Commentary - A comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars and Intended Copy Biologics in treating chemotherapy associated febrile neutropenia.

Filgrastim, human white cell growth factor, Granulocyte colony-stimulating factor (G-CSF), is a core medicine in the WHO list of Essential Medicines. For this reason, recent reporting of statistically significant safety and efficacy differences between reference and Biosimilar brands of filgrastim by Rastogi and the Indian Pharmacopoeia Commission in Toxicology and Applied Pharmacology in 2020 is of great concern [Shruti Rastogi et al. Towards a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars in treating chemotherapy associated febrile neutropenia: Trends from decades of data. Toxicology and Applied Pharmacology Volume 395, 15 May 2020, 114,976. https://doi.org/10.1016/j.taap.2020.114976]. This commentary shows that the alarming report is a result of incorrect statistical tests misapplied to inappropriate data sets compounded by a further problem relating to the strict regulatory definition of a Biosimilar Medicine as opposed that of an Intended Copy Biologic. In contrast, the body of evidence from more than seven and a half thousand participants in Confirmatory Clinical Studies and Post Approval Clinical Studies as well as the Periodic Safety Update Reports confirms that European approved filgrastim Biosimilars show no meaningful difference in quality, safety or efficacy compared to the reference brand.

Predicting the outcome of respiratory disease in wheezing infants using tidal flow-volume loop shape.

INTRODUCTION AND OBJECTIVES: Wheezing (RW) infants with a positive asthma predictive index (API+) have a lower lung function as measured by forced expiratory techniques. Tidal flow-volume loops (TFVL) are easy to perform in infants, and sedation is not necessary. MATERIALS AND METHODS: A total of 216 wheezing infants were successfully measured, and 183 of them were followed for over a year. TFVL loops were classified into one of three categories depending of their geometric shape (symmetric, convex, and concave). Respiratory rate (Rr), presence of API+, and the number of exacerbations during the following year were also recorded. RESULTS: Children with concave loops had more exacerbations in the following year (OR = 6.8 [IC95% 3.33;13.91]). Infants API + were also significantly more related to concave loops (OR = 10.02 [IC 95% 4.53; 22.15]). Rr was higher in infants with concave loops (44+/-15.5 vs. 36.6 +/-12.6; p < 0.01). CONCLUSION: Infants with a concave TFVL have a higher probability of experiencing exacerbations in the following year, and are at a higher risk of suffering asthma.

Supportive care in patients with cancer during the COVID-19 pandemic.

Cancer care has been profoundly impacted by the global pandemic of severe acute respiratory syndrome coronavirus 2 disease (coronavirus disease 2019, COVID-19), resulting in unprecedented challenges. Supportive care is an essential component of cancer treatment, seeking to prevent and manage chemotherapy complications such as febrile neutropenia, anaemia, thrombocytopenia/bleeding, thromboembolic events and nausea/vomiting, all of which are common causes of hospitalisation. These adverse events are an essential consideration under routine patient management, but particularly so during a pandemic, a setting in which clinicians aim to minimise patients' risk of infection and need for hospital visits. Professional medical oncology societies have been providing updated guidelines to support health care professionals with the management, treatment and supportive care needs of their patients with cancer under the threat of COVID-19. This paper aims to review the recommendations made by the most prominent medical oncology societies for devising and modifying supportive care strategies during the pandemic.

Dilating the vagina to prevent damage from radiotherapy: systematic review of the literature.

BACKGROUND: UK guidelines recommend routine vaginal dilation during and after pelvic radiotherapy to prevent stenosis. OBJECTIVE: To examine critically the evidence behind this guideline. SEARCH STRATEGY: Cochrane-style systematic review of the data and literature relevant to vaginal dilation and stenosis attributable to radiotherapy. SELECTION CRITERIA: Any and every measure of vaginal or sexual function after radiotherapy. DATA COLLECTION AND ANALYSIS: Numerous papers gave recommendations on dilation during or immediately after radiotherapy, but only seven contained relevant data. Case reports describe vaginal fistulas or psychological morbidity. Two trials showed that encouraging dilation increased compliance, but the first trial found no difference in sexual function scores. One comparative unmatched trial showed no advantage from inserting mitomycin C. A report of five women implied that stenosis can be treated by dilation many years after radiotherapy. One uncontrolled observational report involving 89 women showed that the median vaginal length 6-10 weeks after therapy was measured at 6 cm, but women tolerated a 9-cm measurer after 4 months of dilation experience. One retrospective report implied that dilation lowered stenosis rates, but the control group is not comparable. MAIN RESULTS: Dilation during or immediately after radiotherapy can cause damage, and there is no evidence that it prevents stenosis. Dilation might stretch the vagina if commenced after the inflammatory phase. AUTHOR'S CONCLUSIONS: Dilation might help treat the late effects of radiotherapy, but it must not be assumed that this applies to the acute toxicity phase. Routine dilation during treatment is not supported by good evidence.

