Showing papers in "Lancet Oncology in 2006"
TL;DR: Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma.
Abstract: Summary Background 5-aminolevulinic acid is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent porphyrins in malignant gliomas—a finding that is under investigation for intraoperative identification and resection of these tumours. We aimed to assess the effect of fluorescence-guided resection with 5-aminolevulinic acid on surgical radicality, progression-free survival, overall survival, and morbidity. Methods 322 patients aged 23–73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670. Findings Median follow-up was 35·4 months (95% CI 1·0–56·7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17–40], p vs 21·1% [14·0–28·2]; difference between groups 19·9% [9·1–30·7], p=0·0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery. Interpretation Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma.
2,838 citations
TL;DR: Rituximab added to six cycles of CHOP is an effective treatment for young patients with good-prognosis diffuse large-B-cell lymphoma and the definition of two prognostic subgroups allows for a more refined therapeutic approach for these patients.
Abstract: Summary Background The role of rituximab in combination with diff erent CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy regimens in young patients with good-prognosis diff use large-B-cell lymphoma remains to be defi ned. We aimed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients. Methods 824 patients who were from 18 countries; aged 18–60 years; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index (IPI), stage II–IV disease, or stage I disease with bulk were enrolled. These patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n=413) or to six cycles of CHOP-like chemotherapy alone (n=411). Bulky and extranodal sites received additional radiotherapy. The primary endpoint was event-free survival; secondary endpoints were response, progression under therapy, progression-free survival, overall survival, and frequency of toxic eff ects. Analyses were done by intention to treat and per protocol. This trial is registered at http://www.clinicaltrials.gov, NCT 00064116. Findings After a median follow-up of 34 months (range 0·03–61), patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone (79% [95% CI 75–83] vs 59% [54–64]; diff erence between groups 20% [13–27], log-rank p<0·0001), and had increased 3-year overall survival (93% [90–95] vs 84% [80–88]; diff erence between groups 9% [3–13], log-rank p=0·0001). Event-free survival was aff ected by treatment group, presence of bulky disease, and age-adjusted IPI: after chemotherapy and rituximab, a favourable subgroup (ie, IPI=0, no bulk) could be defi ned from a less-favourable subgroup (ie, IPI=1 or bulk, or both). Groups did not diff er in the frequency of adverse events.
1,850 citations
TL;DR: Radical nephrectomy is a significant risk factor for the development of chronic kidney disease and might no longer be regarded as the gold standard treatment for small, renal cortical tumours.
Abstract: Summary Background Chronic kidney disease is a graded and independent risk factor for substantial comorbidity and death. We aimed to examine new onset of chronic kidney disease in patients with small, renal cortical tumours undergoing radical or partial nephrectomy. Methods We did a retrospective cohort study of 662 patients with a normal concentration of serum creatinine and two healthy kidneys undergoing elective partial or radical nephrectomy for a solitary, renal cortical tumour (≤4 cm) between 1989 and 2005 at a referral cancer centre. Glomerular filtration rate (GFR) was estimated with the abbreviated Modification in Diet and Renal Disease Study equation. Separate analysis was undertaken, with chronic kidney disease defined as GFR lower than 60 mL/min per 1·73 m 2 and GFR lower than 45 mL/min per 1·73 m 2 . Findings 171 (26%) patients had pre-existing chronic kidney disease before surgery. After surgery, the 3-year probability of freedom from new onset of GFR lower than 60 mL/min per 1·73 m 2 was 80% (95% CI 73–85) after partial nephrectomy and 35% (28–43; p 2 were 95% (91–98) and 64% (56–70; p 2 (hazard ratio 3·82 [95% CI 2·75–5·32]) and 45 mL/min per 1·73 m 2 (11·8 [6·24–22·4]; both p Interpretation Because the baseline kidney function of patients with renal cortical tumours is lower than previously thought, accurate assessment of kidney function is essential before surgery. Radical nephrectomy is a significant risk factor for the development of chronic kidney disease and might no longer be regarded as the gold standard treatment for small, renal cortical tumours.
1,422 citations
TL;DR: Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy.
Abstract: Summary Background Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer (NSCLC) is not known. We aimed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC. Methods 840 patients with stage IB–IIIA NSCLC from 101 centres in 14 countries were randomly assigned to observation (n=433) or to 30 mg/m 2 vinorelbine plus 100 mg/m 2 cisplatin (n=407). Postoperative radiotherapy was not mandatory and was undertaken according to every centre's policy. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN95053737. Findings 367 patients in the chemotherapy group and 431 in the control group received their assigned treatment. 301 (36%) patients had stage IB disease, 203 (24%) had stage II disease, and 325 (39%) had stage IIIA disease. Tolerance to chemotherapy mainly included neutropenia in 335 (92%) patients and febrile neutropenia in 34 (9%); seven (2%) toxic deaths were also recorded. Compliance was greater with cisplatin than with vinorelbine (median dose intensity 89% [range 17–108] vs 59% [17–100]). After a median follow-up of 76 months (range 43–116), median survival was 65·7 months (95% CI 47·9–88·5) in the chemotherapy group and 43·7 (35·7–52·3) months in the observation group. Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls (hazard ratio 0·80 [95% CI 0·66–0·96]; p=0·017). Overall survival at 5 years with chemotherapy improved by 8·6%, which was maintained at 7 years (8·4%). Interpretation Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy.
1,412 citations
TL;DR: Early ADT benefits patients with nodal metastases who have undergone prostatectomy and lymphadenectomy compared with those who receive deferred treatment, and the beneficial effects of early ADT, rather than an imbalance in risk factors, are likely to explain the differences in outcomes.
