Won Park

Postoperative conventional versus hypofractionated intensity-modulated radiation therapy with concurrent chemotherapy in cervical cancer: a prospective multicenter randomized phase III trial (POHIM_P3 trial)

For patients with high-risk factors such as pelvic lymph node metastasis, positive surgical margins, or parametrial involvement, concurrent chemoradiotherapy (CCRT) with whole-pelvic radiotherapy significantly improves survival outcomes. Hypofractionated radiation therapy, which delivers higher radiation doses over fewer sessions, enhances tumor control but raises concerns about increased normal tissue toxicity. A recent Korean phase II study (POHIM-CCRT) evaluated the safety of hypofractionated intensity-modulated radiation therapy (IMRT), delivering 40 Gy in 16 fractions with weekly cisplatin following radical surgery. The results showed minimal acute toxicity. Based on these findings, the present study was designed to assess the oncologic efficacy of hypofractionated CCRT compared to conventional treatment strategies in high-risk cervical cancer patients after radical surgery. The POHIM-P3 trial is a phase 3, randomized, multicenter study designed for women with cervical cancer requiring adjuvant CCRT after radical hysterectomy. Participants in the experimental arm receive hypofractionated IMRT to whole pelvis, delivering a total dose of 40 Gy in 16 fractions, and the control arm receive conventional radiotherapy with a total dose of 45-50.4 Gy in 25-28 fractions in combination with weekly cisplatin. The primary endpoint of the study is the 3-year disease-free survival and the secondary endpoints included acute and late side-effects, local control rates, and overall survival rates. ClinicalTrials.gov Identifier: NCT06509724.

Significance of HPV status on tumor response and treatment outcomes in endocervical adenocarcinoma treated with definitive chemoradiotherapy: a retrospective study

We aimed to compare tumor response and treatment outcomes between human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) endocervical adenocarcinomas (ADCs) treated with definitive concurrent chemoradiotherapy (CCRT) and to identify prognostic factors. We conducted a retrospective review of 40 patients with endocervical ADCs treated with definitive CCRT (stages I-IVA) between 2011 and 2022. Based on pathological review the cases were categorized as HPVA or HPVI ADCs. Statistical analyses were performed to compare the characteristics, complete response (CR) rates, and survival outcomes. Of 40 patients, 22 (55.0%) had HPVA and 18 (45.0%) had HPVI ADCs. HPVI patients had significantly higher rates of parametrial invasion (94.4% vs. 45.5%, p=0.001). CR was achieved in 57.5% of patients and was significantly more common in the HPVA group (81.8% vs. 27.8%, p=0.001). Patients with HPVI had higher recurrence rates (88.9% vs. 50.0%, p=0.016) and lower 3-year progression-free survival (PFS, 16.7% vs. 49.8%, p=0.001), distant metastasis-free survival (DMFS, 38.1% vs. 80.8%, p=0.001), and overall survival (OS, 42.3% vs. 90.7%, p=0.002) rates. HPVA remained a significant factor for PFS (hazard ratio [HR]=3.44; 95% confidence interval [CI]=1.09-10.81; p=0.035) and OS rates (HR=6.83; 95% CI=1.17-39.80; p=0.033) in multivariate analysis. HPVI ADC was associated with a lower response to definitive CCRT and worse prognosis than HPVA ADC. These findings suggest the need for tailored treatment strategies based on the HPV status.

Significance of serum CA125 level in surgically resected cervical adenocarcinoma with adverse features

Unlike cervical squamous cell carcinoma, there are no consensus criteria for serum tumor markers in cervical adenocarcinoma. This study aimed to identify the prognostic value of preoperative carbohydrate antigen 125 (CA125) levels in cervical adenocarcinoma patients with adverse pathologic features. A total of 105 patients who underwent radical hysterectomy followed by adjuvant radiotherapy (RT) or concurrent chemoradiation therapy were included. Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were evaluated using the Cox proportional hazard regression model. Using a cutoff value of 50 U/mL, 83 and 22 patients had low- and high-CA125, respectively. Patients with high-CA125 had a larger tumor size, more frequent parametrial extension, and more frequent lymph node metastasis than those with low-CA125. During a median follow-up of 59.3 (interquartile range, 32.7-97.8) months, patients with high-CA125 showed inferior 5-year LRFS, DMFS, and OS rates compared to those with low-CA125 (38.5% vs. 70.0%; 37.0% vs. 69.4%; 43.6% vs. 78.1%, respectively, all p<0.05). In multivariable analysis, the high-CA125 remained significant prognostic factor for LRFS, DMFS, and OS (all p<0.05). Furthermore, 12 patients with high-CA125 at recurrence exhibited lower 5-year OS rates than 21 patients with low-CA125 at recurrence (0.0% vs. 51.3%, p=0.003). In this retrospective analysis, the serum CA125 level at diagnosis and recurrence was related to the extent of disease and prognosis of cervical adenocarcinoma with adverse pathologic features. A CA125 level of ≥50 U/mL may be a prognostic surrogate marker for cervical adenocarcinoma in patients with the presence of adverse factors.

