Modeling the effect of age in T1-2 breast cancer using the SEER database.

BACKGROUND: Modeling the relationship between age and mortality for breast cancer patients may have important prognostic and therapeutic implications. METHODS: Data from 9 registries of the Surveillance, Epidemiology, and End Results Program (SEER) of the United States were used. This study employed proportional hazards to model mortality in women with T1-2 breast cancers. The residuals of the model were used to examine the effect of age on mortality. This procedure was applied to node-negative (N0) and node-positive (N+) patients. All causes mortality and breast cancer specific mortality were evaluated. RESULTS: The relationship between age and mortality is biphasic. For both N0 and N+ patients among the T1-2 group, the analysis suggested two age components. One component is linear and corresponds to a natural increase of mortality with each year of age. The other component is quasi-quadratic and is centered around age 50. This component contributes to an increased risk of mortality as age increases beyond 50. It suggests a hormonally related process: the farther from menopause in either direction, the more prognosis is adversely influenced by the quasi-quadratic component. There is a complex relationship between hormone receptor status and other prognostic factors, like age. CONCLUSION: The present analysis confirms the findings of many epidemiological and clinical trials that the relationship between age and mortality is biphasic. Compared with older patients, young women experience an abnormally high risk of death. Among elderly patients, the risk of death from breast cancer does not decrease with increasing age. These facts are important in the discussion of options for adjuvant treatment with breast cancer patients.

Statistical interaction in the survival analysis of early breast cancer using registry data: role of breast conserving surgery and radiotherapy.

PURPOSE: To identify subgroup effects that might influence the survival results of postoperative radiotherapy. PATIENTS AND METHODS: Women selected from the Surveillance, Epidemiology, and End Results database, aged 40-69 years, with non-metastasized T1-T2 breast carcinoma, in whom axillary lymph node dissection was performed. Subgroup analyses were performed using proportional hazards models with interactions. Joint significance of subgroups was evaluated with the Wald test. Event was death from any cause. RESULTS: Statistically significant interactions were found between type of surgery (breast-conserving [BCS] or mastectomy [ME]), radiotherapy [RT], T stage, and extent of nodal involvement, but not between treatments and nodal examination. For each treatment combination, ME-no RT, ME+RT, BCS-no RT, BCS+RT, the mortality hazard ratios were respectively: 1, 1.12, 1.11, 0.78 in T1, 0-3 positive nodes; 2.45, 2.77, 2.71, 1.92 in T2, 4+ nodes; 1.31, 1.38, 1.33, 1.19 in T2, 0-3+ nodes; and 3.41, 2.79, 3.44, 2.40 in T2, 4+ nodes. The corresponding joint tests showed: in the absence of radiotherapy, no significant survival disadvantage for breast-conserving surgery vs mastectomy; with radiotherapy, significant survival advantage for breast-conserving surgery irrespective of stage and for mastectomy in T2, 4+ nodes. For mastectomy in less advanced stages receiving radiotherapy, excess breast cancer deaths suggested undocumented adverse selection. The corresponding result was considered inconclusive. CONCLUSIONS: The analyses found subgroup effects that should be taken into account to interpret treatment results in breast cancer.

Percutaneous placement of marking coils before stereotactic radiation therapy of malignant lung lesions.

PURPOSE: To evaluate a technique for implantation of radiopaque markers in lung nodules as an aid in extracranial stereotactic radiation therapy. MATERIALS AND METHODS: An implantation technique was developed for marking intrapulmonary lung lesions by introducing a vascular coil through a coaxial needle in or near the target tumor. The markers were placed percutaneously through 15- or 20-gauge coaxial needles in 41 lesions (25 patients) under computed tomographic fluoroscopic guidance. Two different types of vascular helical coils where used. RESULTS: All lesions were accessible for puncture and coils could be placed in all lesions. Four types of complications were observed, some as a result of the learning curve in the technique: (i) coil misplacement subcutaneously (5%); (ii) small needle trajectory bleeding in the lung (10%); (iii) pneumothorax, for which one patient (10%) in whom the coil was placed through a 15-gauge coaxial needle needed chest tube drainage and required hospitalization; and (iv) one subcutaneous metastasis probably unrelated to the puncture (2.5%). CONCLUSION: With this technique, lung nodules can be marked with radiopaque implants in a safe and accurate way.