Endometrial cysteine-rich secretory protein 3 is inhibited by human chorionic gonadotrophin, and is increased in the decidua of tubal ectopic pregnancy.

Ectopic pregnancy (EP) remains a considerable cause of morbidity and occasional mortality. Currently, there is no reliable test to differentiate ectopic from intrauterine gestation. We have previously used array technology to demonstrate that differences in gene expression in decidualized endometrium from women with ectopic and intrauterine gestations could be used to identify candidate diagnostic biomarkers for EP. The aim of this study was to further investigate the decidual gene with the highest fold increase in EP, cysteine-rich secretory protein-3 (CRISP-3). Decidualized endometrium from gestation-matched women undergoing surgical termination of pregnancy (n = 8), evacuation of uterus for miscarriage (n = 6) and surgery for EP (n = 11) was subjected to quantitative RT-PCR, morphological assessment, immunohistochemistry and western blot analysis. Sera were analysed for progesterone and human chorionic gonadotrophin (hCG) levels. Immortalized endometrial epithelial cells were cultured with physiological concentrations of hCG. CRISP-3 mRNA and protein expression were greater in endometrium from ectopic when compared with intrauterine pregnancies (P < 0.05). CRISP-3 protein was localized to epithelium and granulocytes of endometrium. CRISP-3 serum concentrations were not different in women with ectopic compared with intrauterine pregnancies. CRISP-3 expression in endometrium was not related to the degree of decidualization or to serum progesterone levels. Endometrial CRISP-3 expression was inversely proportional to serum hCG concentrations (P < 0.001). Stimulation of endometrial epithelial cells with hCG in vitro caused a reduction in CRISP-3 expression (P < 0.01). The measurement of CRISP-3 in endometrium could provide an additional tool in the diagnosis of failing early pregnancy of unknown location. The absence of a local reduction in expression of CRISP-3 in decidualized endometrium of women with EP may be due to reduced exposure to hCG due to the ectopic location of the trophoblast.

The role of epoetin beta in the treatment of anaemia in patients with gynaecological malignancies.

Cancer-related anaemia has a major detrimental effect on quality of life (QoL) and adversely affects patient outcome, having a negative impact on local tumour control, disease-free survival and overall survival. The incidence of cancer-related anaemia is particularly high among patients with gynaecological cancers, affecting up to 80% of individuals in this patient group. Anaemia may develop as a consequence of the disease itself; however, the myelosuppressive and nephrotoxic effects of the intensive chemotherapy and/or radiotherapy regimens frequently used in the treatment of gynaecological cancer are major causative factors. Although blood transfusions were traditionally used for the management of anaemia in patients with cancer, associated adverse events and inconvenience of use have meant that they are now reserved for patients with severe anaemia who require rapid improvements in haemoglobin (Hb) levels. As a consequence, epoetins, with their ability to provide stable Hb levels over prolonged periods, are now firmly established in the management of cancer-related anaemia. The efficacy of epoetin beta, a recombinant human erythropoietin, has been investigated in patients with gynaecological malignancies and anaemia in several European trials. These studies confirm that epoetin beta increases Hb levels, reduces transfusion requirements and improves QoL, and support the use of epoetin beta as an integral part of the treatment regimen in patients with ovarian or cervical malignancies receiving radio-and/or chemotherapy.

Survival and recurrent disease after postoperative radiotherapy for early endometrial cancer: systematic review and meta-analysis.

