Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification.

The features of 100 mixed-phenotype acute leukemias (MPALs), fulfilling WHO 2008 criteria, are documented. Myeloid and T-lineage features were demonstrated by cytoplasmic myeloperoxidase and CD3; B-lineage features were demonstrated by at least 2 B-lymphoid markers. There were 62 men and 38 women; 68% were adults. Morphology was consistent with acute lymphoblastic leukemia (ALL; 43%), acute myeloid leukemia (AML; 42%), or inconclusive (15%). Immunophenotyping disclosed B + myeloid (59%), T + myeloid (35%), B + T (4%), or trilineage (2%) combinations. Cytogenetics evidenced t(9;22)/(Ph(+)) (20%), 11q23/MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes. There was no correlation between age, morphology, immunophenotype, or cytogenetics. Response to treatment and outcome were available for 67 and 70 patients, respectively; 27 received ALL, 34 AML, 5 a combination of ALL + AML therapy, and 1 imatinib. ALL treatment induced a response in 85%, AML therapy in 41%; 3 of 5 patients responded to the combination therapy. Forty (58%) patients died, 33 of resistant disease. Overall median survival was 18 months and 37% of patients are alive at 5 years. Age, Ph(+), and AML therapy were predictors for poor outcome (P < .001; P = .002; P = .003). MPAL is confirmed to be a poor-risk disease. Adults and Ph(+) patients should be considered for transplantation in first remission.

Treatment and outcome of children with relapsed ependymoma: a multi-institutional retrospective analysis.

INTRODUCTION: More than a third of children with ependymoma experience relapse, and despite multimodal treatment, less than 25% of them can then achieve long-term survival. Prognostic factors for patients who relapse have not been extensively analyzed. PATIENTS AND METHODS: We retrospectively analyzed 82 patients from four pediatric oncology European institutions in order to identify prognostic factors and influence of treatment modalities in relapsed ependymoma. RESULTS: First relapse occurred after a median of 19 months (1 month-16 years). Five-year progression-free survival and overall survival of the cohort were 17% and 27.6%, respectively. Survival was statistically significantly higher for patients achieving gross total resection. No survival benefit was seen for children receiving chemotherapy whereas patients who were amenable to some form of re-irradiation had a better outcome. Objective responses were found in more than 25% of patients receiving oral etoposide, temozolomide, or vincristine/etoposide/cyclophosphamide regimens. Multivariate analysis confirmed that patients with mixed relapses, no surgery at relapse, and receiving chemotherapy did worse (hazard ratio = 3.6, 3.3, and 1.7, respectively, all p < 0.05). DISCUSSION: Relapsed ependymoma carries a very poor prognosis with an indolent chronic course, leading to death in approximately 90% of the patients. Complete surgical resection whenever possible should be encouraged. Radiation therapy of the relapsed lesions can provide some minor benefit whereas chemotherapy despite the occasional responses provides no benefit in the final outcome which is dismal. Efforts have to be orchestrated internationally to enroll these patients on clinical trials using biology-based therapies.

Clinical benefit of second-line palliative chemotherapy in advanced soft-tissue sarcoma.

Background. This paper aimed to assess the utility of second-line chemotherapy in patients with advanced soft-tissue sarcoma. Materials and Methods. A retrospective search of a prospectively maintained database identified patients treated between 1991 and 2005. Patients with gastrointestinal stromal tumours, small round cell tumours, and Ewing's sarcoma were excluded. Response was assessed using WHO and RECIST. Patients who achieved stable disease for 6 months or more were classified as having disease control. Results. Three hundred and seventy-nine patients received second-line chemotherapy. Eighty-six (22.7%) achieved disease control. Median duration of response was 11 months (95% CI: 9-13). On multivariate analysis, pathological subtype, absence of lung metastases, and the use of combination chemotherapy were independent predictors of disease control. Twenty-eight (16.1%) patients who failed to respond to first-line therapy achieved disease control. Eight (2.1%) patients had sufficient downstaging to enable complete surgical resection. Progression-free survival was 23% at 6 months. Median overall survival was 8 months (95% CI: 7-10 months). On multivariate analysis, synovial histology and absence of lung metastases were associated with improved survival. Conclusion. Second-line chemotherapy can provide clinical benefit in over 20% of soft-tissue sarcoma patients.

