicity. Longer follow-up is necessary to confirm the lack of late complications.

Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882.

PURPOSE: To determine whether the effect of an additional "boost" radiation after breast conservative therapy (BCT) on local control depends on age and evaluate the impact of a treatment policy with a threshold for age. PATIENTS AND METHODS: We used data from EORTC 22881-10882 trial, with median follow-up of 77.4 months. Patients receiving BCT and 50Gy whole breast irradiation were randomized to no boost and 16Gy boost (N=5318). RESULTS: In univariate analysis, a boost reduced local failure by a factor of 2 (P<0.0001). Multivariate analysis showed local control increased with age (P=0.0003). There was no evidence that the relative effect of a boost on local control depends on age (P=0.97) However in younger patients the 5-year local failure was higher, therefore the absolute reduction was greater. If the threshold-age for boost treatment were set at 40 years, 8.4% of the study population would receive a boost, resulting in a 5-year local failure of 6.1% in the study population. Changing the threshold-age to 60 years, 67% of the study population would receive a boost and the 5-year local failure would be reduced to 4.4%. CONCLUSIONS: In younger patients a boost dose resulted in a greater absolute reduction of local failure. The relative risk reduction was however similar for all ages. Applying a treatment policy with a threshold-age of 60 would result in 0.6% increase in local failure in the total study population, while sparing the boost to 1/3 of the patients.

Prognostic influence of retropharyngeal lymph node metastasis in squamous cell carcinoma of the oropharynx.

PURPOSE: To investigate the impact of involvement of retropharyngeal lymph nodes on the prognosis of squamous cell carcinoma of the oropharynx. METHODS AND MATERIALS: The pretreatment computed tomographic scans of 208 patients with squamous cell carcinoma of the oropharynx were reviewed for the presence of metastatic retropharyngeal lymph nodes. All patients were treated at the Leuven department between 1984 and 2003: by radiotherapy alone in 84.1% of patients, by surgery with postoperative radiotherapy in 11.5%, and by concomitant chemoradiotherapy in 4.4%. Retropharyngeal node involvement was present in 34 (16%) patients. The influence on recurrence (local and regional), distant metastasis, and survival was retrospectively analyzed. Median follow-up was 47 months (3.9 years), and results were analyzed for 201 patients. RESULTS: At 5 years, patients with retropharyngeal adenopathy had significantly more regional recurrences (45% vs. 10%, p = 0.004). Involvement of retropharyngeal lymph nodes significantly (relative risk 4.29 [95% confidence interval 3.33-5.25], p = 0.01) and independently predicted regional recurrence in multivariate analysis. Disease-specific survival was significantly lower in the retropharyngeal node positive group (38% vs. 58%, p = 0.03). CONCLUSIONS: Retropharyngeal node involvement has a negative impact on the prognosis of squamous cell cancer of the oropharynx. Patients are particularly at risk for regional recurrence, resulting in worse disease-specific survival. Retropharyngeal node involvement should be taken into account in designing the treatment plan for these patients.

Retropharyngeal nodes in squamous cell carcinoma of oropharynx: incidence, localization, and implications for target volume.

PURPOSE: To investigate the incidence and anatomic localization of retropharyngeal (RP) nodal involvement in patients with squamous cell carcinoma of the oropharynx. METHODS AND MATERIALS: The CT studies of 208 patients presenting with oropharyngeal carcinoma were retrospectively analyzed. The location of the nodal neck disease was registered according to recent consensus guidelines for target volume delineation, and special attention was given to the RP nodes. To obtain statistically significant predictors for RP nodal involvement, univariate and multivariate analyses were performed. RESULTS: RP adenopathies were present in 16% of all patients and in 23% of those patients with nodal disease in other neck sites. Ipsilateral involvement of Level II and contralateral involvement of Level III predicted for involvement of the ipsilateral RP nodes on multivariate analysis (p < 0.05). A solitary ipsilateral RP node was present in 3 (9%) of 34 patients with RP nodes; 2 of these 3 patients had a primary posterior pharyngeal wall tumor. No patients presented with a solitary contralateral RP node. CONCLUSION: Given the high incidence of RP nodal involvement in oropharyngeal cancer-16% of all patients and 23% of patients with pathologic nodal disease in other neck sites-RP nodes should be included in the target volume, especially in node-positive necks. In node-negative necks, inclusion of RP nodes into the target volume is advised in posterior pharyngeal wall tumors.

Economic consequence of local control with radiotherapy: cost analysis of internal mammary and medial supraclavicular lymph node radiotherapy in breast cancer.

