Efficacy and safety of mogamulizumab by patient baseline blood tumour burden: a post hoc analysis of the MAVORIC trial.

BACKGROUND: Mogamulizumab was compared with vorinostat in the phase 3 MAVORIC trial (NCT01728805) in 372 patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) who had failed ≥1 prior systemic therapy. Mogamulizumab significantly prolonged progression-free survival (PFS), with a superior objective response rate (ORR) vs. vorinostat. OBJECTIVES: This post hoc analysis was performed to evaluate the effect of baseline blood tumour burden on patient response to mogamulizumab. METHODS: PFS, ORR, time to next treatment (TTNT), skin response (modified Severity-Weighted Assessment Tool [mSWAT]) and safety were assessed in patients stratified by blood classification (B0 [n = 126], B1 [n = 62], or B2 [n = 184], indicating increasing blood involvement). RESULTS: Investigator-assessed PFS was longer for mogamulizumab versus vorinostat across all blood classes, significantly so for B1 and B2 patients. ORR was higher with mogamulizumab than with vorinostat in all blood classification groups and more markedly so with escalating B class (B0: 15.6% vs. 6.5%, P = 0.0549; B1: 25.8% vs. 6.5%, P = 0.2758; B2: 37.4% vs. 3.2%, P < 0.0001). TTNT was significantly longer for patients treated with mogamulizumab versus vorinostat with B1 (12.63 vs. 3.07 months; HR 0.32 [95% CI 0.16-0.67]; P = 0.0018) and B2 (13.07 vs. 3.53 months; HR 0.30 [95% CI 0.21-0.43]; P < 0.0001) blood involvement. In the mogamulizumab arm, 81 patients (43.5%) had ≥50% change in the mSWAT vs. 41 patients (22.0%) with vorinostat; mSWAT improvements with mogamulizumab occurred most often in B1 and B2 patients. Rapid, sustained reductions were seen in CD4+ CD26- cell counts and CD4:CD8 ratios in mogamulizumab patients for all B classes. Treatment-emergent adverse events were less frequent overall with mogamulizumab and similar in frequency regardless of B class. CONCLUSIONS: This post hoc analysis indicates greater clinical benefit with mogamulizumab vs. vorinostat in patients with MF and SS classified as having B1 and B2 blood involvement.

Pharmacokinetic and tolerability profile of once-daily zibotentan (ZD4054) in Japanese and Caucasian patients with hormone-resistant prostate cancer.

OBJECTIVE: To investigate potential differences in zibotentan pharmacokinetics between Japanese and Caucasian patients with hormone-resistant prostate cancer (HRPC) following single and multiple dosing. METHODS: In the Japanese study, 18 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 26 days' once-daily dosing. In the Caucasian study, 21 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 12 days' once-daily dosing. RESULTS: Pharmacokinetic parameters were similar between populations. Absorption of zibotentan was rapid with maximum plasma concentrations typically achieved within 3 h of dosing. Mean clearance, 17.9 and 18.7 ml/min in Japanese and Caucasian patients, respectively (range 7.0 - 36.3 ml/min in Japanese patients and 7.8 - 29.5 ml/min in Caucasian patients) and volume of distribution, 14.0 and 15.6 l for Japanese and Caucasian patients, respectively (range 7.9 - 29.1 l in Japanese patients and 9.6 - 23.8 l in Caucasian patients) were relatively low, and t1/2 was approximately 12 h (range 5.7 - 18.8 h in Japanese patients and 5.0 - 22.9 h in Caucasian patients) following single dosing. Little accumulation was observed following daily dosing and multiple-dose pharmacokinetics were predictable. Exposure levels achieved in some Japanese patients receiving zibotentan 15 mg were higher than those observed in Caucasian patients, however, this may be due to differences in body weight, as exposure levels were similar when data were normalized for body weight. Zibotentan was well tolerated in both populations. CONCLUSIONS: There are no clinically relevant differences in the disposition and pharmacokinetics of zibotentan between Japanese and Caucasian patients with HRPC.

The UK national breast cancer screening programme for survivors of Hodgkin lymphoma detects breast cancer at an early stage.

