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.

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.

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.

Intensity-modulated radiotherapy for nasopharyngeal carcinoma: clinical correlation of dose to the pharyngo-esophageal axis and dysphagia.

PURPOSE: The aim of this study was to quantify the dose delivered to the pharyngo-esophageal axis using different intensity-modulated radiation therapy (IMRT) techniques for treatment of nasopharyngeal carcinoma and to correlate this with acute swallowing toxicity. METHODS AND MATERIALS: The study population consisted of 28 patients treated with IMRT between February 2002 and August 2005: 20 with whole field IMRT (WF-IMRT) and 8 with IMRT fields junctioned with an anterior neck field with central shielding (j-IMRT). Dose to the pharyngo-esophageal axis was measured using dose-volume histograms. Acute swallowing toxicity was assessed by review of dysphagia grade during treatment and enteral feeding requirements. RESULTS: The mean pharyngo-esophageal dose was 55.2 Gy in the WF-IMRT group and 27.2 Gy in the j-IMRT group, p < 0.001. Ninety-five percent (19/20) of the WF-IMRT group developed Grade 3 dysphagia compared with 62.5% (5/8) of the j-IMRT group, p = 0.06. Feeding tube duration was a median of 38 days for the WF-IMRT group compared with 6 days for the j-IMRT group, p = 0.04. CONCLUSIONS: Clinical vigilance must be maintained when introducing new technology to ensure that unanticipated adverse effects do not result. Although newer planning systems can reduce the dose to the pharyngo-esophageal axis with WF-IMRT, the j-IMRT technique is preferred at least in patients with no gross disease in the lower neck.

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.

Loss of heterozygosity analysis in ductal lavage samples from BRCA1 and BRCA2 carriers: a cautionary tale.

BACKGROUND: Loss of heterozygosity (LOH) in breast ductal lavage (DL) fluid has been reported to be a potential biomarker of malignant change. Interpretation of LOH is reliant on sufficient quality and quantity of DNA. We investigated LOH of the BRCA1/2 loci in DL samples from BRCA1/2 mutation carriers, while also assessing the effect of DNA quantity. METHODS: DNA yield was estimated using quantitative real-time PCR. Allelic status of DL DNA was determined using fluorescently tagged microsatellite markers with the subject's lymphocytic DNA serving as a control. Samples were scored as consistently heterozygous or as demonstrating LOH if the same result was observed in replicate experiments. Additionally, samples were scored as "discordant LOH" if they initially showed LOH, but in replicate experiments either showed heterozygosity or LOH of the opposite allele. RESULTS: In 11 BRCA1 carriers, 46 ducts were assessable, and 39 ducts from 14 BRCA2 carriers were assessable. LOH was observed in 17% and 18% of ducts from BRCA1 and BRCA2, respectively. Discordant results were seen in 23 BRCA1 (50%) and 15 BRCA2 (38%) samples. DNA yield was significantly greater in samples that were consistently heterozygous than those that were either discordant or showed LOH in replicate experiments for both BRCA1 (P = 0.003) and BRCA2 (P = 0.003). CONCLUSIONS: DNA quantity is highly variable between DL samples, with low yields likely to detrimentally affect the interpretation of LOH. In conclusion, LOH may not be an adequate method to detect the early stages of malignant change in samples obtained via DL.

Prognostic factors predictive of response and survival to a modified FOLFOX regimen: importance of an increased neutrophil count.

