Cervical cancer represents a significant portion of the global cancer burden for women, with low- and middle-income countries carrying the bulk of this burden. Additionally, underserved populations ...in countries with sufficient resources may have a higher incidence of cervical cancer and poorer outcomes. Concurrent chemoradiotherapy is the standard-of-care treatment for locally advanced cervical cancer, which includes patients with stage IB3 to IVA disease, and it is effective for many patients; however, cervical cancer-related mortality remains high. The critical nature of cervical cancer treatment is underscored by the recent launch of the World Health Organization global initiative to accelerate the elimination of cervical cancer using a triple-intervention strategy of increased vaccination, screening, and treatment. The initiative calls for 90% of all patients diagnosed with cervical cancer to receive the appropriate treatment, but to reach this global goal there are significant barriers related to radiotherapy that must be addressed. We discuss and review evidence of the lack of adherence to guideline-recommended treatment, brachytherapy underutilization, limited access to radiotherapy in low- and middle-income countries, as well as regional limitations within high-income countries, as the major barriers to radiotherapy treatment for locally advanced cervical cancer. We further review ways these barriers are currently being addressed and, in some cases, make additional recommendations to address these issues. Finally, despite receiving recommended treatments, many patients with locally advanced cervical cancer have a poor prognosis. With effective administration of current standards of care, the global community will be able to shift focus to advancing treatment efficacy for these patients. We review several types of therapies under clinical investigation that are additions to concurrent chemoradiotherapy, including immune checkpoint inhibitors, antiangiogenic agents, DNA repair inhibitors, human papillomavirus vaccines, and radiosensitizing nanoparticles.
To determine current practice patterns with regard to gynecologic high-dose-rate (HDR) brachytherapy among international members of the Gynecologic Cancer Intergroup (GCIG) in Japan/Korea (Asia), ...Australia/New Zealand (ANZ), Europe (E), and North America (NAm).
A 32-item survey was developed requesting information on brachytherapy practice patterns and standard management for Stage IB-IVA cervical cancer. The chair of each GCIG member cooperative group selected radiation oncology members to receive the survey.
A total of 72 responses were analyzed; 61 respondents (85%) used HDR. The three most common HDR brachytherapy fractionation regimens for Stage IB-IIA patients were 6 Gy for five fractions (18%), 6 Gy for four fractions (15%), and 7 Gy for three fractions (11%); for Stage IIB-IVA patients they were 6 Gy for five fractions (19%), 7 Gy for four fractions (8%), and 7 Gy for three fractions (8%). Overall, the mean combined external-beam and brachytherapy equivalent dose (EQD2) was 81.1 (standard deviation SD 10.16). The mean EQD2 recommended for Stage IB-IIA patients was 78.9 Gy (SD 10.7) and for Stage IIB-IVA was 83.3 Gy (SD 11.2) (p = 0.02). By region, the mean combined EQD2 was as follows: Asia, 71.2 Gy (SD 12.65); ANZ, 81.18 (SD 4.96); E, 83.24 (SD 10.75); and NAm, 81.66 (SD, 6.05; p = 0.02 for Asia vs. other regions).The ratio of brachytherapy to total prescribed dose was significantly higher for Japan (p = 0.0002).
Although fractionation patterns may vary, the overall mean doses administered for cervical cancer are similar in Australia/New Zealand, Europe, and North America, with practitioners in Japan administering a significantly lower external-beam dose but higher brachytherapy dose to the cervix. Given common goals, standardization should be possible in future clinical trials.
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.
Background
This study aimed to determine the incidence of pelvic fistulas in cervical cancer patients treated with bevacizumab in Japanese clinical practice.
Methods
A post-marketing surveillance ...(PMS) study was conducted between June 2016 and February 2018 to survey physicians who treated advanced or recurrent cervical cancer patients with bevacizumab (according to the product label). The clinical/treatment status of patients with pelvic fistulas was assessed in an additional retrospective case series study.
