J. M. Horsman

Adjuvant Interferon in High-Risk Melanoma: The AIM HIGH Study—United Kingdom Coordinating Committee on Cancer Research Randomized Study of Adjuvant Low-Dose Extended-Duration Interferon Alfa-2a in High-Risk Resected Malignant Melanoma

PURPOSE To evaluate low-dose extended duration interferon alfa-2a as adjuvant therapy in patients with thick (> or = 4 mm) primary cutaneous melanoma and/or locoregional metastases. PATIENTS AND METHODS In this randomized controlled trial involving 674 patients, the effect of interferon alfa-2a (3 megaunits three times per week for 2 years or until recurrence) on overall survival (OS) and recurrence-free survival (RFS) was compared with that of no further treatment in radically resected stage IIB and stage III cutaneous malignant melanoma. RESULTS The OS and RFS rates at 5 years were 44% (SE, 2.6) and 32% (SE, 2.1), respectively. There was no significant difference in OS or RFS between the interferon-treated and control arms (odds ratio [OR], 0.94; 95% CI, 0.75 to 1.18; P =.6; and OR, 0.91; 95% CI, 0.75 to 1.10; P =.3; respectively). Male sex (P =.003) and regional lymph node involvement (P =.0009), but not age (P =.7), were statistically significant adverse features for OS. Subgroup analysis by disease stage, age, and sex did not show any clear differences between interferon-treated and control groups in either OS or RFS. Interferon-related toxicities were modest: grade 3 (and in only one case, grade 4) fatigue or mood disturbance was seen in 7% and 4% respectively, of patients. However, there were 50 withdrawals (15%) from interferon treatment due to toxicity. CONCLUSION The results from this study, taken in isolation, do not indicate that extended-duration low-dose interferon is significantly better than observation alone in the initial treatment of completely resected high-risk malignant melanoma.

Prevention of Anastrozole-Induced Bone Loss with Monthly Oral Ibandronate during Adjuvant Aromatase Inhibitor Therapy for Breast Cancer

Purpose: The aromatase inhibitor anastrozole is a highly effective well-tolerated treatment for postmenopausal endocrine-responsive breast cancer. However, its use is associated with accelerated bone loss and an increase in fracture risk. The ARIBON trial is a double-blind, randomized, placebo-controlled study designed to evaluate the impact of bisphosphonate treatment on bone mineral density (BMD) in women taking anastrozole. Experimental Design: BMD was assessed in 131 postmenopausal, surgically treated women with early breast cancer at two U.K. centers. Of these, 50 patients had osteopenia (T score −1.0 to −2.5) at either the hip or lumbar spine. All patients were treated with anastrozole 1 mg once a day and calcium and vitamin D supplementation. In addition, osteopenic patients were randomized to receive either treatment with ibandronate 150 mg orally every month or placebo. Results: After 2 years, osteopenic patients treated with ibandronate gained +2.98% (range −8.9, +19.9) and +0.60% (range −9.0, +6.9) at the lumbar spine and hip, respectively. Patients treated with placebo, however, lost −3.22% (range −16.0, +4.3) at the lumbar spine and −3.90% (range −12.3, +7.2) at the hip. The differences between the two treatment arms were statistically significant at both sites (P < 0.01). At 12 months, urinary n-telopeptide, serum c-telopeptide, and serum bone–specific alkaline phosphatase levels declined in patients receiving ibandronate (30.9%, 26.3%, and 22.8%, respectively) and increased in those taking placebo (40.3%, 34.9%, and 37.0%, respectively). Conclusions: Monthly oral ibandronate improves bone density and normalizes bone turnover in patients treated with anastrozole.

