Stage IB2-IVA Cervical Cancer Research Articles

Use of Functional Magnetic Resonance Imaging in Cervical Cancer Patients With Incomplete Response on Positron Emission Tomography/Computed Tomography After Image-Based High-Dose-Rate Brachytherapy

Toinvestigate the correlation between positron emission tomography/computed tomography (PET/CT) response and outcome in the era of magnetic resonance imaging (MRI)-based planning and to assess whether the addition of diffusion-weighted MRI (DW-MRI) could more accurately classify treatment response and prognosis. A retrospective chart review identified 244 consecutive patients with International Federation of Gynecology and Obstetrics stage IB1-IVA cervical cancer treated with concurrent chemoradiation, including high-dose-rate image-based brachytherapy, between 2007 and 2016. Image-based brachytherapy was delivered with 5 intracavitary/interstitial fractions, each 5 to 6Gy per fraction. An complete response on posttreatment PET/CT (PET-CR) was discovered in 50 of 244 patients (20%) at a median interval of 3.3months (range, 2.1-7.7months) after treatment. After a median follow-up of 27months, 2-year overall survival was 83% in all patients. Metabolic response significantly impacted 2-year overall survival (94% complete response on posttreatment PET/CT vs 62.4% PET-IR, P<.001). Of those with a PET-IR, 16 of 50 patients (32%) suffered a local recurrence. A total of 27 of 50 patients with a PET-IR underwent DW-MRI; 11 of 27 posttreatment DW-MRI scans (40%) were interpreted as positive by central review (median apparent diffusion coefficient of 0.973×10-3mm2/s). Of the DW-MRI-positive patients, 9 of 11 (81.8%) suffered a histologically confirmed local recurrence, and 2 of 11 patients are without evidence of disease. Additionally, 16 of 27 DW-MRI studies were interpreted as negative, and 2 of 16 (12.5%) of these patients suffered a local recurrence. Diffusion-weighted MRI findings significantly impacted 2-year overall survival (83% negative DW-MRI vs 36% positive DW-MRI, P=.049). Incomplete PET/CT response was documented in 20% of patients after image-based brachytherapy for locally advanced cervical cancer. Integration of DW-MRI helped accurately identify patients at risk for persistent disease and worse long-term outcome. The value of DW-MRI requires further validation in a large prospective dataset as this modality may allow earlier evaluation and salvage treatment in those with PET-IR.

Long-term outcomes of concomitant chemoradiotherapy incorporating high-dose-rate brachytherapy to treat locally advanced cervical cancer.

We reviewed the long-term clinical outcomes of patients treated with cisplatin-based concurrent chemoradiotherapy (CCRT) incorporating high-dose-rate (HDR) intracavitary brachytherapy (ICBT) in terms of toxicity, local control and survival rates. In addition, we identified prognostic factors for overall and disease-free survival. . Two hundred and nine patients with stage IB2-IVA cervical cancer underwent curative cisplatin-based CCRT plus HDR ICBT. Women with stage IB2-IIB disease were given 41.4 Gy of external radiotherapy followed by 35 Gy (in 7 fractions) of ICBT. Women with stage IIIA-IVA were given 50.4 Gy followed by 30 Gy (in 6 fractions) of ICBT. Patients with parametrial disease or pelvic lymphadenopathy were given parametrial boosts via external beam radiation at a dose of up to 65 Gy to thickened and 60 Gy to unthickened parametrial regions. One hundred and thirty (62%) patients experienced acute grade 3-4 hematological toxicities and 11 (5%) patients had late grade 3 gastrointestinal or genitourinary complications. Complete responses occurred in 168 (80%) women as determined by clinical and imaging studies. The median follow-up period was 52 months for surviving patients and the 5-year overall and disease-free survival rates were 74% and 67%, respectively. Multivariate analysis indicated that tumor size and paraaortic lymph node involvement were prognostically significant in terms of overall survival, and that tumor diameter was a significant prognostic factor and pelvic lymph node status a marginally significant prognostic factor for disease-free survival. Patients treated with our current HDR ICBT protocol have acceptably low late complication rates and local control and survival rates comparable to those reported in other studies. Tumor diameter was an important prognostic factor in terms of both overall and disease-free survival, emphasizing the need for modern ICBT methodologies.

Prophylactic extended-field irradiation with concurrent chemotherapy for pelvic lymph node-positive cervical cancer.