Results
142 patients were included in the PMS study (median age 51 years; 66.9% squamous cell carcinoma; 66.2% recurrent cervical cancer; 64.1% previous radiotherapy). Patients received a median of seven bevacizumab doses. Six patients, all of whom had a history of pelvic irradiation, developed seven fistulas (4.2%; 95% confidence interval, 1.56–8.96), and five patients had also undergone pelvic surgery. The case series study of the patients who developed fistulas indicated that three patients had high cumulative bladder and rectal doses of radiation, and two of them had undergone salvage re-irradiation for pelvic recurrence. The other three patients underwent both radical hysterectomy and adjuvant radiotherapy, but did not receive an excessive radiation dose to the bladder or rectum.
Conclusions
This study found that the upper limit of the 95% confidence interval for pelvic fistula incidence did not exceed the incidence reported in the GOG 240 study. To ensure an adequate benefit-risk assessment of bevacizumab in cervical cancer patients, a comprehensive evaluation of prior treatment is essential and the possibility of unexpected fistulas, even after careful evaluation, should be considered.
There are currently no reliable, established serum biomarkers to predict the prognosis of radiotherapy for advanced cervical cancer. We aimed to identify serum biomarkers for survival after ...radiotherapy for cervical cancer. In this multicenter prospective cohort study, the usefulness of pre- and posttreatment serum protein levels of potential biomarkers, including squamous cell carcinoma antigen (SCC-Ag), apolipoprotein C-II (ApoC-II), matrix metalloproteinase (MMP)1, and MMP2, were evaluated together with clinical factors in 145 cervical cancer patients in order to determine their suitability to predict survival. Progression-free survival (PFS) was the primary endpoint, and overall survival (OS), pelvic PFS (PPFS), and distant metastasis-free survival (DMFS) were the secondary endpoints. Blood samples were collected before and 1 month after radiotherapy to measure serum biomarker levels. ApoC-II was measured using a monoclonal antibody-based enzyme-linked immunosorbent assay, which was developed for this purpose. Kaplan-Meier method, log-rank test, and univariate and multivariate Cox proportional hazards models were used for statistical analyses. In multivariate analysis, larger tumor size was independently associated with shorter PFS, OS, PPFS, and DMFS, while longer overall treatment time was independently associated with shorter PPFS. Higher pretreatment SCC-Ag (P < 0.001) was associated with shorter DMFS. Higher posttreatment SCC-Ag (P = 0.017) was also associated with shorter DMFS. Pretreatment ApoC-II was associated with PPFS in univariate analysis (P = 0.048), but not in multivariate analysis. Patients with pretreatment ApoC-II levels ≤ 25.8 μg/ml had shorter PPFS than those with pretreatment ApoC-II levels > 25.8 μg/ml (P = 0.023, log-rank test). Pre- and posttreatment serum SCC-Ag and pretreatment serum ApoC-II levels may be important biomarkers to predict survival outcomes of patients with cervical cancer after radiotherapy. Pre- and posttreatment SCC-Ag and pretreatment ApoC-II might be useful in clinical settings for screening patients to improve treatment strategies in cervical cancer.
To review the current status of, and labor expended for (in terms of time required), intracavitary brachytherapy (ICBT) in definitive radiotherapy/chemoradiotherapy for cervical cancer patients, two ...national surveys were performed. The first survey was conducted between July and August 2016 and consisted of a questionnaire of 12 items regarding ICBT procedures for cervical cancer, which was sent to 173 centers installed with high-dose-rate remote after-loading brachytherapy systems. Between November and December 2016, another survey was performed in 79 centers to evaluate labor required for ICBT procedures in terms of time spent and number of staff involved. In the first survey, the response rate was 77% of the 173 centers. ICBT was performed for cervical cancer in 118 (89%) centers. Imaging modalities used after applicator insertion were X-ray alone in 46 (40%), computed tomography in 69 (60%) and magnetic resonance imaging in 5 (4%) centers. Three-dimensional (3D) planning was performed in 55 centers (48%). Fifty-five (70%) centers responded to the second survey regarding ICBT-mandated labor. The median cumulative duration of the entire ICBT procedure was 330 min (the sum of the times spent by each staff member) and was longer in the 3D image-guided brachytherapy (3D-IGBT) (405 min) than in the X-ray group (230 min). This trend was significant for the specific processes of image acquisition and treatment planning, especially for radiation oncologists. In definitive radiotherapy/chemoradiotherapy for cervical cancer patients, 3D-IGBT use has been gradually spreading in Japan. The present survey revealed that ICBT, especially 3D-IGBT, requires substantial labor and time from staff.
