Fertility treatment and cancers—the eternal conundrum: a systematic review and meta-analysis

STUDY QUESTION: Does fertility treatment (FT) significantly increase the incidence of breast, ovarian, endometrial or cervical cancer? SUMMARY ANSWER: Overall, FT does not significantly increase the incidence of breast, ovarian or endometrial cancer and may even reduce the incidence of cervical cancer. WHAT IS KNOWN ALREADY: Infertility affects more than 14% of couples. Infertility and nulliparity are established risk factors for endometrial, ovarian and breast cancer, yet the association with FT is more contentious. STUDY DESIGN, SIZE, DURATION: A literature search was carried out using Cochrane Library, EMBASE, Medline and Google Scholar up to December 2019. Peer-reviewed studies stating cancer incidence (breast, ovarian, endometrial or cervical) in FT and no-FT groups were identified. Out of 128 studies identified, 29 retrospective studies fulfilled the criteria and were included (n = 21 070 337). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the final meta-analysis, 29 studies were included: breast (n = 19), ovarian (n = 19), endometrial (n = 15) and cervical (n = 13), 17 studies involved multiple cancer types and so were included in each individual cancer meta-analysis. Primary outcome of interest was cancer incidence (breast, ovarian, endometrial and cervical) in FT and no-FT groups. Secondary outcome was cancer incidence according to specific fertility drug exposure. Odds ratio (OR) and random effects model were used to demonstrate treatment effect and calculate pooled treatment effect, respectively. A meta-regression and eight sub-group analyses were performed to assess the impact of the following variables, maternal age, infertility, study size, outliers and specific FT sub-types, on cancer incidence. MAIN RESULTS AND THE ROLE OF CHANCE: Cervical cancer incidence was significantly lower in the FT group compared with the no-FT group: OR 0.68 (95% CI 0.46-0.99). The incidences of breast (OR 0.86; 95% CI 0.73-1.01) and endometrial (OR 1.28; 95% CI 0.92-1.79) cancers were not found to be significantly different between the FT and no-FT groups. Whilst overall ovarian cancer incidence was not significantly different between the FT and no-FT groups (OR 1.19; 95% CI 0.98-1.46), separate analysis of borderline ovarian tumours (BOT) revealed a significant association (OR 1.69; 95% CI 1.27-2.25). In further sub-group analyses, ovarian cancer incidence was shown to be significantly higher in the IVF (OR 1.32; 95% CI 1.03-1.69) and clomiphene citrate (CC) treatment group (OR 1.40; 95% CI 1.10-1.77), respectively when compared with the no-FT group. Conversely, the incidences of breast (OR 0.75; 95% CI 0.61-0.92) and cervical cancer (OR 0.58; 95% CI 0.38-0.89) were significantly lower in the IVF treatment sub-group compared to the no-FT group. LIMITATIONS, REASONS FOR CAUTION: The large, varied dataset spanning a wide study period introduced significant clinical heterogeneity. Thus, results have to be interpreted with an element of caution. Exclusion of non-English citations, unpublished work and abstracts, in order to ensure data accuracy and reliability was maintained, may have introduced a degree of selection bias. WIDER IMPLICATIONS OF THE FINDINGS: The results for breast, ovarian, endometrial and cervical cancer are reassuring, in line with previously published meta-analyses for individual cancers but the association between IVF and CC treatment and an increase in ovarian cancer incidence requires additional work to understand the potential mechanism driving this association. In particular, focusing on (i) discriminating specific treatments effects from an inherent risk of malignancy; (ii) differential risk profiles among specific patient sub-groups (refractory treatment and obesity); and (iii) understanding the impact of FT outcomes on cancer incidence. STUDY FUNDING/COMPETING INTEREST(S): This study did not receive any funding. The authors have no financial, personal, intellectual and professional conflicts of interest to declare. PROSPERO REGISTRATION NUMBER: CRD42019153404

The intelligent-Knife (i-Knife) and its intraoperative diagnostic advantage for the treatment of cervical disease

Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory m/z features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 samples (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer samples, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

The challenge of improving IVF results in normogonadotrophic (unexpected) young poor ovarian responders: the predictive value of a flexible treatment protocol based on the “biophysical profile of the uterus”

Objective: To study whether the unexpected poor ovarian responders optimization of uterine receptivity with a flexible controlled ovarian hyper stimulation protocol based on the Biophysical Profile of the Uterus, has an impact on their reproductive performance. Design: Observational Prospective study. Setting(s): i) General hospital-IVF and Infertility Centre; ii) University hospital. Patient(s): 44 normogonadotrophic young women (26 - 38 yrs) with previous “unexpected” poor ovarian response underwent IVF/ICSI treatment on a protocol based on the Biophysical Profile of their uterus (Group A). The same patients were used as controls in a preceded IVF cycle on the conventional stimulation protocol. Intervention(s): None. Main outcome measure(s): Pregnancy, miscarriage and home take baby rates, amount and duration of gonadotropins required, number and quality of embryos resulted, Biophysical Profile of the Uterus score. Result(s). Treatment in Group A in comparison to Group B resulted in significantly larger number of eggs retrieved per patient, and improved fertilization rates and higher number of embryos/ET (p = 0.011, 0.010 and 0.034 respectively). Group A also demonstrated a trend for higher rates of clinical pregnancy (29.5% v.s. 15.9%), viable stage pregnancies ≥ 24 weeks (33.3% v.s. 20%) and home take babies (26.6% v.s. 16%). The amount of gonadotropins used per patient (IU) was similar in the two groups (p = 0.264). Cancellation, implantation and miscarriage rates as well as embryos quality, although superior in the treatment Group A, showed no significant difference. The number of pregnancies achieved in Group A, were directly related with the score in the Biophysical Profile of the Uterus 12 point scale. Conclusion(s): Unexpected Poor Ovarian Responders on the flexible IVF/ICSI protocol (Group A), adjusting the management according to the Biophysical Profile of their uterus (duration of stimulation, day of HCG and day of embryo transfer), had a significantly better performance in comparison to the Group B managed on the conventional protocol in this difficult to manage and so far, rather understudied population

Neoadjuvant chemotherapy and surgery versus chemoradiotherapy for locally advanced cervical cancer

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. The aim of this review is to compare neoadjuvant chemotherapy (NACT) followed by radical surgery (RS) versus chemoradiotherapy (CRT) for locally advanced cervical cancer

A novel application of calcium electroporation to cutaneous manifestations of gynaecological cancer

Introduction: Calcium electroporation (CaEP) is a new technique whereby intracellular concentrations of calcium are elevated by transient permeabilisation of the cell membrane using high-voltage electrical pulses. Tumour necrosis is induced with little damage to healthy tissue. Within gynaecological cancer, vulval cancer and vulval intraepithelial neoplasia (VIN) pose challenges for treatment, given the high recurrence rate, persistent symptoms and repeated resections required. In certain cases, CaEP may provide a suitable alternative. Methods: We present a case series of six patients with recurrent vulval squamous cell carcinoma(n=2), VIN III (n=2) and metastatic ovarian cancer (n=2), five of whom were treated with CaEP. This is the first known application of CaEP to gynaecological cancers .Results: The median follow-up time was 14 months (range 2-18 months). Within the cohort of patients, CaEP was applied a total of 10 times, achieving a complete response five times and partial response four times. Symptoms improved within six weeks for eight episodes following CaEP application. Beyond six weeks, symptoms eventually recurred in all patients and four patients required more than one CaEP procedure. CaEP was useful for palliation of distressing symptoms in one case of metastatic ovarian cancer. No intra-operative or post-operative complications have been reported to date. Conclusion: CaEP may be a promising short-term treatment in selected patients with recurrent VIN and vulval cancer, where other treatments had failed. If validated, it could provide an acceptable alternative where surgery is unacceptable. Long term follow-up is required to evaluate effects on recurrence