The prognostic effect of tumor volume, reduction ratio, and cumulative doses on external beam radiotherapy with central-shielding method and image-guided adaptive brachytherapy for cervical cancer.

Objective: To evaluate the prognostic effect of tumor volume at diagnosis, tumor reduction ratio during external beam radiotherapy (EBRT) with central-shielding method, and cumulative minimal dose to 90% of the high-risk clinical target volume (CTVHR D90) on combined EBRT and image-guided adaptive brachytherapy (IGABT) for cervical cancer. Methods: Consecutive patients who underwent definitive radiotherapy or concurrent chemoradiotherapy for cervical cancer at Gunma University Hospital between January 2010 and December 2019 were retrospectively reviewed. Tumor volume at diagnosis and reduction ratio were calculated using magnetic resonance imaging at diagnosis and before the first IGABT session. The cumulative dose of EBRT and IGABT was calculated as an equivalent dose in 2 Gy fractions (EQD2). Optimal cutoff values were determined according to a receiver operating characteristic curve. Treatment outcomes were evaluated using the Kaplan-Meier method and compared using the log-rank test and Cox proportional hazards regression. Results: A total of 254 patients were included in the analysis. The median follow-up for all patients was 57 (2-134) months. The 5-year overall survival (OS) was 81.9%, progression-free survival (PFS) was 71.3%, and local control (LC) was 94.5%. The patients were divided into four groups according to tumor volume at diagnosis and reduction ratio. The group with tumor volume at diagnosis ≥ 34.1 cm3 and reduction ratio < 68.8% showed significantly worse OS, PFS, and LC than the other three groups (All p < 0.05). In this group, the patients with a cumulative CTVHR D90 < 69.6 GyEQD2 showed significantly worse PFS and LC (p = 0.042 and p = 0.027, respectively). In the multivariate analysis of OS, adenocarcinoma/adenosquamous carcinoma, International Federation of Gynecology and Obstetrics 2009 stage III/IV, and a reduction ratio of < 68.8% were independent significant poor prognostic factors (p = 0.045, p = 0.009 and p = 0.001, respectively). In the univariate analysis of LC, a reduction ratio of < 68.8% was the only poor prognostic factor (p = 0.041). Conclusion: The patients with large and poorly responding tumors had significantly worse prognoses in terms of OS, PFS, and LC, suggesting that dose escalation should be considered for such tumors.

Carbon ion radiotherapy for mesonephric adenocarcinoma of the uterine cervix: a case report.

BACKGROUND: Mesonephric adenocarcinoma is an extremely rare subtype of uterine cervical cancer that is associated with a poor prognosis and for which a standardized treatment protocol has not been established. Carbon ion radiotherapy (CIRT) is an emerging radiotherapy modality that has been shown to have a favorable anti-tumor effect, even for tumors resistant to conventional photon radiotherapy or chemotherapy. However, there is no report on CIRT outcomes for mesonephric adenocarcinoma of the uterine cervix. CASE PRESENTATION: We treated a 47-year-old Japanese woman with mesonephric adenocarcinoma of the uterine cervix (T2bN0M0 and stage IIB according to the 7th edition of the Union for International Cancer Control and International Federation of Gynecology and Obstetrics, respectively) with CIRT combined with brachytherapy and concurrent chemotherapy. CIRT consisted of whole pelvic irradiation and boost irradiation to the gross tumor; 36.0 Gy (relative biological effectiveness [RBE]) in 12 fractions and 19.2 Gy (RBE) in 4 fractions, respectively, performed once a day, four times per week. Computed tomography-based image-guided adaptive brachytherapy was performed after completion of CIRT, for which the D90 (i.e., the dose prescribed to 90% of the target volume) for the high-risk clinical target volume was 20.4 Gy in a total of 3 sessions in 2 weeks. A weekly cisplatin (40 mg/m2) dose was administered concomitantly with the radiotherapy for a total of five courses. From 4 months post-CIRT, the patient developed metastasis of the lung, with a total of 10 lung metastases over 70 months; these lesions were treated on each occasion by photon stereotactic body radiotherapy and/or systemic therapy. At 8 years from initial treatment (i.e., 2 years after the last treatment), the patient is alive without any evidence of recurrence and maintains a high quality of life. CONCLUSIONS: This is the first report of CIRT for treatment of mesonephric adenocarcinoma of the uterine cervix. The present case indicates the potential efficacy of CIRT in combination with brachytherapy for treatment of this disease.