PURPOSE: To investigate the financial implications of radiotherapy (RT) to the internal mammary and medial supraclavicular lymph node chain (IM-MS) in postoperative breast cancer. METHODS AND MATERIALS: A cost-effectiveness and cost-utility analysis were performed, using Markov models, comparing the early and delayed costs and effects of IM-MS during a 20-year time span from a societal viewpoint. The outcome estimates were based on Level I evidence from postoperative RT literature and the cost estimates on the standard practice of the Leuven University Hospitals, with the RT costs derived from an activity-based costing program developed in the department. RESULTS: On the basis of the assumptions of the model and seen during a 20-year time span, primary treatment including IM-MS RT results in a cost savings (approximately 10,000) compared with a strategy without RT. Because IM-MS RT also results in better clinical effectiveness and greater quality of life, the treatment with IM-MS dominates the approach without IM-MS. Sensitivity analyses confirmed the robustness of these results in all tested circumstances. Although threshold values were found for the cost of IM-MS, the cost at relapse, and the quality of life after treatment, these were substantially different from the baseline estimates, indicating that it is very unlikely that omitting IM-MS would become superior. CONCLUSION: This ex-ante cost evaluation of IM-MS RT showed that the upfront costs of locoregional RT are easily compensated for by avoiding the costs of treating locoregional and distant relapse at a later stage. The cost-sparing effect of RT should, however, be evaluated for a sufficiently long time span and is most specifically found in tumors with a rather slow natural history and a multitude of available systemic treatments at relapse, such as breast cancer.

CHART in lung cancer: economic evaluation and incentives for implementation.

BACKGROUND AND PURPOSE: To investigate the financial consequences and the impact on daily implementation of CHART in lung cancer. PATIENTS AND METHODS: A cost-effectiveness and cost-utility analysis were performed using Markov models, comparing the early and delayed costs and effects of CHART for NSCLC over a 4-year time span from a societal viewpoint. The outcome estimates were based on the CHART literature, the cost estimates on the standard practice of the Leuven University Hospitals, the radiotherapy costs being derived from an activity-based costing (ABC) programme developed in the department. RESULTS: The additional societal cost per life-year gained was 9164 Euro, the incremental cost per quality-adjusted life-year 11,576 Euro. Sensitivity analyses confirmed the robustness of these results, the incremental cost-utility ratio remaining well under 20,000 Euro/QALY in all tested circumstances. The threshold analyses found the results of the study to be sensitive to the cost of CHART and to the quality of life after treatment. More specifically, standard treatment would become the optimal treatment if CHART would have a higher cost or would result in more long-term side effects. CONCLUSION: CHART should not be denied to patients with NSCLC on the basis of clinical or economic arguments. Other factors such as socio-economical, institutional, practical departmental and physician-bound barriers most probably explain the lack of implementation into daily practice.

Overview of national guidelines for infrastructure and staffing of radiotherapy. ESTRO-QUARTS: work package 1.

BACKGROUND AND PURPOSE: The aim of this study was to collect the available guidelines for infrastructure and staffing throughout Europe and to develop general guidelines. MATERIALS AND METHODS: Questionnaires were sent to representatives in all European countries. Countries were divided into three groups, based on the GDP per capita (low, medium and high resource countries). Based on the results, general guidelines were developed. RESULTS: 41 countries (93.2%), representing over 99% of the European population responded. Guidelines for the number of linear accelerators and personnel were available in about 40% of the countries. For accelerators, the average was 1 per 183,000 inhabitants in the high, 1 per 284,000 in the medium and 1 per 500,000 in the low resource countries. For radiation oncologists, it varied between 1 per 150-400 patients (average: 250) and there was no clear difference between high, medium and low resource countries. For physicists, the average was 1 per 530 patients for high and 1 per 610 for medium or low resource countries. Guidelines for other equipment and staffing are highly dependent on local habits and complexity of the treatments. CONCLUSION: An accurate overview of existing guidelines for radiotherapy infrastructure and staffing is obtained. It is suggested to have one linear accelerator per 450 patients, one radiation oncologist per 200-250 patients and one physicist per 450-500 patients (or one per linac). It should be stressed, however, that these are only crude guidelines and that the actual needs heavily depend on population structure, cancer incidence and treatment strategies, which differ between the various countries.

Towards evidence-based guidelines for radiotherapy infrastructure and staffing needs in Europe: the ESTRO QUARTS project.

