Monitoring treatment response in metastatic breast cancer:impact of FDG-PET/CT on survival and costs

Baggrund: Internationale retningslinjer giver ikke klare anbefalinger om valg af billeddiagnostisk modalitet til diagnostik af metastatisk brystkræft, og forskellige modaliteter anvendes derfor og følger ofte lokal praksis. Der foreligger imidlertid evidens om, at 18FFluordeoxyglucose-positron emissions tomografi /computertomografi (FDG-PET/CT) har høj følsomhed til diagnostik af fjernmetastaser i denne patientgruppe. FDG-PET/CT kan derfor også have potentiale til at forbedre monitoreringen af behandlingsrespons hos patienter med metastatisk brystkræft, men forskning på dette område har været sparsom. Vi havde til formål at sammenligne 1) responskategorier og deres kliniske effekt, 2) overlevelse og 3) omkostningseffektiviteten af FDG-PET/CT versus kontrastforstærket computertomografi (CECT) til responsovervågning hos patienter med metastatisk brystkræft.Metoder: I et observationelt register-baseret studie inkluderede vi 300 patienter med biopsi-verificeret metastatisk brystkræft, diagnosticeret og behandlet mellem 2004 og 2018 på Onkologisk Afdeling, Odense Universitetshospital. Valg af billeddiagnostisk modalitet til responsmonitorering blev foretaget af den behandlende onkolog i klinikken. Valget varierede hovedsageligt mellem CE-CT og FDGPET/CT. Patienterne blev kategoriseret i tre grupper: en CE-CT-gruppe (n=144), FDG-PET/CT-gruppe (n=83) og en kombineret gruppe (n=73). I den kombinerede gruppe blev patienterne overvåget skiftevis med CE-CT og FDG-PET/CT med minimum to scanninger af hver modalitet. Kun én af de modsatte scanningstyper blev accepteret i CE-CT og FDG- PET/CT-grupper. Kliniske og sundhedsrelaterede omkostningsoplysninger blev indsamlet fra patienternes journaler, og patienterne blev fulgt indtil august 2019, hvor analyser af overlevelse og omkostningseffektivitet blev foretaget. Vi analyserede endvidere responskategorierne og deres indvirkning på klinisk beslutningstagning for undergrupper af patienter i CE-CT (n=34, 286 scanninger) og FDG-PET/CT-grupperne (n=31, 189 scanninger). Den samlede overlevelsestid blev defineret som tid fra bekræftelse af metastase til død, idet slutningen af undersøgelsesperioden blev brugt som censureringshændelse. Tiden til den første progression blev defineret til at være fra baseline-scanningen til den første progression, der førte til behandlingsændring i klinikken. Kaplan-Meier kurver blev brugt til at estimere overlevelsesfunktionen i undersøgelsesgrupperne. Cox-regressionsmodellen var begrænset til CE-CT-gruppen (sat som reference) og FDG-PET/CT-gruppen.Resultater: Den mediane (min-max) opfølgningstid var 33,0 (3,6-130,6) måneder. Grupperne var overvejende sammenlignelige med hensyn til baseline-karakteristika. Nogle få karakteristika havde signifikant forskellig fordeling mellem grupperne, men de var ikke var til fordel for nogen af grupperne. For eksempel var det flere patienter i CT-gruppen levermetastaser, mens flere patienter i PET-gruppen var med lungemetastaser. Vi observerede en signifikant forskel (P&lt; 0,001) mellem grupperne i fordeling af responskategorier; FDG-PET/CT rapporterede hyppigere sygdomsregression (46,0% vs. 12,2%), mens CE-CT rapporterede stabil sygdom oftere (70,6% vs. 31,2%). Median samlet overlevelse (måned) var lavere for CE-CT-gruppen (30,0) sammenlignet med FDG-PET/CT-gruppen (44,3) og den kombinerede gruppe (54,0). Hazard-ratio var 0,44 (P=0,001) for FDG-PET/CT-gruppen (vs. CE-CT-gruppen) efter justering for baseline-karakteristika. Femårs overlevelsessandsynligheder var signifikant højere for FDG-PET/CT og de kombinerede grupper end for CE-CT gruppen (fordel på henholdsvis 26,1% og 27,5%). Den første progression, der førte til behandlingsændring, forekom i gennemsnit 4,7 måneder tidligere i FDG-PET/CT-gruppen end i CE-CT-gruppen (12,9 vs. 17,6 måneder, P=0,03). Den gennemsnitlige (min-max) samlede pris pr. patient var €91.547 (9.585-394.275) for CE-CT-gruppen, €83.965 (17.390-341.934) for FDG-PET/CT-gruppen og €165.784 (30.287-585) for den kombinerede gruppe. ”Incremental cost-effectiveness ratio” (ICER) for FDG-PET/CT (vs. CE-CT) var -527, hvilket betyder, at responsmonitorering med FDG-PET/CT resulterede i en ekstra måneds overlevelse til en lavere pris (€527).Konklusioner: Patienter i behandling for metastatisk brystkræft, som fik overvåget behandlingseffekten med FDG-PET/CT alene eller i kombination med CE-CT havde en forbedret samlet overlevelse på 14-24 måneder sammenlignet med patienter monitoreret med CE-CT alene. FDG-PET/CT påviste ændringer i respons (regression/progression) hyppigere end CE-CT, der oftere rapporterede stabil sygdom. FDG-PET/CT ser ud at være en mere følsom og omkostningseffektiv modalitet end CE-CT til overvågning af behandlingsrespons hos patienter med metastatisk brystkræft. Disse resultater ønskes imidlertid efterprøvet, helst i et prospektivt multicenter randomiseret forsøg.Background: Various diagnostic modalities are being used for staging metastatic disease in breast cancer patients since international guidelines do not yet provide clear recommendations on the modality of choice for this indication. Evidence has confirmed that 18F-fluorodeoxyglucose-positron emission tomography with integrated computed tomography (FDG-PET/CT) has a perfect sensitivity for the diagnosis of distant metastases in this patient group. FDG-PET/CT may therefore also have the potential to improve monitoring of treatment response in patients with metastatic breast cancer, but research in this field has been scarce. We aimed to compare 1) response categories and their clinical impact, 2) survival times, and 3) cost-effectiveness of FDG-PET/CT versus contrast-enhanced computed tomography (CECT) for response monitoring in patients with metastatic breast cancer. Methods: In this observational registry-based study, we included 300 biopsy-verified metastatic breast cancer patients, diagnosed and treated between 2004 and 2018 at the Department of Oncology at Odense University Hospital, Denmark. The response monitoring modalities used in the clinic varied mainly between CE-CT and FDG-PET/CT with the choice of the modality made by the oncologist. The patients were categorized into three groups: a CE-CT group (n=144), a FDG-PET/CT group (n=83), and a combined group (n=73). In the combined group, patients were monitored alternately with CE-CT and FDGPET/CT, having a minimum of two scans of each modality, while only one of the opposite scan types was accepted in the CE-CT and FDG-PET/CT groups. The clinical and health-related cost information was gathered from patients’ medical records, and the patients were followed until August 2019 for survival and cost-efficacy analyses. We analyzed the response categories and their impact on clinical decision making for subgroups of patients in the CE-CT (n=34, 286 scans) and the FDG-PET/CT groups (n=31, 189 scans). The overall survival time was defined as the time from confirmation of metastasis until death, using the end of the study period as the censoring event. The time to the first progression was defined to be from the baseline scan to the first progression that led to the patient’s treatment change in the clinic. The Kaplan-Meier curve was used to estimate the survival function within the study groups. Cox regression model was restricted to the CE-CT group (set as reference) and the FDGPET/CT group.Results: The median (range) follow-up time was 33.0 (3.6-130.6) months. The groups were mostly comparable regarding the baseline characteristics, while a few characteristics with significant difference were not in favor of any of the groups. A statistically significant difference (PConclusions: Metastatic breast cancer patients who were response monitored with FDG-PET/CT alone or in combination with CE-CT had an improved overall survival of 14-24 months compared to patients monitored with CE-CT alone. FDG-PET/CT detected changes in response (regression/progression) more frequently than CE-CT, and CE-CT reported stable disease more often. FDG-PET/CT seems to be a more sensitive and cost-effective modality than CE-CT for monitoring treatment response in metastatic breast cancer, while confirmation of these results are warranted in prospective multi-center randomized trials.<br/

