Andrew Gaya

A Prognostic Index for Systemic AIDS-Related Non-Hodgkin Lymphoma Treated in the Era of Highly Active Antiretroviral Therapy

Context The International Prognostic Index (IPI) predicts survival in patients with lymphoma, but its applicability to AIDS-related lymphomas in the era of highly active antiretroviral therapy has not been evaluated. The IPI stratifies patients into risk groups on the basis of age, tumor stage, serum lactate dehydrogenase levels, performance status, and number of extranodal sites. Contribution Among 111 patients with AIDS-related lymphoma diagnosed since 1996, the IPI and CD4 cell count separated patients into 4 strata with 1-year survival rates of 82%, 47%, 20%, and 15%. Implications The IPI and CD4 cell count can help physicians predict the prognosis of patients with AIDS-related lymphoma. The Editors The lymphomas are a diverse group of malignant disorders that vary in their molecular features, genetics, clinical presentation, treatment, and outcome. Major advances in our understanding of the biology of these diseases have been made, leading to new therapies and classifications. Although combination chemotherapy cures intermediate- or high-grade aggressive non-Hodgkin lymphomas in many patients, approximately 50% of patients die of the disease (1). Because Ann Arbor disease staging does not predict outcome (2, 3), the International Prognostic Index was introduced in 1993 to segregate aggressive lymphomas in terms of survival (4). From 2031 patients studied, 4 risk groups were derived on the basis of age, tumor stage, serum lactate dehydrogenase level, performance status, and number of extranodal disease sites. As we enter the third decade of the AIDS epidemic, it is apparent that many cancers are more common in people infected with HIV. Non-Hodgkin lymphoma remains the second most common tumor in such patients (after Kaposi sarcoma), and the rate of death from systemic AIDS-related non-Hodgkin lymphoma remains high (5, 6). The median duration of survival reported with chemotherapy before the availability of highly active antiretroviral therapy (HAART) was 2 to 13 months (7). The outcome of AIDS-related non-Hodgkin lymphoma appears to have improved in the post-HAART era, and phase II studies describe median duration of survival of 15 to 34 months (8-15), an interval similar to that observed among all patients with advanced-stage, high-grade non-Hodgkin lymphoma. It is hypothesized that these improvements are associated with a change in prognostic factors. We sought to develop a new prognostic model for HIV-associated non-Hodgkin lymphoma in the era of HAART, a treatment that has been available in established market economies since 1996. Small prognostic studies of AIDS-related non-Hodgkin lymphoma in patients who presented in the pre-HAART era suggest that application of the International Prognostic Index may be useful in HIV-infected patients (16, 17). We therefore aimed to confirm the validity of the International Prognostic Index, to identify additional prognostic factors for patients with AIDS-related non-Hodgkin lymphoma in the era of HAART, and to devise a new prognostic model for these patients. Methods Patients The Chelsea and Westminster HIV cohort is one of the largest in Europe. Clinical information on 9621 HIV-1 seropositive patients has been accumulated since 1986. All patients in whom lymphoma was diagnosed were identified prospectively; these included 215 patients with AIDS-related non-Hodgkin lymphoma, 60 with primary central nervous system lymphomas, and 26 with Hodgkin disease. We estimated prognostic factors for AIDS-related non-Hodgkin lymphoma in the HAART era in patients receiving HAART. Patients with Hodgkin disease and primary central nervous system lymphomas were excluded. The HAART era is defined as commencing on 1 January 1996, when this treatment became routinely available at our institution and many others. One hundred eleven patients with AIDS-related non-Hodgkin lymphoma received a diagnosis after this date. Highly active antiretroviral therapy is defined as a combination of at least 3 antiretroviral agents, including a nucleoside analogue backbone combined with a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor or both classes of drug, according to generally accepted definitions (18). All patients had histologically confirmed diagnoses of AIDS-related non-Hodgkin lymphoma, and more than 95% had aggressive B-cell disease. All patients had full staging at diagnosis, including examination of bone marrow and cerebrospinal fluid. All patients received a single dose of intrathecal chemoprophylaxis with their staging lumbar puncture. Patients with Burkitt lymphoma or bone marrow, paranasal, or paraspinal involvement received a further 5 doses of intrathecal chemotherapy. Between 1996 and 1998, the patients with AIDS-related non-Hodgkin lymphoma diagnosed in the era of HAART received chemotherapy with bleomycin, etoposide, vincristine, methotrexate, prednisolone/cyclophosphamide, and doxorubicin (18 patients) or cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone (3 patients). A further 21 patients received chemotherapy with cisplatin, vinblastine, and bleomycin (17 patients); radiotherapy alone (3 patients); or best supportive care (1 patient). Since 1999, 59 patients have been treated with infused cyclophosphamide, doxorubicin, and etoposide chemotherapy (13, 19); 2 have received cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone; and 8 (including 3 in whom disease was diagnosed at autopsy) received best supportive care only. The CD4 cell subset analysis was performed by using whole blood stained with murine antihuman monoclonal antibodies to CD4 (TetraOne [Beckman Coulter, High Wycombe, United Kingdom]) on an Epics XL-MCL multiparametric flow cytometer (Beckman Coulter). Statistical Analysis Variables were compared between groups by using the chi-square test for nominal variables and the MannWhitney U test for nonparametric variables. Survival was calculated from the day of diagnosis of AIDS-related non-Hodgkin lymphoma until death or the date of last follow-up. Curves for overall duration of survival were plotted according to the method of Kaplan and Meier (20). The log-rank method was used to test for the significance of differences in survival distributions (21) and univariate Cox proportional hazards regression analysis was used to determine the prognostic significance of clinicopathologic variables at presentation with AIDS-related non-Hodgkin lymphoma. Cox multivariable modeling was used to determine independent variables predictive of survival by entering all variables that were significant in univariate analysis (at a level of P< 0.15). A prognostic model was then constructed from these data by dividing each coefficient in the final multivariable models with significant predictors by the lowest to 2 decimal places. Using these point values, a risk score was assigned to each patient by summing the values for each risk factor present. The prognostic score derived was then grouped into quartiles so that approximately equal numbers of patients were included in each of these categories. The chosen cutoff values for the prognostic risk scores were further investigated by using receiver-operating characteristic methods. Because the performance of prognostic models may be optimistically overestimated when they are determined on the basis of a small sample, a higher apparent performance than that observed in an independent sample of patients not considered in the modeling process may result (22, 23). To formally confirm the validity of the prognostic index based on a small sample, we used the internal empirical distribution function, placing equal probabilities on every original data value, as described elsewhere (24). Nonparametric bootstrapping was used to draw a sample by selecting independent bootstrap values (25-28). Each of these consisted of 111 data points drawn with replacement where each sample unit was replaced in the data set, such that they could be chosen subsequently in random selection. Resampled data were used to generate bootstrap estimates of the hazard ratio, based on the multivariable model presented for the HAART era. These were determined by 2000 iterations of such resampling. Results The overall duration of survival was significantly greater for patients in whom non-Hodgkin lymphoma was diagnosed in the HAART era compared with those in whom the disease was diagnosed in the pre-HAART era (log-rank chi-square, 9.23; P= 0.002) (Figure 1). Among the 215 patients with AIDS-related non-Hodgkin lymphoma, the actuarial overall survival rate, including all causes of death, was 32% at 2 years (95% CI, 25% to 39%) and 26% at 5 years (CI, 19% to 33%). Figure 1. KaplanMeier overall survival curve for 215 patients with systemic AIDS-related non-Hodgkin lymphoma ( NHL ) diagnosed in the era before (104 patients) and after (111 patients) highly active antiretroviral therapy ( HAART ). P Although patients whose disease was diagnosed in the HAART era had significantly higher CD4 cell counts at presentation (median value, 144 106 cells/L vs. 45 106 cells/L; P< 0.001), better Eastern Cooperative Oncology Group performance status (P= 0.003), and fewer previous AIDS-defining illnesses (P< 0.001) than did patients whose disease was diagnosed before the HAART era, the former patients were older (P< 0.001) and had a higher serum lactate dehydrogenase level (P< 0.001) (data not shown). Univariate Cox proportional hazards regression analysis identified many prognostic factors for survival after diagnosis of AIDS-related non-Hodgkin lymphoma in the HAART era, including low CD4 cell count, stage III or IV disease, B-class symptoms, lower Eastern Cooperative Oncology Group performance status, bone marrow and meningeal involvement, and more than 1 extranodal site at presentation (Table 1). Table 1. Clinicopathologic Characteristics of 111 Patients with AIDS-Related Non-Hodgkin Lymphoma Diagnosed in the Era of Highly Active Antiretroviral T