Chemoradiotherapy is not superior to radiotherapy alone after radical surgery for cervical cancer patients with intermediate-risk factor

There is no consensus on whether giving adjuvant concurrent chemoradiotherapy (CCRT) is more effective than adjuvant radiotherapy (RT) alone in patients with early stage cervical cancer and intermediate-risk factor(s). The purpose of this study was to evaluate survival difference according to adjuvant treatment in the intermediate-risk group. From 2000 to 2014, the medical records of patients with stage IB-IIA cervical cancer and a history of radical hysterectomy with pelvic lymph node dissection, followed by pelvic RT at a dose ≥40 Gy were retrospectively reviewed. Among these, 316 patients with one or more intermediate-risk factor(s) and no high-risk factors were included. The criteria defined the intermediate-risk group as those patients with any of the following intermediate-risk factors: lymphovascular space involvement, over one-half stromal invasion, or tumor size ≥4 cm. The median follow-up duration was 70 months (range: 3-203 months). According to adjuvant treatment (adjuvant RT alone vs. adjuvant CCRT), the 5-year recurrence-free survival rates (90.8% vs. 88.9%, p=0.631) and 5-year overall survival rates (95.9% vs. 91.0%, p=0.287) did not show a significant difference in patients with any of the intermediate-risk factors. In multivariate analysis, a distinct survival difference according to adjuvant treatment was not found regardless of the number of risk factors. The present study showed that giving RT together with chemotherapy is not more effective than RT alone for stage IB-IIA cervical cancer patients with intermediate-risk factor(s). ClinicalTrials.gov Identifier: NCT01101451.

Patterns of definitive radiotherapy practice for cervical cancer in South Korea: a survey endorsed by the Korean Radiation Oncology Group (KROG 20-06)

The Korean Radiation Oncology Group conducted a nationwide questionnaire survey to evaluate the patterns of clinical practice for patients with cervical cancer receiving definitive radiation therapy (RT) in South Korea. Practicing radiation oncologists from 93 centers in South Korea were administered a questionnaire survey via e-mail. The survey focused on demographic characteristics, diagnostic evaluation, indications for definitive RT, RT techniques, RT field and dose prescription, lymph node (LN) boost RT, brachytherapy, and chemotherapy. The response rate was 62.4% (58/93 institutions). Of the 2,134 patients treated at the radiation oncology department in 2019, 48.8% underwent definitive RT. The selection of patients for definitive concurrent chemoradiation therapy and RT field, and RT dose prescription varied greatly. The upper border of the pelvis was commonly used as the bony landmark for external beam RT (81%-88% of respondents). Most (96.6%) centers performed LN boost RT with median total doses of 59 Gy and 59.2 Gy for pelvic and retroperitoneal LN, respectively. With 50% of the centers offering brachytherapy, image-guided brachytherapy and volume-based prescription were applied in 48.3% and 37.9%, respectively. Upfront concurrent chemoradiation therapy with varying prescription doses was considered by 60.4% respondents in cases of supraclavicular LN metastasis. Most differences were noted in the indications for treatment, RT field, and prescription dose. This finding can serve as a reference for establishing practical RT guidelines for the management of locally advanced cervical cancer.