PurposeThis study aimed to evaluate whether prophylactic extended-field pelvic radiotherapy (EF-PRT) yields better results than standard whole pelvic radiotherapy (WPRT) in patients with pelvic lymph node-positive cervical cancer treated with concurrent chemoradiotherapy (CCRT).Materials and MethodsA total of 126 cases of stage IB-IVA cervical cancer that had pelvic lymph node involvement in magnetic resonance imaging and were treated with CCRT between 2000 and 2016 were reviewed. None of the patients had paraaortic lymph node (PALN) metastases. The patients were classified to two groups, namely, those treated with EF-PRT, including prophylactic para-aortic radiotherapy, and those treated only with WPRT. The median dose to the PALN area in patients treated with EF-PRT was 45 Gy. All patients received concurrent cisplatin-based chemotherapy.ResultsOverall, 52 and 74 patients underwent EF-PRT and WPRT, respectively. Patient characteristics and irradiated dose were not significantly different, except the dose to the para-aortic area, between the two groups. The median follow-up period was 75.5 months (range, 5 to 195 months). The 10-year cumulative recurrence rate of PALN for EF-PRT vs. WPRT was 6.9% and 10.1% (p = 0.421), respectively. The 10-year disease-free survival and overall survival for EF-PRT vs. WPRT were 69.7% vs. 66.1% (p = 0.748) and 71.7% vs. 72.3% (p = 0.845), respectively. Acute gastrointestinal complications were significantly higher in EF-PRT (n = 21; 40.4%) than WPRT (n = 26; 35.1%) (p = 0.046). Late toxicities were not significantly different in both groups.ConclusionIn this study, prophylactic radiotherapy for PALN does not have an additional benefit in patients with pelvic lymph node-positive cervical cancer treated with CCRT.

Impact of para-aortic recurrence risk-guided intensity-modulated radiotherapy in locally advanced cervical cancer with positive pelvic lymph nodes

ObjectivesA previous study has suggested the benefit of sub-renal vein radiotherapy (SRVRT) for pelvic lymph node (PLN)-positive cervical cancer. In order to better select patients for SRVRT, this study aimed to evaluate the value of a risk-based radiation field based on PLN location and number in PLN-positive cervical cancer. MethodsWe reviewed 198 patients with FIGO stage IB2–IVA cervical cancer, positive PLNs, and negative para-aortic lymph nodes (PALNs) from 2004 to 2015 at two tertiary centers. All patients underwent pelvic radiotherapy (PRT) or SRVRT with IMRT. The SRVRT extended the PRT field cranially to the level of the left renal vein. The prescribed doses were 45–50.4Gy in 1.8Gy per fraction. ResultsOverall, 118 and 80 patients underwent PRT and SRVRT, respectively. The SRVRT group had more advanced disease based on FIGO stage, common iliac PLNs, and number of PLNs. The median follow-up was 63months (range: 7–151months). PALN failure was experienced by 28 patients (23.7%) in the PRT group and 1 patient (1.3%) in the SRVRT group (p<0.001). Compared with PRT, SRVRT significantly improved 5-year PALN recurrence-free survival (56.8% vs. 100%, p<0.001) and cancer-specific survival (56.5% vs. 93.9%, p<0.001) among patients with common iliac PLNs or ≥3 PLNs. No significant differences were observed in these outcomes among patients with PLNs below the common iliac bifurcation and 1–2 PLNs. The SRVRT did not increase severe toxicities. ConclusionsRisk-based radiation field based on PLN location and number could optimize outcomes for PLN-positive cervical cancer.

Early Evaluation For Residual Uterine Cervical Cancer 4 Weeks After Definitive Radiation Therapy to Identify Patients Who May Benefit From Adjuvant Salvage Hysterectomy