Stereotactic Body Radiotherapy: A Review

Stereotactic body radiotherapy (SBRT) combines the challenge of meeting the stringent dosimetric requirements of stereotactic radiosurgery with that of accounting for the physiological movement of tumour and normal tissue. Here we present an overview of the history and development of SBRT and discuss the radiobiological rationale upon which it is based. The published results of SBRT for lung, liver, pancreas, kidney, prostate and spinal lesions are reviewed and summarised. The current evidence base is appraised and important ongoing trials are identified.

A preclinical and clinical review of aflibercept for the management of cancer

Aflibercept, also known as vascular endothelial growth factor (VEGF)-Trap, is a recombinant, decoy receptor fusion protein, rationally designed to block angiogenesis by targeting not only all forms of VEGF-A, but also VEGF-B and placental growth factor. It inhibits VEGF-induced angiogenesis in preclinical models. In tumor models, aflibercept is associated with the reduction of tumor vasculature and size, and the inhibition of ascites formation. Clinical studies are investigating the use of aflibercept alone and in combination with other antineoplastic therapies for the treatment of various cancers. Phase I and II studies have provided proof of principle, and support the continuing clinical investigation of aflibercept. Results from the phase III study, VITAL, of aflibercept in the second-line setting in patients with advanced non-small cell lung cancer [NCT00532155] demonstrated efficacy in progression-free survival and overall objective response rate, but overall survival was not significantly improved. A full report awaits publication. The Phase III VANILLA trial in metastatic pancreatic cancer [NCT00574275] showed no improvement in overall survival. Most recently, the phase III VELOUR study [NCT00561470] of aflibercept plus FOLFIRI compared with placebo plus FOLFIRI in patients with metastatic colorectal cancer following failure of an oxaliplatin regimen showed significant improvements in overall survival, progression-free survival, and response rate and the complete results have been submitted to a peer-reviewed journal. This review summarizes preclinical and clinical data for aflibercept and discusses future directions and clinical trials for this agent.

A Brief Report on the Safety Study of Induction Chemotherapy Followed by Synchronous Radiotherapy and Cetuximab in Stage III Non-small Cell Lung Cancer (NSCLC): SCRATCH Study

Background: In patients with advanced (stage IIIb/IV) NSCLC, the addition of cetuximab to chemotherapy has demonstrated increased activity compared with chemotherapy alone. Furthermore, the additio of cetuximab to RT in patients with locally advanced squamous cell head & neck carcinoma significantly prolongs the duration of locoregional control and median overall survival compared to radiotherapy alone. Therefore, the SCRATCH study was designed to assess the safety of synchronous cetuximab with radical RT in patients with Stage III NSCLC. The safety results of cohort 1 from this phase I study are presented below. Methods: Twelve patients with inoperable stage III NSCLC were enrolled into cohort I. Inclusion criteria were performance status 0–1, adequate organ function, and disease encompassable within a radical RT volume. Exclusion criteria were previous malignancy, thoracic RT or treatment with EGFR (epidermal growth factor receptor) targeted therapy. Patients received platinum-based induction chemotherapy, followed by weekly intravenous cetuximab (initial dose 400mg/m2; maintenance dose 250mg/m2) and concomitant Rt (64Gy/32fractions/45days). The primary end-point was toxicity. NCI Common Toxicity Criteria (CTC) V3.0 assessments were preformed weekly during radiotherapy, and at regular follow-up visits. Results: 9 out of 12 patients coompleted the concomitant therapy as planned, with no dose reductions. 3 patients did not complete the full schedule. One died from bronchopneumonia mid-treatment; one experienced grade 3 lethargy following the first cetuximab dose and declined further cetuximab; one experienced a grade 2 skin reaction following the third dose of cetuximab and declined futher treatment. On follow-up only one patient has developed a grade III reaction – pneumonitis – which settled on steroids with intermittent oxygen. Three patients have died on follow-up (2 from disease progression and one from thromboembolic disease). Of the 12 patients entered ito the study, 8 have survived at least 1 year, measured from the first day of induction chemotherapy. Conclusion: The results suggest that the early and late toxicities of synchronous cetuximab and radical RT are acceptable.

