Definitive Radiotherapy For Cervical Cancer Research Articles

The clinical practice and dosimetric outcome of the manual adaptive planning during definitive radiotherapy for cervical cancer

ProposeTo evaluate the advantage of the manual adaptive plans comparing to the scheduled plans, and explored clinical factors predicting patients suitable for adaptive strategy.Methods and materialsEighty two patients with weekly online cone-beam computed tomography (CBCT) were enrolled. The re-CT simulation was performed after 15 fractions and a manual adaptive plan was developed if a significant deviation of the planning target volume (PTV) was found. To evaluate the dosimetric benefit, D98, homogeneity index (HI) and conformity index (CI) for the planning target volume (PTV), as well as D2cc of the bowel, bladder, sigmoid and rectum were compared between manual adaptive plans and scheduled ones. The clinical factors influencing target motion during radiotherapy were analyzed by chi-square test and logistic regression analysis.ResultsThe CI and HI of the manual adaptive plans were significantly superior to the scheduled ones (P = 0.0002, 0.003, respectively), demonstrating a better dose coverage of the target volume. Compared to the scheduled plans, D98 of the manual adaptive plans increased by 3.3% (P = 0.0002), the average of D2cc to the rectum, bladder decreased 0.358 Gy (P = 0.000034) and 0.240 Gy (P = 0.03), respectively. In addition, the chi-square test demonstrated that age, primary tumor volume, and parametrial infiltration were the clinical factors influencing target motion during radiotherapy. Multivariate analysis further identified the large tumor volume (≥ 50cm3, OR = 3.254, P = 0.039) and parametrial infiltration (OR = 3.376, P = 0.018) as the independent risk factors.ConclusionWe found the most significant organ motion happened after 15 fractions during treatment. The manual adaptive plans improved the dose coverage and decreased the OAR doses. Patients with bulky mass or with parametrial infiltration were highly suggested to adaptive strategy during definitive radiotherapy due to the significant organ motion.

Distribution of human papilloma virus genotypes and treatment outcomes in definitive radiotherapy for cervical cancer.

Most oncogenic human papilloma virus (HPV) genotypes stratify into two species, α-7 HPV and α-9 HPV. There are several studies that evaluate the relationship between HPV species and treatment outcomes and reports that HPV species is prognostic. The HPV genotyping was conducted using biopsy specimens which had been stored in these studies. We conducted the study using the HPV test performed by cytology specimens which is less invasive and more useful in clinical settings. This study enrolled 46 patients who received HPV genotyping before the definitive radiotherapy. The results of the HPV genotyping were classified into HPVα-7, HPVα-9 and negatives. Of the 46 patients, 10 were positive for HPVα-7, 21 positive for HPVα-9 and 15 were negative. The median follow-up period was 38months (range 4-142). The HPVα-7, HPVα-9 and negative groups showed the 3-year overall survival (OS; 59.3%, 80.4% and 72.2% [P = 0.25]); local control (LC; 67.5%, 81% and 80% [P = 0.78]); pelvic control (PC) (50%, 81% and 72.7% [P = 0.032]); pelvic lymph node (PLN) control (78.7%, 95% and 92.3% [P = 0.012]); distant metastasis free (DMF) survival (50%, 75.4% and 42.8% [P = 0.098]); and progression free survival (PFS) rate of patients (30%, 66.7% and 38.9% [P = 0.085]), respectively. Patients with HPVα-7 showed statistically significant poorer PC than the HPVα-9 group, in multivariate analysis. This result is consistent with previous studies for HPV positive patients. The HPV negativity rate was higher in this study than in other studies and further work on this may be needed for clinical use.

Gastric-Type Adenocarcinoma of the Uterine Cervix Associated with Poor Response to Definitive Radiotherapy.