After definitive radiation therapy (RT) for locally advanced uterine cervical cancer, local residual tumor has been subsequently found in approximately 5–10% of patients. Although adjuvant salvage hysterectomy is often attempted for those patients, radiation induced fibrosis and regrowth of the tumor after long elapsed time from RT can lead to high-risk surgery or inoperable cases. The aim of the current study was to clarify the significance of early evaluation for residual cervical cancer after RT to identify patients who may benefit from adjuvant salvage hysterectomy. We performed a retrospective cohort study between February 2012 and July 2016 of 179 patients with FIGO stage IB1–IVA cervical cancer treated with RT. For all patients, we have been conducting early evaluations for residual tumor 4 weeks after RT. In our institution, the decision to perform adjuvant salvage hysterectomy is based on at least 2 of these following 4 criteria: tumor-like cervical mass in magnetic resonance imaging (MRI) findings, abnormal fluorodeoxyglucose uptake in positron emission tomography-computed tomography (PET-CT) images, suspicious cytology or histology, and elevated tumor marker values (SCC, CA19-9, CA125, or CEA). Patients who were strongly suspected to have residual tumor underwent adjuvant salvage hysterectomy. Statistical analyses were conducted with Fisher’s exact test and Mann-Whitney’s U test. Among 179 patients, 11 patients (6%) underwent adjuvant salvage hysterectomy. The histology was squamous cell carcinoma (SqCC) in 6 patients and adenocarcinoma in 5 patients (4 of mucinous adenocarcinoma and 1 of endometrioid adenocarcinoma). The median tumor size prior to RT was 57mm (range: 45-77mm) in patients with SqCC and 42mm (range: 35-67mm) in those with adenocarcinoma (P = 0.12). In all patients, tumor was detected on MRI images after 4 weeks from RT. The median tumor-size of after RT was 22mm (range: 10-30mm) in patients with SqCC, and 30mm (range: 18-55mm) in those with adenocarcinoma, respectively (P = 0.17). No significant difference was observed in the SUV-max values on PET-CT images after RT between patients with SqCC (median: 3.9, range: 1.8-4.1) and those with adenocarcinoma (median: 3.9, range: 3.1-27.8, P = 1.0), and the ratio of the elevated tumor marker values (SCC: 17% vs. CA19-9: 20%, P = 1.0). Pathological examination after adjuvant salvage hysterectomy showed that viable tumor was observed in 1 of 6 patients with SqCC (17%) and all 5 patients with adenocarcinoma (100%): the difference was statistically significant (P < 0.05). After adjuvant salvage hysterectomy, local control was 100% in all 11 patients, and distant metastasis was shown in 1 patient with SqCC and 1 patient with adenocarcinoma. Patients with suspicious residual uterine cervical tumor of adenocarcinoma 4 weeks after RT have a higher incidence of viable tumor compared to those with SqCC, and might benefit from adjuvant salvage hysterectomy for local control.

Phase III randomized trial of image-guided bone marrow-sparing intensity modulated radiation therapy (IG-BMS-IMRT) for locoregionally advanced cervical cancer: The INTERTECC-3 trial.

TPS5600 Background: Cervical cancer is a leading cause of cancer death in women worldwide. Image-guided bone marrow-sparing intensity modulated radiation therapy (IG-BMS-IMRT) has shown potential to reduce acute toxicity of chemoradiotherapy and improve chemotherapy delivery in phase I and II trials (Mell LK, Sirák I, Wei L, et al. Bone Marrow-sparing IMRT With Concurrent Cisplatin For Stage IB-IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC-2). Int J Radiat Oncol Biol Phys 2017;97:536-545. Mell LK, Saenz CC, Yashar CM, et al. Phase I Trial of Bone Marrow Sparing IMRT With Concurrent Cisplatin and Gemcitabine in Stage IB-IVA Cervical Cancer (abstr.) Int J Radiat Oncol Biol Phys 2016; 96: S14.). Methods: INTERTECC-3 is a randomized phase III trial designed to test the effect of IG-BMS-IMRT on progression-free survival (PFS) for women with unresected FIGO stage IB-IVA cervical carcinoma (clinicaltrials.gov #NCT01554397). It presently involves centers in the U.S., Czech Republic, U.K., India, Japan, and China. Women are randomized 3:2 to either (A) IG-BMS-IMRT or (B) standard chemoradiation, with 6 cycles of concurrent cisplatin (40 mg/m2) weekly in both arms. Secondary objectives are to compare overall survival, treatment-related toxicity, disease recurrence, quality of life, chemotherapy delivery, and radiation quality assurance. Planning objectives require maintaining pelvic marrow and active marrow mean doses &lt; 27 Gy and &lt; 28.5 Gy respectively. Correlative studies involve longitudinal collection of magnetic resonance restriction spectrum imaging and 18F-fluorothydimine positron emission tomography scans to assess imaging biomarkers of treatment response in select patients. 415 women will be enrolled to determine if IG-BMS-IMRT improves the median PFS from 3.2 to 5.0 years with 80% power and alpha = 0.05. INTERTECC-3 opened in the U.S. and Czech Republic in 2016. To date, 17 patients have been randomized. The trial will be activated at additional international sites in late 2017 and 2018. We are seeking to recruit sites who wish to collaborate. Clinical trial information: NCT01554397.