Abstract: Summary Background Appropriate timing of androgen deprivation treatment (ADT) for prostate cancer is controversial. Our aim was to determine whether immediate ADT extends survival in men with node-positive prostate cancer who have undergone radical prostatectomy and pelvic lymphadenectomy compared with those who received ADT only once disease progressed. Methods Eligible patients from 36 institutes in the USA were randomly assigned in 1988–93 to receive immediate ADT (n=47) or to be observed (n=51), with ADT to be given on detection of distant metastases or symptomatic recurrences. Patients were followed up every 3 months for the first year and every 6 months thereafter. The primary endpoint was progression-free survival; secondary endpoints were overall and disease-specific survival. Analysis was by intention to treat. To ensure that the treatment groups were comparable, we did a retrospective central pathology review of slides and regraded the Gleason scores for available samples. This trial predates the requirement for clinical trial registration. Findings At median follow-up of 11·9 years (range 9·7–14·5 for surviving patients), men assigned immediate ADT had a significant improvement in overall survival (hazard ratio 1·84 [95% CI 1·01–3·35], p=0·04), prostate-cancer-specific survival (4·09 [1·76–9·49], p=0·0004), and progression-free survival (3·42 [1·96–5·98], p Interpretation Early ADT benefits patients with nodal metastases who have undergone prostatectomy and lymphadenectomy, compared with those who receive deferred treatment. The beneficial effects of early ADT, rather than an imbalance in risk factors, are likely to explain the differences in outcomes between treatments.
832 citations
TL;DR: Investigating the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma found it can be used to improve the outcome of patients with high-risk medullOBlastoma.
Abstract: Summary Background Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. Methods After resection, patients were classified as having average-risk medulloblastoma (≤1·5 cm 2 residual tumour and no metastatic disease) or high-risk medulloblastoma (>1·5 cm 2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23·4 Gy for average-risk disease and 36·0–39·6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. Findings Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75–94) in patients in the average-risk group and 70% (54–84) in those in the high-risk group (p=0·04); 5-year event-free survival was 83% (73–93) and 70% (55–85), respectively (p=0·046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0·04): 84% (74–95) for classic histology, 77% (49–100) for desmoplastic tumours, and 57% (33–80) for large-cell anaplastic tumours. Interpretation Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.
763 citations
TL;DR: A review of the new results in this specialty will be presented here, and an increased understanding of the oncogenic potential of galactic cosmic rays is focussed on.
Abstract: Space programmes are shifting toward planetary exploration, and in particular towards missions by human beings to the moon and Mars. However, exposure to space radiation is an important barrier to exploration of the solar system by human beings because of the biological effects of high-energy heavy ions. These ions have a high charge and energy, are the main contributors to radiation risk in deep space, and their biological effects are understood poorly. Predictions of the nature and magnitude of risks posed by exposure to radiation in space are subject to many uncertainties. In recent years, worldwide efforts have focussed on an increased understanding of the oncogenic potential of galactic cosmic rays. A review of the new results in this specialty will be presented here.
613 citations
TL;DR: In the absence of a phase III study, this new combined treatment should be regarded as the standard of care for epithelial appendiceal neoplasms and pseudomyxoma peritonei syndrome.
Abstract: Appendiceal mucinous neoplasms sometimes present with peritoneal dissemination, which was previously a lethal condition with a median survival of about 3 years. Traditionally, surgical treatment consisted of debulking that was repeated until no further benefit could be achieved; systemic chemotherapy was sometimes used as a palliative option. Now, visible disease tends to be removed through visceral resections and peritonectomy. To avoid entrapment of tumour cells at operative sites and to destroy small residual mucinous tumour nodules, cytoreductive surgery is combined with intraperitoneal chemotherapy with mitomycin at 42 degrees C. Fluorouracil is then given postoperatively for 5 days. If the mucinous neoplasm is minimally invasive and cytoreduction complete, these treatments result in a 20-year survival of 70%. In the absence of a phase III study, this new combined treatment should be regarded as the standard of care for epithelial appendiceal neoplasms and pseudomyxoma peritonei syndrome.
580 citations
TL;DR: D3 nodal dissection, compared with that of D1, offers a survival benefit for patients with gastric cancer when done by well trained, experienced surgeons.
Abstract: Summary Background The survival benefit and morbidity after nodal dissection for gastric cancer remains controversial. We aimed to do a single-institution randomised trial to compare D1 (ie, level 1) lymphadenectomy with that of D3 (ie, levels 1, 2, and 3) dissection for gastric cancer in terms of overall survival and disease-free survival. Methods From Oct 7, 1993, to Aug 12, 1999, 335 patients were registered. 221 patients were eligible, 110 of whom were randomly assigned D1 surgery and 111 of whom were randomly assigned D3 surgery, both with curative intent. Three participating surgeons had done at least 25 independent D3 dissections before the start of the trial, and every procedure was verified by pathological analyses. The primary endpoints were 5-year overall survival and 5-year disease-free survival. We also analysed risk of recurrence. Main analyses were done by intention to treat. This trial is registered at the US National Institute of Health website http://www.clinicaltrials.gov/ct/show/NCT00260884. Findings Median follow-up for the 110 (50%) survivors was 94·5 months (range 62·9–135·1). Overall 5-year survival was significantly higher in patients assigned D3 surgery than in those assigned D1 surgery (59·5% [95% CI 50·3–68·7] vs 53·6% [44·2–63·0]; difference beteween groups 5·9% [−7·3 to 19·1], log-rank p=0·041). 215 patients who had R0 resection (ie, no microscopic evidence of residual disease) had recurrence at 5 years of 50·6% [41·1–60·2] for D1 surgery and 40·3% [30·9–49·7] for D3 surgery (difference between groups 10·3% [−3·2 to 23·7], log-rank p=0·197). Interpretation D3 nodal dissection, compared with that of D1, offers a survival benefit for patients with gastric cancer when done by well trained, experienced surgeons.
