Human papillomavirus vaccine impact on invasive cervical cancer in Japan: Preliminary results from cancer statistics and the MINT study.

The first prophylactic vaccine against human papillomavirus (HPV) 16 and HPV18 was licensed in Japan in 2009. HPV vaccine effectiveness against high-grade cervical lesions has been demonstrated among young Japanese women, but evidence of its effects on invasive cervical cancer (ICC) is lacking. Using data from two different cancer registries, we compared recent trends of new ICC cases by age group using Poisson regression analysis. We also analyzed time trends in HPV16/18 prevalence among 1414 Japanese women aged <40 years newly diagnosed with ICC in the past decade. Based on the population-based cancer registry, the incidence of ICC among young women aged 20-29 years showed a significant decline from 3.6 to 2.8 per 100 000 women-years during 2016-2019, but no similar decline was observed for older age groups (p < 0.01). Similarly, using data from the gynecological cancer registry of the Japan Society of Obstetrics and Gynecology, the annual number of ICCs among women aged 20-29 years also decreased from 256 cases to 135 cases during 2011-2020 (p < 0.0001). Furthermore, a declining trend in HPV16/18 prevalence in ICC was observed only among women aged 20-29 years during 2017-2022 (90.5%-64.7%, p = 0.05; Cochran-Armitage trend test). This is the first report to suggest population-level effects of HPV vaccination on ICC in Japan. Although the declining trend in HPV16/18 prevalence among young women with ICC supports a causal linkage between vaccination and results from cancer registries, further studies are warranted to confirm that our findings are attributable to vaccination.

Prognostic Factors of Cervical Adenocarcinoma With Positive Pelvic Lymph Node Metastases Without Preoperative Lymph Node Enlargement Treated With Radical Hysterectomy.

BACKGROUND/AIM: Pelvic lymph node (LN) metastases are found histopathologically after radical hysterectomy (RH) in some cases of cervical adenocarcinoma with no enlarged LNs on preoperatively. The aim was to clarify whether LN metastasis is a prognostic factor in these patients, and whether any postoperative therapy is advisable. PATIENTS AND METHODS: Sixty-one patients with stage I-II cervical adenocarcinoma [International Federation of Obstetrics and Gynecology (FIGO) 2008] with no enlarged pelvic LNs on preoperative imaging evaluation who underwent RH at our institution were retrospectively examined for clinicopathological, treatment, and prognosis-related factors. RESULTS: The median age was 47 years. FIGO stages were IB1 in 44 patients, IB2 in 10, IIA in 4, and IIB in 3. Seventeen patients (27.9%) had positive pelvic LNs. The multivariate analysis for both overall (OS) and disease-free (DFS) survival showed only pelvic LN metastasis was an independent prognostic factor. In a multivariate analysis of LN-positive cases, multiple LN metastases was an independent prognostic factor for poorer DFS. OS rates were 100%, 83.3%, and 30.0%, and DFS rates were 85.5%, 83.3%, and 12.5% for patients with no LN metastasis, single metastasis, and multiple metastases, respectively, showing a significant difference. Eight recurrences were observed in 10 patients with multiple node-positive disease, and six (75%) had an intrapelvic recurrence. CONCLUSION: Among patients who underwent RH for cervical adenocarcinoma with no preoperative enlarged LN and positive pelvic LNs confirmed postoperatively, multiple positive pelvic LNs are an independent poor prognostic factor. Because pelvic recurrence is common, concurrent chemoradiotherapy, possibly using paclitaxel and cisplatin, should be considered as adjuvant therapy.

Sarcopenia Is an Independent Prognostic Factor for Squamous Cell Carcinoma of the Cervix Treated With Concurrent Chemoradiotherapy.