Anti-angiogenesis therapies: their potential in cancer management

Angiogenesis plays an important role in normal animal growth and development. This process is also vital for the growth of tumors. Angiogenesis inhibitors have a different mechanism of action to traditional chemotherapy agents and radiation therapy. The angiogenesis inhibitors can act synergistically with conventional treatments and tend to have non-overlapping toxicities. There are four drugs which have a proven role in treating cancer patients. Bevacizumab is a humanized monoclonal antibody that binds to and neutralizes vascular endothelial growth factor (VEGF). Sunitinib and sorafenib inhibit multiple tyrosine kinase receptors that are important for angiogenesis. Thalidomide inhibits the activity of basic fibroblast growth factor-2 (bFGF). The licensed indications and the supporting evidence are discussed. Other drugs are currently being tested in clinical trials and the most promising of these drugs are discussed. Aflibercept, also known as VEGF-trap, is a recombinant fusion protein that binds to circulating VEGF. The vascular disrupting agents act by targeting established blood vessels. These exciting new treatments have the potential to transform the management of cancer.

Cardiac complications after radical radiotherapy.

Improvements in cancer therapy have led to increasing numbers of cancer survivors, and the long-term complications of these treatments are now becoming apparent. This article presents the current knowledge of adverse cardiovascular effects of radiotherapy to the chest. Medline literature searches relating to the cardiac complications of radiotherapy and subsequent prognosis were conducted. Potential adverse effects of mediastinal irradiation are numerous and can include coronary artery disease, pericarditis, cardiomyopathy, and valvular disease. Damage seems to be related to radiation dose, volume of irradiated heart, age at exposure, technique of chest irradiation, and patient-specific factors. The advent of technology and the newer sophisticated techniques in treatment planning and delivery are expected to decrease the incidence of cardiovascular diseases after radiation of the mediastinal structures. In any case, patients subjected to irradiation of the mediastinal structures require close multidisciplinary clinical monitoring.

Comparison of Combined X-Ray Radiography and Magnetic Resonance (XMR) Imaging–Versus Computed Tomography–Based Dosimetry for the Evaluation of Permanent Prostate Brachytherapy Implants

PURPOSE To present a method for the dosimetric analysis of permanent prostate brachytherapy implants using a combination of stereoscopic X-ray radiography and magnetic resonance (MR) imaging (XMR) in an XMR facility, and to compare the clinical results between XMR- and computed tomography (CT)-based dosimetry. METHODS AND MATERIALS Patients who had received nonstranded iodine-125 permanent prostate brachytherapy implants underwent XMR and CT imaging 4 weeks later. Four observers outlined the prostate gland on both sets of images. Dose-volume histograms (DVHs) were derived, and agreement was compared among the observers and between the modalities. RESULTS A total of 30 patients were evaluated. Inherent XMR registration based on prior calibration and optical tracking required a further automatic seed registration step that revealed a median root mean square registration error of 4.2 mm (range, 1.6-11.4). The observers agreed significantly more closely on prostate base and apex positions as well as outlining contours on the MR images than on those from CT. Coefficients of variation were significantly higher for observed prostate volumes, D90, and V100 parameters on CT-based dosimetry as opposed to XMR. The XMR-based dosimetry showed little agreement with that from CT for all observers, with D90 95% limits of agreement ranges of 65, 118, 79, and 73 Gy for Observers 1, 2, 3, and 4, respectively. CONCLUSIONS The study results showed that XMR-based dosimetry offers an alternative to other imaging modalities and registration methods with the advantages of MR-based prostate delineation and confident three-dimensional reconstruction of the implant. The XMR-derived dose-volume histograms differ from the CT-derived values and demonstrate less interobserver variability.