A role of FDG-PET/CT for response evaluation in metastatic breast cancer?

Breast cancer prognosis is steadily improving due to early detection of primary cancer in screening programs and revolutionizing treatment development. In the metastatic setting, therapy improvements render breast cancer a chronic disease. Although FDG-PET/CT has emerged as a highly accurate method for staging metastatic breast cancer, there has been no change in response evaluation methods for decades. FDG-PET/CT has proven high prognostic values in patients with metastatic breast cancer when using quantitative PET methods. It has also shown a higher predictive value than conventional CT when applying the respective response evaluation criteria, RECIST and PERCIST. Response categorization using FDG-PET/CT is more sensitive in detecting progressive and regressive disease, while conventional imaging such as CT and bone scintigraphy deem stable disease more often. These findings reflect the higher accuracy of FDG-PET/CT for response evaluation in this patient group. But does the higher accuracy of FDG-PET/CT translate into a patient benefit when implementing it for monitoring response to palliative treatment? We have evidence of survival benefit from a retrospective study indicating the superiority of using FDG-PET/CT compared with conventional imaging for response evaluation in metastatic breast cancer patients. The survival benefit seems to result from earlier detection of progression with FDG-PET/CT than conventional imaging, leading to an earlier change in treatment with potentially better efficacy of the subsequent treatment line. FDG-PET/CT can be used semiquantitatively as suggested in PERCIST. However, we still need to improve clinically applicable methods based on neural network modeling to better integrate the quantitative information in a smart and standardized way, enabling relevant comparability between scans, patients, and institutions. Such innovation is warranted to support imaging specialists in diagnostic response assessment. Prospective multicenter studies analyzing patients’ survival, quality of life, societal and patient costs of replacing conventional imaging with FDG-PET/CT are needed before firm conclusions can be drawn on which type of scan to recommend in future clinical guidelines.</p

Spontaneous Rupture of Pyometra

Spontaneous perforation is a very rare complication of pyometra. The clinical findings of perforated pyometra are similar to perforation of the gastrointestinal tract and other causes of acute abdomen. In most cases, a correct and definite diagnosis can be made only by laparotomy. We report two cases of diffuse peritonitis caused by spontaneous perforated pyometra. The first case is a 78-year-old woman with abdominal pain for which laparotomy was performed because of suspected incarcerated hernia. The second case is a 61-year-old woman with abdominal pain for which laparotomy was performed because of symptoms of peritonitis. At laparotomy of both cases, 1 liter of pus with the source of uterine was found in the abdominal cavity. The ruptured uterine is also detected. More investigations revealed no malignancy as the reason of the pyometra

Effect of Flushing the Endometrial Cavity With Follicular Fluid on Implantation Rates in Sub-Fertile Women Undergoing Invitro Fertilization:A Randomized Clinical trial

