Patricia Tai

Chemotherapy in Neuroendocrine/Merkel Cell Carcinoma of the Skin: Case Series and Review of 204 Cases

PURPOSE To study the use of chemotherapy for Merkel cell carcinoma (MCC) of the skin. PATIENTS AND METHODS Twenty-five cases of MCC were treated at the London Regional Cancer Center between 1987 and 1997. Thirteen cases treated with chemotherapy were reviewed with 191 cases from the literature. RESULTS At presentation, 24 patients had localized skin lesions (stage I) and one had locoregional involvement (stage II). Among the nine cases with recurrent nodal disease, six had chemotherapy as a component of salvage treatment. They were all free of disease at a median of 19 months (range, 12 to 37 months). In contrast, two patients who had salvage radiotherapy alone died of disease. Overall survival (OS) and disease-free survival (DFS) were 59% and 43%, respectively, at two years. Median OS and DFS were 29 months (range, 1 to 133 months) and 9 months (range, 1 to 133 months), respectively. Nodal disease developed in 12 (50%) of 24 patients with stage I disease, and distant metastases developed in six (25%) of 24. Including those from the literature, there were 204 cases treated with chemotherapy. Cyclophosphamide/doxorubicin (or epirubicin)/vincristine combination +/- prednisone was the most commonly used chemotherapy regimen (47 cases), with an overall response rate of 75.7% (35.1% complete, 35. 1% partial, and 5.4% minor responses). Etoposide/cisplatin (or carboplatin) was the next most commonly used regimen (27 cases), with an overall response rate of 60% (36% complete and 24% partial responses). The difference in response rate was not statistically significant (P =.19). Among the 204 cases, there were seven (3.4%) toxic deaths. CONCLUSION Chemoradiation for locally recurrent or advanced disease may be an option for patients with a good performance status.

Prognostic Value of Nodal Ratios in Node-Positive Breast Cancer

PURPOSE The American Joint Committee on Cancer staging system for breast cancer was recently updated to reflect the impact of increasing the absolute number of positive lymph nodes on prognosis. However, numerous studies suggest that nodal ratios (absolute number of involved nodes-number of nodes resected) may have greater prognostic value than absolute numbers of involved nodes. Here we examine the data supporting the use of nodal ratios in breast cancer prognosis and consider the potential advantages and disadvantages of including nodal ratios in breast cancer staging. METHODS A systematic review of the literature was conducted using the following search engines: http://www.google.com; Thomsons ISI Web of Science; PubMed. RESULTS In multiple reports from both prospective and retrospectively collected data sets, nodal ratios have been shown to be significant predictors of outcome, including locoregional recurrence and overall survival. These studies span all stages of breast cancer and include various treatments as well as various statistical approaches. CONCLUSION There is considerable data supporting the use of nodal ratios in breast cancer prognosis. A thorough and methodological evaluation of the potential prognostic importance of nodal ratios in large multicenter data sets is merited and is currently being undertaken by the International Nodal Ratio Working Group.

Ratios of involved nodes in early breast cancer

IntroductionThe 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.MethodsThe 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.ResultsIn 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).DiscussionRatios 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.

VARIABILITY OF TARGET VOLUME DELINEATION IN CERVICAL ESOPHAGEAL CANCER

PURPOSE Three-dimensional (3D) conformal radiation therapy (CRT) assumes and requires the precise delineation of the target volume. To assess the consistency of target volume delineation by radiation oncologists, who treat esophageal cancers, we have performed a transCanada survey. MATERIALS AND METHODS One of three case presentations, including CT scan images, of different stages of cervical esophageal cancer was randomly chosen and sent by mail. Respondents were asked to fill in questionnaires regarding treatment techniques and to outline boost target volumes for the primary tumor on CT scans, using ICRU-50 definitions. RESULTS Of 58 radiation oncologists who agreed to participate, 48 (83%) responded. The external beam techniques used were mostly anterior-posterior fields, followed by a multifield boost technique. Brachytherapy was employed by 21% of the oncologists, and concurrent chemotherapy by 88%. For a given case, and the three volumes defined by ICRU-50 (i.e., gross tumor volume [GTV], clinical target volume [CTV], and planning target volume [PTV]) we determined: 1. The total length in the cranio-caudal dimension; 2. the mean diameter in the transverse slice that was located in a CT slice that was common to all participants; 3. the total volume for each ICRU volume; and 4. the (5, 95) percentiles for each parameter. The PTV showed a mean length of 14.4 (9.6, 18.0) cm for Case A, 9.4 (5.0, 15.0) cm for Case B, 11.8 (6.0, 16.0) cm for Case C, a mean diameter of 6.4 (5.0, 9.4) cm for Case A, 4.4 (0.0, 7.3) cm for Case B, 5.2 (3.9, 7.3) cm for Case C, and a mean volume of 320 (167, 840) cm3 for Case A and 176 (60, 362) cm3 for Case C. The results indicate variability factors (95 percentile divided by 5 percentile values) in target diameters of 1.5 to 2.6, and in target lengths of 1.9 to 5.0. CONCLUSION There was a substantial inconsistency in defining the planning target volume, both transversely and longitudinally, among radiation oncologists. The potential benefits of 3D treatment planning with high-precision dose delivery could be offset by this inconsistency in target-volume delineation by radiation oncologists. This may be particularly important for multicenter clinical trials, for which quality assurance of this step will be essential to the interpretation of results.