We aimed to evaluate the response to definitive radiotherapy (RT) for cervical cancer based on histological subtypes and investigate prognostic factors in adenocarcinoma (AC). Of the 396 patients treated with definitive RT between January, 2010 and July, 2020, 327 patients met the inclusion criteria, including 275 with squamous cell carcinoma (SCC) and 52 with AC restaged based on the 2018 International Federation of Gynecology and Obstetrics staging system. Patient characteristics, response to RT, and prognoses of SCC and AC were evaluated. The complete response (CR) rates were 92.4% and 53.8% for SCC and AC, respectively (p < 0.05). Three-year overall survival and progression-free survival (PFS) rates of SCC were significantly higher than those of AC (88.6% vs. 74.1%, p < 0.05 and 76.3% vs. 59.3%, p < 0.05, respectively). Among the AC population, univariate and multivariate analyses were performed to examine prognostic factors associated with non-complete response (CR). In the multivariate analysis, gastric-type adenocarcinoma (GAS) was associated with non-CR in AC (adjusted odds ratio, 12.2; 95% confidence interval 1.0−145.6; p < 0.05). The 3-year PFS rate in patients with GAS was significantly lower than that in patients with other histological types of AC (44.4% vs. 66.7%, p < 0.05). Definitive RT for cervical cancer was significantly less effective for AC than for SCC. GAS was the only independent prognostic factor associated with non-CR in AC.

Differences in Treatment Outcomes and Prognosis between Elderly and Younger Patients Receiving Definitive Radiotherapy for Cervical Cancer.

The aim was to compare the clinical outcomes and prognostic factors of cervical cancer between elderly and younger women, and to explore which treatment strategy is more appropriate for elderly patients. We retrospectively reviewed patients with cervical cancer receiving definitive radiotherapy (RT) between 2007 and 2016, and divided them into two age groups: age < 70 vs. age ≥ 70. The clinical outcomes were compared between the two age groups. The median follow-up was 32.2 months. A total of 123 patients were eligible, 83 patients in group 1 (age < 70), and 40 patients in group 2 (age ≥ 70). Patients in group 2 received less intracavitary brachytherapy (ICRT) application, less total RT dose, and less concurrent chemoradiotherapy (CCRT), and tended to have more limited external beam radiotherapy (EBRT) volume. The treatment outcomes between the age groups revealed significant differences in 5-year overall survival (OS), but no differences in 5-year cancer-specific survival (CSS), 66.2% vs. 64.5%, and other loco-regional control. In multivariate analyses for all patients, the performance status, pathology with squamous cell carcinoma (SCC), International Federation of Gynecology and Obstetrics (FIGO) stage, and ICRT application were prognostic factors of CSS. The elderly patients with cervical cancer had comparable CSS and loco-regional control rates, despite receiving less comprehensive treatment. Conservative treatment strategies with RT alone could be appropriate for patients aged ≥ 70 y/o, especially for those with favorable stages or histopathology.

Long-term follow-up of volumetric modulated arc therapy in definitive radiotherapy for cervical cancer: A single-center retrospective experience

ObjectiveTo evaluate the treatment outcomes and toxicity of volumetric modulated arc therapy (VMAT) in definitive radiotherapy for patients with cervical cancer. MethodsMedical records of 440 patients with cervical cancer treated with VMAT in definitive radiotherapy with or without concurrent chemotherapy between January 2010 and June 2015 in our institution were retrospectively reviewed. A dose of 45 ​Gy was prescribed to the planning target volume with VMAT in 25 fractions, followed by high-dose rate intracavitary brachytherapy with 28–36 ​Gy in 4–6 fractions. Survival time was estimated using Kaplan-Meier method. Risk factors for treatment failure were identified using Cox proportional hazards regression model. ResultsThe median follow-up periods were 58.3 months (range: 2.7–112.9 months). The 3- and 5-year survival rates were overall survival (OS) 79.4% and 74.4%, cancer-specific survival (CSS) 81.4% and 77.1%, progression-free survival (PFS) 73.3% and 71.1%, locoregional control (LC) 83.3% and 82% and distant metastasis-free survival (DMFS) 80.8% and 77.7%, respectively. The 5-year OS for patients with different stages was IB1 91.6%, IB2 100%, IIA 82.5%, IIB 74.4%, IIIA 57.1%, IIIB 61.7% and IVB 17.6%, respectively. Of the 124 patients with recurrence, 93 patients (75.0%) experienced distant failure. Multivariate analysis showed that non-squamous cell carcinoma of the cervix (P ​< ​0.001), more advanced stage (P ​= ​0.004), pelvic lymph node metastasis (P ​< ​0.001) and para-aortic lymph node metastasis (P ​= ​0.019) were all independent risk factors of PFS. The incidence of grades 3–4 late bowel toxicities was 2.7%. No grades 3–4 bladder toxicity was observed. ConclusionThis study demonstrated that the use of VMAT in definitive radiotherapy resulted in satisfactory outcomes with acceptable toxicities for patients with cervical cancer. Distant metastasis predominated as the pattern of disease relapse. Further studies are needed to investigate the intensified systemic therapies.