Objective: To examine the effectiveness of intrauterine injection of follicular fluid in in vitro fertilization (IVF). Materials and methods: A parallel randomized control clinical study was conducted on 110 patients attending Al-Zahra Educational-Medical Center of Tabriz University of Medical Sciences. Female candidates for IVF were categorized into intervention (n = 55) and control (n = 55) groups using Randlast software (version 1.2). Following an identical protocol of gonadotropin-releasing hormone (Gnrh) antagonist stimulating ovulation, in the intervention group a total of 2mL of follicular fluid was injected as intrauterine after the accomplishment of follicular puncture. Embryo transfer was carried out after 2-3 days. The rates of implantation, as well as chemical and clinical pregnancy were compared between the two groups. Results: There were no significant differences in chemically proven pregnancy (19 in intervention group (34.5%) vs. 23 (41.8%) in control group p = 0.43), or in clinical pregnancy (30.9% vs. 38.2%, respectively p = 0.42), and in implantation rates (11.52 ± 2.57 % (range, 0-66.7) vs 18.79 ± 3.72 % (range, 0-100), respectively). Conclusion: Injection of follicular fluid into the uterine cavity in candidates for IVF neither improves nor adversely affects the outcome of the therapy.</p

Effect of Flushing the Endometrial Cavity With Follicular Fluid on Implantation Rates in Sub-Fertile Women Undergoing Invitro Fertilization:A Randomized Clinical trial

Objective: To examine the effectiveness of intrauterine injection of follicular fluid in in vitro fertilization (IVF). Materials and methods: A parallel randomized control clinical study was conducted on 110 patients attending Al-Zahra Educational-Medical Center of Tabriz University of Medical Sciences. Female candidates for IVF were categorized into intervention (n = 55) and control (n = 55) groups using Randlast software (version 1.2). Following an identical protocol of gonadotropin-releasing hormone (Gnrh) antagonist stimulating ovulation, in the intervention group a total of 2mL of follicular fluid was injected as intrauterine after the accomplishment of follicular puncture. Embryo transfer was carried out after 2-3 days. The rates of implantation, as well as chemical and clinical pregnancy were compared between the two groups. Results: There were no significant differences in chemically proven pregnancy (19 in intervention group (34.5%) vs. 23 (41.8%) in control group p = 0.43), or in clinical pregnancy (30.9% vs. 38.2%, respectively p = 0.42), and in implantation rates (11.52 ± 2.57 % (range, 0-66.7) vs 18.79 ± 3.72 % (range, 0-100), respectively). Conclusion: Injection of follicular fluid into the uterine cavity in candidates for IVF neither improves nor adversely affects the outcome of the therapy.</p

Age at diagnosis of breast cancer in iran:A systematic review and meta-analysis

Background: Breast cancer is responsible for up to 25% of all cancers in Iran. The age at diagnosis of Iranian breast cancer patients starts a decade earlier than most of developed countries. This study aimed to evaluate the mean age at diagnosis of Iranian breast cancer patients. Methods: In this systematic review and meta-analysis, the mean age at diagnosis of Iranian breast cancer patients and its pattern between 2008 and 2017, were evaluated. All papers with age at diagnosis of histopathological verified breast cancer patients were considered eligible to enter to the analysis. We used databases including Medline/PubMed, Scopus, Embase, Cochrane Library, Iranmedex and SID for the search process. The meta-analysis was performed only on studies with separate data for female patients, using random-effects model, Mantel and Haenszel method and the Comprehensive Meta-analysis software. Results: Finally, 92 studies with 19,784 patients (both-genders) were included. The mean age at diagnosis had increased from 47.93 (2008) to 49.91 (2016) years. The meta-analysis was done on 78 studies containing of 15,071 female patients and the mean age at diagnosis was 46.76±1.19. There was a wide range of age at diagnosis within different provinces. The mean age at Hamadan and Khuzestan provinces were the lowest and high-est, respectively (42.48±7.96 vs. 51.00±11.47). The heterogeneity of studies was statistically significant (I2=99.744). Conclusion: Mean age at diagnosis of Iranian women with breast cancer was 46.76±1.19. There was an increasing pattern in mean age of diagnosis at breast cancer patients within the past 10 years.</p

Relationship Between Serum Vitamin D Level and Ectopic Pregnancy:A Case-Control Study