BACKGROUND/AIM: To investigate sarcopenia as a predictor of prognosis before concurrent chemoradiotherapy (CCRT) in patients with squamous cell carcinoma (SCC) of the cervix using the new psoas muscle index (PMI) cutoff value for sarcopenia in Japanese women. PATIENTS AND METHODS: We included 134 patients with SCC of the cervix treated with CCRT. CT images were taken within one month before treatment. Measurements of PM and skeletal muscle (SM) area were taken at the L3 level using a CT image analysis system (Synapse Vincent). Whole-pelvic external beam radiotherapy (EBRT) with 50 Gy was performed. High-dose-rate intracavitary brachytherapy and boost EBRT doses were administered. The patients received 40 mg/m2 of cisplatin weekly during CCRT. Kaplan-Meier analysis and the log-rank test were used to compare survival rates. RESULTS: The five-year overall survival (OS) and five-year progression-free survival of all 134 patients were 86.1% and 77.3%, respectively. Univariate analysis revealed that only PMI had a significant association with OS (PMI <3.92 cm2/m2 in the sarcopenia group vs. PMI ≥3.92 cm2/m2 in the non-sarcopenia group, p=0.0112), with no significant differences in age, advanced stage of disease, tumor size, lymph node enlargement, serum SCC, or SMI. Multivariate analysis revealed that PMI is the only independent prognostic factor for OS, but none of the factors were found to have a significant association with PFS. CONCLUSION: PMI as an indicator of sarcopenia was found to be an independent prognostic factor for patients with SCC of the cervix who underwent CCRT.

Effects of Pegylated Liposomal Doxorubicin and CA125 Level Variability Analysis in Platinum-refractory/resistant Recurrent Ovarian Cancer.

BACKGROUND/AIM: Ovarian cancer is a disease with significant impact, because more than half of cases exhibit recurrence despite platinum therapy. The choice of drug for cases of recurrence remains controversial, but the current option is pegylated liposomal doxorubicin (PLD). PATIENTS AND METHODS: We retrospectively reviewed the use of PLD in patients with ovarian cancer refractory or resistant to platinum-based therapy at our Department. We also examined efficacy, predictive indices of efficacy, and adverse events as well. RESULTS: In this study of PLD monotherapy for 60 platinum-refractory/resistant recurrent ovarian cancers, there was a median progression-free survival (PFS) of 4 months, median overall survival (OS) of 11 months, and the disease control rate (DCR) was 71.7%. The treatment effect can be predicted by the reduction of CA125 level after 2 courses. Patients with an increase and decrease in CA125 after 2 cycles of PLD, respectively, had a median OS of 14.5 (2-60) and 8 (2-51) months and a median PFS of 6 (2-38) months and 3 (0-47) months. CONCLUSION: PLD is clinically effective and useful because it provides a high DCR and is tolerable to adverse events. These findings can help support the use of PLD and guide physicians in their choice of treatment when encountering such cases.

Comprehensive Genomic Profiling for Therapeutic Decision and Identification of Gene Mutation in Uterine Endometrial Dedifferentiated Carcinoma.

Endometrial dedifferentiated carcinoma is a new concept among endometrial malignancies, is rare, and has a poor prognosis as it is discovered in advanced stages and has no established treatment. It has higher rates of gene mutations, such as mismatch repair, than general endometrial cancer and has been associated with Lynch syndrome. However, due to its heterogeneity, case-by-case searches are needed. Comprehensive genomic profiling by Foundation One® CDx can comprehensively identify over 300 gene mutations via a next-generation sequencer and can evaluate biomarkers, such as the microsatellite status and tumor mutation burden. Therefore, it may be beneficial in identifying therapeutic targets and drugs for diseases whose treatment has not been established. In this case, 13 therapies, including immune checkpoint inhibitor therapy for microsatellite instability-High and 40 clinical trials for several gene mutations might be beneficial. We report a case of endometrial dedifferentiated carcinoma for which Foundation One® CDx gene profiling was used to propose treatment.

Human papillomavirus vaccine effectiveness by age at first vaccination among Japanese women.