BACKGROUND AND PURPOSE: Adequate and equitable access to radiotherapy (RT) must be a reasonable health care goal for the EU. However, there are large variations among the EU countries and even regional variations within countries in the provision of RT. In this report, we combine the best available evidence on the indications for RT with national epidemiological data to arrive at estimates for the appropriate level of RT infrastructure in the 25 EU countries. PATIENTS AND METHODS: Data from three systematic overviews of the best available evidence for the indication for RT in 23 main cancer types are combined with epidemiological data from the EUCAN and GLOBOCAN databases on the crude incidence of each of these cancers in the 25 EU countries. Together with published benchmarks for accelerator throughput this allows estimation of the number of linear accelerators per million people required to facilitate appropriate RT utilization rates in each country. Where possible, the estimates are compared with the detailed data available from Sweden. RESULTS: The crude incidence of the main cancer types shows large variation among the 25 EU countries. This reflects in part differences in exposure to aetiological risk factors and partly differences among the countries in population age structure. Correspondingly, the estimate of the required number of linear accelerators per million people showed considerable variation: ranging from 4.0 in Cyprus to 8.1 in Hungary. The average for the 25 countries was 5.9 per million people. These estimates were compared with available national guidelines and actual data on RT infrastructure and large shortfalls were found in many countries. Implications for health economics and capacity planning are briefly discussed. CONCLUSIONS: The QUARTS project has developed a model that establishes a direct and transparent link between epidemiological data and indications for RT based on the best available evidence. Comparison of the model estimates with current levels of RT infrastructure has revealed major inequalities in provision of RT in the 25 EU countries. Continuation of this study is recommended as a way of improving RT provision on rational grounds throughout the European community and as a model for health care planning in the EU.

Activity-based costing: a practical model for cost calculation in radiotherapy.

PURPOSE: The activity-based costing method was used to compute radiotherapy costs. This report describes the model developed, the calculated costs, and possible applications for the Leuven radiotherapy department. METHODS AND MATERIALS: Activity-based costing is an advanced cost calculation technique that allocates resource costs to products based on activity consumption. In the Leuven model, a complex allocation principle with a large diversity of cost drivers was avoided by introducing an extra allocation step between activity groups and activities. A straightforward principle of time consumption, weighed by some factors of treatment complexity, was used. The model was developed in an iterative way, progressively defining the constituting components (costs, activities, products, and cost drivers). RESULTS: Radiotherapy costs are predominantly determined by personnel and equipment cost. Treatment-related activities consume the greatest proportion of the resource costs, with treatment delivery the most important component. This translates into products that have a prolonged total or daily treatment time being the most costly. The model was also used to illustrate the impact of changes in resource costs and in practice patterns. CONCLUSION: The presented activity-based costing model is a practical tool to evaluate the actual cost structure of a radiotherapy department and to evaluate possible resource or practice changes.

Tumor perfusion rate determined noninvasively by dynamic computed tomography predicts outcome in head-and-neck cancer after radiotherapy.

PURPOSE: To investigate the value of CT-determined tumor perfusion as a predictive factor of local and regional failure and cause-specific survival in head-and-neck cancer treated by radiotherapy. MATERIALS AND METHODS: In 105 patients, the perfusion of a primary head-and-neck squamous cell carcinoma was estimated using dynamic CT. A contrast agent bolus was rapidly injected i.v., while during the first pass a dynamic data acquisition was performed at the level of the largest axial tumor surface. The perfusion in the selected tumor region of interest was calculated by dividing the slope of the tumor-time density curve by the maximal value in arterial density. Primary and nodal tumor volume was calculated from the CT images. All patients were treated by radiotherapy with curative intent; in 15 patients, adjuvant concomitant chemotherapy was administered. Mean follow-up time was 2.2 years. Actuarial (life-table) statistical analysis was done; multivariate analysis was performed using the Cox proportional hazards model. RESULTS: When the patients were stratified according to the median perfusion value (83.5 mL/min/100 g), those with the lower perfusion rate had a significantly higher local failure rate (p < 0.05). In the multivariate analysis, perfusion rate (p = 0.01) and T category (p = 0.03) were found to be the independent predictors of local failure. Perfusion rate had predictive value regarding neither regional control nor cause-specific survival. CONCLUSIONS: CT-determined tumor perfusion rate was found to be an independent predictor of local outcome in irradiated head-and-neck cancer. The results of this study confirm the hypothesis that less-perfused tumors respond poorly to radiotherapy.

Compliance to the prescribed dose and overall treatment time in five randomized clinical trials of altered fractionation in radiotherapy for head-and-neck carcinomas.

PURPOSE: To investigate compliance to the prescribed dose-fractionation schedule in five randomized controlled trials of altered fractionation in radiotherapy for head-and-neck carcinoma. METHODS AND MATERIALS: Individual patient data from 2566 patients participating in the European Organization for Research and Treatment of Cancer (EORTC) 22791, EORTC 22811, EORTC 22851, Princess Margaret Hospital (PMH), and continuous hyperfractionated accelerated radiotherapy (CHART) head-and-neck trials were merged in the fractionation IMPACT (Intergroup Merger of Patient data from Altered or Conventional Treatment schedules) study database. The ideal treatment time was defined as the minimum time required to deliver a prescribed schedule. Compliance to the prescribed overall treatment time was quantified as the difference between the actual and the ideal overall time. An overall measure of compliance in an individual patient, the total dose lost (TDL), was calculated as the dose lost due to prolongation of therapy (assuming a D(prolif) of 0.64 Gy/day) plus the difference between the prescribed and the actual dose given. RESULTS: The time in excess of the ideal ranged up to 97 days (average 3.9 days), and 25% of the patients had delays of 6 days or more. World Health Organization (WHO) performance status and nodal stage had a significant effect on TDL. TDL was significantly higher in the conventional than in the altered arm of the EORTC 22851 and CHART trials. In the PMH trial, TDL was significantly higher in the hyperfractionation than in the conventional arm. Centers participating in the three EORTC trials varied significantly in their compliance. There was a significant improvement in compliance in patients treated more recently. CONCLUSIONS: Even in randomized controlled trials, compliance to the prescribed radiation therapy schedule may be relatively poor, especially after conventional fractionation. This affects the interpretation of the outcome of these trials.