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.
Abstract
This study evaluated the oncologic outcomes and complications of cervical cancer patients in terms of CT-based image-guided brachytherapy (IGBT) parameters. Of 68 cervical cancer patients ...treated with definitive radiotherapy/concurrent chemoradiotherapy, most received whole-pelvis external beam RT (EBRT) of 40 Gy in 20 fractions, pelvic EBRT with central shield of 10 Gy in 5 fractions, and CT-based IGBT of 18 Gy in 3 fractions prescribed to point A. Cumulative EBRT and IGBT doses were calculated as the total equivalent dose in 2 Gy fractions (EQD2). The median follow-up was 31 (3–52) months. The 2-year overall survival, local control, pelvic control, and disease-free survival rates of the 68 patients were 92%, 83%, 82% and 73%, respectively. The HR-CTV D90, length from the tandem axis to left/right margin of the HR-CTV (T-LR), and HR-CTV volume were significant IGBT parameters for predicting local/pelvic control. Patients who received an HR-CTV D90 of >60 Gy, compared with ≤60 Gy, had significantly better local/pelvic control. Furthermore, 70 Gy was a marginally significant HR-CTV D90 cut-off affecting local control. T-LR was an independent IGBT parameter predicting local/pelvic control on multivariate analysis. Three patients developed Grade 3 or higher treatment-related complications. The D2cm3 of organs at risk were not significant predictors of complications. Future challenges for further improving outcomes include additional interstitial needles for irregularly shaped HR-CTVs, and moderate dose escalation, especially for patients with poor tumor responses.
To investigate pelvic insufficiency fractures (IF) after definitive pelvic radiation therapy for early-stage uterine cervical cancer, by analyzing subjects of a prospective, multi-institutional ...study.
Between September 2004 and July 2007, 59 eligible patients were analyzed. The median age was 73 years (range, 37-84 years). The International Federation of Gynecologic Oncology and Obstetrics stages were Ib1 in 35, IIa in 12, and IIb in 12 patients. Patients were treated with the constant method, which consisted of whole-pelvic external-beam radiation therapy of 50 Gy/25 fractions and high-dose-rate intracavitary brachytherapy of 24 Gy/4 fractions without chemotherapy. After radiation therapy the patients were evaluated by both pelvic CT and pelvic MRI at 3, 6, 12, 18, and 24 months. Diagnosis of IF was made when the patients had both CT and MRI findings, neither recurrent tumor lesions nor traumatic histories. The CT findings of IF were defined as fracture lines or sclerotic linear changes in the bones, and MRI findings of IF were defined as signal intensity changes in the bones, both on T1- and T2-weighted images.
The median follow-up was 24 months. The 2-year pelvic IF cumulative occurrence rate was 36.9% (21 patients). Using Common Terminology Criteria for Adverse Events version 3.0, grade 1, 2, and 3 IF were seen in 12 (21%), 6 (10%), and 3 patients (5%), respectively. Sixteen patients had multiple fractures, so IF were identified at 44 sites. The pelvic IF were frequently seen at the sacroileal joints (32 sites, 72%). Nine patients complained of pain. All patients' pains were palliated by rest or non-narcotic analgesic drugs. Higher age (>70 years) and low body weight (<50 kg) were thought to be risk factors for pelvic IF (P=.007 and P=.013, Cox hazard test).
Cervical cancer patients with higher age and low body weight may be at some risk for the development of pelvic IF after pelvic radiation therapy.
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