Dyspnea in Patients Receiving Radical Radiotherapy for Non-Small Cell Lung Cancer: A Prospective Study.

BACKGROUND AND PURPOSE: Dyspnea is an important symptomatic endpoint for assessment of radiation-induced lung injury (RILI) following radical radiotherapy in locally advanced disease, which remains the mainstay of treatment at the time of significant advances in therapy including combination treatments with immunotherapy and chemotherapy and the use of local ablative radiotherapy techniques. We investigated the relationship between dose-volume parameters and subjective changes in dyspnea as a measure of RILI and the relationship to spirometry. MATERIAL AND METHODS: Eighty patients receiving radical radiotherapy for non-small cell lung cancer were prospectively assessed for dyspnea using two patient-completed tools: EORTC QLQ-LC13 dyspnea quality of life assessment and dyspnea visual analogue scale (VAS). Global quality of life, spirometry and radiation pneumonitis grade were also assessed. Comparisons were made with lung dose-volume parameters. RESULTS: The median survival of the cohort was 26 months. In the evaluable group of 59 patients there were positive correlations between lung dose-volume parameters and a change in dyspnea quality of life scale at 3 months (V30 p=0.017; V40 p=0.026; V50 p=0.049; mean lung dose p=0.05), and a change in dyspnea VAS at 6 months (V30 p=0.05; V40 p=0.026; V50 p=0.028) after radiotherapy. Lung dose-volume parameters predicted a 10% increase in dyspnea quality of life score at 3 months (V40; p=0.041, V50; p=0.037) and dyspnea VAS score at 6 months (V40; p=0.027) post-treatment. CONCLUSIONS: Worsening of dyspnea is an important symptom of RILI. We demonstrate a relationship between lung dose-volume parameters and a 10% worsening of subjective dyspnea scores. Our findings support the use of subjective dyspnea tools in future studies on radiation-induced lung toxicity, particularly at doses below conventional lung radiation tolerance limits.

90-Days mortality rate in patients treated within the context of a phase-I trial: how should we identify patients who should not go on trial?

BACKGROUND: The primary objectives of phase-I trials include the definition of drug toxicities and the recommendation of phase-II doses. In order to safeguard the well-being of its participants, a common inclusion criterion is that of life expectancy >3 months. However, previous studies have shown that about 20% of these patients do not survive beyond this time-point. METHODS: We identified 97 patients who died within the first 90 days of treatment out of a total of 654 consecutively treated phase-I patients, from June 2003 to June 2007. This cohort was compared to a control group comprising 215 patients who lived >90 days on phase-I studies and were treated from January 2005 to June 2006. RESULTS: In keeping with our recently reported phase-I survival risk score, multivariate analysis demonstrated that patients who died within the first 90 days had lower albumin (p=0.010), greater number of metastatic sites (p=0.00001) and higher frequency of elevated LDH (p=0.0002). This analysis also showed that 86% of patients who died during the first 90 days had an increased risk score of 2/3 compared to 39% in the control group. Furthermore, three additional factors were identified, namely younger age (p=0.024), higher white cell count (p=0.028) and poorer ECOG PS (p=0.012) but the addition of these did not improve the ability to predict 90-day mortality compared to the afore-mentioned risk score. CONCLUSIONS: There is good evidence that our easily derivable scoring system provides an objective method to identify patients with a very limited life expectancy in whom participation in phase-I trials should be carefully evaluated.

Erlotinib, docetaxel, and gefitinib in sequential cohorts with relapsed non-small cell lung cancer.

BACKGROUND: Both docetaxel and erlotinib improve overall survival over best supportive care in non-small cell lung cancer (NSCLC). We assessed the effectiveness of erlotinib (E) and gefitinib (G) in patients with relapsed NSCLC in both second- and third-line settings, and compared this with that of docetaxel (D), in our clinical practice. METHODS: Sequential cohorts of patients with relapsed advanced stage NSCLC who had been treated with erlotinib (150 mg), gefitinib (250 mg), or docetaxel (75 mg/m(2)) were retrospectively identified from our database. The primary endpoint was overall survival. Secondary endpoints were response rate and progression-free survival. RESULTS: After adjusting for covariates, there was no significant difference in overall survival between the three drugs in both second-line (median E=24; G=25; D=43 weeks, p=0.17), and third-line (median E=31; G=24; D=29 weeks, p=0.61) settings. Response rates were also not statistically significant between the three drugs across both lines of treatment. CONCLUSIONS: Erlotinib, gefitinib, and docetaxel have similar effectiveness in this non-trial setting.