BACKGROUND: Supradiaphragmatic radiotherapy (SRT) to treat Hodgkin's lymphoma (HL) at a young age increases the risk of breast cancer (BC). A national notification risk assessment and screening programme (NRASP) for women who were treated with SRT before the age of 36 years was instituted in the United Kingdom in 2003. In this study, we report the implementation and screening results from the largest English Cancer Network. METHODS: A total of 417 eligible women were identified through cancer registry/hospital databases and from follow-up (FU) clinics. Screening results were collated retrospectively, and registry searches were used to capture BC cases. RESULTS: Of the 417 women invited for clinical review, 243 (58%) attended. Of these 417 women, 23 (5.5%) have been diagnosed with BC, a standardised incidence ratio of 2.9 compared with the age-matched general population. Of five invasive BCs diagnosed within the NRASP, none involved axillary lymph nodes compared with 7 of 13 (54%) diagnosed outside the programme (P<0.10). The mean latency for BC cases was 19.5+/-8.35 years and the mean FU duration for those unaffected by BC was 14.6+/-9.11 years (P<0.01), suggesting that those unaffected by BC remain at high risk. Recall and negative biopsy rates were acceptable (10.5 and 0.8%, respectively). CONCLUSIONS: The NRASP appears to detect BC at an early stage with acceptable biopsy rates, although numbers are small. Determination of NRASP results on a national basis is required for the accurate evaluation of screening efficacy in women previously treated with SRT.

External-beam radiotherapy in T1-2 N0 penile carcinoma.

AIMS: To review the outcome of 41 patients with invasive carcinoma of the penis treated with external-beam radiotherapy using a consistent technique and dose. MATERIALS AND METHODS: Forty-one patients with carcinoma of the penis treated at Christie Hospital, Manchester, UK, between 1995 and 2000 were reviewed retrospectively. Radiotherapy was delivered using 4 MV linear accelerators with a dose of 50 Gy or 52.5 Gy in 16 fractions over 22 days. RESULTS: The distribution of patients according to stage was T1=37, T2=4, N0=40, N3=1. Median follow-up was 4.5 years. The local control rate was 62%, nodal relapse-free rate of 88%, relapse-free rate of 51% and overall survival of 88% at 5 years. All recurrences were salvaged by surgery. Penile ulceration occurred in 8% and urethral stenosis requiring dilatation in 29%. There were no penectomies for penile necrosis. CONCLUSION: EBXRT may be offered for T1-2 cancer of the penis with close surveillance to detect local recurrences early for salvage surgery without jeopardising overall survival. It remains an alternative option to penis-preserving surgery and should be discussed in a multidisciplinary setting and with the patient.

Adjuvant and salvage treatment after radical prostatectomy: current practice in the UK.

OBJECTIVE: To survey UK urologists and radiation oncologists in the evaluation and treatment of localised prostate cancer in the adjuvant and salvage setting. METHODS: Postal questionnaires were mailed to 292 urologists and 98 radiation oncologists in the UK. RESULTS: In all, 188 (48%) questionnaires were returned. In total, 72/128 (56%) of the urologist respondents and 58/60 (97%) of the oncologist respondents perform routine radical prostate treatment. Among 43 (60%) of the urologist, 40 (69%) recommended adjuvant treatment, which could be radiotherapy, hormonal treatment or combined hormonal and radiation treatment. There is no significant difference between the modality of treatment recommended. The poor prognostic factors that would influence the decision to offer adjuvant treatment include a detectable postoperative PSA, seminal vesicle involvement, positive margins, Gleason score>8 and pathological T3. With regard to the choice of hormonal treatment, most urologists preferred antiandrogens, whereas most oncologists prefer lutienising hormone releasing hormone (LHRH) analogue (P=0.03). Regarding salvage treatment, there is a wide variation in the PSA threshold and number of PSA rises before initiation of investigations and treatment. Significantly more urologists recommended salvage radiotherapy (P=0.02), whereas oncologists recommended combined hormonal radiation therapy (P=0.03). There is a wide variation of practice regarding the duration of hormonal treatment, the type of investigations initiated, range of radiotherapy doses and treatment volumes. CONCLUSION: There is a wide variation in practice among UK clinicians.

Controversies in the radiotherapeutic management of poor prognosis locally advanced prostate cancer.

The Grand Round was held at the Christie Hospital, Manchester, U.K., on 30 November 2002. It followed a presentation by Dr David Dearnaley from the Royal Marsden Hospital in Sutton on 'Novel approaches and trials in prostate cancer'. Controversies in the management of locally advanced prostate cancer were illustrated by a case presentation and followed by a discussion on the evaluation of disease extent, and the roles of radiotherapy and hormone ablation.