A multi-scanner study of MRI radiomics in uterine cervical cancer: prediction of in-field tumor control after definitive radiotherapy based on a machine learning method including peritumoral regions.

This study aimed to identify the most appropriate volume of interest (VOI) setting in prognostic prediction using pretreatment magnetic resonance imaging (MRI) radiomic analysis for cervical cancer (CC) treated with definitive radiotherapy. The study participants were 87 patients who had undergone pretreatment MRI and definitive radiotherapy for CC. VOItumor was created with tumor alone and VOI+4mm-VOI+20mm mechanically expanded by 4-20mm around each VOItumor in axial T2-weighted images (T2WI) and an apparent diffusion coefficient (ADC) map. A model was constructed to predict recurrence within the irradiation field within 2years after treatment using imaging features from the VOI of each sequence. Sorting ability was evaluated by area under the receiver operator characteristic curve (AUC-ROC) analysis. VOI expansion improved AUC-ROCs compared with the predictive models of VOItumor (0.59 and 0.67 in T2WI and ADC, respectively). The AUC-ROCs of the models with imaging features from expanded VOI+4mm in T2WI and VOI+4mm and VOI+8mm in ADC were 0.82, 0.82, and 0.86, respectively. Recurrence could be predicted with high accuracy using expanded VOI for CC treated with definitive radiotherapy, suggesting that including the pathological characteristics of invasive margins in radiomics may improve predictive ability.

Cervical Cancer Outcomes in Elderly Women Treated with EBRT and Brachytherapy +/- Concurrent Chemotherapy

Cervical cancer is commonly viewed as a cancer affecting middle-aged women. However, more than 15% of cervical cancer cases occur in women over age 65. It is uncertain whether literature from trials, in which older women are a minority of the study population, appropriately guides their treatment and describes their natural history. The goal of this study was to evaluate cervical cancer treatment patterns and outcomes in older women in order to better counsel patients and optimize management. We performed a retrospective institutional analysis on women 69 and above with primary cervical cancer treated from 1999 - 2018. Included patients were treated with definitive, curative intent radiotherapy. We excluded patients with distant metastases, those treated palliatively, and those receiving surgery as primary treatment. We evaluated overall patient survival, use of chemotherapy, and recurrence patterns. This study was IRB approved. 65 eligible patients were included. Median age was 77 years (range 69-88), ranging in stage from IB1 to IIIB (IB1: 15 pts; IB2: 6 pts; IIA (NOS): 6 pts; IIA1: 3 pts; IIA2: 3 pts, IIB: 17 pts; IIIA: 2 pts, IIIB: 13 pts). Most were squamous cell carcinoma (83.1%), followed by adenocarcinoma (13.9%) and other (3%). Median external beam radiation (EBRT) dose was 45 Gy and median brachytherapy (BT) dose was 27.5 Gy. BT varied by era, but the majority were treated with HDR BT, with 53/65 (81.5%) HDR, 10/65 (15.4%) LDR, and 2/65 (3.1%) discontinuing treatment prior to brachytherapy. 86.2% received intracavitary BT and 10.8% received combined intracavitary/interstitial BT. Median total duration of therapy (EBRT + BT) was 50 days. The vast majority of women completed their intended course of radiation therapy, with a completion rate of 90.8%. 37 pts (56.9%) received concurrent chemotherapy, most commonly weekly cisplatin. Of those women, 5 (13.5%) discontinued chemotherapy due to adverse effects. With a median follow up of 24 months, 15 pts (24.6%) developed a recurrence, with 3 relapsing locally, 1 relapsing regionally, 9 relapsing with distant metastases only, and 2 relapsing both distantly and regionally. The 2-year local control rate was 91.4% and the loco-regional control rate was 82.9%. The 2-year overall survival was 75.1%. The 2-year disease-free survival was 61.4%. Due to small patient numbers and imbalance in stage between those receiving/not receiving concurrent chemotherapy, no conclusions can be made about the impact of chemotherapy on disease outcomes. The outcomes of elderly patients treated with definitive radiotherapy for cervical cancer are comparable to those of younger women, with the vast majority of patients able to complete therapy, resulting in 2-year loco-regional control rates over 80%. In conclusion, definitive radiation therapy, including brachytherapy, should be encouraged for older women presenting with cervical cancer.