In Japan, the National Immunization Program against human papillomavirus (HPV) targets girls aged 12-16 years, and catch-up vaccination is recommended for young women up to age 26 years. Because HPV infection rates increase soon after sexual debut, we evaluated HPV vaccine effectiveness by age at first vaccination. Along with vaccination history, HPV genotyping results from 5795 women younger than 40 years diagnosed with cervical intraepithelial neoplasia grade 2-3 (CIN2-3), adenocarcinoma in situ (AIS), or invasive cervical cancer were analyzed. The attribution of vaccine-targeted types HPV16 or HPV18 to CIN2-3/AIS was 47.0% for unvaccinated women (n = 4297), but 0.0%, 13.0%, 35.7%, and 39.6% for women vaccinated at ages 12-15 years (n = 36), 16-18 years (n = 23), 19-22 years (n = 14), and older than 22 years (n = 91), respectively, indicating the greater effectiveness of HPV vaccination among those initiating vaccination at age 18 years or younger (P < .001). This finding was supported by age at first sexual intercourse; among women with CIN2-3/AIS, only 9.2% were sexually active by age 14 years, but the percentage quickly increased to 47.2% by age 16 and 77.1% by age 18. Additionally, the HPV16/18 prevalence in CIN2-3/AIS was 0.0%, 12.5%, and 40.0% for women vaccinated before (n = 16), within 3 years (n = 8), and more than 3 years after (n = 15) first intercourse, respectively (P = .004). In conclusion, our data appear to support routine HPV vaccination for girls aged 12-14 years and catch-up vaccination for adolescents aged 18 years and younger in Japan.

Small dose of oral gastrografin for computed tomography-based image-guided brachytherapy in patients with uterine cervical cancer.

Oral administration of a water-soluble iodine contrast agent (gastrografin) was reported to assist in the appropriate contouring of the small intestine on computed tomography (CT)-based radiotherapy (RT) planning. The efficacy and optimal dose of gastrografin in CT-based image-guided brachytherapy (IGBT) for cervical cancer remain unknown. This study aimed to investigate the efficacy of pretreatment oral administration of gastrografin at a small dose of 50 ml in CT-based IGBT for cervical cancer. A total of 422 sessions in 137 patients who underwent CT-based IGBT with 50 ml of oral gastrografin (concentration, 3% or 4%) were analyzed. Preparation of gastrografin was judged as effective when the small intestine was contrast-enhanced at the area where the small intestine was in contact with the uterus/adnexa. About 287 out of 422 sessions (68%) were judged as effective with gastrografin preparation. The 135 ineffective sessions were considered as follows: (i) the contrast enhancement of the small intestine was not confirmed (n = 36), (ii) the small intestine was not in contact with the uterus/adnexa despite the confirmation of the contrast enhancement of the small intestine (n = 34), and (iii) gastrografin was absent in the small intestine at the area in contact with the uterus/adnexa, even when gastrografin was observed in the small intestine at the area not in contact with the uterus/adnexa (n = 65). In conclusion, pretreatment oral administration of a small dose gastrografin achieved moderate efficacy for accurate contouring of the small intestine close to the uterus/adnexa in CT-based IGBT for cervical cancer.

Hyperbaric Oxygen Therapy for Suburethral Vaginal Mucosal Necrosis after Interstitial Irradiation for Recurrent Cervical Cancer.

Patients with gynecological malignancies can develop radiation injuries, such as cystitis, proctitis, and soft tissue necrosis which have approved indications for hyperbaric oxygen therapy (HBOT). A 76-year-old Japanese woman with vaginal recurrence of cervical cancer was treated with the high-dose rate interstitial brachytherapy. Twenty-one months after the irradiation, she developed radiation necrosis on the external urethral opening. Two cycles of HBOT were performed. HBOT consisted of delivering 100% oxygen for 60 minutes at 2.4 atmospheres absolute. Pressure exposure was performed once daily, 5 days a week for 6 weeks. Eventually, the necrotic mucosa was completely replaced by the normal mucosa. No adverse effects were observed. We successfully treated a case of late adverse events of radiation therapy with HBOT. It was noninvasive and appears to be a useful treatment option which should be considered standard treatment practice.

A high-risk gestational trophoblastic neoplasia derived from a complete hydatidiform mole with coexisting fetus identified by short tandem repeats analysis: A case report.