OBJECTIVE: To clarify the effect of postoperative (adjuvant) external-beam pelvic radiotherapy (EBRT) for different grades of early endometrial cancer. SEARCH STRATEGY: Meta-analysis of data from randomised trials stratified by histological risk factors supported by cohort studies. SELECTION CRITERIA: Cochrane methodology. DATA: Seven randomised trials were identified. Five were eligible for meta-analysis. Homogeneity was confirmed (I2 < 25%). MAIN OUTCOME MEASURES: Survival, site of recurrence and added complications. MAIN RESULTS: EBRT after hysterectomy for low-risk disease increases the odds of death (OR for overall survival 0.71; 95% CI 0.52-0.96). EBRT does not appear to alter survival for intermediate-risk cancers (stage ICG1/2 and IBG3) (OR 0.97; 95% CI 0.69-1.35). In contrast, EBRT offers a significant disease-free survival advantage for high-risk cancer (OR 1.76; 95% CI 1.07-2.89). The survival advantage benefits one in ten women. The definition of high risk is variable across studies but focuses on ICG3 (deeply invasive, poorly differentiated) tumours. Pelvic EBRT reduces the risk of pelvic recurrent disease in all types of invasive endometrial cancer (OR 0.27; 95% CI 0.16-0.44), but local recurrence may respond to salvage treatment. The risk of distant metastasis appears to be increased significantly by prophylactic EBRT (OR 1.58; 95% CI 1.07-2.35), but this might be because pelvic relapse in untreated women alters reporting of metastatic disease. AUTHORS' CONCLUSIONS: Adjuvant EBRT should not be used for low- (IA, IBG1) or intermediate-risk (IBG2) cancer, but it is associated with a 10% survival advantage for high-risk (stage ICG3) endometrial cancer. This challenges the role of a staging lymphadenectomy.

Adjuvant radiotherapy for stage I endometrial cancer.

BACKGROUND: The role of adjuvant radiotherapy (both pelvic external beam radiotherapy and vaginal intracavity brachytherapy) in stage I endometrial cancer following total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH and BSO) remains unclear. OBJECTIVES: To assess the efficacy of adjuvant radiotherapy following surgery for stage I endometrial cancer. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CancerLit, Physician Data Query (PDQ) of National Cancer Institute. Handsearching was also carried out where appropriate. SELECTION CRITERIA: Randomised controlled trials (RCTs) which compared adjuvant radiotherapy versus no radiotherapy following surgery for patients with stage I endometrial cancer were included. DATA COLLECTION AND ANALYSIS: Quality of the studies was assessed and data collected using a predefined data collection form. The primary endpoint was overall survival. Secondary endpoints were locoregional recurrence, distant recurrence and endometrial cancer death. Data on quality of life (QOL) and morbidity were also collected. A meta-analysis on included trials was performed using the Cochrane Collaboration Review Manager Software 4.2. MAIN RESULTS: The meta-analysis was performed on four trials (1770 patients). The addition of pelvic external beam radiotherapy to surgery reduced locoregional recurrence, a relative risk (RR) of 0.28 (95% confidence interval (CI) 0.17 to 0.44, p < 0.00001), which is a 72% reduction in the risk of pelvic relapse (95% CI 56% to 83%) and an absolute risk reduction of 6% (95% CI of 4 to 8%). The number needed to treat (NNT) to prevent one locoregional recurrence is 16.7 patients (95% CI 12.5 to 25). The reduction in the risk of locoregional recurrence did not translate into either a reduction in the risk of distant recurrence or death from all causes or endometrial cancer death. A subgroup analysis of women with multiple high risk factors (including stage 1c and grade 3) showed a trend toward the reduction in the risk of death from all causes and endometrial cancer death in patients who underwent adjuvant external beam radiotherapy. AUTHORS' CONCLUSIONS: Patients with stage I endometrial carcinoma have different risks of local and distant recurrence depending on the presence of risk factors including stage 1c, grade 3, lymphovascular space invasion and age. Though external beam pelvic radiotherapy reduced locoregional recurrence by 72%, there is no evidence to suggest that it reduced the risk of death. In patients with multiple high risk factors, including stage 1c and grade 3, there was a trend towards a survival benefit and adjuvant external beam radiotherapy may be justified. For patients with only one risk factor, grade 3 or stage 1c, no definite conclusion can be made and data from ongoing studies ( ASTEC; Lukka) are awaited. External beam radiotherapy carries a risk of toxicity and should be avoided in stage 1 endometrial cancer patients with no high risk factors.

Quantification and reduction of cardiac dose in radical radiotherapy for oesophageal cancer.