Patterns and risk factors of recurrence in low-risk early-stage cervical adenocarcinoma treated with surgery alone: implications on risk group stratification

Cervical adenocarcinoma has poorer outcomes compared with squamous cell carcinoma; however, treatment is identical irrespective of histologic sub-types. This study aimed to investigate the patterns and risk factors of recurrence following surgery alone for low-risk early-stage cervical adenocarcinoma. We retrospectively reviewed patients who underwent surgery alone for low-risk early-stage cervical adenocarcinoma between January 2001 and December 2018 in a single institution. Baseline clinicopathological characteristics were collected to identify the factors associated with recurrence-free survival. A total of 252 patients met the inclusion criteria. Most patients underwent radical hysterectomy (218 patients, 86.5%) and had usual type endocervical adenocarcinoma (190 patients, 75.4%). The International Federation of Gynecology and Obstetrics 2018 stage was IA1 in 72 patients (27.4%), IA2 in 58 (22.1%), IB1 in 51 (19.4%), and IB2 in 71 patients (27.0%). With a median follow-up of 70.4 months (range 6.2-252.5 months), 5-year survival rates were as follows: locoregional recurrence-free survival, 93.0%; recurrence-free survival, 89.6%; overall survival, 94.7%. The recurrence patterns were local in nine patients (32.1%), regional in five patients (17.8%), distant in 10 patients (35.7%), local and distant in one patient (3.6%), regional and distant in two patients (7.2%), and locoregional and distant in one patient (3.6%). In multivariable analysis, negative human papillomavirus (HPV) status (HR 7.314; p<0.001) and deep cervical stromal invasion (HR 5.110; p=0.003) were associated with poor locoregional recurrence-free survival. Patients were stratified based on the number of risk factors and a statistically significant difference in locoregional recurrence-free survival was observed: 5-year survival rates of 99.0%, 84.2%, and 50.0% for patients with 0, 1, and 2 risk factors (0 vs 1, p=0.001; 1 vs 2, p=0.011). Surgery alone for low-risk early-stage cervical adenocarcinoma was associated with favorable outcomes over a long follow-up period. Patients with the highest risk of recurrence were those with a negative HPV status and deep cervical stromal invasion. Additional management following surgery may be considered in patients with these risk factors.

Predicting prognosis according to the updated WHO classification in patients with endocervical adenocarcinoma treated with surgery and radiotherapy

The recently updated World Health Organization classification divides endocervical adenocarcinomas (ADCs) into human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) ADCs. This study aimed to investigate the differences in the clinical features and treatment outcomes between patients with HPVA and HPVI. We retrospectively reviewed the electronic medical records and pathology slides of 123 patients with endocervical ADC who underwent radical hysterectomy and adjuvant radiation therapy. Tumor characteristics, patterns of failure, and survival outcomes were compared between HPVA and HPVI ADCs. Eighty-one (65.9%) and 42 (34.1%) patients were diagnosed with HPVA and HPVI ADCs, respectively. HPVI ADC showed more frequent positive vaginal resection margin (VRM) and peritoneal seeding than HPVA ADC. After a median follow-up of 58.1 months, local recurrence and distant metastasis were more frequently observed in HPVI ADC than in HPVA ADC. Both local recurrence-free survival (77.3% vs. 91.8%) and distant metastasis-free survival (50.1% vs. 73.7%) rates of HPVI ADC were lower than those of HPVA ADC. Disease-free survival was not significantly different between HPVI and HPVA ADCs. We demonstrated that HPVI ADC exhibited higher rates of VRM involvement and peritoneal seeding than those of HPVA ADC, resulting in higher rates of local recurrence and distant metastasis. Further studies with larger populations are warranted to explore optimal treatment strategies based on the histological subtypes of endocervical ADC.

Clinical outcomes after positron emission tomography/computed tomography‐based image‐guided brachytherapy for cervical cancer