Ratios of involved nodes in early breast cancer.

INTRODUCTION: The number of lymph nodes found to be involved in an axillary dissection is among the most powerful prognostic factors in breast cancer, but it is confounded by the number of lymph nodes that have been examined. We investigate an idea that has surfaced recently in the literature (since 1999), namely that the proportion of node-positive lymph nodes (or a function thereof) is a much better predictor of survival than the number of excised and node-positive lymph nodes, alone or together. METHODS: The data were abstracted from 83,686 cases registered in the Surveillance, Epidemiology, and End Results (SEER) program of women diagnosed with nonmetastatic T1-T2 primary breast carcinoma between 1988 and 1997, in whom axillary node dissection was performed. The end-point was death from breast cancer. Cox models based on different expressions of nodal involvement were compared using the Nagelkerke R2 index (R2N). Ratios were modeled as percentage and as log odds of involved nodes. Log odds were estimated in a way that avoids singularities (zero values) by using the empirical logistic transform. RESULTS: In node-negative cases both the number of nodes excised and the log odds were significant, with hazard ratios of 0.991 (95% confidence interval 0.986-0.997) and 1.150 (1.058-1.249), respectively, but without improving R2N. In node-positive cases the hazard ratios were 1.003-1.088 for the number of involved nodes, 0.966-1.005 for the number of excised nodes, 1.015-1.017 for the percentage, and 1.344-1.381 for the log odds. R2N improved from 0.067 (no nodal covariate) to 0.102 (models based on counts only) and to 0.108 (models based on ratios). DISCUSSION: Ratios are simple optimal predictors, in that they provide at least the same prognostic value as the more traditional staging based on counting of involved nodes, without replacing them with a needlessly complicated alternative. They can be viewed as a per patient standardization in which the number of involved nodes is standardized to the number of nodes excised. In an extension to the study, ratios were validated in a comparison with categorized staging measures using blinded data from the San Jose-Monterey cancer registry. A ratio based prognostic index was also derived. It improved the Nottingham Prognostic Index without compromising on simplicity.

Adjuvant radiotherapy for breast cancer: effects of longer follow-up.

BACKGROUND AND PURPOSE: Recent and large trials of adjuvant radiotherapy for breast cancer have shown an overall survival benefit in favour of radiotherapy. However, with longer follow-up the late lethal toxicity of radiotherapy might reduce the overall survival benefits. In this paper we investigate more deeply this hypothesis. PATIENTS AND METHODS: Overviews of the Early Breast Cancer Trialists' Collaborative Group provide uniform data on more than 50 unconfounded trials on adjuvant radiotherapy for early breast cancer. These data were published at regular intervals: 1987, 1990, 1995, and 2000. The odds ratios (death of any cause) were borrowed to compare the benefits of adjuvant radiotherapy between the early publications and the more mature data of the same trials. Statistical significance is calculated following logrank statistics. The comparison of odds ratios (radiotherapy versus surgery only) was done for the whole group of trials, for the older (patients accrual started in 1970 or earlier) and the more recent trials (patient accrual started after 1970), and for the large (>or=600 patients) and the small trials (<600 patients). RESULTS: Comparison of early with more mature data reveals that the odds ratios for overall survival remain stable as data become more mature. The analyses of trials' age and trials' size, as predictors of overall survival benefit, indicate that these factors become statistically more significant with increasing maturity of the trials. In the large recent trials an overall survival benefit due to radiotherapy (odds reduction) of 10, 10, 12 and 13%, respectively P<0.3, 0.2, 0.005 and 0.00005 is found in the successive publications. The difference in survival benefit of radiotherapy between the group of large recent trials and group of old or small trials becomes more significant at the successive updates: 10 via 9% and 12 to 13% (odds reductions), with respectively P=0.2, 0.2, 0.004 and 0.00005. CONCLUSIONS: These results support the hypothesis that the survival benefit in the recent trials is an inherent characteristic of the recent and large trials, not influenced by follow-up duration. The effect of radiotherapy as performed in the large recent trials is clinically and statistically significantly different from the effect of radiotherapy in the old or small trials. As a consequence, predictions based on pooled data including old radiotherapy trials should not be extrapolated to modern radiotherapy.