An analysis of intraoperative versus post-operative dosimetry with CT, CT-MRI fusion and XMR for the evaluation of permanent prostate brachytherapy implants.

BACKGROUND AND PURPOSE To assess the agreement between intraoperative and post-operative dosimetry and to identify factors that influence dose calculations of prostate brachytherapy implants. MATERIALS AND METHODS Patients treated with prostate brachytherapy implants underwent post-operative CT and XMR (combined X-ray and MR) imaging. Dose-volume histograms were calculated from CT, XMR and CT-MR fusion data and compared with intraoperative values for two observers. Multiple linear regression models assessed the influences of intraoperative D90, gland oedema, gland volume, source loss and migration, and implanted activity/volume prostate on post-operative D90. RESULTS Forty-nine patients were studied. The mean D90 differences (95% confidence limits) between intraoperative and post-operative CT, XMR and CT-MR fusion assessments were: 11 Gy (-22, 45), 18 Gy (-13, 49) and 20 Gy (-17, 58) for Observer 1; and 15 Gy (-34, 63), 13 Gy (-29, 55) and 14 Gy (-27, 54) for Observer 2. Multiple linear regression modelling showed that the observed oedema and intraoperative D90 were significant independent variables for the prediction of post-operative D90 values for both observers using all modalities. CONCLUSION This is the first study to report Bland-Altman agreement analysis between intraoperative and post-operative dosimetry. Agreement is poor. Post-operative dosimetry is dependent on the intraoperative D90 and the subjectively outlined gland volume.

Rectal tumour volume (GTV) delineation using T2-weighted and diffusion-weighted MRI: Implications for radiotherapy planning.

PURPOSE To compare the rectal tumour gross target volume (GTV) delineated on T2 weighted (T2W MRI) and diffusion weighted MRI (DWI) images by two different observers and to assess if agreement is improved by DWI. MATERIAL AND METHODS 27 consecutive patients (15 male, range 27.1-88.8 years, mean 66.9 years) underwent 1.5T MRI prior to chemoradiation (45Gy in 25 fractions; oral capecitabine 850mg/m(2)), including axial T2W MRI (TR=6600ms, TE=90ms) and DWI (TR=3000ms, TE=77ms, b=0, 100, 800s/mm(2)). 3D tumour volume (cm(3)) was measured by volume of interest (VOI) analysis by two independent readers for the T2W MRI and b800 DWI axial images, and the T2W MRI and DWI volumes compared using Mann-Whitney test. Observer agreement was assessed using Bland-Altman statistics. Significance was at 5%. RESULTS Artefacts precluded DWI analysis in 1 patient. In the remaining 26 patients evaluated, median (range) T2W MRI MRI and DWI (b=800s/mm(2)) 3D GTVin cm(3) were 33.97 (4.44-199.8) and 31.38 (2.43-228), respectively, for Reader One and 43.78 (7.57-267.7) and 42.45 (3.68-251) for Reader Two. T2W MRI GTVs were slightly larger but not statistically different from DWI volumes: p=0.52 Reader One; p=0.92 Reader Two. Interobserver mean difference (95% limits of agreement) for T2W MRI and DWI GTVs were -9.84 (-54.96 to +35.28) cm(3) and -14.79 (-54.01 to +24.43) cm(3) respectively. CONCLUSION Smaller DWI volumes may result from better tumour conspicuity but overall observer agreement is not improved by DWI.

Stereotactic ablative body radiotherapy (SABR) for primary and secondary lung tumours

Abstract Stereotactic ablative body radiotherapy (SABR) represents a technological breakthrough in radiotherapy technique, with proven benefits to patients in terms of improved tumour control and overall survival. The key components of SABR are described. The current evidence base for SABR for the treatment of primary and secondary lung tumours is appraised, and key ongoing trials are identified.