Prophylactic lower para-aortic irradiation using intensity-modulated radiotherapy mitigates the risk of para-aortic recurrence in locally advanced cervical cancer: A 10-year institutional experience

ObjectiveTo evaluate the effects of prophylactic sub-renal vein radiotherapy (SRVRT) using intensity-modulated radiotherapy (IMRT) for cervical cancer. MethodsA total of 206 patients with FIGO stage IB2–IVA cervical cancer and negative para-aortic lymph nodes (PALNs) who underwent pelvic IMRT (PRT) or SRVRT between 2004 and 2013 at our institution were reviewed. SRVRT cranially extended the PRT field for PALNs up to the left renal vein level. The prescribed dose was consistent 50.4Gy in 28 fractions. ResultsOverall, 110 and 96 patients underwent PRT and SRVRT, respectively. The SRVRT group had more advanced disease based on FIGO stage and positive pelvic lymph nodes (PLNs). The median follow-up time was 60months (range, 7–143). For the total study population, the 5-year PALN recurrence-free survival (PARFS) and overall survival (OS) for PRT vs. SRVRT were 87.6% vs. 97.9% (p=0.03) and 74.5% vs. 87.8% (p=0.04), respectively. In patients with FIGO III–IVA or positive PLNs, the 5-year PARFS and OS for PRT vs. SRVRT were 80.1% vs. 96.4% (p=0.02) and 58.1% vs. 83.5% (p=0.012), respectively. However, there were no significant differences in these outcomes for patients with FIGO IB–IIB and negative PLNs. In a multivariate analysis, only SRVRT was associated with better PARFS (HR, 0.21; 95% CI, 0.06–0.78; p=0.02). The SRVRT did not significantly increase severe late toxicities. ConclusionProphylactic SRVRT using IMRT reduced PALN recurrence with tolerable toxicities, supporting the application of risk-based radiation fields for cervical cancer.

18]Fluorodeoxyglucose Positron Emission Tomography for the Textural Features of Cervical Cancer Associated with Lymph Node Metastasis and Histological Type.

In this study, we investigated the correlation between the lymph node (LN) status or histological types and textural features of cervical cancers on 18F-fluorodeoxyglucose positron emission tomography/computed tomography. We retrospectively reviewed the imaging records of 170 patients with International Federation of Gynecology and Obstetrics stage IB-IVA cervical cancer. Four groups of textural features were studied in addition to the maximum standardized uptake value (SUVmax), metabolic tumor volume, and total lesion glycolysis (TLG). Moreover, we studied the associations between the indices and clinical parameters, including the LN status, clinical stage, and histology. Receiver operating characteristic curves were constructed to evaluate the optimal predictive performance among the various textural indices. Quantitative differences were determined using the Mann-Whitney U test. Multivariate logistic regression analysis was performed to determine the independent factors, among all the variables, for predicting LN metastasis. Among all the significant indices related to pelvic LN metastasis, homogeneity derived from the gray-level co-occurrence matrix (GLCM) was the sole independent predictor. By combining SUVmax, the risk of pelvic LN metastasis can be scored accordingly. The TLGmean was the independent feature of positive para-aortic LNs. Quantitative differences between squamous and nonsquamous histology can be determined using short-zone emphasis (SZE) from the gray-level size zone matrix (GLSZM). This study revealed that in patients with cervical cancer, pelvic or para-aortic LN metastases can be predicted by using textural feature of homogeneity from the GLCM and TLGmean, respectively. SZE from the GLSZM is the sole feature associated with quantitative differences between squamous and nonsquamous histology.

In-room computed tomography-based brachytherapy for uterine cervical cancer: results of a 5-year retrospective study.

Herein, we investigate the long-term clinical outcomes for cervical cancer patients treated with in-room computed tomography–based brachytherapy. Eighty patients with Stage IB1–IVA cervical cancer, who had undergone treatment with combined 3D high-dose rate brachytherapy and conformal radiotherapy between October 2008 and May 2011, were retrospectively analyzed. External beam radiotherapy (50 Gy) with central shielding after 20–40 Gy was performed for each patient. Cisplatin-based chemotherapy was administered concurrently to advanced-stage patients aged ≤75 years. Brachytherapy was delivered in four fractions of 6 Gy per week. In-room computed tomography imaging with applicator insertion was performed for treatment planning. Information from physical examinations at diagnosis, and brachytherapy and magnetic resonance imaging at diagnosis and just before the first brachytherapy session, were referred to for contouring of the high-risk clinical target volume. The median follow-up duration was 60 months. The 5-year local control, pelvic progression-free survival and overall survival rates were 94%, 90% and 86%, respectively. No significant differences in 5-year local control rates were observed between Stage I, Stage II and Stage III–IVA patients. Conversely, a significant difference in the 5-year overall survival rate was observed between Stage II and III–IVA patients (97% vs 72%; P = 0.006). One patient developed Grade 3 late bladder toxicity. No other Grade 3 or higher late toxicities were reported in the rectum or bladder. In conclusion, excellent local control rates were achieved with minimal late toxicities in the rectum or bladder, irrespective of clinical stage.