Dynamics of High Risk Clinical Target Volume reduction during Brachytherapy and impact on its coverage in patients with inoperable cervical cancer.

Cervical cancer is the third most common cancer in women worldwide. Standard of care for patients with node positive or locally advanced tumors >4 cm is definitive radiotherapy and concurrent chemotherapy. Brachytherapy is an integral part of definitive radiotherapy for cervical cancer. The aim of the study was to show a dynamics of High Risk Clinical Target Volume (HR-CTV) reduction during Brachytherapy (BT) as a part of definitive treatment (External Beam Radiotherapy /EBRT/ +/- Chemotherapy /ChT/) depending on the initial Gross Tumor Volume (GTV) and its impact on HR-CTV coverage in patients with inoperable cervical cancer. We analyzed the dosimetric data for BT of 54 patients who have had Three Dimensional Planning of BT (3D BT). The Gross Tumor Volume, HR-CTV and organs at risk (OARs) were contoured on the magnetic resonance imaging (MRI), subsequently on the co-registered MRI images with computed tomography (CT). Point A and ICRU 38 rectal and bladder points were defined on reconstructed CT images. Patients were categorized on the basis of whether the 100% isodose line of the point-A prescription dose encompassed the HR-CTV (1st group) or not (2nd group). The 30cc volume has been determined as a cut-off value, which represented the most acceptable value of intermediate size of volumes. The initial mean value of GTV was 42cc. After completion of EBRT/ChT, the mean GTV was 3.24cc what was 91% reduction rate in relation to the initial value. We followed the dynamics of HR-CTV reduction during BT and have noted its minimal reduction from 24.3cc (mean value) at the time of the first fraction to the 24.1cc before fourth fraction. The mean V100 was 98% and increased with decreasing of the volume size (p=0.0063, Fisher's exact test). D90 (mean value was 96.3 Gy10) has been correlated with V100 and also, it increased with decreasing of the volume size (p=0.0003). The mean D0.1cc and D2cc of rectum doses were 80 Gy3 and 65.6 Gy3, respectively. The mean ICRU rectal dose for all patients was 67.2 Gy3. The mean D0.1cc (99.5 Gy3), D2cc (79.5 Gy3) and ICRU (75.2 Gy3) of bladder doses were acceptable. Dynamics of HR-CTV reduction during BT was minimal, although, significant reduction of the GTV was achieved after EBRT/ChT. This study revealed that the dose prescription of 7 Gy × 4 fractions to point A was not sufficient indicator for dose coverage of the HR-CTV. However, dosimetric parameters as V100 and D90 were strong indicators for coverage of HR-CTV which was inversely related to the volume of the target and the extension of tumor. However, dosimetric parameters for rectum and bladder (D0.1cc, D2cc and ICRU) did not show dependence on the target volumes.