573 citations
TL;DR: It is shown that despite an increase in the delivery of cancer services via this method, research showing the effectiveness of MDT working is scarce.
Abstract: Cancer care can be complex, and given the wide range and numbers of health-care professionals involved, an enormous potential for poor coordination and miscommunication exists. Multidisciplinary teams (MDTs) should improve coordination, communication, and decision making between health-care team members and patients, and hopefully produce more positive outcomes. This review describes the many practical barriers to the successful implementation of MDT working, and shows that despite an increase in the delivery of cancer services via this method, research showing the effectiveness of MDT working is scarce.
545 citations
TL;DR: Overall cancer risk was significantly associated with a doubling of 24-h cadmium excretion, and historical pollution from non-ferrous smelters continues to present a serious health hazard, necessitating targeted preventive measures.
Abstract: Summary Background Cadmium is a ubiquitous environmental pollutant, which accumulates in the human body such that 24-h urinary excretion is a biomarker of lifetime exposure. We aimed to assess the association between environmental exposure to cadmium and cancer. Methods We recruited a random population sample (n=994) from an area close to three zinc smelters and a reference population from an area with low exposure to cadmium. At baseline (1985–89), we measured cadmium in urine samples obtained over 24 h and in the soil of participants' gardens, and followed the incidence of cancer until June 30, 2004. We used Cox regression to calculate hazard ratios for cancer in relation to internal (ie, urinary) and external (ie, soil) exposure to cadmium, while adjusting for covariables. Findings Cadmium concentration in soil ranged from 0·8 mg/kg to 17·0 mg/kg. At baseline, geometric mean urinary cadmium excretion was 12·3 nmol/day for people in the high-exposure area, compared with 7·7 nmol/day for those in the reference (ie, low-exposure) area (p Interpretation Historical pollution from non-ferrous smelters continues to present a serious health hazard, necessitating targeted preventive measures.
TL;DR: This work appraised the consistency between protocols in terms of eligibility criteria, definition and assessment of response and progression, statistical design, and endpoints, and suggested a survival benefit with some strategies.
Abstract: Summary Diffuse intrinsic brainstem gliomas constitute 15–20% of all CNS tumours in children, and are the main cause of death in children with brain tumours. Many clinical trials have been done over the past three decades, but survival has remained static. More than 90% of children die within 2 years of diagnosis, and conventional fractionated radiation remains the standard treatment. However, median survival differs substantially between clinical trials, suggesting a survival benefit with some strategies. We appraised the consistency between protocols in terms of eligibility criteria, definition and assessment of response and progression, statistical design, and endpoints. Study designs varied substantially, which could explain the differences in outcome, and no treatment has shown a benefit over conventional radiotherapy. However, consistency between protocols (eg, eligibility criteria and outcome measures) is important to measure the progress in management of diffuse pontine gliomas.
TL;DR: An overview of the use of clinically applicable nanoparticles in oncology, with particular focus on the diagnosis and treatment of breast cancer, is given.
Abstract: The biological application of nanoparticles is a rapidly developing area of nanotechnology that raises new possibilities in the diagnosis and treatment of human cancers. In cancer diagnostics, fluorescent nanoparticles can be used for multiplex simultaneous profiling of tumour biomarkers and for detection of multiple genes and matrix RNA with fluorescent in-situ hybridisation. In breast cancer, three crucial biomarkers can be detected and accurately quantified in single tumour sections by use of nanoparticles conjugated to antibodies. In the near future, the use of conjugated nanoparticles will allow at least ten cancer-related proteins to be detected on tiny tumour sections, providing a new method of analysing the proteome of an individual tumour. Supermagnetic nanoparticles have exciting possibilities as contrast agents for cancer detection in vivo, and for monitoring the response to treatment. Several chemotherapy agents are available as nanoparticle formulations, and have at least equivalent efficacy and fewer toxic effects compared with conventional formulations. Ultimately, the use of nanoparticles will allow simultaneous tumour targeting and drug delivery in a unique manner. In this review, we give an overview of the use of clinically applicable nanoparticles in oncology, with particular focus on the diagnosis and treatment of breast cancer.
TL;DR: Breast cancer tissue is probably just as sensitive to fraction size as dose-limiting healthy tissues, and radiotherapy schedules can be greatly simplified by the delivery of fewer, larger fractions without compromising effectiveness or safety, and possibly improving both.
Abstract: Summary Background Standard curative schedules of radiotherapy to the breast deliver 25 fractions of 2·0 Gy over 5 weeks. In a randomised trial, we tested whether fewer, larger fractions were at least as safe and as effective as standard regimens. In this analysis, we assessed the long-term results of tumour control in the same population. Methods In 1986–98, we randomly assigned 1410 women with invasive breast cancer (tumour stage 1–3 with a maximum of one positive node and no metastasis) who had had local tumour excision of early stage breast cancer to receive 50 Gy radiotherapy given in 25 fractions, 39 Gy given in 13 fractions, or 42·9 Gy given in 13 fractions, all given over 5 weeks. The primary endpoint was late change in breast appearance, which has been reported elsewhere. Here, we report ipsilateral tumour relapse, one of the secondary endpoints. Relapse was defined as any appearance of cancer in the irradiated breast. Analysis was by intention to treat. Findings After a median follow-up of 9·7 years (IQR 7·8–11·8) for the 838 (95%) patients who survived, the risk of ipsilateral tumour relapse after 10 years was 12·1% (95% CI 8·8–15·5) in the 50 Gy group, 14·8% (11·2–18·3) in the 39 Gy group, and 9·6% (6·7–12·6) in the 42·9 Gy group (difference between 39 Gy and 42·9 Gy groups, χ 2 test, p=0·027). The sensitivity of breast cancer to dose per fraction was estimated to be 4·0 Gy (95% CI 1·0–7·8), similar to that estimated for the late adverse effects in healthy tissue from breast radiotherapy. Interpretation Breast cancer tissue is probably just as sensitive to fraction size as dose-limiting healthy tissues. If this finding is confirmed, radiotherapy schedules can be greatly simplified by the delivery of fewer, larger fractions without compromising effectiveness or safety, and possibly improving both.