Bone Marrow-sparing Intensity Modulated Radiation Therapy With Concurrent Cisplatin For Stage IB-IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC-2)

To test the hypothesis that intensity modulated radiation therapy (IMRT) reduces acute hematologic and gastrointestinal (GI) toxicity for patients with locoregionally advanced cervical cancer. We enrolled patients with stage IB-IVA cervical carcinoma in a single-arm phase II trial involving 8 centers internationally. All patients received weekly cisplatin concurrently with once-daily IMRT, followed by intracavitary brachytherapy, as indicated. The primary endpoint was the occurrence of either acute grade ≥3 neutropenia or clinically significant GI toxicity within 30days of completing chemoradiation therapy. A preplanned subgroup analysis tested the hypothesis that positron emission tomography-based image-guided IMRT (IG-IMRT) would lower the risk of acute neutropenia. We also longitudinally assessed patients' changes in quality of life. From October 2011 to April 2015, 83 patients met the eligibility criteria and initiated protocol therapy. The median follow-up was 26.0months. The incidence of any primary event was 26.5% (95% confidence interval [CI] 18.2%-36.9%), significantly lower than the 40% incidence hypothesized a priori from historical data (P=.012). The incidence of grade ≥3 neutropenia and clinically significant GI toxicity was 19.3% (95% CI 12.2%-29.0%) and 12.0% (95% CI 6.7%-20.8%), respectively. Compared with patients treated without IG-IMRT (n=48), those treated with IG-IMRT (n=35) had a significantly lower incidence of grade ≥3 neutropenia (8.6% vs 27.1%; 2-sided χ2P=.035) and nonsignificantly lower incidence of grade ≥3 leukopenia (25.7% vs 41.7%; P=.13) and any grade ≥3 hematologic toxicity (31.4% vs 43.8%; P=.25). IMRT reduces acute hematologic and GI toxicity compared with standard treatment, with promising therapeutic outcomes. Positron emission tomography IG-IMRT reduces the incidence of acute neutropenia.

Phase 1 Trial of Bone Marrow Sparing Intensity Modulated Radiation Therapy With Concurrent Cisplatin and Gemcitabine in Stage IB-IVA Cervical Cancer

Author(s): Mell, LK; Saenz, CC; Yashar, CM; McHale, MT; Einck, JP; Wright, ME; Noticewala, SS; Xu, R; Plaxe, SC; Mundt, AJ

Prospective Validation of a High-Dimensional Shape Model for Organ Motion in Intact Cervical Cancer

Validated models are necessary for developing appropriate planning target volumes (PTVs) for intact cervical cancer, particularly when using intensity modulated radiation therapy (IMRT). A model proposed by Khan et al. (PMID 2227016) serves as the basis for a PTV recipe for several IMRT trials. Our objective was to independently validate this model using prospectively collected clinical trial data. We analyzed 37 patients with stage IB-IVA cervical cancer registered in one of two prospective IMRT trials. This validation study was a prespecified aim for the one of the trials. Patients received daily fractionated pelvic IMRT with concurrent chemotherapy. The clinical target volume (CTV) included gross tumor, cervix, uterus, parametria, upper vagina, and pelvic lymph nodes. The PTV consisted of an expansion of 5mm around nodes, 10mm around the vagina and parametria, and 15mm around the uterus, cervix, and tumor. Daily on-line kV-kV images were used for initial setup verification. We collected cone beam computed tomography (CBCT) scans before each fraction. The planning CT was rigidly registered to each CBCT. CTVs from the planning CT were cast onto each CBCT and manually redrawn, while blinded to the PTV, to account for organ motion and deformation, creating a new CTV for each fraction. For each fraction, the 95% isodose cloud from the planning CT was applied to the CBCT, and the CTV volume outside the 95% isodose cloud was computed. The primary aim was to determine the proportion of CTVs that were encompassed within the 95% isodose volume. A one-sided, one sample t-test was used to test the hypothesis that the probability of complete coverage was at least 95%. We used repeated measures analysis of variance (ANOVA) to measure inter- and intra-patient variation and paired t-tests to test differences in CTV volumes. The 95% isodose line completely encompassed 91.3% of all CTVs (95% CI 86.8, 95.8%), not significantly different from the 95% probability anticipated a priori (P = 0.052). The percentage of fractions missed per patient ranged from 0-45.8%. The overall proportion of missed CTV was small: the grand mean of the volume of CTV falling within the 95% isodose cloud was 99.9%, and 33.2% of misses were less than 1 cm3. There were no significant differences between the mean CTV volumes from the planning CT and either the first CBCT or the mean CTV from all CBCTs (P = 0.42 and 0.53, respectively). Treatment day did not affect coverage (P = 0.83). Using the model developed by Khan et al., the probability of CTV coverage was high, and the volume of CTV missed was minimal. This PTV expansion strategy is acceptable for clinical trials and practice; however, daily image guidance is recommended to avoid systematic large misses in select patients.