A complete hydatidiform mole coexisting with a fetus (CHMCF) is a rare form of twin pregnancy. High-risk gestational trophoblastic neoplasia (GTN) can occur after a CHMCF pregnancy, although the frequency is low. In cases of GTN, the clinical diagnosis and that based on the International Federation of Gynecology and Obstetrics (FIGO) scoring system can differ. This case report concerns a patient with a choriocarcinoma that was initially diagnosed and treated as a low-risk stage III GTN following a live birth from a CHMCF pregnancy. We used short tandem repeat (STR) analysis to identify the causative pregnancy as the patient's earlier complete hydatidiform mole. Clinicians should anticipate a high-risk GTN when treating persistent trophoblastic disease (PTD) in patients with a non-typical course.

A randomized phase II/III trial of conventional paclitaxel and carboplatin with or without bevacizumab versus dose-dense paclitaxel and carboplatin with or without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311): Primary analysis.

OBJECTIVE: To assess the efficacy and safety of dose-dense weekly paclitaxel plus carboplatin (ddTC) with or without bevacizumab compared to conventional, tri-weekly paclitaxel plus carboplatin (cTC) with or without bevacizumab, in metastatic or recurrent cervical carcinoma not amenable to curative local therapy. METHODS: Patients were randomly assigned to either the cTC or ddTC arm. The cTC regimen was paclitaxel 175 mg/m2 and carboplatin at an area under the curve (AUC) of 5 on day 1. The ddTC regimen was paclitaxel 80 mg/m2 on day 1, 8, 15 and carboplatin at AUC of 5 on day 1. Both cTC and ddTC treatments were repeated every 3 weeks for up to 9 cycles. After bevacizumab was approved in Japan, patients in both arms received bevacizumab 15 mg/kg if not contraindicated. The primary endpoint of phase II part was response rate (RR). If the RR of ddTC+bevacizumab was found to be at least 5% better than to cTC + bevacizumab, the study would proceed to phase III part, which had overall survival as its primary endpoint. CLINICAL TRIAL INFORMATION: jRCTs031180007. RESULTS: In total, 122 patients were randomly assigned to either the cTC arm (cTC + bevacizumab: 32; cTC:29) or the ddTC arm (ddTC+bevacizumab: 30; ddTC:31). The RR for patients on cTC + bevacizumab was 67.9%, and for patients on ddTC+bevacizumab 60.7%, cTC: 55.2%, and ddTC: 50.0%. CONCLUSIONS: The study did not meet the primary endpoint of phase II portion. Dose-dense, weekly paclitaxel plus carboplatin is not promising for metastatic or recurrent cervical carcinoma.

A case of nasal septal perforation caused by bevacizumab for advanced cervical cancer.

Nasal septal perforation caused by bevacizumab is rarely reported in other cancers such as ovarian cancer and breast cancer, but it has not been reported in cervical cancer. A 48-year-old woman with a medical history of chronic allergic rhinitis was diagnosed stage 4B (T2bN1M0) cervical cancer and paclitaxel and carboplatin along with bevacizumab (triweekly) were administered. After eight courses of chemotherapy, nasal septal perforation was noted. The possibility of nasal septal perforation by bevacizumab was considered by excluding other causes. We report the first case of nasal septal perforation caused by bevacizumab for advanced cervical cancer.

Predictive factors of posttreatment fracture by definitive radiotherapy for uterine cervical cancer.

PURPOSE: Fractures are known to shorten life expectancy and worsen the quality of life. The risk of fractures after radiation therapy in cervical cancer patients is known to be multifactorial. In this study, we examined risk factors for fractures in cervical cancer patients, especially by evaluating bone densities and DVH parameters for fractured bones. MATERIALS AND METHODS: For 42 patients, clinical characteristics, pretreatment CT bone densities, and radiation dose were compared between patients with and without fractures. RESULTS: Posttreatment fractures occurred in 25 bones among ten patients. Pretreatment CT bone densities were significantly lower in patients with fractures (P < 0.05-0.01 across sites, except for the ilium and the ischium). Although DVH parameters were also significantly associated with fractures in univariate analysis, only CT densities were significantly associated with fractures in multivariate analysis. CONCLUSION: Pretreatment CT densities of spinal and pelvic bones, which may reflect osteoporosis, have a significant impact on the risk for posttreatment fractures.