Limited field radiotherapy for early stage, infra-diaphragmatic Hodgkin's lymphoma.

AIMS: To analyse the treatment outcome for patients with stage I and II infra-diaphragmatic Hodgkin's lymphoma. MATERIALS AND METHODS: A retrospective review of case notes for 33 consecutive patients treated between 1988 and 2000. Twenty-five out of 33 patients received radiotherapy alone, three out of 33 patients received minimal initial chemotherapy (MIT) (4 weeks VAPEC B) and five patients received six cycles of ChlVPP EVA hybrid chemotherapy before radiotherapy. Radiotherapy was given as a limited field in 32 out of 33 patients. RESULTS: Twenty-seven out of 33 patients were men (82%), and the median age was 47 years. Fifteen of the 33 patients were stage IA, 15 were IIA, 1 was IB and 2 were IIB. The median follow-up was 71 months. Histological subtype was lymphocyte predominant (15/33), nodular sclerosis (11/33), mixed cellularity (4/33), lymphocyte-rich classical (1/33) and unclassifiable (2/33). The 5-year overall survival was 89% and 5-year relapse-free survival was 85%. The median time to relapse was 37 months (range 7-65 months). One out of five relapses was within the previous radiotherapy field. All five relapses had received radiotherapy alone and four were salvaged with chemotherapy. There have been four second malignancies and one patient transformed to high-grade non-Hodgkin's lymphoma. No patient has died of Hodgkin's lymphoma. CONCLUSIONS: In our cohort of patients with infra-diaphragmatic stage I and II Hodgkin's lymphoma treated with limited-field radiotherapy, no patients died from uncontrolled disease. The use of MIT may reduce the risk of relapse and obviate the need for conventional salvage chemotherapy. Late relapses may occur, and second malignancies are a cause for concern underlining the need for long-term follow-up.

Hypofractionated radiotherapy as salvage for rising prostate-specific antigen after radical prostatectomy.

AIMS: To review the outcome of men receiving hypofractionated salvage radiotherapy for rising prostate-specific antigen (PSA) after radical prostatectomy. MATERIALS AND METHODS: A retrospective analysis of 61 men referred for salvage radiotherapy for biochemical relapse after radical prostatectomy was conducted. Twenty-four men receiving hormonal therapy or with follow-up of less than 12 months were excluded. Thirty-seven men were identified, median age 64 years, median preoperative PSA 11 ng/ml (5.6-60 ng/ml), Gleason scores <7: 70%, Gleason scores > or = 7: 30%. Twenty-seven men had positive surgical resection margins, eight had seminal-vesicle involvement and one had lymph-node involvement. Diagnosis of failure after radical prostatectomy was made on rising PSA in all cases; 19 men also had positive magnetic resonance imaging, 11 abnormal digital rectal examination and nine positive biopsy. Radiotherapy was delivered conformally to the prostatic fossa, 50-52.5 Gy in 20 fractions over 4 weeks. Date of failure after radiotherapy was defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria or as date of commencement of hormonal therapy for rising PSA. RESULTS: Median time from radical prostatectomy to radiotherapy was 30.6 months (8-68 months); median pre-radiotherapy PSA was 2.9 ng/ml (0.5-11.4 ng/ml). PSA response after radiotherapy was seen in 33 out of 37 (89%) patients. At median follow-up of 36 months (20-85 months), 28 out of 37 remained disease-free. Thirteen more patients have had two consecutive PSA rises. Actuarial 3-year disease-free survival is 74%. No patient has developed metastases or died of prostate cancer. Pre-radiotherapy PSA less than 2 ng/ml predicted disease-free survival (P = 0.027). No acute toxicity greater than Radiation Therapy Oncology Group (RTOG) G2 was observed. CONCLUSIONS: Salvage radiotherapy after radical prostatectomy achieved durable biochemical control in most patients. Outcome is improved if radiotherapy is delivered when PSA is less than 2 ng/ml. A policy of close monitoring after radical prostatectomy with early referral for salvage radiotherapy is advocated.

Small-cell carcinoma of the urinary bladder: 10-year experience.