Efficacy and toxicity of image-guided intensity-modulated radiation therapy combined with dose-escalated brachytherapy for stage IIB cervical cancer.

Considering internal organ motion and tumor regression, it is controversial to use intensity-modulated radiation therapy (IMRT) in definitive radiotherapy for cervical cancer. In this study, we evaluated the efficacy and toxicity of IMRT combined with dose-escalated intracavitary brachytherapy (ICBT) for cervical cancer. In total, 373 consecutive FIGO-stage-IIB cervical cancer patients treated with IMRT combined with ICBT and concurrent chemotherapy were included in this study. A dose of 50.4 Gy in 28 fractions was delivered to the pelvis for IMRT. Weekly cone-beam computed tomography or daily megavoltage computed tomography was used for image guiding. For ICBT, 30–36 Gy in five to seven fractions were prescribed to point A. All patients received concurrent chemotherapy. The median follow-up duration was 32.5 months (range, 3.1–119.8 months). The three-year overall survival, disease-free survival and local control rates were 87.5%, 82.2% and 92.5%, respectively. Sixty patients (16.1%) experienced treatment failure, including 23 patients (6.2%) with pelvic relapse. The incidences of ≥grade 3 chronic gastrointestinal and genitourinary toxicity were 2.7% and 2.4%, respectively. These findings indicate that image-guided IMRT combined with dose-escalated ICBT results in good survival with acceptable toxicity in stage IIB cervical cancer patients.

Socioeconomic status as an independent risk factor for severe late bowel toxicity after primary radiotherapy for cervical cancer.

To evaluate the frequency of and risk factors for severe late bowel toxicity after curative radiotherapy in women treated for locally advanced cervical cancer. Included were 515 women treated for locally advanced cervical cancer with primary radiotherapy with curative intent from 1992 to 2013. Bowel toxicity was graded according to the Common Terminology Criteria for Adverse Events. Associations between risk factors and severe late bowel toxicity were assessed using Cox proportional hazards regression models. Median follow-up was 78months. Fifty-nine patients developed severe late bowel toxicity. The actuarial 3-year and 5-year severe late bowel toxicity rates were both 13%. In the multivariable analysis, factors significantly associated with severe late bowel toxicity were: smoking (HR 2.59 [1.48-4.55]), severe acute bowel toxicity (HR 2.46 [1.24-4.49]), previous major abdominal surgery (HR 2.35 [1.20-4.60]), hypertension (HR 2.33 [1.23-4.40]), parametrial boost (HR 2.18 [1.10-4.33]), low socioeconomic status (HR 2.05 [1.17-3.59]) and low BMI (HR 0.93 [0.88-0.99]). First symptoms of severe late bowel toxicity were reported after a median follow-up of 9months, but occurred up to 10years after end of treatment. Only one third of the patients with severe late bowel toxicity were referred to a gastroenterologist. Severe late bowel toxicity is a frequent complication of definitive radiotherapy for cervical cancer. Several independent risk factors were found which warrant further research. A standardized and structured approach in the early diagnostics and management of bowel toxicity is needed.

Predictive factors of uterine movement during definitive radiotherapy for cervical cancer.

To determine the predictive factors affecting uterine movement during radiotherapy (RT), we quantified interfraction uterine movement using computed tomography (CT) and cone-beam CT (CBCT). A total of 38 patients who underwent definitive RT for cervical cancer were retrospectively analyzed. We compared pre-RT planning CT (n = 38) and intratreatment CBCT (n = 315), measuring cervical and corporal movement in each direction. Correlations between uterine movement and volume changes of the bladder and rectum on all CBCT scans were analyzed using Spearman rank correlation analysis. Relationships between the mean uterine movement and patient factors were analyzed using the Mann–Whitney test. The mean corpus movement was: superior margin (cranio–caudal direction), 7.6 ± 5.9 mm; anterior margin (anteroposterior direction), 8.3 ± 6.3 mm; left margin (lateral direction), 3.3 ± 2.9 mm; and right margin (lateral direction), 3.0 ± 2.3 mm. Generally, the mean values for cervical movement were smaller than those for the corpus. There was a significant, weak correlation between changes in bladder volume and the movement of the superior margin of the corpus (ρ = 0.364, P < 0.001). There was a significant difference in movement of the superior margin of the corpus between the subgroups with and without a history of previous pelvic surgery (P = 0.007). In conclusion, change in bladder volume and a history of previous surgery were significantly related to intrafractional corpus movement; however, our observations suggest that the accurate prediction of uterine movement remains challenging.