Hypofractionated stereotactic radiotherapy in the management of recurrent or residual medulloblastoma/PNET.

PURPOSE: To evaluate the efficacy and toxicity of hypofractionated stereotactic radiotherapy in the management of locally recurrent or residual central nervous system (CNS) primitive neuroectodermal tumors (PNETs). PATIENTS AND METHODS: Between 1991 and 2005, 12 patients with locally recurrent medulloblastoma and two patients with residual supratentorial PNET were treated with hypofractionated stereotactic conformal radiotherapy (SCRT). Nine patients were treated for first recurrence, two patients after the 2nd, and one patient after 3rd recurrence. Median age at diagnosis was 20 years (range: 4-35 years) and median age at SCRT 25 years (range: 7-41 years). Nine of 12 patients underwent resection at recurrence and 13 patients received at least one cycle of chemotherapy prior to SCRT. All received focal SCRT (30-40 Gy/6-8 #) using non-coplanar arcs (n = 6) or fixed conformal non-coplanar fields (n = 8). RESULTS: Median overall survival was 29 months (95% CI: 6-51 months) and median progression-free survival was 12 months (95% CI: 5-19 months). Local progression-free survival at 1 and 3 years was 80% (95% CI: 55-100%) and 48% (95% CI: 11-85%). Causes of death were recurrent CNS disease (n = 7), herpes encephalitis (n = 1), and metastatic PNET outside the CNS (n = 1). CONCLUSION: Hypofractionated SCRT provides effective local control with acceptable toxicity for patients with recurrent localized PNET. However, overall long-term disease control is rare and limited by the occurrence of CSF mediated relapses, which thus could benefit from intensive systemic chemotherapy as part of the primary relapse strategy even in local recurrences. Larger multi-national studies will be necessary to assess the value of such combined treatment approaches.

Time trends in the outcome of elderly patients with breast cancer.

Mortality rates for breast cancer are improving in most countries. Life expectancy is also improving, and as age is the major risk factor for the development of breast cancer, we sought to determine whether survival of elderly women with breast cancer has improved over the past 20 years in our institution. In a retrospective study using a prospectively maintained database, we identified 950 women aged > or =70 years diagnosed with breast cancer between 1980 and 2000. Overall survival of patients was compared between two different time cohorts--those diagnosed from 1980 to 1990 and from 1991 to 2000--and between three age cohorts, 70-74, 75-79, and 80+ years. In all age groups, advanced stage, the need for mastectomy, and having chemotherapy were associated with a worse outcome on univariate analysis. Endocrine therapy (tamoxifen) was given to 60-70% of all age groups. After adjustment for clinical stage, we found no significant improvement in survival between the two time cohorts in any age groups. Compared with an age-matched group in the general population, these elderly breast cancer patients have a 62% increased risk of death. The results are likely to reflect lack of data to promote treatment guidelines. More clinical trials for older women are needed, if the benefits of recent advances in the management of this disease are to be extended to the over 70s. These data should, however, act as a benchmark for future audits.

A study to look at the effects of a hydrolat spray on hot flushes in women being treated for breast cancer.

Women undergoing treatment for breast cancer may experience hot flushes, which greatly impact on quality of life. The use of water sprays or moist wipes to lower skin temperature is often recommended. A peppermint and neroli hydrolat spray was compared to a plain water spray to assess which was preferred, in a single-blind randomised control crossover trial. Only 18 of the 44 patients (41%) preferred the hydrolat spray to a plain water spray, which was less than the 80% required to offer this spray as a standard suggestion for hot flush management. However a small number of those choosing it found it extremely helpful. Both sprays appeared to lessen hot flush annoyance. Previous chemotherapy appeared to be a factor influencing the choice of spray.