Chemoradiation is increasingly used in the management of localized oesophageal cancer and has been shown in randomized controlled trials to improve overall survival. Although early toxicity of radiotherapy is well documented, this is not the case for late toxicity. As patients with oesophageal cancer have a high incidence of co-morbidities including cardiac problems, the aim of this paper was to quantify the extent of cardiac radiation and discuss the influence of beam arrangement to reduce this. Eight patients with localized oesophageal cancer treated with radical chemoradiation were selected. The mean cardiac dose and the volumes of heart receiving 30 Gy, 40 Gy and 45 Gy from the conventional two-phase technique were compared with those of single-phase 3-field and 4-field conformal beam arrangements. The 4-field arrangement reduced the mean cardiac dose by at least 3.3 Gy compared with the other two beam arrangements (p=0.01). The mean volume of heart receiving high doses between the three techniques widened as the dose increased in the range 30-45 Gy. There is no statistically significant difference in volumes receiving more than 30 Gy and 40 Gy. 65% of the cardiac volume received more than 45 Gy using a two-phase technique, compared with 57% using three fields and 26% using four fields (p<0.01). With a 4-field beam arrangement, therefore, there is a significant reduction in cardiac dose compared with the other two techniques. Cardiac toxicity and a 4-field beam arrangement should be considered when planning radical radiotherapy for localized oesophageal cancer.

Long-term morbidity following short-course, pre-operative radiotherapy and total mesorectal excision for rectal cancer.

AIM: Short-course pre-operative radiotherapy (SCPRT) and total mesorectal excision (TME) have been shown to reduce the rate of relapse and improve survival in patients with rectal cancer. Concerns about morbidity have limited its application in some centres. The aim of this study was to assess long-term toxicity of pre-operative RT in patients with rectal cancer. METHODS: Permanent toxicity was assessed in 20 patients who were alive >12 months after pre-operative RT (25Gy/ 5#), using a validated LENT SOMA scoring system. Ten patients with rectal cancer who had been operated on >12 months ago, but had not received pre-operative RT were assessed similarly. RESULTS: Patients who had received SCPRT appeared to have a significantly higher rectal toxicity, urinary and male sexual dysfunction, compared with the controls. No significant difference was noted in female sexual dysfunction. CONCLUSION: The combination of pre-operative RT and TME appears to be associated with significant long-term toxicity. Better methods of staging the tumours may improve selection of patients for SCPRT.

Cervical lymph node relapses of head-and-neck squamous cell carcinoma: is brachytherapy a therapeutic option?

PURPOSE: To report the results of interstitial brachytherapy (IBT) without salvage surgery for isolated cervical lymph node relapses. PATIENT AND METHODS: From 1970 to 1989, 84 patients were treated; 76 patients had relapsed in sites of previous external beam radiation. In 72 patients, IBT was sole salvage treatment (mean, 56.5 Gy). In 12 patients IBT (mean, 38 Gy) was combined with further external beam radiotherapy (mean, 41 Gy). RESULTS: Local control in the neck was 49% at 1 year, 31% at 2 years, and 0% at 5 years. Overall survival was 33% at 1 year, 13% at 2 years, and 1% at 5 years. Significant toxicity occurred in 35% (7% fatal). Multivariate analysis shows survival after salvage was better for patients who had achieved initial control for > or =18 months before relapse (0% vs. 13% at 3 years, p < 0.0002). Lymph node control was better for patients who received total salvage dose > or =60 Gy (0% vs. 56% at 3 years, p = 0.0004). CONCLUSION: Given its poor efficiency and its toxicity, IBT must be considered only when surgery is contraindicated and if lymph node relapse occurs after a minimal interval of 18 months.

Amlodipine gynaecomastia.

We report only the second published confirmed case of gynaecomastia caused by amlodipine (a dihydropyridine calcium channel blocker). Gynaecomastia developed in a 70-year-old male within 3 months of starting amlodipine, and symptoms resolved within 3 weeks of drug withdrawal suggesting a strong relationship between amlodipine and gynaecomastia in this patient. Recent research has suggested possible interesting novel mechanisms for amlodipine gynaecomastia, which are discussed.

Heterotopic bone formation: irradiation of high risk patients.