Impact of the revised FIGO/WHO system on the management of patients with gestational trophoblastic neoplasia

OBJECTIVE To study the effect of a change in disease scoring systems on the management of patients with gestational trophoblastic neoplasia (GTN) in our supra-regional treatment centre. METHODS We reviewed disease characteristics and treatment outcomes in 632 GTN patients managed at our centre from 1973 to 2006. Two disease scoring systems were used sequentially, the Sheffield modification of the Charing Cross Scoring System (SCCSS) before 2000, and the revised FIGO/modified WHO system (FIGO 2000) thereafter. RESULTS Using the SCCSS 573 (90.7%) patients were classified as low risk (LR) and 59 (9.3%) as high risk (HR). With FIGO 2000, 587 (92.9%) were LR and 45 (7.1%) HR. For LR patients, the complete response (CR) to first line single agent chemotherapy was 77% before 2000 and 61.6% from 2000 to 2006. For HR patients, the CR rates with first line chemotherapy were 79.5% and 75% respectively. The higher threshold for assigning a patient as HR using FIGO 2000 had an impact on the success of treatment; only 7/19 patients (37%) who were scored 6 by FIGO 2000, and thus treated as LR with methotrexate/folinic acid, achieved a CR. CONCLUSION In our experience, the revised FIGO/modified WHO scoring system has down scored some patients who would have been considered as high risk with the previous scoring system. A trend to lower CR with first line chemotherapy and an increase in the need for second line chemotherapy was seen.

Prevention of anastrozole induced bone loss with monthly oral ibandronate: Final 5 year results from the ARIBON trial

Purpose The ARIBON trial is a double blind, randomised, placebo controlled study designed to evaluate the impact of ibandronate on bone mineral density (BMD) in women taking anastrozole for adjuvant treatment of breast cancer. Methods 131 postmenopausal women with early breast cancer were recruited to the study. Of these, 13 had osteoporosis, 50 osteopenia and 68 normal BMD. Patients with osteoporosis at baseline were treated with monthly oral ibandronate 150 mg for 5 years; osteopenic patients were randomised to receive either ibandronate or placebo for two years and offered open label ibandronate depending upon the results of their 2-year BMD result. Results Of the 20 patients with osteopenia who were randomised to ibandronate and evaluable at the 2 year visit, 17/20 were not offered a bisphosphonate and the improvements in BMD accrued during the first 2 years were lost both at the LS (−3.21%) and TH (−5.0%). Of the 16 patients randomised to placebo 8/16 with high rates of bone loss during years 0–2 received ibandronate over the next 3 years with improvements in BMD of +5.01 and +1.19 at the LS and TH respectively. The 8 patients who were not offered a bisphosphonate experienced relatively little change in BMD throughout the 5 years of the study (LS +0.15%, TH −2.72%). BMD increased steadily in the 9/13 patients initially identified as having osteoporosis (LS +9.65%, TH +2.72%). Conclusions Monthly oral ibandronate provides an option to clinicians considering use of a bisphosphonate to prevent bone loss during aromatase inhibitor therapy.

The use of a point of care device for monitoring the bone resorption biomarker urinary N-telopeptide in cancer patients with bone metastases

Type I collagen is the major constituent of bone and its breakdown products are increasingly used as sensitive markers of bone resorption. The N-terminal peptide-bound crosslinks of type I collagen (NTX) can be measured in urine and is useful for the monitoring of patients with metastatic bone disease. Studies have shown that raised NTX levels in metastatic bone disease correlate with an increased risk of complications and pathological fracture. The development of accurate and instantaneous point of care devices (POCD) would facilitate patient treatment and avoid delays in awaiting results from specialist laboratories. This study assesses the clinical performance of a single use POCD (OSTEOMARK NTx Point of Care Rx Home Use) to monitor NTX levels in patients with metastatic bone disease. NTX was measured in duplicate in 136 urine samples from patients attending clinic with metastatic bone disease using the POCDs. In our centre the frequency of bisphosphonate treatment is dependent on the NTX level, which is categorised into three groups (0-50, 50-100 and >100 nmol BCE/mmol creatinine). We used these categories to compare the clinical performance of the POCDs to that of a laboratory immunoassay. From a total of 272 devices, 231 (84.9%) successfully recorded a value in nM BCE/mM creatinine. Statistical analysis of the measure of agreement between POCD and laboratory assay found moderate agreement between the two assays (kappa 0.508). Out of the 72 samples with a laboratory assay value of <50, 53 (73.6%) were found to be within the same group recorded by POCD. From the 20 samples with a laboratory assay value of >100, 19 (95.0%) were found to be within the same category using POCDs. The measurement of urinary NTX by POCD appears to be a viable option for the monitoring of metastatic cancer patients. Whilst POCDs appear to record higher values than laboratory assays, the correlation between devices is good and with further research the NTX categories could be modified to accommodate this variation.