Significance of definitive concurrent chemoradiotherapy for vulvar cancer: a Japanese Gynecologic Oncology Group nationwide survey study.

OBJECTIVE: This study aimed to show the results of radical radiation therapy (RT) and concurrent chemoradiotherapy (CCRT) for vulvar cancer (VC) based on data from a Japanese nationwide survey. MATERIALS AND METHODS: We collected data from 108 institutions on cases of VC diagnosed between January 2001 and December 2010. Patients with histologically proven squamous cell carcinoma and adenocarcinoma with curative intent were selected, and 172 patients with VC were included in this study. The collected data were analyzed for overall survival (OS) using the Kaplan-Meier method. Univariate and multivariate analyses were performed to examine the prognostic factors for patients with VC. RESULTS: The median follow-up period was 16.8 (range; 3.2-154.8) months. Fifty-five patients received CCRT, and 117 patients received RT alone. The 2-year OS rates (95% confidence interval [CI]) for stages I, II, III, and IV were 77.9% (55.8-100.0), 71.9% (53.8-89.9), 55.4% (42.5-68.3), and 41.5% (27.3-55.7) respectively. Univariate analyses showed that the FIGO stage (p = 0.001), tumor diameter (p = 0.005), and lymph node (LN) status (p = 0.001) were associated with OS. The concurrent use of chemotherapy resulted in a significantly longer OS in Stage III (p = 0.013). Multivariate analysis showed that the hazard ratios (95% CI) for tumor diameter, positivity for LN metastasis, and RT alone (no concurrent chemotherapy) were 1.502 (1.116-2.021), 1.801 (1.287-2.521), and 1.936 (1.187-3.159), respectively. CONCLUSIONS: Our analysis revealed that CCRT should be recommended, especially for Stage III VC patients. Further studies are warranted to determine who benefits from CCRT, considering primary tumor size and LN status. The study was registered at the University Hospital Medical Information Network (protocol number: UMIN000017080) on April 8th, 2015.

Utility of vaginal vault cytology in the local recurrence of cervical cancer.

BACKGROUND: In Japan, 8000 women were newly diagnosed with cervical cancer in 2018. The healthcare insurance policy in Japan allows physicians to utilize vaginal volt cytology tests and serum biomarker measurement at every visit and imaging analysis at an adequate interval with screening for recurrence after initial treatment. However, the major surveillance guidelines published in the United States and European countries recommend focusing on pelvic examinations and symptom reviews to avoid unnecessary tests. This study aimed to reassess the benefits of standard surveillance methods adopted in this study by retrospective analysis. METHODS: From January 2009 to December 2015, the medical records of patients with recurrence who were initially diagnosed with International Federation of Gynecology and Obstetrics stage I-III cervical cancer were collected for this study. Clinicopathological data were statistically analyzed to identify significant factors. In the first 2 years, the patients underwent regular surveillance, including pelvic examination, serum tumor marker tests, vaginal vault cytology every 1-3 months, and imaging analysis at 6- to 12-month intervals. In the following 2 years, the patients received a regular check with the same methods every 4 months and an annual imaging analysis. Afterward, the patients had regular screening every 6 to 12 months. RESULTS: In the study period, 84 of the 981 patients experienced recurrence, and 88.1% had an asymptomatic recurrence. The disease-free interval was not related to the recurrence site. In univariate analysis, primary treatment, recurrence site, and diagnostic method were significant factors for survival outcomes. In contrast, multivariate analysis indicated that only primary treatment was a significant factor. In patients with local recurrence, multivariate analysis demonstrated that radiation as salvage therapy was an independent predictive factor for overall survival after recurrence. CONCLUSIONS: In this retrospective study, routine imaging analysis and serum biomarker measurement did not contribute to patient prognosis after recurrence. In contrast, vaginal vault cytology can improve survival after recurrence in some patients. Tailored surveillance methods based on individual disease conditions and treatment modalities can improve post-recurrent survival outcomes.

