Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design.

The poly(ADP-ribose) polymerase inhibitor olaparib (Lynparza™) is approved for maintenance treatment of platinum-sensitive relapsed ovarian cancer. OPINION is a single-arm, open-label, multicenter, Phase IIIb study to assess the efficacy and safety of olaparib tablet maintenance therapy in women with high-grade serous or endometrioid platinum-sensitive relapsed ovarian cancer without a germline BRCA1 or BRCA2 mutation. Eligible patients should have received ≥2 prior lines of platinum-based chemotherapy and be in complete or partial response following their most recent course or have no evidence of disease. Patients will receive olaparib tablets (300 mg twice daily) until disease progression, unacceptable toxicity or another discontinuation criterion. The primary end point is investigator-assessed progression-free survival; secondary end points include progression-free survival according to tumor homologous recombination deficiency status. Clinical trial registration: NCT03402841.

Randomized double-blind trial of amifostine versus placebo for radiation-induced xerostomia in patients with head and neck cancer.

INTRODUCTION: The role of the radioprotector amifostine in ameliorating radiotherapy side effects in head and neck squamous cell carcinoma (HNSCC) is controversial. This trial aimed to determine whether pretreatment with amifostine reduced the incidence of Radiation Therapy Oncology Group grade ≥2 acute and late xerostomia in patients receiving definitive or adjuvant radiotherapy for HNSCC, without reducing tumour control or survival. METHODS: Between 14 September 2001 and 8 November 2004, 44 Royal Adelaide Hospital patients were randomized double-blind to receive amifostine (200 mg/m2 IV) or placebo (normal saline IV) 5 days/week, prior to standard radiotherapy (60-70 Gy), each having ≥75% of the parotids treated to ≥40 Gy. Side effects were assessed weekly during treatment, at 3 and 5 months after radiotherapy, then every 6 months until disease progression or death. RESULTS: The accrual target was 200 patients over 4-5 years, but the trial closed prematurely when only 44 patients had been randomized after 3 years. Of 41 evaluable patients, 80% (16/20) in the amifostine arm had grade ≥2 acute radiation salivary toxicity versus 76% (16/21) in the placebo arm (P = 1.00). The rate of grade ≥2 late radiation salivary toxicity at 12 months was 66% in the amifostine arm and 82% in the placebo arm (estimated hazard ratio 1.61, 95% confidence interval 0.74-3.49, P = 0.22). Other toxicities tended to be worse in the amifostine arm: acute grade 3-4 skin 35% vs 5% and mucous membrane 40% vs 5%; grade ≥2 vomiting 35% vs 5%, hypocalcaemia 25% vs 5% and fatigue 85% vs 33%, with only the latter retaining statistical significance after adjusting for multiple comparisons. There were no significant differences in failure-free (P = 0.70) or overall survival (P = 0.86), with estimated 4-year rates of 48% vs 54% and 49% vs 59% for the amifostine vs placebo arms respectively. CONCLUSION: There was no clear evidence that pretreatment with amifostine made any difference to the incidence of grade ≥2 acute or late xerostomia. Other toxicity tended to be more severe with amifostine. There was no effect on failure-free or overall survival. Acknowledging the low statistical power, these results do not support the use of IV amifostine pre-radiotherapy in HNSCC.

A randomised, double-blind, placebo-controlled study to assess the safety and efficacy of methoxyflurane for procedural pain of a bone marrow biopsy.

CONTEXT: Pain during bone marrow biopsy (BMB) under local anaesthesia (LA) is reported in 70% of patients, of whom 35% rate the pain as severe. Pain is experienced during both the biopsy and the marrow aspiration. Many medical centres use conscious sedation involving benzodiazepines and/or opioids administered orally or intravenously for BMB analgesia. Methoxyflurane (MEOF) is self-administered by a handheld device (the Penthrox inhaler), which is licensed in Australia for the relief of pain associated with short surgical procedures. OBJECTIVES: To evaluate the efficacy and safety of MEOF analgesia in patients with cancer undergoing BMB. METHODS: Patients received LA plus either MEOF or placebo. The primary endpoint was worst pain intensity measured with the Numerical Rating Scale. Anxiety was assessed with the State Trait Anxiety Inventory (STAI-Y-1). Patients, operators and the research nurse rated global medication performance using a 5-point Likert scale. RESULTS: Forty-nine of the 50 patients randomised to MEOF and 48 of the 50 patients randomised to placebo effectively received the allocated intervention. Mean±SD worst pain overall was 4.90±2.07 in MEOF group and 6.0±2.24 in placebo group (p=0.011). Worst pain during the aspiration was 3.3±2.0 in MEOF group and 5.0±2.4 in placebo group (p<0.001). 49% of patients treated with MEOF rated the medication as very good or excellent compared with 16.5% of the patients treated with placebo (p=0.005). 20.4% of patients treated with MEOF had an adverse event (AE) compared with 4.2% in the placebo arm (p=0.028). All AEs were grade 1. CONCLUSIONS: MEOF was safe and performed better than placebo for analgesia in BMB procedures.