Risk-adjusted prognostic models for Hodgkin's disease (HD) and grade II non-Hodgkin's lymphoma (NHL II): validation on 6728 British National Lymphoma Investigation patients.

Summary. Using significant factors from multivariate analyses, based on 20 putative markers from a consecutive series of 1198 Sheffield Lymphoma Group patients, risk‐adjusted prognostic models had been previously derived for Hodgkins disease (HD) (using age, albumin and lymphocyte count) and non‐Hodgkins lymphoma (NHL) grade II (based on albumin, age, erythrocyte sedimentation rate, lactate dehydrogenase and stage). Data from 6728 patients on the British National Lymphoma Investigation database were used for validation: thus the models were applied to 4411 patients with HD and 2317 patients with NHL grade II. Survival curves derived from these validation groups confirmed our risk models.

T Cell Non-Hodgkin’s Lymphoma: Treatment Outcomes and Survival in 3 Large UK Centres

the study. Cases of mycosis fungoides were excluded. In total, there were 401 patients available for analysis: 162 with PTCL, 47 with angio-immunoblastic lymphoma (AIL), 147 with ALCL, 37 with enteropathy-associated T cell NHL and 8 with extranodal natural killer (NK) cell lymphoma. Median age was 58 years (range 1.2–91.2), 242 patients were male. Initial stage, treatment and outcome were recorded on all patients. Patients underwent staging with standard computed tomography scans and bone marrow examination. The International Prognostic Index could not be applied because of incomplete data on earlier patients. A variety of treatment regimens have been employed. These have been divided into 5 categories for the purposes of analysis: watch and wait, local radiotherapy or excision, single-agent chemotherapy with/ without radiotherapy, CHOP or CHOP-like therapy with/without radiotherapy, and autologous stem cell transplant. Overall survival was calculated from date of presentation until death. Survival curves were constructed using the Kaplan-Meier method. The estimated median overall survival (OS) for all patients was 30 months. Assessed by histological subtype, survival was marginally better in the patients with ALCL (median survival 36.5 months, 95% CI 7.8–65.2), though this did not attain statistical significance. Similarly, survival of patients with PTCL was greater than in patients In the Western world, T cell non-Hodgkin’s lymphomas (NHL) represent about 12% of all NHL [1] . T cell lymphomas are regarded as aggressive tumours with a poorer prognosis than their B cell counterparts [2] . The majority are classified as (post-thymic) peripheral T cell lymphomas (PTCL); however, this is a heterogenous group of neoplasms, some of which are very rare. Occasional subtypes such as anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphomas (ALCL) are recognised to have a better prognosis with high remission rates achievable with standard CHOP-like chemotherapy. Because of the rarity of these disorders and the lack of clinical trials specific to T cell NHL, there are few data to guide the clinician about prognosis and treatment options. The main aims of this study were to analyse management, outcome and prognostic factors in a large group of patients with T cell NHL. We undertook a retrospective review of the clinical outcome of patients with T cell NHL, using patient information collected on 3 separate databases (Sheffield, Southampton and the British National Lymphoma Investigation, BNLI). These cases were diagnosed between 1977 and 2004. Histological diagnoses over this period were made according to Kiel, Rappaport, Working Formulation and latterly the WHO/REAL classification. Only those cases of proven T cell origin were included in Received: April 24, 2007 Accepted after revision: June 14, 2007 Published online: September 4, 2007