TL;DR: Patient reporting of symptoms could add to the current approach to symptom monitoring in cancer treatment trials, and the use of real-time collection of patient-reported outcomes for early detection of potentially serious adverse events.
Abstract: Summary Background The Common Terminology Criteria for Adverse Events (CTCAE) are used as standard practice in trials of cancer treatments by clinicians to elicit and report toxic effects. Alternatively, patients could report this information directly as patient-reported outcomes, but the accuracy of these reports compared with clinician reports remains unclear. We aimed to compare the reporting of symptom severity reported by patients and clinicians. Methods Between March and May, 2005, a questionnaire with 11 common CTCAE symptoms was given to consecutive outpatients and their clinicians (physicians and nurses) in lung and genitourinary cancer clinics in the Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Patients completed a version that used language adapted from the CTCAE for patient self-reporting. The results from the questionnaire were compared with clinician reporting of the same symptoms. Findings Of 435 patients and their clinicians asked to take part in the study, 400 paired surveys were completed. For most symptoms, agreement between patient and clinician was high, and most discrepancies were within a grade difference of one point. Agreement was higher for symptoms that could be observable directly, such as vomiting and diarrhoea, than for more subjective symptoms, such as fatigue and dyspnoea. Differences in symptom reporting rarely would have changed treatment decisions or dosing, and patients assigned greater severity to symptoms more than did clinicians. No significant differences were recorded between the results when the questionnaire was completed by the patient before or after the clinician. Interpretation Patient reporting of symptoms could add to the current approach to symptom monitoring in cancer treatment trials. Future research should assess the effect of self reporting on clinical outcomes and efficiency, and the use of real-time collection of patient-reported outcomes for early detection of potentially serious adverse events.
TL;DR: In this article, the authors investigate survival patterns in a population-based sample of women who had received an oophorectomy and compare these with women who did not undergo oophorectomy.
Abstract: Summary Background A statistical model of death due to ovarian cancer, breast cancer, coronary heart disease, hip fracture, and stroke has suggested that women who undergo prophylactic bilateral oophorectomy are at increased risk of death for all causes. We aimed to investigate survival patterns in a population-based sample of women who had received an oophorectomy and compare these with women who had not received an oophorectomy. Methods From an existing cohort of all women who underwent unilateral or bilateral oophorectomy while residing in Olmsted County, MN, USA, in 1950–87, we analysed those who had received an oophorectomy for a non-cancer indication before the onset of menopause. Every member of the cohort was matched by age to a referent woman in the same population who had not undergone oophorectomy. 1293 women with unilateral oophorectomy, 1097 with bilateral oophorectomy, and 2390 referent women were eligible for the study. Women were followed up until death or the end of the study (staggered over 2001–06) by use of direct or proxy interviews, medical records in a records-linkage system, and death certificates. Findings Overall, mortality was not increased in women who underwent bilateral oophorectomy compared with referent women. However, mortality was significantly higher in women who had received prophylactic bilateral oophorectomy before the age of 45 years than in referent women (hazard ratio 1·67 [95% CI 1·16–2·40], p=0·006). This increased mortality was seen mainly in women who had not received oestrogen up to the age of 45 years. No increased mortality was recorded in women who underwent unilateral oophorectomy in either overall or stratified analyses. Interpretation Although prophylactic bilateral oophorectomy undertaken before age 45 years is associated with increased mortality, whether it is causal or merely a marker of underlying risk is uncertain.
TL;DR: The identification of barriers to the participation in clinical trials should help trialists to develop strategies that will keep to a maximum participation and cooperation in cancer trials, while informing and protecting prospective participants adequately.
Abstract: Summary Background Enrolling participants onto clinical trials of cancer presents an important challenge. We aimed to identify the concerns of patients with cancer about, and the barriers to, participation in clinical trials. Methods We did a systematic review to assess studies of barriers to participation in experimental trials and randomised trials for validity and content. We estimated the frequency with which patients identified particular issues by pooling across studies that presented data for barriers to participation in clinical trials as proportions. Findings We analysed 12 qualitative studies (n=722) and 21 quantitative studies (n=5452). Two qualitative studies inquired of patients who were currently enrolled onto clinical trials, and ten inquired of patients who were eligible for enrolment onto various clinical trials. Barriers to participation in clinical trials were protocol-related, patient-related, or physician-related. The most common reasons cited as barriers included: concerns with the trial setting; a dislike of randomisation; general discomfort with the research process; complexity and stringency of the protocol; presence of a placebo or no-treatment group; potential side-effects; being unaware of trial opportunities; the idea that clinical trials are not appropriate for serious diseases; fear that trial involvement would have a negative effect on the relationship with their physician; and their physician's attitudes towards the trial. Meta-analysis confirmed the findings of our systematic review. Interpretation The identification of such barriers to the participation in clinical trials should help trialists to develop strategies that will keep to a maximum participation and cooperation in cancer trials, while informing and protecting prospective participants adequately.
TL;DR: The finding that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND could be explained by various hypotheses, including those from cancer-stem-cell research.