AIMS: Small-cell carcinoma of the urinary bladder is rarely encountered in clinical practice. We report on our clinical experience with affected patients presenting to our institution from 1986 to 1996. MATERIALS AND METHODS: We retrospectively analysed 14 pathologically confirmed cases, specifically looking at stage, presenting features, treatment and overall survival. The median age at presentation was 74 years (range 54-91 years). RESULTS: Ten patients presented with stage III disease, and four patients with stage IV disease (1 = nodal, 3 = distant metastases). Four patients were treated with radical radiotherapy (one patient receiving neoadjuvant chemotherapy) and two underwent a radical cystoprostatectomy. Five patients received palliative bladder radiotherapy and three were too frail for treatment at presentation. The overall median survival was 5 months. Patients receiving radical treatment had a median overall survival of 21 months, with only one long-term survivor. CONCLUSION: This highly aggressive tumour tends to affect an elderly population who are generally frail and have significant comorbidity. Many are unfit for radical treatment. In patients with disease confined to the pelvis who are able to tolerate radical intervention, the results of local therapy alone are poor. It therefore remains incumbent on treating clinicians to explore means of improving these results. Initial chemotherapy analogous to small-cell lung cancer may offer a durable response with a better chance for long-term survival.

ChlVPP/EVA hybrid versus the weekly VAPEC-B regimen for previously untreated Hodgkin's disease.

PURPOSE: To test the hypothesis that a chemotherapy regimen of relatively low toxicity and 11 weeks' duration (doxorubicin, cyclophosphamide, etoposide, vincristine, bleomycin, and prednisolone [VAPEC-B]) is at least as effective in terms of disease control as 6 months' treatment with chlorambucil, vinblastine, procarbazine, and prednisone/etoposide, vincristine, and doxorubicin (ChlVPP/EVA hybrid), which is associated with a high risk of permanent sterility. PATIENTS AND METHODS: Two hundred eighty-two patients with previously untreated Hodgkin's disease, clinical stages I/II (plus mediastinal bulk and/or B symptoms) and clinical stages III/IV were randomized at three United Kingdom and one Italian center to receive either six monthly cycles of ChlVPP/EVA hybrid or 11 weekly cycles of VAPEC-B. After chemotherapy and a restaging evaluation, radiotherapy was administered to sites of previous bulk or residual radiographic abnormality before patients were observed off treatment. RESULTS: Further accrual to the trial was halted at the planned third interim analysis in September 1996. After a median follow-up of 4.9 years, freedom from progression (FFP), event-free survival (EFS), and overall survival (OS) are all significantly better in the population treated with ChlVPP/EVA than VAPEC-B, where the comparative 5-year results are 82% and 62% (FFP), 78% and 58% (EFS), and 89% and 79% (OS), respectively. The superiority of ChlVPP/EVA was seen in both low-risk and intermediate/high-risk patients, although subset analysis suggested that ChlVPP/EVA and VAPEC-B produce equivalent results in the best-prognosis patients (Hasenclever score

Prediction of scattered dose to the testes in abdominopelvic radiotherapy.

Radical abdominal radiotherapy in men runs the risk of impairing their fertility owing to scattered dose to the testes, outside of the treated volume. In patients for whom this is a concern it is important to be able to predict the dose to the testes before treatment in order to determine whether semen cryopreservation should be undertaken and testicular shielding performed during treatment. Measurements have been made on an anthropomorphic phantom to determine the magnitude of these doses for a four-field treatment consisting of an anterior-posterior parallel pair and a lateral parallel pair. A dataset is presented, which, together with a correction for patients size, allows an estimate of testicular dose to be made given only the photon energy, interfield distances and the distance from the testes to the nearest beam edge. Thermoluminescent dosimetry has been carried out in 17 patients to validate the use of the data tables. The results indicate that testicular doses may be estimated with a standard deviation corresponding to 1%-2% of the tumour dose, which is sufficient for the purpose of determining whether fertility is threatened by a planned treatment.

Bone marrow toxicity in mice treated with indium-114m-labelled blood cells.