The Royal Marsden Hospital has adopted a policy for patient selection for the use of adjuvant radiotherapy to prevent heterotopic new bone formation (HTBF) limited to those at greater than 50% risk. The treatment protocol is 7 Gy post-operative megavoltage radiotherapy at mid-plane, in one fraction, given within 72 h of surgery. Since the introduction of this protocol in 1993, 26 joints have been treated in 25 patients. The majority of cases were young people with acetabular fractures resulting from road traffic accidents, often alcohol related. Follow-up studies in this group of patients has proved difficult, as many fail to attend for follow up, and others have moved out of the catchment area. Of the 14 cases for which follow-up data is available, 13 remain fully mobile. One has not mobilized since the time of treatment and continues to use crutches. There is one case of recurrent HTBF seen on X-ray after 8 months, but the joint was mobile. By 5 years, all cases have failed to attend for follow-up. The true long-term risks of this treatment policy may not be known for 30 years. The failure of patients to attend even short-term follow-up is a potential problem for clinical oncologists.

Medical reports on persons claiming compensation for personal injury.

An audit of one insurance company's files on all employer's liability and third party motor claims settled over two years for 5000 pounds or more presented an opportunity to review the medical reports on the patients involved. A stratified random sample of files on 203 patients contained 602 reports prepared by 400 consultants. Content analysis was undertaken to evaluate compliance with published guidance on reports prepared for medico-legal purposes and to ascertain how well reports met recipients' requirements. While clinical topics were well covered, generally to a high standard, other functional, psychosocial and occupational topics, reflecting the wider clinical and non-clinical frame of reference within which lawyers and insurers normally seek information and advice, were covered less frequently, extensively and comprehensively--leaving considerable scope to improve these aspects of assessment and reporting. Further review of this aspect of professional practice should include attention to the appropriateness of existing guidance, postgraduate training requirements and the involvement of other agencies or professions in some aspects of assessment for medico-legal purposes.

Rehabilitation and return to work of employers' liability claimants.

Examination of employers' liability (workers' compensation) claims files confirms that accidents at work, resulting in major injury, continue to present a significant challenge to rehabilitation. This review of 209 patients who have pursued such claims describes them from relevant socio-economic, clinical and occupational perspectives; records their return to work; examines medical opinion on their residual disabilities and potential occupational handicap and traces their involvement with rehabilitation and resettlement services. A major finding is an interval of almost two years, on average, between patients' discharge from medical treatment and settlement of their claims. Given the severity of injuries, length of absences from work and the relatively high proportions who either lost their jobs or who were advised to seek less physically demanding alternative occupations, the rate of referral to specialist vocational rehabilitation services during this period was very low. Timely and effective delivery of relevant rehabilitation and resettlement services to such patients should be made a priority for future policy and practice. One half of the sample returned to work before settlement, with more who were unsuccessful in their attempts to do so. The adversarial climate of personal injury claims negotiation in Great Britain therefore may be a less formidable barrier to return to work than is sometimes supposed. Nevertheless, conventional practices and procedures in medicine, law and insurance may still delay or prevent resettlement in some cases. Any attempt to enhance the effectiveness of the present medicolegal system should pay at least as much attention to these iatrogenic factors as to the psychological explanations that have dominated previous thinking on this subject.

Vaginal vault brachytherapy in endometrial cancer: verifying target coverage with image-guided applicator placement.

OBJECTIVE: This quality assurance study assesses whether CT image-guided verification has led to improvements in the technique when compared with previous studies. METHODS: The CT images were studied from a cohort of 105 consecutive patients with endometrial cancer having adjuvant brachytherapy to the vaginal vault in 2010. Images were taken at first insertion, checked for air gaps and treatment delivered. Images were later transferred to the planning system and air gaps between vaginal mucosa and vaginal cylinder were measured. Comparisons were made with the 2008 results from this centre and the literature series. RESULTS: Images from two patients were not assessable owing to artefacts from hip replacements. Air gaps >2 mm were seen in 11/103 patients. Repositioning or use of a larger cylinder reduced air gaps to 7/103 patients. In total, 96/103 patients (over 93%) were able to achieve good vaginal contact throughout the treatment volume. This shows a significant improvement in applicator positioning in our centre since 2008 and also a significant improvement over the total data published in 2010 (Pearson χ(2) test=46.19; p<0.0001). CONCLUSION: The vaginal cylinder technique with CT imaging was proven to be effective for 96/103 patients. It is necessary to consider whether there is a better technique for the few patients with air gaps >2 mm. ADVANCES IN KNOWLEDGE: For the vast majority of patients, this technique is well tolerated, without the need for analgesia, and will continue to be the first choice technique in this centre.