Abstract: Summary Background In women with breast cancer, sentinel-lymph-node biopsy (SLNB) provides information that allows surgeons to avoid axillary-lymph-node dissection (ALND) if the SLN does not have metastasis, and has a favourable effect on quality of life. Results of our previous trial showed that SLNB accurately screens the ALN for metastasis in breast cancers of diameter 2 mm or less. We aimed to update this trial with results from longer follow-up. Methods Women with breast tumours of diameter 2 cm or less were randomly assigned after breast-conserving surgery either to SLNB and total ALND (ALND group), or to SLNB followed by ALND only if the SLN was involved (SLN group). Analysis was restricted to patients whose tumour characteristics met eligibility criteria after treatment. The main endpoints were the number of axillary metastases in women in the SLN group with negative SLNs, staging power of SLNB, and disease-free and overall survival. Findings Of the 257 patients in the ALND group, 83 (32%) had a positive SLN and 174 (68%) had a negative SLN; eight of those with negative SLNs were found to have false-negative SLNs. Of the 259 patients in the SLN group, 92 (36%) had a positive SLN, and 167 (65%) had a negative SLN. One case of overt clinical axillary metastasis was seen in the follow-up of the 167 women in the SLN group who did not receive ALND (ie, one false-negative). After a median follow-up of 79 months (range 15–97), 34 events associated with breast cancer occurred: 18 in the ALND group, and 16 in the SLN group (log-rank p=0·6). The overall 5-year survival of all patients was 96·4% (95% CI 94·1–98·7) in the ALND group and 98·4% (96·9–100) in the SLN group (log-rank p=0·1). Interpretation SLNB can allow total ALND to be avoided in patients with negative SLNs, while reducing postoperative morbidity and the costs of hospital stay. The finding that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND (whereas eight cases were expected) could be explained by various hypotheses, including those from cancer-stem-cell research.
TL;DR: Anastrozole is tolerated better than tamoxifen by postmenopausal women with early-stage breast cancer, and results in fewer serious adverse events, and has a more favourable overall risk-benefit profile and lower recurrence rate than tamxifen.
Abstract: BACKGROUND: The Arimidex (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole with tamoxifen as adjuvant treatment for postmenopausal women with early-stage breast cancer. After an extended follow-up beyond the 5 years of treatment, we aimed to assess the safety, tolerability, and risk-benefit indices of these compounds. METHODS: We analysed postmenopausal women (mean age 64 years [SD 9]) with localised breast cancer randomly assigned to anastrozole (n=3125) or tamoxifen (n=3116). Efficacy measures, including death and risk-benefit indices, were analysed by intention to treat. Safety analyses were based on treatment first received (n=3092 for anastrozole and n=3094 tamoxifen). We calculated a risk-benefit analysis using the two global indices for the Women's Health Initiative and for Disease-Free Survival and Serious Adverse Events. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. FINDINGS: At median follow-up of 68 months (range 1-93), treatment-related adverse events occurred significantly less often with anastrozole than with tamoxifen (1884 [61%] vs 2117 [68%]; p<0.0001), as did treatment-related serious adverse events (146 [5%] vs 277 [9%]; p<0.0001) and adverse events leading to withdrawal (344 [11%] vs 442 [14%]; p=0.0002). Patients given anastrozole had significantly fewer overall events for the Global Index of the Women's Health Initiative (744 [24%] vs 851 [27%]; hazard ratio 0.85 [95% CI 0.77-0.94], p=0.001) and the Global Index of Disease-Free Survival and Serious Adverse Events (1453 [46%] vs 1594 [51%]; 0.88 [0.82-0.94]; p=0.0004). INTERPRETATION: Anastrozole is tolerated better than tamoxifen by postmenopausal women with early-stage breast cancer, and results in fewer serious adverse events. Furthermore, it has a more favourable overall risk-benefit profile and lower recurrence rate than tamoxifen.
TL;DR: Validation of a highly specific biomarker pattern for urothelial carcinoma in a large group of patients with various urological disorders could be used in the diagnosis of other diseases that are identified in urine samples or in other body fluids.
Abstract: Summary Background Non-invasive methods for diagnosis of urothelial carcinoma have reduced specificity in patients with non-malignant genitourinary disease or other disorders. We aimed to use mass spectrometry and bioinformatics to define and validate a cancer-specific proteomic pattern. Methods We used capillary-electrophoresis-coupled mass spectrometry to obtain polypeptide patterns from urine samples of 46 patients with urothelial carcinoma and 33 healthy volunteers. From signatures of polypeptide mass, we established a model for predicting the presence of cancer. The model was refined further by use of 366 urine samples obtained from other healthy volunteers and patients with malignant and non-malignant genitourinary disease. We estimated the proportion of correct classifications from the refined model by applying it to a masked group containing 31 patients with urothelial carcinoma, 11 healthy individuals, and 138 patients with non-malignant genitourinary disease. We also sequenced several diagnostic polypeptides for urothelial carcinoma. Findings We identified a diagnostic urothelial-carcinoma pattern of 22 polypeptide masses. On masked assessment, prediction models based on these polypeptides correctly classified all samples of urothelial carcinoma (sensitivity 100% [95% CI 87–100) and all healthy samples (specificity 100% [84–100]). Correct identification of patients with urothelial carcinoma from those with other malignant and non-malignant genitourinary disease ranged from 86% to 100%. A prominent polypeptide from the diagnostic pattern for urothelial carcinoma was identified as fibrinopeptide A—a known biomarker of ovarian cancer and gastric cancer. Interpretation Validation of a highly specific biomarker pattern for urothelial carcinoma in a large group of patients with various urological disorders could be used in the diagnosis of other diseases that are identified in urine samples or in other body fluids.
TL;DR: Future high throughput microarray studies that compare changes at a genomic and gene expression level between primary ovarian tumours and their peritoneal metastases are hoped to lead to a more conclusive picture of transcoelomic metastasis, and to delineate the key molecular players in this process.