The number of positive nodes and the ratio of positive to excised nodes are significant predictors of survival in women with micrometastatic node-positive breast cancer

BACKGROUND To evaluate the prognostic impact of the number of positive nodes and the lymph node ratio (LNR) of positive to excised nodes on survival in women diagnosed with nodal micrometastatic breast cancer before the era of widespread sentinel lymph node biopsy. METHODS Subjects were 62,551 women identified by the Surveillance Epidemiology and End Results database, diagnosed with pT1-2pN0-1 breast cancer between 1988 and 1997. Kaplan-Meier breast cancer-specific survival (BCSS) and overall survival (OS) were compared between three cohorts: node-negative (pN0, n=57,980) nodal micrometastasis all <or=2mm (pNmic, N=1818), and macroscopic nodal metastasis >2mm but <2 cm (pNmac, n=2753). Nodal subgroups were examined by the number of positive nodes (1-3 versus >or= 4) and the LNR (<or=0.25 versus >0.25). RESULTS Median follow-up was 7.3 yr. Ten-year BCSS and OS in pNmic breast cancer were significantly lower compared to pN0 disease (BCSS 82.3% versus 91.9%, p<0.001 and OS 68.1% versus 75.7%, p<0.001). BCSS and OS with pNmic disease progressively declined with increasing number of positive nodes and increasing LNR. OS with pNmic was similar to pNmac disease when matched by the number of positive nodes and by the LNR. Both pN-based and LNR-based classifications were significantly prognostic of BCSS and OS on Cox regression multivariate analysis. CONCLUSION Nodal micrometastasis is associated with poorer survival compared to pN0 disease. Mortality hazards with nodal micrometastasis increased with increasing number of positive nodes and increasing LNR. The number of positive nodes and the LNR should be considered in risk estimates for patients with nodal micrometastatic breast cancer.

Merkel Cell Carcinoma of the Skin

Background: Neuroendocrine/Merkel cell carcinoma (MCC) of the skin is an uncommon tumour. Currently, there are only limited data available on the natural history, prognostic factors, and patient management of MCC. Objective: To review our experience and build the largest database from the literature. Methods: Twenty-eight cases from the London Regional Cancer Center were combined with 633 cases obtained from the literature searched in English, French, German, and Chinese for the years 1966 to 1998. The database included age, sex, initial disease status at presentation to the clinic, site of primary, any coexisting disease, any previous irradiation, sizes of primary/nodal/distant metastases, management details, and final disease status. A new modified staging system was used: stage Ia (primary disease only, size < 2 cm), stage Ib (primary disease only, size > 2 cm); stage II (regional nodal disease), and stage III (beyond regional nodes and/or distant disease). Results: Age > 65 years, male sex, size of primary > 2 cm, truncal site, nodal/distant disease at presentation, and duration of disease before presentation (< 3 months) were poor prognostic factors. Surgery was the initial treatment of choice and it significantly improved overall survival (p = .004). Conclusion: We identified poor prognostic factors that may necessitate more aggressive treatment. The suggested staging system, incorporating primary tumour size, accurately predicted outcomes.