BRCA1/BRCA2 mutation status and analysis of cancer family history in participants of the Royal Marsden Hospital tamoxifen chemoprevention trial.

We have analysed the pedigrees of all 70 women who developed cancer in the Royal Marsden Hospital (RMH) tamoxifen chemoprevention trial, using the Claus model, to assess breast cancer susceptibility heterozygote risk (HR) and screened the entire coding regions of BRCA1 and 2 genes in 62 of these cases. We found a reduced incidence of breast cancers developing on tamoxifen in women who have a lower HR, but not in women with higher HR. There were too few BRCA1/2 mutations (4 cases) to be able to determine the efficacy of tamoxifen by BRCA status. Immunohistochemical analysis showed a significantly lower frequency of median ER (p=0.03) in the cancers developing in tamoxifen-treated patients. These results suggest that tamoxifen is less likely to be effective at reducing breast cancers which are ER negative and also in some individuals at higher HR.

Factors determining outcome after third line chemotherapy for metastatic breast cancer.

Patients with metastatic breast cancer (MBC) are increasingly offered third line chemotherapy. We have reviewed the response rate (RR), time to progression (TTP) and survival of 149 patients in this setting and have investigated factors that influence their outcome. The RR, TTP and survival were 30%, 4 and 8 months, respectively, and should serve as a benchmark for future studies. Response to previous chemotherapy was the only independent variable predicting RR, TTP and survival, p=0.025, 0.04 and 0.004, respectively. Thirty-two percent of patients did not respond to the first two lines of chemotherapy and had a lower RR and a significantly shorter TTP and survival. In conclusion, third line chemotherapy for MBC is sometimes effective in patients who have responded to previous chemotherapy. Patients who do not respond to the first two lines of chemotherapy should be considered for clinical trials or supportive care.

Combined use of diffusion-weighted MRI and 1H MR spectroscopy to increase accuracy in prostate cancer detection.

OBJECTIVE: The objective of our study was to establish the sensitivity and specificity for prostate cancer detection using a combined 1H MR spectroscopy and diffusion-weighted MRI approach. SUBJECTS AND METHODS: Forty-two men (mean age +/- SD, 69.3 +/- 4.7 years) with prostate cancer were studied using endorectal T2-weighted imaging, 2D chemical shift imaging (CSI), and isotropic apparent diffusion coefficient (ADC) maps. Regions of interest (ROIs) were drawn around the entire gland, central gland, and peripheral zone tumor, diagnostically defined as low signal intensity on T2-weighted images within a sextant that was biopsy-positive for tumor. Lack of susceptibility artifact on a gradient-echo B0 map through the slice selected for CSI and no high signal intensity on external array T1-weighted images confirmed the absence of significant hemorrhage after biopsy. CSI voxels were classified as nonmalignant or as tumor (ROI included > or = 30% or > or = 70% tumor). Choline-citrate (Cho/Cit) ratios and average ADCs were calculated for every voxel. A plot of Cho/Cit ratios versus ADCs yielded a line of best separation of tumor voxels from nonmalignant voxels. Receiver operating characteristic (ROC) curves were plotted for Cho/Cit ratios alone, ADCs alone, and a combination of the two. RESULTS: The Cho/Cit ratios were significantly higher (p < 0.001) and the ADCs were significantly lower (p < 0.006) in tumor-containing voxels than in non-tumor-containing voxels. When voxels containing 30% or more tumor were considered positive, the area under the ROC curves using combined MR spectroscopy and ADC (0.81) was similar to that of Cho/Cit alone (0.79) and better than ADC alone (0.66). When voxels containing 70% or more tumor were considered positive and cutoffs to achieve a 90%-or-greater sensitivity chosen, a combination of Cho/Cit and ADC achieved a significant improvement in specificity compared with Cho/Cit alone (p < 0.0001) or ADC alone (p < 0.0001). CONCLUSION: When voxels containing > or = 70% tumor are considered positive, the combined use of MR spectroscopy and diffusion-weighted MRI increases the specificity for prostate cancer detection while retaining the sensitivity compared with MR spectroscopy alone or diffusion-weighted MRI alone.