Effect of self-selected music on adults' anxiety and subjective experiences during initial radiotherapy treatment: a randomised controlled trial and qualitative research.

INTRODUCTION: Patients may experience radiotherapy as anxiety provoking, especially during unfamiliar initial treatment. This study examines whether patients' use of self-selected music while undergoing first radiotherapy treatment reduces anxiety, and how patients describe their first radiotherapy experience with or without self-selected music. METHODS: Using quantitative and qualitative methods, 100 participants preparing to commence radiotherapy were assigned to the initial radiotherapy session either with self-selected music or without music. In both participant groups, the Spielberger State Anxiety Inventory measured pre- and post-radiotherapy levels, music preference questions examined future music desires during treatment and a semistructured questionnaire examined additional subjective experiences. RESULTS: Overall, participants were not highly anxious pre-radiotherapy, anxiety decreased in both music and control groups following radiotherapy (P = 0.008) and this change was not different between groups (P = 0.35). However, music group participants were significantly more likely to want music in future radiotherapy sessions (P = 0.007). Some reported a benefit from the music in terms of feeling supported, distracted or that treatment time seemed faster. Participants in both groups often commended helpful staff. Negative reactions were only occasional. CONCLUSIONS: Although preferred music does not reduce anxiety, it can support some patients undergoing initial radiotherapy and departmental staff should invite patients to bring music to radiotherapy, provide music libraries and offer to play patient selected music during treatments.

Impact of point spread function reconstruction on thoracic lymph node staging with 18F-FDG PET/CT in non-small cell lung cancer.

AIM: The aim of the present study was to evaluate the impact of point spread function (PSF) reconstruction on quantitative values and diagnostic accuracy of FDG PET/CT for nodal staging in non-small cell lung cancer. PATIENTS AND METHODS: Fifty-eight consecutive PET/CT examinations were reconstructed with both ordered subset expectation maximization (OSEM) and PSF algorithms. Two readers independently performed a randomized blinded review of PET/CT examinations and gave a nodal status (N0, N1, N2, or N3) to each PET data set. When discordant, a consensus was reached with a third reader. Sensitivity, specificity, positive and negative predictive values (NPV), and positive and negative likelihood ratios (LRs) were assessed and compared using a McNemar test. All PET data sets were then independently analyzed to extract quantitative PET values in 208 nodes and compare them using Bland-Altman analysis. RESULTS: Bland-Altman analysis showed that, on average, PSF reconstruction increased SUVmax, SUVmean, and node/background ratios by 48%, 28%, and 27%, respectively. This increase was more marked for nodes less than 1 cm than for nodes 1 cm or greater (P < 0.0001 for SUVmax, SUVmean, and node/background ratios). Point spread function PET had higher sensitivity (97%) and NPV (92%) than OSEM PET (78% and 57%, respectively; P = 0.01 and P = 0.04, respectively). Negative LR was 0.04 for PSF PET and 0.31 for OSEM PET. CONCLUSIONS: By improving activity recovery, especially for nonenlarged nodes, PSF significantly improves the sensitivity, NPV, and negative LR of FDG-PET for nodal staging in non-small cell lung cancer. These data suggest that preoperative invasive nodal staging may be omitted in the case of a negative PSF FDG-PET/CT.

Effect of PET/CT on management of patients with non-small cell lung cancer: results of a prospective study with 5-year survival data.