Temporo-spatial cell-cycle kinetics in HeLa cells irradiated by Ir-192 high dose-rate remote afterloading system (HDR-RALS).

BackgroundIntracavitary irradiation plays a pivotal role in definitive radiotherapy for cervical cancer, and the Ir-192 high dose-rate remote afterloading system (HDR-RALS) is often used for this purpose. Under this condition, tumor tissues receive remarkably different absorption doses, with a steep gradient, depending on distance from the radiation source. To obtain temporo-spatial information regarding cell-cycle kinetics in cervical cancer following irradiation by Ir-192 HDR-RALS, we examined HeLa cells expressing the fluorescence ubiquitination-based cell cycle indicator (Fucci), which allowed us to visualize cell-cycle progression.MethodsHeLa-Fucci cells, which emit red and green fluorescence in G1 and S/G2/M phases, respectively, were grown on 35-mm dishes and irradiated by Ir-192 HDR-RALS under normoxic and hypoxic conditions. A 6 French (Fr) catheter was used as an applicator. A radiation dose of 6 Gy was prescribed at hypothetical treatment point A, located 20 mm from the radiation source. Changes in Fucci fluorescence after irradiation were visualized for cells from 5 to 20 mm from the Ir-192 source. Several indices, including first green phase duration after irradiation (FGPD), were measured by analysis of time-lapse images.ResultsCells located 5 to 20 mm from the Ir-192 source became green, reflecting arrest in G2, in a similar manner up to 12 h after irradiation; at more distant positions, however, cells were gradually released from the G2 arrest and became red. This could be explained by the observation that the FGPD was longer for cells closer to the radiation source. Detailed observation revealed that FGPD was significantly longer in cells irradiated in the green phase than in the red phase at positions closer to the Ir-192 source. Unexpectedly, the FGPD was significantly longer after irradiation under hypoxia than normoxia, due in large part to the elongation of FGPD in cells irradiated in the red phase.ConclusionUsing HeLa-Fucci cells, we obtained the first temporo-spatial information about cell-cycle kinetics following irradiation by Ir-192 HDR-RALS. Our findings suggest that the potentially surviving hypoxic cells, especially those arising from positions around point A, exhibit different cell-cycle kinetics from normoxic cells destined to be eradicated.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0669-8) contains supplementary material, which is available to authorized users.

PO-0732: Predictive factors for inter-fraction uterine motion in definitive radiotherapy for cervical cancer

PO-0732: Predictive factors for inter-fraction uterine motion in definitive radiotherapy for cervical cancer

Pelvic insufficiency fracture after definitive radiotherapy for uterine cervical cancer: retrospective analysis of risk factors

The purpose of this study is to determine the incidence, clinical characteristics and risk factors of postradiation pelvic insufficiency fracture (PIF) in women with uterine cervical cancer. We reviewed the medical records of 126 patients who received definitive radiotherapy (RT) for uterine cervical cancer between 2003 and 2009 at our institution. Among them, 99 patients who underwent at least one computed tomography (CT) or magnetic resonance imaging of the pelvis during their follow-up at more than 6 months were included in this analysis. The relationship between the incidence of PIF and several patient- and treatment-related factors was analyzed. The median follow-up period was 21 months. Of the 126 patients, 33 (with a total of 50 lesions) were diagnosed with PIF. The 2-year cumulative incidence was 32%. Univariate analysis showed that age ≥70 years (P= 0.0010), postmenopausal state (P = 0.0013), and lower CT density of bone and bone marrow (P= 0.020) significantly related to PIF. In a multivariate analysis, of the 59 patients whose CT densities were evaluable, lower CT density was the only significant factor associated with PIF (P = 0.0026). In conclusion, postradiation PIFs were detected in a considerable number of patients after definitive RT for cervical cancer. Predisposing factors were older age, postmenopausal state, and decreased density of bone and bone marrow on CT.