Late toxicity is not increased in BRCA1/BRCA2 mutation carriers undergoing breast radiotherapy in the United Kingdom.

PURPOSE: To undertake the first substantial clinical study of breast radiotherapy toxicity in BRCA1 and BRCA2 mutation carriers in the United Kingdom. EXPERIMENTAL DESIGN: Acute and late radiation effects were evaluated in a retrospective study of 55 BRCA1 and BRCA2 mutation carriers treated with radiotherapy for breast cancer at four centers between 1983 and 2002. Individual matching with controls who had sporadic breast cancer was undertaken for age at diagnosis, time since completion of radiation, and treatment variables. Detailed assessments were undertaken by one examiner. Median follow-up was 6.75 years for carriers and 7.75 years for controls. Rates of late events (rib fractures, lung fibrosis, necrosis of soft tissue/bone, and pericarditis) as well as LENT-SOMA scores and clinical photography scores of breast size, shape, and skin telangiectasia were the primary end points. RESULTS: No increase in clinically significant late toxicity was seen in the mutation carriers. CONCLUSIONS: These data add substantial weight to the evidence that the outcomes in the treated breast from radiotherapy in women with BRCA1 or BRCA2 mutations are comparable with those in women with sporadic breast cancer.

Acute chemotherapy-related toxicity is not increased in BRCA1 and BRCA2 mutation carriers treated for breast cancer in the United Kingdom.

PURPOSE: To evaluate acute toxicity induced by chemotherapy for breast cancer in a retrospective study of 62 BRCA1/2 mutation carriers matched 1:1 with women who had treatment for sporadic disease in the United Kingdom between 1983 and 2003. EXPERIMENTAL DESIGN: All participants were interviewed by one of two researchers using standardized questionnaires, and their medical records were reviewed by one research nurse. The two main regimens received were cyclophosphamide, methotrexate, and fluorouracil and fluorouracil, epirubicin, and cyclophosphamide. The proportion of cases and controls receiving anthracycline-based treatment was equivalent, but fewer BRCA1 cases received this treatment than did BRCA2 mutation carriers. Toxicity was documented using the Eastern Cooperative Oncology Group Common Toxicity Criteria for hematologic, infective, and gastrointestinal toxicities. No increase in toxicity was seen in BRCA1/2 mutation carriers. RESULTS: The only significant difference was that neutropenia was less evident in BRCA2 mutation carriers than in either BRCA1 mutation carriers or controls. As a result, there was no requirement for dose reduction among BRCA2 mutation carriers, in contrast to 10 of 39 BRCA1 carriers and 16 of 62 controls (P = 0.02). CONCLUSIONS: This result has implications for therapy and indicates that women with mutations in BRCA1 and BRCA2 may be given the same doses of chemotherapy as noncarriers.

Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026].

INTRODUCTION: Experimental and clinical data show that the oral bisphosphonate clodronate (Bonefos) can inhibit tumor-induced osteoclastic bone resorption. This randomized, double-blind, placebo-controlled, multicenter trial was designed to determine if the addition of oral clodronate to standard treatment for primary operable breast cancer could reduce the subsequent occurrence of bone metastases and thereby improve overall survival. METHODS: 1,069 patients with primary operable stage I-III breast cancer were randomized to receive oral clodronate (1,600 mg/day) or placebo for 2 years, in conjunction with standard treatment for primary breast cancer including surgery, radiotherapy, adjuvant chemotherapy, and/or tamoxifen. All patients were assessed for bone metastases at two and five years and additionally when clinically indicated. Survival status was determined as of the close of the study on 30 June 2000 with a median follow up of 5.6 years. The treatment arms were compared using the unstratified log-rank test. Hazard ratios (HRs) with 95% confidence intervals were calculated. RESULTS: Oral clodronate significantly reduced the risk of bone metastases in all patients over the 5 year study period (51 patients versus 73 patients with placebo; HR = 0.692, P = 0.043); the difference was also statistically significant over the 2 year medication period (19 patients versus 35 patients with placebo; HR = 0.546, P = 0.031). These differences were most pronounced in patients with stage II/III disease (39 patients versus 64 patients with placebo, HR = 0.592, P = 0.009 over 5 years; 16 patients versus 32 patients with placebo, HR= 0.496, P = 0.020 over 2 years). Survival data also favoured the clodronate arm (HR for all patients = 0.768, P = 0.048; HR for stage II/III disease = 0.743, P = 0.041), although this was not significant due to multiple analyses. Oral clodronate was well tolerated, with mild-to-moderate diarrhoea being the most frequently reported adverse event. CONCLUSION: These results confirm that oral clodronate will significantly improve the 5 year bone relapse free survival when used as a supplementary adjuvant treatment for patients receiving standard treatment for primary operable breast cancer.