Recurrences after conformal parotid-sparing radiotherapy for head and neck cancer.

BACKGROUND AND PURPOSE: Evaluation of loco-regional failure patterns and survival after parotid-sparing three-dimensional conformal and intensity modulated radiotherapy (IMRT) for head and neck cancer. PATIENTS AND METHODS: From June 1999 to July 2002, seventy-two patients with lateralised head and neck tumours, excluding nasopharyngeal tumours and patients with bilateral or contralateral neck disease, were irradiated with a parotid-sparing technique. Three-dimensional conformal planning was used in 68 patients, 4 patients were treated with dynamic IMRT. Bilateral neck node irradiation was performed in all patients, the junctional (or high level II) nodes, contralateral to the tumour, however, were excluded from the clinical target volume to spare the adjacent parotid from irradiation. In 20 patients with persistent or recurrent loco-regional disease, the localisation and volume of the treatment failure, as determined by computed tomography (CT), was copied on the pre-treatment CT-study used for treatment planning. Minimum, mean and maximum doses administered to the region of the failure were calculated and dose--volume histograms were computed of each failure. The failures were divided in three groups depending on the percentage of their volume receiving 95% of the prescribed dose. Recurrences were defined to be in-field (IF) if >95% of their volume received 95% of the prescribed dose and out-field (OF) if <20% of their volume received 95% of the prescribed dose. When 20-95% of the volume of the recurrence received 95% of the prescribed dose, this recurrence was defined as extending outside the field (EOF). RESULTS: With a median follow-up time of 19 months, the 2-year loco-regional control rate was 69% with primary radiotherapy and 63.5% with surgery followed by irradiation (P = 0.77). The 2-year overall survival rate for the entire patient population was 67.4%. At the time of analysis, 20 of the 72 patients had developed a loco-regional failure; 2 patients (2/20) presented with a loco-regional relapse combined with distant metastasis. Fifteen of the 20 loco-regional failures (15/20) occurred within the high dose region (IF). Five patients (5/20) developed a failure of which the bulky tumour mass was located within the high dose region but extending outside the treatment volume (EOF). No relapses were seen out-field (OF) and no patients relapsed in the spared junctional area contralateral to the tumour. CONCLUSIONS: The selection of patients treated with parotid-sparing radiotherapy, by omitting irradiation to the junctional nodes contralateral to the tumour, proved to be safe in our hands, since no recurrences developed in the spared area. As this parotid-sparing technique reduces significantly the dose to the contralateral parotid and is easy to perform, it should be considered for all selected patients.

De Gustibus: time scale of loss and recovery of tastes caused by radiotherapy.

PURPOSE: To quantify the prevalence and distress of taste loss at different intervals after radiotherapy (RT) for head and neck cancer. MATERIALS AND METHODS: In four different groups of head and neck cancer patients (73 patients in total), taste loss and distress due to taste loss were evaluated by taste acuity tests and taste questionnaires. Group 1 (n=17) was analyzed prior to RT. Groups 2 (n=17), 3 (n=17) and 4 (n=22) were at 2, 6 and 12-24 months after treatment, respectively. A cross-sectional analysis was performed between these four groups. RESULTS: Prior to initiation of RT (group 1), partial taste loss was observed in 35, 18 and 6% of patients for bitter, salt and sweet, respectively. At 2 months after RT (group 2), taste loss (partial or total) was seen in 88, 82, 76 and 53% for bitter, salt, sweet and sour, respectively. At 6 months (group 3), partial taste loss was seen in 71, 65, 41 and 41% (bitter, salt, sweet, sour) and after 1-2 years (group 4) in 41, 50, 27 and 27% (bitter, salt, sweet, sour). Distress caused by taste loss was most frequent in group 2 (82%). CONCLUSIONS: In this study, loss of taste after RT was found to be most pronounced after 2 months. Bitter and salt qualities were most impaired. Gradual recovery was seen during the first year after treatment. Partial taste loss still persisted 1-2 years after treatment and was responsible for slight to moderate discomfort.