UNLABELLED: We investigated the incremental management impact and prognostic value of staging with (18)F-FDG PET/CT in patients with non-small cell lung cancer (NSCLC) being considered for potentially curative therapies. METHODS: Information on 168 consecutive patients with NSCLC being considered for surgery or definitive radiotherapy with curative intent before PET/CT was entered into a prospective database. The pre-PET/CT management plan, based on conventional imaging (conventional CT, appropriately supplemented by bone scintigraphy or other modalities), was defined prospectively by referring clinicians before PET/CT results became available. After PET/CT, actual clinical management was recorded, and patients were followed up until 5 y or death. The appropriateness of PET/CT management plans was assessed by biopsy when available, clinical follow-up, and survival analysis. RESULTS: Stage was discordant on PET/CT and conventional imaging in 50.6% of patients (41.1% upstaged, 9.5% downstaged), with high management impact (change in treatment modality or curative intent) in 42.3% of patients. Both conventional imaging stage and PET/CT stage were strongly predictive of overall survival (OS) but there were greater differences between hazard rates and separations in the OS curves for stage groupings determined using PET/CT. OS was also strongly predicted by PET/CT-directed choice of therapy (P < 0.0001). CONCLUSION: PET/CT frequently affects patient management and strongly predicts OS in NSCLC, supporting the appropriateness of such changes.

Randomized phase 2 sequencing and pharmacokinetic study of gemcitabine and oxaliplatin in advanced non-small cell lung cancer.

AIM: This multicentre phase II trial examined the combination of gemcitabine and oxaliplatin in patients with advanced non-small cell lung cancer (NSCLC). The effect of sequence administration was randomized and pharmacokinetics (PK) assessed. METHODS: Eligible patients had stage IIIB or IV or recurrent NSCLC, no prior chemotherapy, World Health Organization performance status ≤2 and measurable disease. Treatment comprised: gemcitabine (1250 mg/m(2)) and oxaliplatin (70 mg/m(2)), each given on days 1 and 8 of a 21-day cycle. Patients were randomized 1:1 to the sequencing of the two drugs for the duration of their treatment. The primary end-point was response rate (RR). Secondary end-points included progression-free survival (PFS), overall survival (OS), toxicity, PK and the effect of drug sequencing. RESULTS: A total of 46 patients were enrolled of whom 43 were evaluable for response. Overall 13 patients (30%) achieved a partial response, PFS was 4.2 months (95% CI 2.8-5.8 months), and OS was 6.8 months (95% CI 4.4-10.1 months). There was only one case of grade 3 neurosensory toxicity despite a median cumulative oxaliplatin dose in excess of 500 mg/m(2) . No differences in clinical or PK end-points were observed between the two different sequencing arms. CONCLUSION: This oxaliplatin and gemcitabine schedule has shown activity in advanced NSCLC with modest toxicity. Neither clinical nor PK outcomes were influenced by the sequencing of these agents, although definite conclusions are limited by small patient numbers. The favorable toxicity profile of this doublet, in light of an encouraging RR, warrants its further investigation in NSCLC.

Short-term warfarin reversal for elective surgery--using low-dose intravenous vitamin K: safe, reliable and convenient*.

Peri-procedural management of warfarin reflects an intricate balance between the restoration of haemostasis and appropriate thromboprophylaxis. This prospective single-arm study assessed the safety and efficacy of a convenient schedule, incorporating low-dose intravenous vitamin K (vitK(IV) ) for short-term warfarin reversal prior to elective surgery, as well as vitK-dependent factor levels (vitK-Factors) and International Normalized Ratio (INR) pre- and post-vitK(IV) . One seventy eight patients on long-term warfarin received 3mg vitK(IV) 12-18 h pre-procedure with no adverse reactions. 167/178 (94%) achieved an INR≤1·5 post-vitK(IV) on the day of surgery, while all achieved INR≤1·7. Four patients had procedure-associated major bleeding, but importantly had achieved a pre-procedure INR<1·5 and vitK-Factors >0·30iu/ml. No patient suffered a symptomatic thromboembolism during the 6-week follow-up. Median days to re-establish a therapeutic INR were 4 (range 2-11). VitK(IV) near normalized all vitK-Factors, with a uniform pattern of depletion and repletion in association with an increase and decrease in INR, respectively; and from the data, INR<1·5 correlated with vitK-Factors >0·30iu/ml. Low-dose vitK(IV) for short-term warfarin reversal was reliable and safe, and successfully lowered the INR to an acceptable level for planned surgery, with no excess of bleeding, thromboembolism, delayed discharge, or resistance to warfarin. The protocol was simple and convenient for both the patients and the healthcare institution.