Propensity score-matched analysis of systemic chemotherapy versus salvage hysterectomy for persistent cervical cancer after definitive radiotherapy/concurrent chemoradiotherapy.

BACKGROUND: The aim of the current study was to evaluate oncologic outcomes of patients who were treated with salvage hysterectomy (HT), compared to systemic chemotherapy (CT) for persistent cervical cancer after definitive radiotherapy (RT)/ concurrent chemoradiotherapy (CCRT). METHODS: Patients with persistent cervical cancer treated with definitive RT/CCRT at 35 institutions from 2005 to 2014 were reviewed retrospectively (n = 317). Those who underwent a HT for persistent cervical cancer after definitive RT/CCRT were matched with propensity scores for patients who underwent systemic CT. Oncologic outcomes between the two groups using a propensity score matched-cohort analysis were compared. RESULTS: A total of 142 patients with persistent cervical cancer after definitive RT/CCRT were included after matching (HT: 71, systemic CT: 71). All background factors between HT and CT groups were well balanced. Median overall survival was 3.8 and 1.5 years in the HT and CT groups, respectively (p = 0.00193, hazards ratio [HR] 0.41, 95% confidence interval [CI] 0.23-0.73), Increasing residual tumor size was significantly associated with a high incomplete resection rate (p = 0.016, Odds Ratio 1.11, 95%CI 1.02-1.22). Severe late adverse events occurred in 7 patients (9.9%) in the HT cohort. CONCLUSION: The current study demonstrated that, when compared to systemic CT, the adoption of salvage HT for patients with persistent cervical cancer after definitive RT/CCRT reduced mortality rate by about 60%. This indicates that salvage HT could be curative treatment for those patients. Further prospective clinical trials with regard to salvage HT after RT/CCRT are warranted.

Long-term Outcomes of Cervical Adenocarcinoma Treated With Concurrent Chemoradiotherapy Using Paclitaxel and Cisplatin.

BACKGROUND/AIM: We retrospectively analyzed the locally advanced adenocarcinoma (AC)/adenosquamous carcinoma (ASC) of the uterine cervix treated with concurrent chemoradiotherapy using cisplatin plus paclitaxel (TP-CCRT). PATIENTS AND METHODS: Thirty patients with stage IB-IVA AC/ASC were treated with whole pelvis external beam radiotherapy. A high-dose-rate intracavitary brachytherapy was delivered once per week at a fractional dose of 6 Gy. For TP-CCRT, the patients received cisplatin and paclitaxel. RESULTS: A complete response was achieved in 17 patients (77.3%) in the TP-CCRT group and 4 patients (50.0%) in the P-CCRT group. The 5-year OS rate in the TP-CCRT and P-CCRT groups was 74.2% and 25.0% (p=0.0094), the central DFS rate was 58.0% and 12.5% (p=0.0267), and the distant DFS rate was 63.6% and 12.5% (p=0.0042), respectively. CONCLUSION: TP-CCRT achieves a considerably better disease control for AC of the cervix, leading to a better OS.

Definitive radiotherapy consisting of whole pelvic radiotherapy with no central shielding and CT-based intracavitary brachytherapy for cervical cancer: feasibility, toxicity, and oncologic outcomes in Japanese patients.