Abstract: Metastasis from epithelial ovarian cancer can occur via the transcoelomic, haematogeneous, or lymphatic route. Of these, transcoelomic metastasis is the most common, and is responsible for the greatest morbidity and mortality in women with this disease. Unfortunately, very little is known about the mechanisms behind this process. This review assesses the current evidence and ideas about the biology of transcoelomic dissemination. The mechanisms of cell detachment, migration, and implantation in transcoelomic metastasis are placed within the context of clinical observations of ovarian cancer to derive a stepwise hypothesis of this process. Evidence for transcoelomic dissemination versus transcoelomic metaplasia in ovarian cancer is presented. Future high throughput microarray studies that compare changes at a genomic and gene expression level between primary ovarian tumours and their peritoneal metastases are hoped to lead to a more conclusive picture of transcoelomic metastasis, and to delineate the key molecular players in this process. These studies might also result in the identification of potential new therapeutic targets in ovarian cancer.
TL;DR: In conclusion, broad consent and consent for future research are valid ethically and should be recommended for biobank research provided that: personal information related to research is handled safely; donors of biological samples are granted the right to withdraw consent; and new research studies or changes to the legal or ethical authority of a biobanks are approved by an ethics-review board.
Abstract: Summary Large international biobank studies can make substantial contributions to scientific research by validation of the biological importance of previous research and by identification of previously unknown causes of disease. However, regulations for patient consent that are too strict and discrepancies in national policies on informed consent might hinder progress. Therefore, establishment of common ground for ethical review of biobank research is essential. In this essay, broad consent is defined on a scale between strictly specified (eg, for a specific study) and blanket consent (ie, with no restrictions regarding the purpose of the research). Future research includes that which might not be planned or even conceptualised when consent is obtained. In conclusion, broad consent and consent for future research are valid ethically and should be recommended for biobank research provided that: personal information related to research is handled safely; donors of biological samples are granted the right to withdraw consent; and new research studies or changes to the legal or ethical authority of a biobank are approved by an ethics-review board.
TL;DR: Because LTA does not improve survival after TH and leads to increased morbidity in patients with cancer of the cardia or subcardia, LTA cannot be justified to treat these tumours.
Abstract: Summary Background Because of the inaccessibility of mediastinal nodal metastases, the left thoracoabdominal approach (LTA) has often been used to treat gastric cancer of the cardia or subcardia. In a randomised phase III study, we aimed to compare LTA with the abdominal-transhiatal approach (TH) in the treatment of these tumours. Methods Between July, 1995, and December, 2003, 167 patients were enrolled from 27 Japanese hospitals and randomly assigned to TH (n=82) or LTA (n=85). The primary endpoint was overall survival, and secondary endpoints were disease-free survival, postoperative morbidity and hospital mortality, and postoperative symptoms and change of respiratory function. The projected sample size was 302. After the first interim analysis, the predicted probability of LTA having a significantly better overall survival than TH at the final analysis was only 3·65%, and the trial was closed immediately. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00149266. Findings 5-year overall survival was 52·3% (95% CI 40·4–64·1) in the TH group and 37·9% (26·1–49·6) in the LTA group. The hazard ratio of death for LTA compared with TH was 1·36 (0·89–2·08, p=0·92). Three patients died in hospital after LTA but none after TH. Morbidity was worse after LTA than after TH. Interpretation Because LTA does not improve survival after TH and leads to increased morbidity in patients with cancer of the cardia or subcardia, LTA cannot be justified to treat these tumours.
TL;DR: Current knowledge of bisphosphonate-associated osteonecrosis, a new oral complication in oncology, is presented and pathobiology, clinical features, management, and future directions for the disorder are discussed.
Abstract: We present current knowledge of bisphosphonate-associated osteonecrosis, a new oral complication in oncology. It was first described in 2003, and hundreds of cases have been reported worldwide. The disorder affects patients with cancer on bisphosphonate treatment for multiple myeloma or bone metastasis from breast, prostate, or lung cancer. Bisphosphonate-associated osteonecrosis is characterised by the unexpected appearance of necrotic bone in the oral cavity. Osteonecrosis can develop spontaneously or after an invasive surgical procedure such as dental extraction. Patients might have severe pain or be asymptomatic. Symptoms can mimic routine dental problems such as decay or periodontal disease. Intravenous use of pamidronate and zoledronic acid is associated with most cases. Other risk factors include duration of bisphosphonate treatment (ie, 36 months and longer), old age in patients with multiple myeloma, and a history of recent dental extraction. We also discuss pathobiology, clinical features, management, and future directions for the disorder.
National Institutes of Health1, University of California, Berkeley2, The Royal Marsden NHS Foundation Trust3, University of British Columbia4, University of York5, University of Cagliari6, International Agency for Research on Cancer7, Yale University8, University of California, San Francisco9, University of Sydney10, University of Southern California11, University of Leeds12, Mayo Clinic13, University of Verona14, University of Bristol15, University of Washington16, Wayne State University17
TL;DR: Common polymorphisms in TNF and IL10, key cytokines for the inflammatory response and Th1/Th2 balance, could be susceptibility loci for non-Hodgkin lymphoma.