Interfraction prostate rotation determined from in-room computerized tomography images.

Fiducial markers (FMs) are commonly used as a correction technique for interfraction translations of the prostate. The aim of this investigation was to determine the magnitude of prostate rotations using 2 methods: FM coordinates and the anatomical border of the prostate and rectum. Daily computed tomography (CT) scans (n = 346) of 10 prostate cancer patients with 3 implanted FMs were acquired using the CT on rails. FM coordinates were used to determine rotation in the sagittal, transverse, and coronal planes, and CT contours of the prostate and rectum were used to determine rotation along the sagittal plane. An adaptive technique based on a subset of images (n = 6; planning and first 5 treatment CTs) to reduce systematic rotation errors in the sagittal plane was tested. The standard deviation (SD) of systematic rotation from FM coordinates was 7.6°, 7.7°, and 5.0° in the sagittal, transverse and coronal planes. The corresponding SD of random error was 10.2°, 15.8°, and 6.5°. Errors in the sagittal plane, determined from prostate and rectal contours, were 10.1° (systematic) and 7.7° (random). These results did not correlate with rotation computed from FM coordinates (r = -0.017; p = 0.753, n = 337). The systematic error could be reduced by 43% to 5.6° when the mean prostate position was estimated from 6 CT scans. Prostate rotation is a significant source of error that appears to be more accurately determined using the anatomical border of the prostate and rectum rather than FMs, thus highlighting the utility of CT image guidance.

Intraoperative radiotherapy in women with early breast cancer treated by breast-conserving therapy.

BACKGROUND: Previous studies demonstrated the feasibility of intraoperative radiotherapy (IORT) to the primary tumour bed using a miniature electron beam driven X-ray source for early breast cancer. This study aimed to evaluate the feasibility of IORT as a tumour bed boost after whole breast irradiation (WBI) in breast conserving therapy. METHODS: This was a single-arm prospective trial for women with breast cancer measuring <3 cm. After breast-conserving surgery, a single IORT dose of 5 Gray (Gy) prescribed to 10 mm from the applicator surface was delivered to the breast tissues using 50 kV X-ray followed by standard WBI. The feasibility rate of protocol therapy was defined as the percentage of all women who completed both IORT and WBI. A desirable completion rate was >90%. The protocol therapy would be considered unsuitable for further development if the completion rate was <75% or severe acute toxicity occurred in >15% of women who received IORT. RESULTS: Sixty patients were recruited for the study. IORT and WBI were delivered in 58 and 55 patients, respectively. Thus, the feasibility rates of IORT alone and both IORT and WBI were 97% (95% confidence interval (CI), 89-99%) and 92% (95% CI, 83-97%), respectively. A severe surgical complication or grade 3 or 4 acute radiation toxicity were identified in 10% (6/58) of women who had IORT. CONCLUSION: Tumour bed boost using IORT in women with early breast cancer treated with conservative surgery and WBI was shown to be feasibly consistent with previous studies.

Adjuvant chemoradiation for gastric cancer using epirubicin, cisplatin, and 5-fluorouracil before and after three-dimensional conformal radiotherapy with concurrent infusional 5-fluorouracil: a multicenter study of the Trans-Tasman Radiation Oncology Group.

PURPOSE: The INT0116 study has established postoperative chemoradiotherapy as the standard of care for completely resected gastric adenocarcinoma. However, the optimal chemoradiation regimen remains to be defined. We conducted a prospective, multicenter study to evaluate an alternative chemoradiation regimen that combines more current systemic treatment with modern techniques of radiotherapy delivery. METHODS AND MATERIALS: Patients with adenocarcinoma of the stomach who had undergone an R0 resection were eligible. Adjuvant therapy consisted of one cycle of epirubicin, cisplatin, and 5-FU (ECF), followed by radiotherapy with concurrent infusional 5-FU, and then two additional cycles of ECF. Radiotherapy was delivered using precisely defined, multiple-field, three-dimensional conformal techniques. RESULTS: A total of 54 assessable patients were enrolled from 19 institutions. The proportion of patients commencing Cycles 1, 2, and 3 of ECF chemotherapy were 100%, 81%, and 67% respectively. In all, 94% of patients who received radiotherapy completed treatment as planned. Grade 3/4 neutropenia occurred in 66% of patients with 7.4% developing febrile neutropenia. Most neutropenic episodes (83%) occurred in the post-radiotherapy period during cycles 2 and 3 of ECF. Grade 3/4 gastrointestinal toxicity occurred in 28% of patients. In all, 35% of radiotherapy treatment plans contained protocol deviations that were satisfactorily amended before commencement of treatment. At median follow-up of 36 months, the 3-year overall survival rate was estimated at 61.6%. CONCLUSIONS: This adjuvant regimen using ECF before and after three-dimensional conformal chemoradiation is feasible and can be safely delivered in a cooperative group setting. A regimen similar to this is currently being compared with the INT0116 regimen in a National Cancer Institute-sponsored, randomized Phase III trial.