Objective: To compare the difference in Vitamin D level between women with ectopic pregnancy and control group. Materials and methods: In the present case-control study, 150 patients with ectopic pregnancy were included as case group and 150 women with normal pregnancy as a control group. Then, serum vitamin D levels were measured in both groups and they were then compared with each other. P less than 0.05 was considered statistically significant. Results: The mean age in ectopic pregnancy group was 28.12 ± 5.91 and 27.35 ± 6.21 years old in control group; the difference between two groups was not statistically significant (p = 0.43). The vitamin D level in control group was higher than that of ectopic pregnancy group (p = 0.002). Of all patients, 182 patients (60.66%) had vitamin D deficiency and 64 patients (21.33%) had vitamin D insufficiency. Conclusion: Serum vitamin D level among patients with ectopic pregnancy was statistically lower than women with normal pregnancy.</p

Age at diagnosis of breast cancer in iran:A systematic review and meta-analysis

Background: Breast cancer is responsible for up to 25% of all cancers in Iran. The age at diagnosis of Iranian breast cancer patients starts a decade earlier than most of developed countries. This study aimed to evaluate the mean age at diagnosis of Iranian breast cancer patients. Methods: In this systematic review and meta-analysis, the mean age at diagnosis of Iranian breast cancer patients and its pattern between 2008 and 2017, were evaluated. All papers with age at diagnosis of histopathological verified breast cancer patients were considered eligible to enter to the analysis. We used databases including Medline/PubMed, Scopus, Embase, Cochrane Library, Iranmedex and SID for the search process. The meta-analysis was performed only on studies with separate data for female patients, using random-effects model, Mantel and Haenszel method and the Comprehensive Meta-analysis software. Results: Finally, 92 studies with 19,784 patients (both-genders) were included. The mean age at diagnosis had increased from 47.93 (2008) to 49.91 (2016) years. The meta-analysis was done on 78 studies containing of 15,071 female patients and the mean age at diagnosis was 46.76±1.19. There was a wide range of age at diagnosis within different provinces. The mean age at Hamadan and Khuzestan provinces were the lowest and high-est, respectively (42.48±7.96 vs. 51.00±11.47). The heterogeneity of studies was statistically significant (I2=99.744). Conclusion: Mean age at diagnosis of Iranian women with breast cancer was 46.76±1.19. There was an increasing pattern in mean age of diagnosis at breast cancer patients within the past 10 years.</p

Radiological findings in patients with H1N1:A report from the referral center of Northwest of Iran

Background: Influenza viruses are classified into three types of A, B, and C, with H1N1 being a member of the influenza A subtype. The majority of people infected with influenza, namely H1N1, exhibit self-limited, uncomplicated, and acute febrile respiratory symptoms, or are asymptomatic. However, severe disease and complications due to infection, including hospitalization and death may occur. One of the most prominent features of influenza infections are radiologic findings in chest X-rays, computed tomographic scan, and angiographies. Methods: In a descriptive-analytical study, all patients who were diagnosed with H1N1 at the Sina Educational-Medical Center of Tabriz University of Medical Sciences (Tabriz, Iran) from September 2015 to September 2016 were analyzed based on age, clinical presentation, and radiological findings. Results: A total of 53 cases, 30 females (57%) and 23 males (43%), were included in the study. The mean age was 48.45 ± 1.7. The most common clinical presentation was myalgia (92.5%). Chest X-ray (CXR) was done in all patients, 35 cases (66%) were found with bilateral abnormality, 11 cases (20.8%) without abnormality, and seven cases (13.2%) with unilateral abnormality. Chest computerized tomography (CT) scan was also done on all patients, 33 cases (62.2%) were found with bilateral abnormality, 17 cases (32%) without abnormality, and three cases (5.6%) with unilateral abnormality. CT angiography was done in eight patients; none of the patients showed any signs of pulmonary embolism. It was observed that CXR and CT-scan were both precise in studying radiological findings in H1N1. Conclusions: The majority of patients had revealed bilateral abnormality in radiographic findings, and unilateral involvement was less common; in addition, involvement in the superior lobes of the lungs were more common than the basal lobes. CXR and CT scans had no significant difference in diagnosing the disease.</p