Phase 2 Multicenter Clinical Trial of Bone Marrow–Sparing Intensity Modulated Radiation Therapy With Concurrent Cisplatin for Stage IB-IVA Cervical Cancer

Author(s): Mell, LK; Sirak, I; Wei, L; Tarnawski, RR; Mahantshetty, UM; Yashar, CM; McHale, MT; Wright, ME; Pritz, J; Straube, W; Xu, R; Kasaova, L; Michalski, JM; Bosch, WR; Followill, DS; Schwarz, JK; Honerkamp-Smith, G; Leif, JL; Saenz, CC; Einck, JP; Koonings, PP; Harrison, TA; Khorprasert, C; Shi, M; Plaxe, SC; Mundt, AJ

Radiation Duration in Women with Cervical Cancer Treated with Primary Chemoradiation: A Population-Based Analysis

ABSTRACTThis study examines factors associated with prolonged radiation duration and its impact on survival in women with cervical cancer treated with primary chemoradiation. Women in the National Cancer Database with stage IB2-IVA cervical cancer from 2003 to 2011 who received radiation and chemotherapy were included. Of 7209 women, who met inclusion criteria, 3401 (47.1%) and 3808 (52.8%) completed radiation in ≤ 8 and > 8 weeks, respectively. There was no overall survival difference for radiation duration ≤ 8 vs. > 8 weeks. Sensitivity analyses showed that inferior overall survival is only seen with radiation duration of > 10–12 weeks.

Determinants of Quality Care and Mortality for Patients With Locally Advanced Cervical Cancer in Virginia.

Outcomes for patients with locally advanced cervical cancer are influenced by receipt of all indicated components of quality care: early diagnosis and receipt of external beam radiation therapy, chemotherapy, and brachytherapy. We performed an observational cohort study to evaluate receipt of quality cancer care and mortality after cancer diagnosis among patients with locally advanced cervical cancer in Virginia.We queried the Virginia state cancer registry to identify patients with International Federation of Gynecology and Obstetrics Stage IB-IVA cervical cancer who were diagnosed during 2002 to 2012. We evaluated the influence of tumor-related, demographic, and geospatial factors on the receipt of indicated therapies and mortality. Treatment quality score of 0 to 3 was defined based upon the extent of receipt of the components of indicated therapy.A total of 1048 patients were identified; 33.1% received all 3 components of treatment and only 54.0% received brachytherapy. Predictors of higher quality score included younger age group versus 66+ years at diagnosis (18–42 odds ratio [OR] = 12.3, 95% confidence interval: 6.6, 23.0; 42–53 OR = 5.6, CI: 3.3, 9.5; 53–66 OR = 5.5, CI: 3.3, 9.1), lower tumor stages versus IVA (IB2 OR = 3.3, CI: 1.8, 6.2; II OR = 2.7, CI: 1.6, 4.5; IIIx OR = 2.1, CI: 1.3, 3.6), and treatment at a high-volume facility (OR 2.2, CI: 1.2, 4.2). Predictors of increased mortality included earlier year of diagnosis, higher tumor stage, treatment at a lower volume facility, and lower treatment quality score.In a cohort of locally advanced cervical cancer patients in Virginia, we identified a low rate of receipt of complete quality care for cervical cancer and a strong effect of facility volume on quality treatment and survival. Further research is needed to develop strategies to improve access to quality treatment and outcomes for cervical cancer.