The lymph node ratio as prognostic factor in node-positive breast cancer.

BACKGROUND AND PURPOSE: The clinical records of the node-positive breast cancer patients treated at our department were reviewed, to evaluate if there is a correlation between the ratio of involved axillary lymph nodes and the overall and cause specific survival. PATIENTS AND METHODS: From 1984 until July 2001, 2073 files from patients with an invasive breast carcinoma were submitted to retrospective analyses. In 810 cases, a node positive status was diagnosed. All pT-stages were included. The total number of dissected nodes (pNtot) and the number of involved nodes (pN+) were available for 741 patients. The ratio of nodal involvement (pN+%) was categorized into three groups, pN+%< or =10% (n = 212) between 11 and 50% (n = 346) and between 51 and 100% (n = 183). RESULTS: The actuarial overall survival (OS) at 5 and 10 years was, respectively, 78.2 and 59.1%. Cause specific survival (CSS) rates were, respectively, 83.6 and 69.1%. In univariate analyses, age (P = 0.01), grade (P = 0.02), pT-stage (P < 0.0001), chemotherapy (P = 0.0002), the number of involved nodes < or =3 versus >3 (pN+) (P < 0.0001) and ratio pN+% (P < 0.0001) were associated significantly with overall survival. A multivariate analysis using the Cox proportional hazards model found that pN+% was the most significant prognostic factor; pN+lost significance when pN+% was taken into account. CONCLUSIONS: The percentage of positive lymph nodes in an axillary lymph node dissection appears to be an important prognostic factor for survival. The nodes ratio improved on the absolute numbers of involved axillary lymph nodes for assessment of prognosis.

Adjuvant radiotherapy after mastectomy for pT1-pT2 node negative (pN0) breast cancer: is it worth the effort?

PURPOSE: Postoperative radiotherapy (RT) for pT1-2 pN0 breast cancer was the standard treatment in our department. Since little data on the importance of RT in this subgroup are known, we reviewed the clinical records with regard to overall survival. MATERIAL AND METHODS: From 1984 until 2000, 1789 files were submitted to retrospective analyses; 731 had a pT1 (n=427) or pT2 (n=304) pN0 lesion. They were treated with breast conserving surgery (BCS) (n=343) or mastectomy (ME) (n=388), axillary lymph node dissection (ALND) and post-operative RT. The outcome was analyzed and compared with the patients included in the SEER-Data 1988-1997 (NCI-Surveillance, Epidemiology and End Results, release 2000) that were treated according to the standard treatment: BCS+ALND+RT, or ME+ALND no RT. RESULTS: The actuarial overall survival (OS) at 5 and 10 years after BCS was 93.3% and 85.1% for pT1 and 88.3% and 75.4% for pT2 tumors. These results are comparable with the SEER (93.9%, 84.9% for pT1, and 87.3%, 76.7% for pT2, respectively). For our ME patients the OS was 91.8% and 79.9%, respectively (pT1 at 5 and 10 years, respectively), and 83.6% and 70.4% (pT2 at 5 and 10 years). In the SEER data the analyses resulted in 89.3% and 73.8% (pT1), and 81.1% and 63.5% (pT2), respectively. DISCUSSION: Although both databases are retrospective, the comparable survival in BCS patients pleads for the similarity of the two populations. The better OS observed in ME patients treated with RT compared to the SEER patients argues in favor of a benefit due to adjuvant radiotherapy. CONCLUSION: Radiotherapy after mastectomy might improve survival in low-risk node negative patients. Our data shows an absolute benefit of between 2.5% and 6.9% OS in favor of post ME radiotherapy, compared to the SEER data.

Omission of radiotherapy after breast-conserving surgery: survival impact and time trends.