Metabolic Response on Post-therapy FDG-PET Predicts Patterns of Failure After Radiotherapy for Cervical Cancer

To determine the patterns of failure in patients with cervical cancer treated with definitive radiotherapy and evaluated for metabolic response with early posttherapy (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET). The records of 238 patients with cervical cancer were reviewed. All patients were treated with a combination of external radiotherapy and intracavitary brachytherapy. Two hundred and nineteen patients (92%) received concurrent chemotherapy. All patients underwent pretreatment FDG-PET, and posttherapy FDG-PET was performed within 8-16 weeks of the completion of radiotherapy. Posttherapy FDG-PET results were categorized as complete metabolic response (CMR), partial metabolic response (PMR), and progressive disease (PD). Failure patterns were categorized as none, isolated local failure (central pelvis ± pelvic lymph nodes), distant failure, or combined local plus distant failure. Of the 91 patients (38%) who had a recurrence, 22 had isolated local failures, and 69 had distant failures (49 distant failures and 20 combined local plus distant failures). Of the 173 patients with a CMR, 40 (23%) experienced treatment failure. All 25 patients with PD experienced treatment failure, which was distant in 24 patients (96%). Among the 40 patients with PMR, no failure has been observed for 14 patients (35%). Of the 26 failures within the PMR group, 15 (58%) were limited to the pelvis. Differences in the patterns of failure between the three groups (CMR, PMR, PD) were statistically significant (chi-square test; p < 0.0001). The majority of failures after definitive radiotherapy for cervical cancer include distant failures, even in the setting of concurrent chemotherapy. PMR within the cervix or lymph nodes is more commonly associated with isolated local recurrence.

Patterns of Regional Recurrence After Definitive Radiotherapy for Cervical Cancer

To determine the patterns of regional recurrence in patients treated with definitive radiotherapy (RT) for cervical cancer. The records of 198 patients treated with definitive RT for cervical cancer between 1980 and 2000 who experienced a regional recurrence without a central or distal vaginal recurrence were reviewed. All patients received a combination of external-beam RT and intracavitary brachytherapy. In the 180 patients with a documented location of regional recurrence, the relationship between the recurrence and the radiation fields was determined. The median time to regional recurrence was 13 months (range, 2-85 months). Of the 180 patients who had an evaluable regional recurrence, 119 (66%) had a component of marginal failure; 71 patients recurred above-the-field, 2 patients occurred in the inguinal nodes, and 2 patients recurred above-the-field and in the inguinal nodes. In addition, 105 patients (58%) had a component of in-field failure; 59 patients recurred in-field only, 39 patients recurred in-field and above-the-field, 2 patients recurred in-field, above-the-field, and in the inguinal nodes, and 5 patients recurred in-field and in the inguinal nodes. The median survival after regional recurrence was 8 months (range, 0-194 months). Most regional recurrences after definitive RT for cervical cancer include a component of marginal failure, usually immediately superior to the radiation field. These recurrences suggest a deficiency in target volume. Recurrences also occur in-field, suggesting a deficiency in dose. Developments in pretreatment staging, field delineation, dose escalation, and posttreatment surveillance may help to improve outcome in these patients.