Lymphopenia and its association with survival in patients with locally advanced cervical cancer

ObjectiveTo evaluate the association between lymphopenia and survival in women with cervical cancer treated with primary chemoradiation. MethodsA single institution, retrospective analysis of patients with stage IB2-IVA cervical cancer who received upfront chemoradiation from 1998 to 2013 was performed. Complete blood counts from pre-treatment to 36months post-treatment were analyzed. Lymphopenia and known prognostic factors were evaluated for an association with progression-free (PFS) and overall survival (OS). ResultsSeventy-one patients met study criteria for whom 47 (66%) had a documented total lymphocyte count (TLC) two months after initiating chemoradiation. FIGO stage distribution was 6% Stage I, 46% Stage II, 45% Stage III and 3% Stage IV. Pre-treatment TLC was abnormal (<1000 cells/mm3) in 15% of patients. The mean reduction in TLC was 70% two months after initiating chemoradiation. Severe post-treatment lymphopenia (TLC <500cells/mm3) was observed in 53% of patients; they experienced inferior median OS (21.2 vs 45.0months, P=0.03) and similar 25th percentile PFS (6.3 vs 7.7months, P=0.06) compared to patients without severe lymphopenia. Multivariate analysis demonstrated pre-treatment TLC ≥1000cells/mm3 and post-treatment TLC >500cells/mm3 had a 77% (HR: 0.23; 95%CI 0.05–1.03; P=0.053) and 58% decrease in hazards of death (HR: 0.42; 95%CI 0.12–1.46; P=0.17) respectively. ConclusionMore than half of cervical cancer patients treated with chemoradiation experienced severe and prolonged lymphopenia. Although statistical significance was not reached, the findings suggest that pre- and post-treatment lymphopenia may be associated with decreased survival. Further research is warranted, given that lymphopenia could be a reversible prognostic factor.

Association of Apparent Diffusion Coefficient with Disease Recurrence in Patients with Locally Advanced Cervical Cancer Treated with Radical Chemotherapy and Radiation Therapy.

To investigate whether volumetrically derived apparent diffusion coefficient (ADC) from pretreatment diffusion-weighted (DW) magnetic resonance (MR) imaging is associated with disease recurrence in women with locally advanced cervical cancer treated with chemotherapy and radiation therapy. An ethics board-approved, retrospective study was conducted in 85 women with stage IB-IVA cervical cancer treated with chemo- and radiation therapy in 2009-2013. All patients underwent MR imaging for staging, including T2-weighted and DW MR imaging series, by using a 1.5- or 3.0-T imager. The mean, median, 75th, 90th, and 95th percentile ADCs (ADCmean, ADC50, ADC75, ADC90, and ADC95, respectively) of all voxels that comprised each tumor were extracted and normalized to the mean urine ADC (nADCmean, nADC50, nADC75, nADC90, and nADC95, respectively) to reduce variability. The primary outcome was disease-free survival (DFS). Uni- and multivariable Cox regression analyses were used to evaluate the association of ADC parameters and relevant clinical variables with DFS. Of the 85 women included, 62 were free of disease at last follow-up. Median follow-up was 37 months (range, 5-68 months). Significant variables at univariable analysis included T2-weighted derived tumor diameter, para-aortic nodal involvement, advanced stage, ADC90 and ADC95, nADC75, nADC90, and nADC95. Normalized parameters were more highly associated (hazard ratio per 0.01 increase in normalized ADC, 0.91-0.94; P < .04). Because nADC75, nADC90, and nADC95 were highly correlated, only nADC95 (which had the lowest P value) was included in multivariable analysis. At multivariable analysis, absolute and normalized ADC95 remained associated with DFS (hazard ratio, 0.90-0.98; P < .05). The volumetric ADC95 may be a useful imaging metric to predict treatment failure in patients with locally advanced cervical cancer treated with chemo- and radiation therapy.

Clinical outcomes of definitive chemoradiation followed by intracavitary pulsed-dose rate image-guided adaptive brachytherapy in locally advanced cervical cancer

ObjectiveTo report the outcomes and late toxicities of patients with locally advanced cervical cancer treated with concomitant chemoradiation (CRT) followed by intracavitary image-guided adaptive brachytherapy (IGABT). MethodsData from consecutive patients with histologically proven stage IB-IVA cervical cancer treated with curative intent in a single institution were analyzed. After pelvic +/− para-aortic external-beam radiation therapy, they received pulsed-dose rate IGABT following GEC-ESTRO recommendations. ResultsTwo hundred and twenty-five patients were enrolled. Sixty-five percent were stage≥IIB according to FIGO classification. Ninety-five percent received CRT. Mean D90 to HR and IR-CTV were 80.4+/−10.3Gy and 67.7+/−6.1Gy. After a median follow-up of 38.8months, 3-year local control and overall survival rates were 86.4% and 76.1%, respectively. A trend for a detrimental effect of tumor stage on local control rates was observed with 3-year local control rates of 100% for stages IB1 and IIA, 90.5 for IB2, 85.8% for IIB, 50% for IIIA, 77.1 for IIIB, and 66.7% for IVA tumors (p=0.06). Local control rates at 3years were 95.6% in the group of patients with D90 of HR-CTV≥85Gy, 88.8% in those with D90 between 80 and 85Gy, and 80% when D90<80Gy (p=0.018). Eighteen severe late gastrointestinal and urinary effects affecting 14 patients were reported corresponding with a crude incidence of 6.6%. ConclusionsCRT followed by IGABT provides high local control rates with limited toxicity. Reaching high doses is mandatory to achieve local control and interstitial brachytherapy is necessary in advanced diseases.