A comparison of in-room computerized tomography options for detection of fiducial markers in prostate cancer radiotherapy.

PURPOSE: To compare volumetric in-room computed tomography (CT) and kilovoltage (kV) cone-beam CT (CBCT) to planar imaging with respect to their ability to localize fiducial markers (FMs) for radiotherapy of prostate cancer. METHODS AND MATERIALS: Image guidance options from two linear accelerators were compared in terms of identifying the center of gravity (COG) of FMs from the isocenter: a Siemens Primatom, where the couch is rotated 180 degrees from the treatment isocenter to the in-room CT vs. electronic portal imaging (EPI); and a Varian OBI system, where kV CBCT, EPI, and planar kV radiographs were compared. In all, 387 image pairs (CBCT = 133; CT = 254) from 18 patients were analyzed. A clinical tolerance of 3 mm was predefined as the acceptable threshold for agreement. RESULTS: COG location on in-room CT and EPI was in agreement 96.9%, 85.8%, and 89.0% of the time in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) directions, respectively, vs. 99.2%, 91.7%, and 93.2% for the CBCT and EPI analysis. The CBCT vs. kV radiographs were in agreement 100% (LR), 85.4% (SI), and 88.5% (AP), and EPI vs. kV radiographs were in agreement 100% (LR), 94.6% (SI), and 91.5% (AP) of the time. CONCLUSION: Identification of FMs on volumetric or planar images was found to be not equivalent (+/-3 mm) using either linear accelerator. Intrafraction prostate motion, interpretation of FM location, and spatial properties of images are contributing factors. Although in-room CT has superior image quality, the process of realigning the treatment couch to acquire a CT introduces an error, highlighting the benefits of a single isocentric system.

Phase II study of autologous stem cell transplant using busulfan-melphalan chemotherapy-only conditioning followed by interferon for relapsed poor prognosis follicular non-Hodgkin lymphoma.

Alpha interferon has proven efficacy in prolonging remissions in patients with follicular non-Hodgkin lymphoma (NHL) when given concurrently with or after conventional-dose anthracycline-based chemotherapy, but there are limited data on its use after myeloablative conditioning. We prospectively evaluated the toxicity and efficacy of interferon given thrice weekly for up to 5 years post-engraftment in patients with relapsed follicular NHL undergoing autologous stem cell transplant using busulfan-melphalan conditioning. Thirty-seven patients were enrolled in this Australasian Leukaemia & Lymphoma Group study and transplanted between 1995 and 1999. Only one patient had received prior rituximab. Two patients died of transplant-related toxicity; 28 of the remainder commenced interferon, but it was discontinued prematurely in most patients due to toxicity (mainly fatigue and depression) or relapse. While the majority of patients (29/36 evaluable: 81%) achieved a complete remission based on clinical and CT scan criteria post-transplant, most relapsed relatively early, with a median progression-free survival of 2.4 years. The overall survival at 7 years was 49%. Eight patients (22%), however, remain alive a median of 9.3 years post-transplant, having never relapsed, and another six patients (16%) remain alive in durable remission after salvage therapy. These results demonstrate that interferon is poorly tolerated post-autograft and hence is unlikely to positively contribute to patient outcome. Long-term follow-up demonstrates that autografting may result in durable remissions in a meaningful minority of patients with relapsed follicular NHL.

Gene methylation in breast ductal fluid from BRCA1 and BRCA2 mutation carriers.