PURPOSE: The aim of this study was to identify prognostic indicators of survival and response in a homogeneous population of chemotherapy-naive patients treated with oxaliplatin as part of 3 successive trials. PATIENTS AND METHODS: Patient data were derived from 3 successive phase II trials evaluating modifications of the FOLFOX4 (oxaliplatin/5-fluorouracil/leucovorin) regimen. Clinical and laboratory prognostic factors were identified from the literature. Multifactor analyses stratified by treatment cohort were performed to identify independent prognostic factors for progression-free survival (PFS), overall survival (OS), and response rate. RESULTS: One hundred thirty-four patients were enrolled across all 3 studies. Reduced PFS (n = 128) was associated with patients with the following characteristics: no previous surgery (P = 0.003); previous adjuvant chemotherapy (P = 0.015); > 1 organ involvement (P = 0.001); baseline absolute neutrophil count (ANC) > or = upper limit of normal (P = 0.001); and time from diagnosis to metastases < 9 months (P = 0.043). Poor OS (n = 128) was associated with patients with the following characteristics: performance status > 1 (P < 0.001); > 1 organ involvement (P = 0.018); and baseline ANC > or = upper limit of normal (P < 0.001). Response rate was related to previous surgery (P = 0.017) and performance status (P = 0.02). CONCLUSION: This analysis has identified the additional prognostic importance of an increased ANC for PFS and OS. Further consideration needs to be given to include markers of systemic inflammation such as ANC as well as relevant cytokine levels in a larger cohort of identically treated patients.

A randomized, double-blind, crossover trial of the effect of oxygen on dyspnea in patients with advanced cancer.

Dyspnea is a common symptom in palliative care. Despite this, there is uncertainty regarding the role of oxygen to treat the symptom in patients with advanced illness. This randomized, double-blind, crossover trial examined the effect of oxygen versus air on the relief of dyspnea in patients with advanced cancer. Following the blinded administration of air and oxygen via nasal prongs, 51 patients rated dyspnea and indicated preferences for the blinded treatments. On average, patients improved symptomatically with both air and oxygen, and there were no significant differences between the treatments. The subgroup of 17 hypoxic patients overall did not demonstrate a significant difference between air and oxygen, despite having improved oxygen saturations when administered oxygen. Hypoxia was corrected in 13 of 17 patients using the treatment dose of 4 L/min of oxygen. The experience of dyspnea is a complex, multifactorial phenomenon, with oxygen tension not correlating with the subjective experience. The administration of either air or oxygen via nasal prongs on average confers improvement of the symptom.

A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma.

Preclinical data indicates that cyclooxygenase-2 (COX-2) inhibition impairs plasma cell growth and potentially synergizes with thalidomide. We performed a trial in previously treated patients with myeloma using thalidomide up to a maximum dose of 800 mg/d with celecoxib (400 mg bid). Outcomes were compared with a prior trial of thalidomide. Sixty-six patients with median age of 67 (range, 43-85) received a median dose of thalidomide and celecoxib of 400 and 800 mg/d, respectively, with median durations of treatment of 27 and 13 weeks, respectively. The most common toxicities associated with premature discontinuation of celecoxib (n = 30 of 53, 57%) were fluid retention and deterioration of renal function. Overall response rate (RR) was 42% and with 20 months median follow-up; the actuarial median progression-free survival and overall survival were 6.8 and 21.4 months, respectively. Unlike our prior study, age >65 years was not predictive of inferior RR due to improvement in RR in older patients with the combination (37% versus 15%, P = 0.08). The RR was superior in patients who received a total dose of celecoxib exceeding 40 g in the first 8 weeks of therapy (62% versus 30%, P = 0.021). Progression-free survival and overall survival were also improved. Other predictors for inferior progression-free survival were age >65 years (P = 0.016) and elevated beta(2)-microglobulin (P = 0.017). This study provides evidence that the addition of high-dose celecoxib adds to the antimyeloma activity of thalidomide but this comes with unacceptable toxicity. Future studies should use newer COX-2 inhibitors with thalidomide, or their respective derivatives.

Nipple aspiration and ductal lavage in women with a germline BRCA1 or BRCA2 mutation.