Site of relapse after chemotherapy alone for stage I and II Hodgkin's disease.

BACKGROUND: Short course chemotherapy followed by radiotherapy is a standard treatment for early Hodgkin's disease. There is yet no consensus regarding the appropriate radiotherapy portal following chemotherapy. A good guide to the adjuvant radiotherapy field is the site of relapse in patients treated with chemotherapy alone. PATIENTS AND METHODS: From 1980 to 1996, 61 patients with stage I and II supradiaphragmatic Hodgkin's disease were treated with chemotherapy alone at the Royal Marsden Hospital. We undertook a retrospective review and failure analysis to define the pattern of recurrence. RESULTS: After a median follow-up of 6.5 years, 24 patients had relapsed giving a 5-year relapse rate of 40%. The 5 and 10-year actuarial survival rates were 94 and 89%, respectively with cause-specific survival being 94% at 5 and 10 years. Two-thirds of the relapses were nodal and supradiaphragmatic. Twenty patients (83%) relapsed in the initially involved sites of disease and this was the sole site of recurrence in 11 (45%) of patients. In retrospect, it appeared that at least 12 recurrences could have been prevented by involved field radiotherapy. Review of detailed imaging data (available in 9 out of 11 patients with recurrences in initial sites of disease) showed that the relapses were always in the initially involved nodes. CONCLUSION: After chemotherapy alone in early stage HD most initial recurrences are nodal. Loco-regional recurrences are in the originally involved nodes. Based on limited data it appears that involved nodal RT is equivalent to involved field radiotherapy and may halve the risk of recurrence.

Comparison of forward planning with automated inverse planning for three-dimensional conformal radiotherapy of non-small cell lung cancer without IMRT.

The forward and inverse treatment plans of 10 patients with lung cancer were compared in terms of PTV coverage, sparing of normal lung and time required to generate a plan. The inverse planning produced as good treatment plans as an experienced dosimetrist with considerable reduction in staff time. When translated to other complex sites, inverse non-IMRT planning may have considerable impact on manpower requirements.

The association of chemotherapy induced neutropenia on treatment outcomes in small cell lung cancer.

BACKGROUND: Chemotherapy induced neutropenia has been shown to be associated with improved treatment outcomes in selected solid tumours. We studied the association of chemotherapy induced neutropenia with treatment related outcomes in small cell lung cancer (SCLC). METHODS: This is a retrospective analysis of patients receiving chemotherapy for SCLC at the Royal Marsden Hospital, UK over an 8 year period. The chemotherapy included Carboplatin AUC 5, IV and Etoposide 100mg/m(2) IV on day 1 and 100mg/m(2) PO, B.I.D. on day 2 and 3 every 21 days. Patients were stratified into two groups (A) those experiencing grades 0-2 neutropenia and group (B) those experiencing grades 3-4 neutropenia. The outcomes studied were response rate, time to progression (TTP) and overall survival (OS). RESULTS: 173 patients were studied. The median age 64 (range 39-83) and M/F ratio was 112:61. The response rates in groups A and B was 90% versus 90%, p=1.0. The median TTP in groups A and B was 30 and 38 weeks, p=0.05. The median OS in groups A and B was 47 weeks versus 60 weeks, p=0.008. The differences in TTP and OS were not significant in patients with extensive stage disease. CONCLUSIONS: Occurrence of chemotherapy induced grade 3 or 4 neutropenia correlated with OS in patients with SCLC receiving carboplatin and etoposide chemotherapy. Trials exploring controlled, safe intra-patient dose escalation with the intent of achieving grade 3 or 4 neutropenia in patients with SCLC are warranted.