PURPOSE: Genomic alterations (including gene hypermethylation) are likely to precede the phenotypic changes associated with breast tumorigenesis. From a prospective collection of ductal lavage (DL) samples from women with a known mutation in BRCA1 or BRCA2, we have assessed promoter methylation with a comparison of results with several variables, including breast cancer (BC) outcome. EXPERIMENTAL DESIGN: Hypermethylation of p16, RASSF1A, twist, and RARbeta was assessed using a qualitative, real-time, nested PCR assay. Associations between methylation status and variables were tested using Fisher's exact test or logistic regression. Analyses were done at three levels: a single breast, a single duct (both over time), and each DL sample in isolation. RESULTS: A total of 168 samples from 93 ducts in 54 breasts have been analyzed in 34 women (16 BRCA1 and 18 BRCA2 mutation carriers). A median of 2 DL was done (range, 1-5), with 7 women developing BC on study, 1 bilateral. Methylation of p16 was associated with a known BRCA1 mutation (P = 0.001, P < 0.001, and P < 0.001 for breast, duct, and sample levels, respectively) and women with a history of contralateral BC (P = 0.001 and P < 0.001 for duct and sample levels, respectively). An association was seen for women who developed BC on study and RASSF1A methylation (P = 0.001 for sample level). CONCLUSIONS: Genetic methylation patterns could potentially be used to predict future BC risk. In addition, p16 methylation may be a predictor of BRCA1 mutation status. Further research is required to corroborate these findings.

Comparison of CT on rails with electronic portal imaging for positioning of prostate cancer patients with implanted fiducial markers.

PURPOSE: The objective of this investigation was to measure the agreement between in-room computed tomography (CT) on rails and electronic portal image (EPI) radiography. METHODS AND MATERIALS: Agreement between the location of the center of gravity (COG) of fiducial markers (FMs) on CT and EPI images was determined in phantom studies and a patient cohort. A secondary analysis between the center of volume (COV) of the prostate on CT and the COG of FMs on CT and EPI was performed. Agreement was defined as the 95% probability of a difference of

Prospective study of percutaneous endoscopic gastrostomy tubes versus nasogastric tubes for enteral feeding in patients with head and neck cancer undergoing (chemo)radiation.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) tubes have largely replaced nasogastric tubes (NGTs) for nutritional support of patients with head and neck cancer undergoing curative (chemo) radiotherapy without any good scientific basis. METHODS: A prospective study was conducted to compare PEG tubes and NGTs in terms of nutritional outcomes, complications, patient satisfaction, and cost. RESULTS: There were 32 PEG and 73 NGT patients. PEG patients sustained significantly less weight loss at 6 weeks post-treatment (median 0.8 kg gain vs 3.7 kg loss, p < .001), but had a high insertion site infection rate (41%), longer median duration of use (146 vs 57 days, p < .001), and more grade 3 dysphagia in disease-free survivors at 6 months (25% vs 8%, p = .07). Patient self-assessed general physical condition and overall quality of life scores were similar in both groups. Overall costs were significantly higher for PEG patients. CONCLUSION: PEG tube use should be selective, not routine, in this patient population.

Predicting durable remissions following thalidomide therapy for relapsed myeloma.

In multiple myeloma (MM), it remains unclear whether the depth of response correlates with progression-free survival (PFS) and overall survival (OS). We updated long-term follow-up data on the two previously published multi-centre phase-II trials in patients with relapsed or refractory MM using thalidomide +/- IFN alpha-2B (n = 75, median follow-up 6.1 years) celecoxib-thalidomide combination (n = 66, median follow-up 4.0 years), and assessed the predictors of durable response and impact of depth of response. Twenty-seven of the 141 (19%) patients remained progression-free beyond 24 months. The most significant baseline predictor for durable PFS and OS was a serum beta(2)-microglobulin 69.8, 35.4 and 11.7 months, respectively (p < 0.001). These findings support the therapeutic goal of achieving 'maximum depth of response' in patients with relapsed myeloma.

Efficacy and safety of imatinib in patients with chronic myeloid leukemia and complete or near-complete cytogenetic response to interferon-alpha.