PURPOSE: To evaluate the survival impact of omission of radiotherapy after breast-conserving surgery and the changes with time. MATERIAL AND METHODS: Women aged 40-69 with non-metastasized T1-T2 breast cancer, who underwent breast-conserving surgery with axillary node dissection, with or without post-surgery radiotherapy, selected from the SEER (Surveillance, Epidemiology, and End Results) database. The analysis uses proportional hazards models. RESULTS: Omission of radiotherapy as compared to delivery of radiotherapy was associated with an overall increased mortality hazard ratio of 1.346 (95% confidence interval: 1.204-1.504). Test of constancy showed significant changes with time. The time profile suggested an exponential-like increase from a baseline mortality hazard ratio of 1.17, or 17% excess of relative mortality risk, to a projected hazard ratio of 2.26, or more than doubling of relative mortality risk, for omission of radiotherapy. CONCLUSION: Omission of radiotherapy in breast-conserving surgery is found to be independently associated with an increase in mortality. The data do not give support to omitting radiation or give rationale to clinical trials that would omit radiation.

Quality assurance of a system for improved target localization and patient set-up that combines real-time infrared tracking and stereoscopic X-ray imaging.

BACKGROUND AND PURPOSE: The aim of this study is to investigate the positional accuracy of a prototype X-ray imaging tool in combination with a real-time infrared tracking device allowing automated patient set-up in three dimensions. MATERIAL AND METHODS: A prototype X-ray imaging tool has been integrated with a commercially released real-time infrared tracking device. The system, consisting of two X-ray tubes mounted to the ceiling and a centrally located amorphous silicon detector has been developed for automated patient positioning from outside the treatment room prior to treatment. Two major functions are supported: (a) automated fusion of the actual treatment images with digitally reconstructed radiographs (DRRs) representing the desired position; (b) matching of implanted radio opaque markers. Measurements of known translational (up to 30.0mm) and rotational (up to 4.0 degrees ) set-up errors in three dimensions as well as hidden target tests have been performed on anthropomorphic phantoms. RESULTS: The system's accuracy can be represented with the mean three-dimensional displacement vector, which yielded 0.6mm (with an overall SD of 0.9mm) for the fusion of DRRs and X-ray images. Average deviations between known translational errors and calculations varied from -0.3 to 0.6mm with a standard deviation in the range of 0.6-1.2mm. The marker matching algorithm yielded a three-dimensional uncertainty of 0.3mm (overall SD: 0.4mm), with averages ranging from 0.0 to 0.3mm and a standard deviation in the range between 0.3 and 0.4mm. CONCLUSIONS: The stereoscopic X-ray imaging device integrated with the real-time infrared tracking device represents a positioning tool allowing for the geometrical accuracy that is required for conformal radiation therapy of abdominal and pelvic lesions, within an acceptable time-frame.

Effect of the number of uninvolved nodes on survival in early breast cancer.

A high number of uninvolved axillary nodes was found by some authors to be associated with poor survival in node-negative breast cancer. We searched for confirmation and extend the investigation to node-positive cases, using population data from the SEER Program. Patients selected were women aged 40-69 years, diagnosed 1988-1997, T1-T2 breast cancer, undergoing axillary dissection with 4-35 nodes examined. Survivals were estimated by the product-limit method and were computed on pooled data. Results in node-negative patients (n=37,519) showed a 5-year overall survival from 92% (95% confidence interval: 88-95%) with 4 uninvolved nodes, to 93% (87-98%) with 34 uninvolved nodes. In node-positive patients (n=16,978), the 5-year survival increased from 50% (44-56%) with 0 uninvolved nodes, to 91% (82-100%) with 30 uninvolved nodes. Survival graphs indicated an improvement or a plateau with higher number of uninvolved nodes. The graphs also suggested that the ratio of involved and uninvolved nodes might be correlated with survival. We conclude that there was no evidence of poor outcome associated with a high number of uninvolved nodes. The incidental finding that ratio-based characterization of node involvement might be a prognostic factor will be further investigated.

Functional form of the effect of the numbers of axillary nodes on survival in early breast cancer.