Clinical trials with autologous indium-114m-labelled lymphocytes have revealed significant anti-tumour effects in chronic lymphocytic leukaemia patients with highly resistant disease. Substitution of the lymphocyte vector with heat-damaged red blood cells (HDRBC) may make this treatment more universally applicable and reduce the dose-limiting myelosuppression encountered with labelled lymphocytes. Therefore, the bone marrow localization and toxicities of indium-labelled lymphocytes or HDRBC have been investigated in BDFI mice. At 24 hours approximately 4% and 1.2% of 114In(m) administered as labelled lymphocytes or HDRBC respectively was localized within the bone marrow and remained constant for 57 days thereafter. Toxicity towards bone marrow stem cells, measured as CFU-S, was equivalent for both cellular vectors. However, at clinically relevant activities, 114In(m) HDRBC were less toxic than labelled lymphocytes towards committed progenitors, assayed as in vitro-CFC and CFU-Meg. These data suggest that substitution of HDRBC for lymphocytes as the 114In(m) vector may be beneficial in reducing the myelosuppression associated with this technique.

A doxorubicin-based regimen used in the treatment of elderly patients with high-grade non-Hodgkin's lymphoma.

A retrospective analysis was performed on 66 patients, aged 70 years or older, who received treatment with a weekly doxorubicin-containing regimen (VAPEC-B) for high grade non-Hodgkin's lymphoma (NHL). Two dosing schedules were employed. The choice of regimen was at the discretion of the treating clinician and reflected the performance status of the patient and the predicted tolerance to chemotherapy. Forty-nine patients received a half-dose schedule and 17 the full-dose schedule. Those receiving the half-dose regimen had a lower median performance status and received a lower dose intensity of chemotherapy (45% versus 83%). However, the outcomes of the two groups were similar: complete remission rate 41% versus 47%, and 5-year overall survival 36% versus 23%, for the half- and full-dose groups, respectively. A similar proportion of patients (51% versus 59%) completed each regimen, although there were more delays in treatment delivery experienced in those receiving the full dose. Half-dose VAPEC-B is an effective treatment option for elderly patients with high-grade NHL and has comparable efficacy with other published regimens. The use of such low-dose doxorubicin-containing regimens in elderly patients with high-grade NHL requires further investigation.

Relationship of MRI and clinical staging to outcome in invasive bladder cancer treated by radiotherapy.

AIM: To compare MRI and clinical staging of invasive bladder cancer prospectively and identify additional prognostic features on MRI before radiotherapy. METHODS AND MATERIALS: 143 patients with a pathological diagnosis of transitional cell carcinoma underwent MRI (1.0 T) of the abdomen and pelvis before radical radiotherapy. Tumour size, site, degree of infiltration, presence of adenopathy and hydronephrosis were assessed and an appropriate radiological stage assigned. Following radiotherapy all patients received regular cystoscopic follow-up. Date of first relapse and date of death were recorded. RESULTS: The median follow-up was 2.8 years for survivors. Those patients upstaged from T2a clinically to T3b on MRI had a significantly worse outcome (P = 0.0078). In univariate analysis a number of MRI features were significantly associated with adverse outcome: tumour size, circumferential tumour extent, and presence of hydronephrosis (all P < 0.05). After adjustment for clinical T stage and histological grade, all these MRI features and the MRI T stage were found to confer additional prognostic information in predicting early disease relapse and death (P < 0.05). CONCLUSION: This study demonstrates that MRI before radiotherapy provides valuable additional prognostic information compared to clinical staging.

The diagnostic value of positron emission tomography (PET) with radiolabelled fluorodeoxyglucose (18F-FDG) in head and neck cancer.

Positron emission tomography (PET) scanning has recently been introduced into clinical practice but its usefulness in the management of head and neck cancer is not well defined. The aim of this prospective preliminary study was to examine the clinical value of fluorodeoxyglucose (FDG)--PET in patients with head and neck cancer treated by radiotherapy with surgery in reserve by (i) relating quantitative uptake of isotope to tumour type and histological grade and (ii) comparing the imaging findings of PET and magnetic resonance imaging (MRI) in post-radiotherapy assessment of tumour response. Twenty-one patients had pre-treatment PET and MRI scans and these were repeated four and eight months after treatment if there was no clinical relapse. Pre-treatment uptake of FDG using tumour to cerebellar ratio parameters was significantly related to the histological grade of squamous cancer (p = 0.04) but not to tumour type. Discordance of post-treatment PET/MRI findings in one case indicates a possible role for PET in the early detection of tumour recurrence. Other potential uses of PET scanning in the management of head and neck cancer are discussed.