BACKGROUND: Interferon-alpha (IFN-alpha) confers a survival advantage for the minority of patients with chronic myeloid leukemia (CML) who achieve a complete cytogenetic response. The question of whether IFN-alpha-responsive patients can experience further improvements with imatinib has not been answered. Imatinib offers clear quality of life advantages. Furthermore, patients who achieve a major molecular response (MMR) while receiving imatinib are likely to remain progression free. METHODS: A total of 23 patients treated for a median of 4.5 years with IFN-alpha (range, 1.6-14.3 years) who had achieved a complete (Philadelphia chromosome [Ph] negative, n = 15 patients) or near-complete (1-10% Ph, n = 8 patients) cytogenetic response were studied. The primary objective was to determine whether ceasing therapy with IFN-alpha and switching to 12 months of imatinib treatment at a dose of 400 mg/day could improve the molecular response as assessed by real-time quantitative polymerase chain reaction of BCR-ABL transcript levels. Safety was also assessed. RESULTS: Every patient who had not achieved an MMR while receiving IFN-alpha (n = 16 patients) achieved an MMR after a median of 3 months of imatinib treatment. Significant BCR-ABL reductions (median, 63-fold; range, 18-425-fold) occurred in 15 of these patients. Every patient who had already achieved an MMR while receiving IFN-alpha (n = 7 patients) maintained an MMR while receiving imatinib. No patients discontinued imatinib due to toxicity, but 1 patient withdrew consent. CONCLUSIONS: These data suggest that switching IFN-alpha-responsive patients to imatinib leads to a rapid improvement in achieving an MMR, a response with established prognostic value, and is well tolerated. The study should help patients and their physicians make evidence-based decisions regarding the potential benefits and risks of switching to imatinib.

Patients with multiple myeloma treated with thalidomide: evaluation of clinical parameters, cytokines,angiogenic markers, mast cells and marrow CD57+ cytotoxic T cells as predictors of outcome.

BACKGROUND AND OBJECTIVES: In vitro studies suggest that thalidomide has an immunoregulatory role and alters the marrow microenvironment. We assessed laboratory and clinical parameters in patients with myeloma treated with thalidomide as potential prognostic markers and looked for changes with therapy. DESIGN AND METHODS: Seventy-five patients with relapsed/refractory myeloma received thalidomide in a phase II trial. Serial samples of platelet-poor plasma and bone marrow were tested for angiogenic cytokines including vascular endothelial growth factor (VEGF), marrow microvessel-density (MVD), mast cells and CD57+ cell expression. The effects of these parameters on response rate (RR), progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: Elevated baseline VEGF predicted for a superior RR (p=0.018) and PFS. Elevated CD57+ cells also predicted superior PFS (p=0.012). MVD did not predict for RR, PFS or OS, but MVD and VEGF fell significantly in responders. Multivariate analysis identified that inferior OS was associated with age >65 years (p=0.017), raised lactate dehydrogenase (p=0.001), raised hepatocyte growth factor levels (p=0.012) and low pre-treatment CD57+ cells (p<0.001). INTERPRETATION AND CONCLUSIONS: Our findings support the suggestion that thalidomide has anti-angiogenic and immunomodulatory effects in myeloma. The preferred method for assessing angiogenesis is plasma VEGF levels and the assessment of CD57+ cells for patients with myeloma receiving novel immunomodulatory drugs should be further investigated.

Clinical impact of, and prognostic stratification by, F-18 FDG PET/CT in head and neck mucosal squamous cell carcinoma.

BACKGROUND: The aim of this study was to determine prospectively the incremental value of positron emission tomography/computed tomography (PET/CT) over conventional assessment (clinical examination and CT/MRI imaging). METHODS: All patients undergoing (18)F-fluorodeoxyglucose (FDG)-PET/CT for primary head and neck mucosal squamous cell carcinoma between January 2002 and December 2003 (inclusive) were included in this study provided they had undergone contemporaneous conventional assessment of the head and neck region and had 12 months minimum follow-up. RESULTS: Seventy-six patients underwent 100 PET/CT scans. The majority of patients (74%) were treated with definitive (chemo)radiotherapy. Median follow-up time was 28 months. PET/CT led to a TNM classification alteration in 34% (12/35), a change in radiotherapy planning technique and/or dose in 29% (10/35), and altered treatment response assessment in 43% (13/30). A complete metabolic response was predictive of overall survival (p = .037). CONCLUSION: Our results support incorporation of PET/CT into the management paradigm of head and neck mucosal squamous cell carcinoma.