The change in survival in function of the numbers of involved and uninvolved axillary nodes in early breast cancer - i.e. the functional form - was investigated to search for prognostic cutoffs and to assess if ratio-based characterization of node involvement is a significant prognostic factor or not. Women aged 40-69, diagnosed in 1988-1997 with T1-T2 invasive breast carcinoma, who underwent axillary dissection, are selected from the SEER public database. The method determines the functional form by applying smoothed plots to the martingale residuals obtained from a proportional hazards model. The results on 55,267 selected patients find that the ratio of involved nodes on examined nodes, in a multivariate model that takes into account known prognostic factors (age, race, tumor size, topography, histology, grade, hormone receptors), is associated with a relative mortality hazard of 1.012 (95% confidence interval 1.010-1.014; relative increase of mortality of 1.2% for each 1% increase in the percentage of involved nodes). The functional form for the number of uninvolved nodes shows that the relative mortality hazard initially steeply decreases and then tends to level off beyond 5-10 uninvolved nodes. For the number of involved nodes, the relative mortality hazard continues to increase with each involved node without any obvious cutpoint. Even when the number of involved nodes is already large, each additional involved node increases the relative mortality hazard by at least 1.3%.

Clinical use of stereoscopic X-ray positioning of patients treated with conformal radiotherapy for prostate cancer.

PURPOSE: To evaluate accuracy and time requirements of a stereoscopic X-ray-based positioning system in patients receiving conformal radiotherapy to the prostate. METHODS AND MATERIALS: Setup errors of the isocenter with regard to the bony pelvis were measured by means of orthogonal verification films and compared to conventional positioning (using skin drawings and lasers) and infrared marker (IR) based positioning in each of 261 treatments. In each direction, the random error represents the standard deviation and the systematic error the absolute value of the mean position. Time measurements were done in 75 treatments. RESULTS: Random errors with the X-ray positioning system in the anteroposterior (AP), lateral, and longitudinal direction were (average +/- 1 standard deviation) 2 +/- 0.6 mm, 1.7 +/- 0.6 mm, and 2.4 +/- 0.7 mm. The corresponding values of conventional as well as IR positioning were significantly higher (p < 0.01). Systematic errors for X-ray positioning were 1.1 +/- 1.2 mm AP, 0.6 +/- 0.5 mm laterally, and 1.5 +/- 1.6 mm longitudinally. Conventional and IR marker-based positioning showed significantly larger systematic errors AP and laterally, but longitudinally, the difference was not significant. Depending on the axis looked at, errors of >or=5 mm occurred in 2%-14% of treatments after X-ray positioning, 13%-29% using IR markers, and 28%-53% with conventional positioning. Total linac time for one treatment session was 14 min 51 s +/- 4 min 18 s, half of which was used for the X-ray-assisted positioning procedure. CONCLUSION: X-ray-assisted patient positioning significantly improves setup accuracy, at the cost of an increased treatment time.

Post-surgery radiation in early breast cancer: survival analysis of registry data.

BACKGROUND AND PURPOSE: Overviews of randomized trials have shown a small survival advantage with post-surgery radiation in early breast cancer. The present study attempts to extend this observation through a systematic analysis of population data. MATERIALS AND METHODS: This retrospective cohort study used the Surveillance, Epidemiology, and End Results (SEER) data on 83,776 women with breast cancer diagnosed between 1988 and 1997, stage T1-T2, node negative or node positive. The analysis was performed using the proportional hazard models. RESULTS: Radiation was associated with a reduced mortality after breast-conserving surgery in node negative patients (hazard ratio 0.757; 95% confidence interval 0.709-0.809; using total mastectomy without radiation as reference) and in node positive patients (hazard ratio 0.777; 0.717-0.842), and after total mastectomy in node positive patients (hazard ratio 0.885; 0.815-0.961). Radiation was associated with an increased hazard ratio of 1.271 (1.080-1.496) after total mastectomy in node negative patients. Without radiation, breast-conserving surgery in node negative patients was associated with an increased hazard ratio (1.167; 1.036-1.314); a similar increase was not observed in node positive patients (hazard ratio 1.011; 0.884-1.155). In all cases, the best survival rates were found with combined breast-conserving surgery and radiation. CONCLUSION: The available data indicate that post-surgery radiation provides a survival advantage irrespective of the type of surgery in node positive patients. Likewise, survival advantage was observed with post-surgery radiation and breast-conserving procedure in node negative patients.

Initial clinical experience with infrared-reflecting skin markers in the positioning of patients treated by conformal radiotherapy for prostate cancer.