Abstract: Summary Background Common genetic variants in immune and inflammatory response genes can affect the risk of developing non-Hodgkin lymphoma. We aimed to test this hypothesis using previously unpublished data from eight European, Canadian, and US case-control studies of the International Lymphoma Epidemiology Consortium (InterLymph). Methods We selected 12 single-nucleotide polymorphisms for analysis, on the basis of previous functional or association data, in nine genes that have important roles in lymphoid development, Th1/Th2 balance, and proinflammatory or anti-inflammatory pathways ( IL1A, IL1RN, IL1B, IL2, IL6, IL10, TNF, LTA, and CARD15 ). Genotype data for one or more single-nucleotide polymorphisms were available for 3586 cases of non-Hodgkin lymphoma and for 4018 controls, and were assessed in a pooled analysis by use of a random-effects logistic regression model. Findings The tumour necrosis factor ( TNF ) −308G→A polymorphism was associated with increased risk of non-Hodgkin lymphoma (p for trend=0·005), particularly for diffuse large B-cell lymphoma, the main histological subtype (odds ratio 1·29 [95% CI 1·10–1·51] for GA and 1·65 [1·16–2·34] for AA, p for trend (IL10) −3575T→A polymorphism was also associated with increased risk of non-Hodgkin lymphoma (p for trend=0·02), again particularly for diffuse large B-cell lymphoma (p for trend=0·006). For individuals homozygous for the TNF −308A allele and carrying at least one IL10 −3575A allele, risk of diffuse large B-cell lymphoma doubled (2·13 [1·37–3·32], p=0·00083). Interpretation Common polymorphisms in TNF and IL10, key cytokines for the inflammatory response and Th1/Th2 balance, could be susceptibility loci for non-Hodgkin lymphoma. Moreover, our results underscore the importance of consortia for investigating the genetic basis of chronic diseases like cancer.
University of Pennsylvania1, University of California, Irvine2, St Mary's Hospital3, Georgetown University4, Harvard University5, Fox Chase Cancer Center6, National Health Service7, Yale University8, University of Texas Southwestern Medical Center9, Netherlands Cancer Institute10, Creighton University11, University of Chicago12, GlaxoSmithKline13
TL;DR: If confirmed, the finding that BPSO improves overall survival and cancer-specific survival in women with BRCA mutations will complement the existing knowledge of cancer-risk reduction associated with B PSO and give information to women who are considering genetic testing.
Abstract: Summary Background Bilateral prophylactic salpingo-oophorectomy (BPSO) is used widely used to reduce the risk of breast and ovarian cancer in women with BRCA1 and BRCA2 mutations. However, the reduction in mortality after this surgery is unclear. We aimed to assess whether BPSO improves overall mortality or cancer-specific mortality in BRCA1 and BRCA2 mutation carriers. Methods We identified a prospective cohort of 666 women with disease-associated germline mutations in BRCA1 or BRCA2 and no previous cancer diagnosis. In our primary analysis, we compared 155 women who had had BPSO and 271 women matched for age at BPSO who had not had BPSO. In our secondary analysis, we compared 188 women who had had BPSO with 478 women who had not. In both analyses, we compared overall mortality and cancer-specific mortality. All analyses were adjusted for centre, mutation ( BRCA1 vs BRCA2 ), and birth year. Findings In the primary analysis, mean follow-up from BPSO to censoring was 3·1 years [SD 2·4] in the BPSO group and 2·1 years [2·0] in the non-BPSO group. The hazard ratio (HR) for overall mortality was 0·24 (95% CI 0·08–0·71), for breast-cancer-specific mortality was 0·10 (0·02–0·71), and for ovarian-cancer-specific mortality was 0·05 (0·01–0·46) for women who had BPSO compared with those who had not. In secondary analysis, BPSO was associated with reduced overall mortality (HR 0·28 [95% CI 0·10–0·74]), but not with breast-cancer-specific mortality (0·15 [0·02–1·18] or ovarian-cancer-specific mortality (0·23 [0·02–1·87]. When regarded as a time-dependent covariate, BPSO was not associated significantly with mortality. Interpretation If confirmed, the finding that BPSO improves overall survival and cancer-specific survival in women with BRCA mutations will complement our existing knowledge of cancer-risk reduction associated with BPSO. Together, these data could give information to women who are considering genetic testing.
TL;DR: This Review focuses on the multifactorial causes of so-called radiation caries and presents possible treatment strategies to avoid loss of dentition.
Abstract: Because of typical tissue reactions to ionising radiation, radiotherapy in the head and neck region usually results in complex oral complications affecting the salivary glands, oral mucosa, bone, masticatory musculature, and dentition. When the oral cavity and salivary glands are exposed to high doses of radiation, clinical consequences including hyposalivation, mucositis, taste loss, trismus, and osteoradionecrosis should be regarded as the most common side-effects. Mucositis and taste loss are reversible consequences, usually subsiding early post-irradiation, whereas hyposalivation is commonly irreversible. Additionally, the risk of rampant tooth decay with its sudden onset and osteonecrosis is a lifelong threat. Thus, early, active participation of the dental profession in the development of preventive and therapeutic strategies, and in the education and rehabilitation of patients is paramount in consideration of quality-of-life issues during and after radiotherapy. This Review focuses on the multifactorial causes of so-called radiation caries and presents possible treatment strategies to avoid loss of dentition.
TL;DR: The working group concluded that the epidemiological studies of carbon black provided inadequate evidence of carcinogenicity, and no clear dose-response relation between exposure to carbon black and lung cancer was noted.