Current status and perspectives of brachytherapy for cervical cancer

Standard definitive radiotherapy for cervical cancer consists of whole pelvic external beam radiotherapy (EBRT) and intracavitary brachytherapy (ICBT). In Japan, high-dose-rate ICBT (HDR-ICBT) has been utilized in clinical practice for more than 40 years. Several randomized clinical trials demonstrated that HDR-ICBT achieved comparative outcomes, both for pelvic control and incidences of late complications, to low-dose-rate (LDR) ICBT. In addition, HDR-ICBT has some potential advantages over LDR-ICBT, leading to further improvement in treatment results. Prior to the current computer planning systems, some excellent treatment planning concepts were established. At present, systems modified from these concepts, or novel approaches, such as image-guided brachytherapy (IGBT) are under investigation. One serious problem to be solved in HDR-ICBT for cervical cancer is that of the discrepancy in standard treatment schedules for combination HDR-ICBT and EBRT between the United States and Japan. Prospective studies are ongoing to assess the efficacy and toxicity of the Japanese schedule.

Prognostic Impact of HIF-1α Expression in Patients with Definitive Radiotherapy for Cervical Cancer

To investigate the relationship between the hypoxia-inducible factor-(HIF-)1alpha expression in tumor tissue, tumor oxygenation and hemoglobin levels in patients with advanced cervical cancers prior to radiotherapy and the effect on clinical outcome. The investigation included 44 patients who underwent definitive radiotherapy for advanced cervical cancers between May 1995 and March 1999. Tumor biopsies were taken prior to treatment, and HIF-1alpha expression was determined by immunohistochemistry. In the same tumor area, tumor tissue oxygenation (pO2) was measured using the Eppendorf device. The 5-year cancer-specific survival of all patients was 60%. Twelve of 44 tumor specimens were HIF-1alpha-negative with a significantly better 5-year survival (92 +/- 8%) versus 32 patients who were HIF-1alpha-positive (45 +/- 10%; p < 0.02). There was no correlation between HIF-1alpha expression and tumor oxygenation (p = 0.57 both for pO2 median and hypoxic fraction < 5 mmHg vs. HIF-1alpha expression). However, patients with hemoglobin levels < 11 g/dl showed elevated HIF-1alpha expression compared to patients with hemoglobin levels > 12.5 g/dl (p = 0.04). Furthermore, HIF-1alpha correlated with vascular endothelial growth factor expression (p = 0.002). In a multivariate Cox regression model, HIF-1alpha expression (relative risk [RR] = 7.5; p = 0.05) revealed an increased risk of tumor-related death. The study indicates, that endogenous tumor markers such as HIF-1alpha may serve as prognostic markers of clinical outcome concerning cervical cancer after primary radiotherapy.

A single institutional experience with definitive radiotherapy for cervical cancer using both high- and low-dose-rate brachytherapy

Objective. To evaluate outcomes in cervical cancer patients treated with high-dose-rate (HDRB) or low-dose-rate (LDRB) brachytherapy. Methods. A retrospective chart review compared control rates, survival, and complications in the two groups. Results. All patients received pelvic EBRT (45 Gy/5 weeks). 106 patients receiving LDRB were compared to 107 treated with HDRB. The median point A LDRB and HDRB dose was 42 Gy and 25 Gy/5, respectively. Tumor size and stage (I B 23% LDRB, 30% HDRB, II A 22% LDRB, 11% HDRB, II B 44% LDRB, 48% HDRB, III B 11% LDRB and HDRB) were similar, but more HDRB patients received chemosensitization (44% versus 6%). After adjusting for lymph node status with cox regression, no difference in 5-year survival (53% HDRB and 61% LDRB P = 0.088) or 5-year DFS (54% both groups, P = 0.089) was found between the two groups. Local recurrences occurred in 19% of the LDRB and 5% of the HDRB cohort. The time to LR was significantly longer in the HDRB group, and this persisted after adjusting for the increased used of chemotherapy in these patients. There was no significant difference in grade III or IV toxicity (6.6% LDRB and 3.7% HDRB). Conclusions. This HDRB dose fractionation schedule yielded improved local control but similar survival compared to LDRB.