PURPOSE: To evaluate an infrared (IR) marker-based positioning system in patients receiving conformal radiotherapy for prostate cancer. METHODS AND MATERIALS: During 553 treatments, the ability of the IR system to automatically position the isocenter was recorded. Setup errors were measured by means of orthogonal verification films and compared to conventional positioning (using skin drawings and lasers) in 184 treatments. RESULTS: The standard deviation of anteroposterior (AP) and lateral setup errors was significantly reduced with IR marker positioning compared to conventional: 2 vs. 4.8 mm AP (p < 0.01) and 1.6 vs. 3.5 mm laterally (p < 0.01). Longitudinally, the difference was not significant (3.5 vs. 3.0 mm). Systematic errors were on the average smaller AP and laterally for the IR method: 4.1 vs. 7.8 mm AP (p = 0.01) and 3.1 vs. 5.6 mm lateral (p = 0.07). Longitudinally, the IR system resulted in somewhat larger systematic errors: 5.0 vs. 3.4 mm for conventional positioning (p = 0.03). The use of an off-line correction protocol, based on the average deviation measured over the first four fractions, allowed virtual elimination of systematic errors. Inability of the IR system to correctly locate the markers, leading to an executional failure, occurred in 21% of 553 fractions. CONCLUSION: IR marker-assisted patient positioning significantly improves setup accuracy along the AP and lateral axes. Executional failures need to be reduced.

Definition of gross tumor volume in lung cancer: inter-observer variability.

BACKGROUND AND PURPOSE: To determine the inter-observer variation in gross tumor volume (GTV) definition in lung cancer, and its clinical relevance. MATERIALS AND METHODS: Five clinicians involved in lung cancer were asked to define GTV on the planning CT scan of eight patients. Resulting GTVs were compared on the base of geometric volume, dimensions and extensions. Judgement of invasion of lymph node (LN) regions was evaluated using the ATS/LCSG classification of LN. Clinical relevance of the variation was studied through 3D-dosimetry of standard conformal plans: volume of critical organs (heart, lungs, esophagus, spinal cord) irradiated at toxic doses, 95% isodose volumes of GTVs, normal tissue complication probabilities (NTCP) and tumor control probabilities (TCP) were compared for evaluation of observer variability. RESULTS: Before evaluation of observer variability, critical review of planning CT scan led to up- (two cases) and downstaging (one case) of patients as compared to the respective diagnostic scans. The defined GTVs showed an inter-observer variation with a ratio up to more than 7 between maximum and minimum geometric content. The dimensions of the primary tumor had inter-observer ranges of 4.2 (transversal), 7.9 (cranio-caudal) and 5.4 (antero-posterior) cm. Extreme extensions of the GTVs (left, right, cranial, caudal, anterior and posterior) varied with ranges of 2.8-7.3 cm due to inter-observer variation. After common review, only 63% of involved lymph node regions were delineated by the clinicians (i.e. 37% are false negative). Twenty-two percent of drawn in lymph node regions were accepted to be false positive after review. In the conformal plans, inter-observer ranges of irradiated normal tissue volume were on average 12%, with a maximum of 66%. The probability (in the population of all conformal plans) of irradiating at least 95% of the GTV with at least 95% of the nominal treatment dose decreased from 96 to 88% when swapping the matched GTV with an unmatched one. The average (over all patients) inter-observer range in NTCP varied from 5% (spinal cord) to 20% (ipsilateral lung), whereas the maximal ranges amounted 16% (spinal cord) to 45% (heart). The average TCP amounted 51% with an average range of 2% (maximally 5%) in case of matched GTVs. These values shifted to 42% (average TCP) with an average range of 14% (maximally 31%) when defining unmatched GTVs. Four groups of causes are suggested for the large inter-observer variation: (1) problems of methodology; (2) impossible differentiation between pathologic structures and tumor; or (3) between normal structures and tumor, and (4); lack of knowledge. Only the minority of these can be resolved objectively. For most of the causal factors agreements have to be made between clinicians, intra- and inter-departmentally. Some of the factors will never be unequivocally solved. CONCLUSIONS: GTV definition in lung cancer is one of the cornerstones in quality assurance of radiotherapy. The large inter-observer variation in GTV definition jeopardizes comparison between clinicians, institutes and treatments.