INTRODUCTION: The aim of this study was to collect serial samples of nipple aspirate (NA) and ductal lavage (DL) fluid from women with germline BRCA1/2 mutations in order to create a biorepository for use in identifying biomarkers of breast cancer risk. METHODS: Between March 2003 and February 2005, 52 women with germline BRCA1 or BRCA2 mutations (median age 43 years, range 27 to 65 years) were scheduled for six-monthly NA, DL and venesection. DL was attempted for all NA fluid-yielding (FY) and any non-FY ducts that could be located at each visit. RESULTS: Twenty-seven (52%) women were postmenopausal, predominantly (19/27) from risk reducing bilateral salpingo-oophorectomy (BSO). FY ducts were identified in 60% of all women, 76% of premenopausal women versus 44% of postmenopausal (P = 0.026). Eighty-five percent of women had successful DL. Success was most likely in women with FY ducts (FY 94% versus non-FY 71% (P = 0.049). DL samples were more likely to be cellular if collected from FY ducts (FY 68% versus non-FY 43%; P = 0.037). Total cell counts were associated with FY status (FY median cell count 30,996, range 0 to >1,000,000 versus non-FY median cell count 0, range 0 to 173,577; P = 0.002). Four women (8%) had ducts with severe atypia with or without additional ducts with mild epithelial atypia; seven others had ducts with mild atypia alone (11/52 (21%) in total). Median total cell count was greater from ducts with atypia (105,870, range 1920 to >1,000,000) than those with no atypia (174, 0 to >1,000,000; P

Long-term follow-up of salvage radiotherapy in Hodgkin's lymphoma after chemotherapy failure.

PURPOSE: To evaluate the long-term results of salvage radiotherapy (SRT) for Hodgkin's lymphoma after chemotherapy failure. METHODS AND MATERIALS: We reviewed 81 patients undergoing SRT for persistent or recurrent Hodgkin's lymphoma after chemotherapy; 19 also received conventional-dose salvage chemotherapy. RESULTS: At SRT, the median patient age was 31 years. Of the 81 patients, 81% had Stage I-II, 25.9% had B symptoms, 14.8% had bulky disease, and 7.4% had extranodal disease. A less than a complete response (CR) to the last chemotherapy regimen occurred in 47%. SRT was generally limited to one side of the diaphragm, and the median dose was 36 Gy. After SRT, 75% of patients achieved a CR, with 82% retaining durable in-field control. In-field failure was associated with less than a CR to the last chemotherapy regimen (p = 0.0287). Most failures were at distant sites, with 60% in previously involved sites. The 10-year freedom from treatment failure and overall survival rates were 32.8% and 45.7%, respectively. The adverse prognostic factors for freedom from treatment failure were age >50 years (p < 0.001), B symptoms (p < 0.001), extranodal disease (p = 0.012), and less than a CR to the last chemotherapy regimen (p = 0.001). The adverse prognostic factors for overall survival were male gender (p = 0.034), age >50 years (p < 0.001), B symptoms (p = 0.002), and less than a CR to the last chemotherapy regimen (p = 0.002). Favorable cohorts had a 10-year freedom from treatment failure rate of 51% and overall survival rate of 92%. CONCLUSIONS: Salvage radiotherapy is effective for selected patients with Hodgkin's lymphoma after chemotherapy failure and should be considered for incorporation into salvage programs.

The 'QUAD SHOT'--a phase II study of palliative radiotherapy for incurable head and neck cancer.

BACKGROUND AND PURPOSE: The primary objective of this study was to estimate the rate of tumour response to a cyclical hypofractionated palliative radiotherapy regimen (QUAD SHOT) in previously untreated patients with incurable squamous cell carcinoma of the head and neck. Secondary objectives were to prospectively evaluate toxicity, quality of life (QoL) and survival in these patients. PATIENTS AND METHODS: The QUAD SHOT consisted of 14 Gy in four fractions, given twice a day and at least 6h apart, for 2 consecutive days. This regimen was repeated at 4 weekly intervals for a further two courses if there was no tumour progression. The QoL tool used was an abbreviation of the EORTC QLQ-C30. RESULTS: Thirty eligible patients (29 Stage IV, 20 performance status 2-3) had at least one treatment and 16 patients completed all three cycles. Sixteen patients (53%) had an objective response (2CR, 14PR) and a further seven had stable disease. Median overall survival was 5.7 months, median progression free survival was 3.1 months. The treatment was very well tolerated, with improved QoL in 11 of 25 evaluable patients (44%). CONCLUSION: The QUAD SHOT regimen is an effective palliative treatment with minimal toxicity and a good response rate, which impacts positively on patients' QoL.

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.

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.

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.

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.

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.