CD8-positive Tumor-infiltrating Lymphocytes and Prognosis in Radiotherapy for Uterine Cervical Squamous Cell Carcinoma.

BACKGROUND/AIM: Prognostic factors, including CD8-positive tumor-infiltrating lymphocytes (CD8+TILs), in definitive radiotherapy (RT) for squamous cell carcinoma (SqCC) of the uterine cervix need to be studied. This study aimed to explore these factors in a retrospective cohort. PATIENTS AND METHODS: Patients with SqCC who underwent definitive RT comprising external beam RT and intracavitary brachytherapy at our facility between April 2006 and November 2013 were evaluated. CD8 immunohistochemistry was performed in pre-treatment biopsy samples to analyze the prognostic significance of CD8+TILs in the tumor nest. Positive staining was defined as at least one CD8+ lymphocyte infiltrating the tumor area in the specimen. RESULTS: In total, 150 consecutive patients were included. Among them, 66 (43.7%) patients had International Federation of Gynecology and Obstetrics (FIGO, 2008 edition) stage IIIA or higher progressive disease. The median follow-up period was 61 months. In the entire cohort, the 5-year cumulative rates of overall survival (OS), progression-free survival (PFS), and pelvic recurrence-free rate (PRFR) were 75.6%, 69.6%, and 84.8%, respectively. Of the 150 patients, 120 (80.0%) patients were CD8+TIL positive. The independent favorable prognostic factors were FIGO stage I or II disease, administration of concurrent chemotherapy, and CD8+TILs for OS (p=0.028, 0.005, and 0.038, respectively); FIGO stage I or II disease and CD8+TILs for PFS (p=0.015 and <0.001, respectively); and CD8+TILs for PRFR (p=0.017). CONCLUSION: The presence of CD8+TILs in the tumor nest may be a favorable prognostic factor of survival after definitive RT in patients with SqCC of the uterine cervix.

Association between Tumor Mutational Burden, Stromal CD8+ Tumor-Infiltrating Lymphocytes, and Clinical Factors in Cervical Cancers Treated with Radiotherapy.

BACKGROUND: Tumor mutational burden (TMB) and stromal CD8-positive tumor-infiltrating lymphocytes (CD8+TILs) serve important roles in antitumor immune responses to radiotherapy. This study aimed to elucidate the association between TMB, CD8+TILs, and clinical factors in patients with cervical cancer treated with radiotherapy. METHODS: Patients with squamous cell carcinoma of the uterine cervix treated with definitive radiotherapy, and with available somatic mutation data and immunohistochemical staining data from identical tumor tissues, were enrolled retrospectively. The association between TMB and/or CD8+TIL density and patient characteristics, mutation profiles, and treatment outcome was analyzed. RESULTS: The study analyzed 44 patients (median follow-up period, 61 months). There was no significant correlation between TMB and CD8+TIL density, or between TMB or CD8+TIL density and patient characteristics. TMB-high or CD8+TIL density-low status was associated with worse overall survival and distant metastasis-free survival; the predictive value of these factors became greater when used in combination. TMB-high or CD8+TIL density-high status was associated with ARID1A mutations. CONCLUSIONS: These data indicate independence of TMB and CD8+TIL density and the involvement of ARID1A alterations in antitumor immune responses in patients with cervical cancers treated with radiotherapy, warranting further mechanistic research and prospective validation.

Phase I/II prospective clinical trial for the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer.