Abstract: In February, 2006, 19 scientists from eight countries met at the International Agency for Research on Cancer (IARC), Lyon, France, to reassess the carcinogenicity of carbon black, titanium dioxide, and non-asbestiform talc. These assessments will be published as volume 93 of the IARC Monographs, and are the fi rst assessments since the IARC Monograph preamble was amended. All three of the above agents are poorly soluble particles that are weakly toxic, and were chosen for assessment because evidence suggests that they cause cancer in the respiratory tract of rats through similar mechanisms: after exposure to high concentrations of these agents, deposition of particles onto the respiratory epithelium can lead to enhanced particle retention, impaired lung clearance, infl ammatory response, production of reactive oxygen species, cell injury, cell proliferation, fi brosis, induction of mutations, and, ultimately, cancer. Because many of these steps arise in people who work in dusty environments (eg, coal miners), data on cancer in animals obtained in conditions of impaired lung clearance could be relevant to human beings. Furthermore, impaired lung clearance and adverse eff ects in the lungs of rats that have been exposed to ultrafi ne particles (<100 nm) occur at much lower mass concentrations than in rats exposed to fi ne particles (<10 μm), increasing the potential relevance to human beings. Carbon black is a particulate form of elemental carbon. About 90% of carbon black is used in rubber products, mainly tyres. Carbon black is also used as a pigment in inks, paints and coatings, and in plastics. Exposure to carbon-black particles occurs mainly in the form of aggregates (ie, particle size, 50−600 nm) and agglomerates (227 μm). Most types of carbon black have small quantities (ie, <1%) of organic compounds, including polycyclic aromatic hydrocarbons, adsorbed onto their surface. The highest exposures to carbon black arise during its manufacturing. Exposure in industries that use carbon black is diffi cult to assess because data are scarce. No substantial exposure to carbon black is thought to occur when it is bound to other materials such as rubber, printing ink, or paint. Workers who produced carbon black in Germany and the UK had an excess risk of lung cancer. Confounding by smoking was unlikely to explain the entire excess risk, but no clear dose-response relation between exposure to carbon black and lung cancer was noted. A US study of workers in carbon black production found no excess risk of lung cancer, but no data according to level of exposure were reported. A study of workers in the rubber industry in Germany who were exposed to carbon black showed no signifi cant excess risk of lung cancer after adjustment for potential confounding by asbestos and talc. The working group concluded that the epidemiological studies of carbon black provided inadequate evidence of carcinogenicity. Carbon black and its extracts have been tested in rats and mice by inhalation, intratracheal instillation, dermal application, and subcutaneous injection. The overall results provided suffi cient evidence in laboratory animals for the carcinogenicity of carbon black and carbon-black extracts. The working group classifi ed carbon black as possibly carcinogenic to human beings (ie, group 2B). Titanium dioxide accounts for 70% of the total production volume of pigments worldwide. The primary particles are typically 200–300 nm in diameter, but larger aggregates and agglomerates are formed readily. Ultrafi ne grades of titanium dioxide (ie, 10–50 nm) are used in sunscreens and plastics to block ultraviolet light, and in catalysts. Highest expo sures occur in titanium-dioxide produc tion during packing, milling, site cleaning, and maintenance. Exposure data for industries that use titanium dioxide are scarce. The largest epidemiological cohort study considered included workers in the titanium dioxide production industry in six European countries, and showed a small but signifi cant increase in risk of lung cancer compared with that for the general population; however, the data did not suggest an exposure-response relation. Two cohort studies undertaken in the USA did not report excess risks of lung cancer, neither did a Canadian population-based casecontrol study. Overall, the working group concluded that the epidemiological studies on titanium dioxide provide inadequate evidence of carcinogenicity. Pigment-grade titanium dioxide and ultrafi ne titanium dioxide have been tested in rats, mice, and hamsters by various routes of administration. Overall, results from studies of inhalation and intratracheal instillation provided suffi cient evidence in animals for the carcinogenicity of titanium dioxide. The working group classifi ed titanium dioxide as possibly carcinogenic to human beings (ie, group 2B). Talc refers to both mineral talc and industrial products that contain 35% to >95% mineral talc. Mineral talc Upcoming meetings
TL;DR: Increased precision and accuracy of radiotherapy are expected to augment tumour control, reduce incidence and severity of toxic effects after radiotherapy, and facilitate development of more efficient shorter schedules than currently available.
Abstract: Technological advances have greatly enhanced the specialty of radiation oncology by allowing more healthy tissue to be spared for the same or better tumour coverage. Developments in medical imaging are integral to radiation oncology, both for design of treatment plans and to localise the target for precise administration of radiation. At planning, definition of the tumour and healthy tissue is based on CT, augmented frequently with MRI and PET. At treatment, three-dimensional soft-tissue imaging can also be used to localise the target and tumour motion can be tracked with fluoroscopic imaging of radio-opaque markers implanted in or near the tumour. These developments allow changes in tumour position, size, and shape that take place during radiotherapy to be measured and accounted for to boost geometric accuracy and precision of radiation delivery. Image-guided treatment also enhances uniformity in doses administered in a population of patients, thus improving our ability to measure the effect of dosimetric and non-dosimetric factors on tumour and healthy tissue outcomes in clinical trials. Increased precision and accuracy of radiotherapy are expected to augment tumour control, reduce incidence and severity of toxic effects after radiotherapy, and facilitate development of more efficient shorter schedules than currently available.
TL;DR: Safe and effective development of services would benefit from links with established facilities in other countries, particularly those within the same region; access to information, such as free online journal access; and better education of all medical staff about the roles and benefits of radiotherapy.
Abstract: Summary More than half the cases of cancer in the world arise in people in low-income and middle-income countries. This proportion will rise to 70% by 2020. These are regions where the annual gross national income per person is less than US$9386. Radiotherapy is an essential part of the treatment of cancer. In high-income countries, 52% of new cases of cancer should receive radiotherapy at least once and up to 25% might receive a second course. Because of the different distribution of tumour types worldwide and of the advanced stage at presentation, patients with cancer in low-income and middle-income regions could have a greater need for radiotherapy than those in high-income countries. Radiotherapy for cure or palliation has been shown to be cost effective. Many countries of low or middle income have limited access to radiotherapy, and 22 African and Asian countries have no service at all. In Africa in 2002, the actual supply of megavoltage radiotherapy machines (cobalt or linear accelerator) was only 155, 18% of the estimated need. In the Asia-Pacific region, nearly 4 million cases of cancer arose in 2002. In 12 countries with available data, 1147 megavoltage machines were available for an estimated demand of nearly 4000 megavoltage machines. Eastern Europe and Latin America showed similar shortages. Strategies for developing services need planning at a national level and substantial investment for staff training and equipment. Safe and effective development of services would benefit from: links with established facilities in other countries, particularly those within the same region; access to information, such as free online journal access; and better education of all medical staff about the roles and benefits of radiotherapy.