Daily low-dose Cisplatin-based concurrent chemoradiotherapy for the treatment of cervical cancer in patients 70 years or older.

It has been established that concurrent chemoradiotherapy (CCRT) is efficacious for cervical cancer, but adherence is unsatisfactory among elderly patients. To improve adherence, we have developed and initiated a daily low-dose cisplatin-based CCRT regimen. Here, we retrospectively evaluated the use of CCRT, especially for elderly patients. The study included a total of 53 patients who were 70 years or older, had stage IB-IVA cervical cancer, and were initially treated with daily CCRT. The daily CCRT comprised pelvic external beam radiotherapy (2 Gy/d × 25) with daily low-dose cisplatin (8.0 mg/m(2) per day) and either low- or high-dose-rate intracavitary brachytherapy. The median age was 72 years (range, 70-85 years). The median follow-up duration was 32 months (range, 2-104 months). The 3-year overall survival rate was 79.0%. Daily cisplatin chemotherapy was successfully completed in 32 (60.4%) of the 53 patients. Grade 3 or 4 neutropenia was observed in 19 patients (36%). A late complication of grade 3 rectal hemorrhage occurred in 3 patients who received high-dose-rate brachytherapy. All primary tumors responded to daily CCRT; complete response was observed in 43 patients (91.5%) and partial response was observed in 4 patients (8.5%). Daily CCRT in patients 70 years and older had acceptable compliance and safety. Daily CCRT is suggested to be a good treatment option for elderly patients who have advanced cervical cancer and require concurrent cisplatin.

Assessment of cumulative external beam and intracavitary brachytherapy organ doses in gynecologic cancers using deformable dose summation

PurposeDue to inter-fraction variation in applicator position, organ displacement and deformation, doses to targets and normal tissues may not be accurately represented by adding the doses from external beam radiation therapy (EBRT) and intracavitary brachytherapy (ICBT) using rigid image registration. Deformable image registration permits organ and applicators to be spatially matched in 3D, enabling more accurate tracking of the accumulated volumetric dose to the target as well as organs at risk (OAR). This study assesses the dosimetric impact of using deformable image registration to determine the cumulative EBRT and ICBT doses to the rectum and bladder. Methods and materialsData from 20 patients with stage IB1-IVA cervical cancer were analyzed. Nine of the patients were treated with ICBT and EBRT which included a nodal or parametrium boost while eleven were treated with ICBT and EBRT with no boost. Dose summation was performed in two stages. For the first stage, only the ICBT fractional doses were added using both “parameter adding” and deformable registration techniques. In the second stage, the ICBT and EBRT doses were combined using “parameter adding” in two ways. Partial “parameter adding” considers the cumulative ICBT dose from deformable registration as one parameter while full “parameter adding” uses fractional ICBT parameters. The cumulative minimum doses to 2cc (D2cc) of the rectum and bladder were compared between deformable registration and “parameter adding” techniques. ResultsDose summation of ICBT fractions only using deformable registration yielded D2cc values that were (10.1±9.5)% lower for the rectum and (7.2±6.3)% lower for the bladder compared to “parameter adding”. When ICBT and EBRT doses were summed deformably, the group without EBRT boost had D2cc that were (0.0±4.6)% and (−1.2±2.9)% lower for the rectum and bladder respectively compared to partial “parameter adding”. With EBRT boost, the differences were (−2.9±4.0)% and (−3.2±3.3)% for the rectum and bladder respectively. For full “parameter adding”, the differences from deformable sum were (2.7±5.0)%, (2.6±5.0)% without EBRT boost and (0.6±4.8)%, (−1.5±3.7)% with EBRT boost. ConclusionComparison of deformable dose summation with the technique of “parameter adding” suggests that “parameter adding” can be used as a good approximation of D2cc when adding ICBT and EBRT doses with or without boost. With EBRT boosts, deformable dose summation may more accurately represent dose to normal critical structures but these differences remain small compared to “parameter adding”.