BACKGROUND: This prospective study investigated the feasibility, toxicity, and oncologic outcomes of definitive radiotherapy (RT) consisting of whole pelvic radiotherapy with no central shielding (noCS-WPRT) and CT-based intracavitary brachytherapy (ICBT) in Japanese patients with cervical cancer. METHODS: Patients with cervical cancer of FIGO stages IB1-IVA were eligible. The treatment protocol consisted of noCS-WPRT of 45 Gy in 25 fractions and CT-based high dose-rate ICBT of 15 or 20 Gy in 3 or 4 fractions prescribed at point A. The prescribed ICBT dose was decreased if the manual dwell time/position optimization failed to meet organs-at-risk constraints. Graphical optimization and additional interstitial needles were not applied. RESULTS: We enrolled 40 patients. FIGO stages were IB1: 11, IB2: 13, IIA2: 1, IIB: 11, IIIB: 3, and IVA: 1. Median (range) pretreatment tumor diameter was 47 (14-81) mm. Point A doses were decreased in 19 of 153 ICBT sessions (12%). The median follow-up duration was 33 months. The 2-year rates of pelvic control, local control (LC), and progression-free survival were 83%, 85%, and 75%, respectively. Pre-ICBT tumor diameter, high-risk clinical target volume (HR-CTV), total HR-CTV D90, and overall treatment time (OTT) significantly affected LC. Late adverse events (grade ≥ 3) were observed in 3 patients (2 in the bladder, 1 in the rectum). CONCLUSIONS: Definitive RT consisting of noCS-WPRT and CT-based ICBT was feasible for Japanese patients with cervical cancer. To further improve LC, additional interstitial needles for patients with a large HR-CTV and shorter OTT should be considered.

Hysterectomy for Recurrent/Residual Cervical Cancer Following Definitive Radiotherapy.

BACKGROUND/AIM: Radical hysterectomy has been used for local recurrent or persistent (LR) cervical cancer after radiotherapy (RT), but the rate of serious complications is high and tolerance is low. This study determined the efficacy, safety, and prognostic factors of adjuvant simple hysterectomy in LR cervical cancer post-RT. PATIENTS AND METHODS: A total of 21 patients who underwent hysterectomy for LR cervical cancer post-RT in our Department between May 2007 and September 2018 were included in the study. Primary, definitive RT was performed. Histological response by definitive RT in the extirpated uterus was classified on the basis of histological response criteria: effect (Ef) 0-3. RESULTS: The 5-year overall survival (OS) and disease-free survival (DFS) rates were 51.9% and 50.1%, respectively. Ef 1 was significantly associated with poorer prognosis compared to Ef 2 or Ef 3. CONCLUSION: Adjuvant hysterectomy could be a treatment of choice for LR cervical cancer post-RT.

A Phase II Study of Neoadjuvant Chemotherapy Followed by Extended Field Concurrent Chemoradiotherapy for Para-aortic Lymph Node Positive Cervical Cancer.

BACKGROUND/AIM: We conducted a phase II study of neoadjuvant chemotherapy followed by extended field concurrent chemoradiotherapy in patients with cervical cancer with para-aortic node metastasis. PATIENTS AND METHODS: Thirty-seven women with stage IB1-IVA cervical cancer were enrolled. RESULTS: The median age was 52 years. Thirty-four patients other than 3 progressive disease, proceeded to extended field concurrent chemoradiotherapy. The 3-year overall survival and progression-free survival rates were 70.1% and 48.5%, respectively. The 3-year overall survival according to stages was significantly worse in stage IIIB. Twelve of the 17 patients with stage IIIB died of the disease. CONCLUSION: Neoadjuvant chemotherapy followed by extended field concurrent chemoradiotherapy may improve the prognosis of patients with stages IB and II cervical cancer with positive para-aortic node. However, new strategies should be investigated to improve a poor prognosis in stage IIIB disease with positive para-aortic node.

Methotrexate-induced hemothorax in a woman with low-risk metastatic gestational trophoblastic disease.

•Patients with invasive mole have a risk of bleeding to fragility and vascularity of the tumor.•Some patients may experience life-threatening bleeding.•Chemotherapy of patients with invasive/metastatic mole may induce bleeding.•In our patient with pulmonary metastatic mole, massive hemorrhage occurred 2 h after the first dose of MTX.•Our patient was successfully treated with partial resection of the bleeding tumor and additional 2 cycles of MTX.