AbstractIntroductionAlthough positron‐emission tomography (PET) plays an integral role in cervix cancer diagnosis, there are limited data on PET‐based image‐guided brachytherapy (IGBT). We aimed to report the long‐term outcomes of PET‐based IGBT.MethodsWe reviewed 151 patients treated with definitive radiotherapy (RT), including PET‐based IGBT between 2009 and 2018. After median 45 Gy of external beam RT with the four‐field technique, a median 24 Gy of high‐dose‐rate iridium‐192 IGBT was delivered in six fractions with Fletcher‐Suit tandem and ovoids. All patients underwent 18F‐fluorodeoxyglucose‐PET/computed tomography planning with a brachytherapy applicator. Multivariable analysis of local control (LC) was performed using Cox regression analysis.ResultsThe median high‐risk clinical target volume (HRCTV) and HRCTV D90% were 51.8 (interquartile range [IQR] 35.9–79.4) cm3 and 77.7 (IQR 74.7–81.2) Gy, respectively. With a median follow‐up of 57 (IQR 24.3–81.4) months, the 5‐year LC rate was 89.2%. HRCTV ≥72 cm3 was associated with inferior LC (hazard ratio, 3.72, p = .017) after multivariable analysis: the 5‐year LC rates were 94.0% and 77.9% for HRCTVs ≥72 and &lt; 72 cm3, respectively (p = .002). The impact of HRCTV D90% ≥70 Gy on LC was significant in patients with an HRCTV ≥72 cm3 compared to that in those with HRCTV &lt; 72 cm3. Patients with adeno/adenosquamous carcinoma demonstrated inferior LC in both groups. There were 13 (8.6%) and 11 (7.3%) patients with acute and late severe toxicities after RT.ConclusionPET‐based IGBT leads to favorable LC, and HRCTV ≥72 cm3 requires further dose escalation to improve outcomes.

Oncologic outcomes according to the level of disease burden in patients with metachronous distant metastases from uterine cervical cancer: a Korean Radiation Oncology Group study (KROG 18-10)

This study aimed to evaluate the oncologic outcomes according to disease burden in uterine cervical cancer patients with metachronous distant metastases. Between 2005 and 2015, 163 patients with metachronous distant metastases from uterine cervical cancer after receiving a definitive therapy were evaluated at seven institutions in Korea. Low metastatic burden was defined as less than 5 metastatic sites, whereas high metastatic burden was others. Each metastasis site was divided based on the lymph node (LN) and organs affected. The overall survival (OS) and progression-free survival (PFS) were assessed. Cox proportional hazards models, including other clinical variables, were used to evaluate the survival outcomes. The median follow-up duration was 22.2 months (range: 0.3-174.8 months). Para-aortic LNs (56.4%), lungs (26.4%), supraclavicular LNs (18.4%), and peritoneum (13.5%) were found to be the common metastasis sites. Among 37 patients with a single metastasis, 17 (45.9%) had LN metastases and 20 (54.1%) had organ metastases. The 1- and 2-year OS rates were 73.9% and 55.0%, respectively, whereas the PFS rates were 67.2% and 42.9%, respectively. SCC Ag after recurrence and high metastatic burden were significant factors affecting the OS (p=0.004 and p<0.001, respectively). Distant organ recurrence, short disease-free interval (≤2 years), and high metastatic burden were unfavorable factors for PFS (p=0.003, p=0.011, and p=0.002, respectively). A favorable oncologic outcome can be expected by performing salvage treatments in selected patients with a long disease-free interval, low metastatic burden, and/or lymphatic-only metastasis.

Comparison of Conventional and Hypofractionated IMRT in High-Risk Cervical Cancer Post-Radical Hysterectomy

Radical hysterectomy and radiation therapy are standard treatments for cervical cancer. However, there are no reported studies on the frequency of side effects and treatment outcomes when hypofractionated radiation therapy and intensity modulated radiation therapy(IMRT) are used during radiation therapy. Hypofractionated radiation therapy increases the daily dose and reduces the number of treatment sessions, which may increase the risk of side effects, but its safety has been confirmed in some cases of early cervical cancer and endometrial cancer. Additionally, applying IMRT, a technique designed to protect normal tissue, during concurrent chemoradiotherapy has shown positive results in reducing the incidence of acute side effects. Investigators previously demonstrated that combining hypofractionated IMRT with chemotherapy for high-risk postoperative cervical cancer patients resulted in high survival rates and low toxicity in a phase 2 exploratory study. Base on this result, this study aimed to compare the efficacy and safety of conventional fractionated radiation therapy and hypofractionated radiation therapy.

Radiation Therapy With or Without Chemotherapy in Patients With Stage I-IIA Cervical Cancer Who Previously Underwent Surgery

This randomized phase III trial studies radiation therapy with chemotherapy to see how well they work compared to radiation therapy alone in treating patients with stage I-IIA cervical cancer who previously underwent surgery. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving radiation therapy together with chemotherapy is more effective than radiation therapy alone in treating patients with cervical cancer.