Modeling the Effect of Tumor Size in Early Breast Cancer

Summary Background Data:The purpose of this study was to determine the type of relationship between tumor size and mortality in early breast carcinoma. Methods:The data was abstracted from 83,686 cases registered in the Surveillance, Epidemiology, and End Results Program of women diagnosed with primary breast carcinoma between 1988 and 1997 presenting with a T1–T2 lesion and no metastasis in whom axillary node dissection was performed: 58,070 women were node-negative (N0) and 25,616 were node-positive (N+). End point was death from any cause. Tumor size was modeled as a continuous variable by proportional hazards using a generalized additive models procedure. Results:Functionally, a Gompertzian expression exp(-exp(-(size-15)/10)) provided a good fit to the effect of tumor size (in millimeters) on mortality, irrespective of nodal status. Quantitatively, for tumor size between 3 and 50 mm, the increase of crude cumulative death rate (number of observed deaths divided by the number of patients at risk) increased with size from 10% to 25% for N0 and from 20% to 40% for N+. Conclusions:The functional relationship of tumor size with mortality is concordant with current knowledge of tumor growth. However, its qualitative and quantitative independence of nodal status is in contradiction with the prevailing concept of sequential disease progression from primary tumor to regional nodes. This argues against the perception that nodal metastases are caused by the primary tumor.

Planning target volume margins for prostate radiotherapy using daily electronic portal imaging and implanted fiducial markers

BackgroundFiducial markers and daily electronic portal imaging (EPI) can reduce the risk of geographic miss in prostate cancer radiotherapy. The purpose of this study was to estimate CTV to PTV margin requirements, without and with the use of this image guidance strategy.Methods46 patients underwent placement of 3 radio-opaque fiducial markers prior to prostate RT. Daily pre-treatment EPIs were taken, and isocenter placement errors were corrected if they were ≥ 3 mm along the left-right or superior-inferior axes, and/or ≥ 2 mm along the anterior-posterior axis. During-treatment EPIs were then obtained to estimate intra-fraction motion.ResultsWithout image guidance, margins of 0.57 cm, 0.79 cm and 0.77 cm, along the left-right, superior-inferior and anterior-posterior axes respectively, are required to give 95% probability of complete CTV coverage each day. With the above image guidance strategy, these margins can be reduced to 0.36 cm, 0.37 cm and 0.37 cm respectively. Correction of all isocenter placement errors, regardless of size, would permit minimal additional reduction in margins.ConclusionsImage guidance, using implanted fiducial markers and daily EPI, permits the use of narrower PTV margins without compromising coverage of the target, in the radiotherapy of prostate cancer.

Pelvic fractures following irradiation of endometrial and vaginal cancers-a case series and review of literature.

PURPOSE To review the induction of pelvic fractures as a result of radiation therapy and to assess their management. MATERIALS AND METHODS The charts of patients with endometrial and vaginal cancers irradiated between 1991 and 1995 were reviewed. All patients were treated with megavoltage machines, energy ranging from cobalt to 25 MV photons. RESULTS We treated 336 patients, with a median follow-up duration of 28.9 months (range 0-73.3). Sixteen patients had symptomatic pelvic fractures. The 5-year actuarial incidence of symptomatic pelvic fracture was 2.1%. All patients had pain as the first symptom. The median time of onset was 11 months (range 4-46). Imaging studies of 37.5% (6/16) were initially interpreted to be recurrent malignancy. All patients were managed conservatively and nine patients showed radiological evidence of healing over a median time of 13 months (range 2-34). Six patients had specific drug treatment including provera, premarin, calcium supplements, or pamidronate. Of these, five healed. For the ten patients who did not have any specific treatment, only four showed signs of healing at the time of last follow-up. There was a trend toward earlier healing with specific drug treatment (P=0.11). CONCLUSIONS Fractures can easily be mistaken for metastatic lesions (37.5% in this series) which might be treated with further irradiation. Although not statistically significant, there was a trend towards early healing with drug therapy. More studies are required to generate quantitative data for dose-response relationships and to evaluate the effect of drug therapy on the healing of such fractures.

Prognostic value of nodal ratios in node-positive breast cancer: a compiled update

The number of positive axillary nodes is a strong prognostic factor in breast cancer, but is affected by variability in nodal staging technique yielding varying numbers of excised nodes. The nodal ratio of positive to excised nodes is an alternative that could address this variability. Our 2006 review found that the nodal ratio consistently outperformed the number of positive nodes, providing strong arguments for the use of nodal ratios in breast cancer staging and management. New evidence has continued to accrue confirming the prognostic significance of nodal ratios in various worldwide population settings. This review provides an updated summary of available data, and discusses the potential application of the nodal ratio to breast cancer staging and prognostication, its role in the context of modern surgical techniques such as sentinel node biopsy, and its potential correlations with new biologic markers such as circulating tumor cells and breast cancer stem cells.