OBJECTIVE: The purposes of this trial were to demonstrate the feasibility and effectiveness of the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced cervical cancer patients in the phase I/II prospective clinical trial. METHODS: Patients with FIGO stage IB2-IVA uterine cervical cancer pretreatment width of which was ≥5 cm measured by magnetic resonance imaging were eligible for this clinical trial. The protocol therapy included 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP, followed by 24 Gy in 4 fractions of HBT and pelvic radiotherapy with a central shield up to 50-50.4 Gy in 25-28 fractions. The primary endpoint of phase II part was 2-year pelvic progression-free survival (PPFS) rate higher than historical control of 64%. RESULTS: Between October 2015 and October 2019, 73 patients were enrolled in the initial registration and 52 patients proceeded to the secondary registration. With the median follow-up period of 37.3 months (range, 13.9-52.9 months), the 2- PPFS was 80.7% (90% confidence interval [CI]=69.7%-88%). Because the lower range of 90% CI of 2-year PPFS was 69.7%, which was higher than the historical control ICBT data of 64%, therefore, the primary endpoint of this study was met. CONCLUSION: The effectiveness of HBT were demonstrated by a prospective clinical study. Because the dose goal determined in the protocol was lower than 85 Gy, there is room in improvement for local control. A higher dose might have been needed for tumors with poor responses.

An Asian multi-national, multi-institutional, retrospective study on image-guided brachytherapy in cervical adenocarcinoma and adenosquamous carcinoma.

Purpose: There are limited reports on outcomes of three-dimensional image-guided brachytherapy (3D-IGBT) for cervical adenocarcinoma in Asia. In a multi-institutional retrospective study, we assessed the clinical outcomes of three-dimensional image-guided brachytherapy for cervical adenocarcinoma or adenosquamous carcinoma (CA/CAC) in Asian countries. Material and methods: Patients who had undergone definitive radiation therapy/concurrent chemoradiotherapy for untreated cervical cancer between 2000 and 2016 were registered. Those who had undergone 3D-IGBT for histologically proven CA/CAC were included. Data on patients' characteristics and treatment were collected, including tumor reduction rate (defined as a percentage of reduction in tumor size before brachytherapy compared with that at diagnosis) and high-risk clinical target volume D90. Overall survival (OS), local control (LC), and progression-free survival (PFS) rates were calculated using Kaplan-Meier method. Late toxicities were assessed using common terminology criteria for adverse events version 4.0. Results: Anonymized data of 498 patients were collected. Of the 498 patients, 36 patients met inclusion criteria. The median follow-up period was 39 months. The 3-year OS, LC, and PFS rates were 68.4%, 68.5%, and 44.4%, respectively. After treatment, five patients had tumor re-growth without complete disappearance of the tumor. Two patients developed grade 3 vaginal toxicity or grade 4 rectal toxicity; none developed other severe late toxicities. A tumor reduction rate of > 26.3% was the only significant factor in multivariate analyses, and was associated with significantly better OS (p = 0.018), LC (p = 0.022), and PFS (p = 0.013). There were no significant trends in local control or dose to high-risk clinical target volume D90. Conclusions: LC rate of CA/CAC was insufficient despite 3D-IGBT. Meanwhile, tumor reduction rate was associated with LC, OS, and PFS rates. Therefore, CA/CAC may require a different treatment strategy than that applied in cervical squamous cell carcinoma.

Comparative Analysis of the Antitumor Immune Profiles of Paired Radiotherapy-naive and Radiotherapy-treated Cervical Cancer Tissues.

BACKGROUND/AIM: This study aimed to elucidate the effect of radiotherapy on expression of immune response-related genes in cervical cancer tissues. MATERIALS AND METHODS: Tumor tissues were obtained from 16 patients with cervical cancer before initiation of radiotherapy and after treatment with 10 Gy X-rays, delivered in five fractions. Expression of 730 immune response-related genes was assessed using an nCounter PanCancer Immune Profiling Panel (NanoString Technologies. Seattle, WA, USA). RESULTS: Of the 730 genes examined, 41 showed significant changes (fold change of >1.5 or <0.66) in expression in post-radiotherapy samples (28 up-regulated and 13 down-regulated). Analysis of immune cell type-specific genes suggested predominant upregulation of those related to innate immunity postradiotherapy. Interestingly, cytotoxic T-lymphocyte-associated protein (CTLA4), a key negative regulator of T-cell activation, was marked down-regulated in 93.7% of patients, with an average fold-change of 2.0. CONCLUSION: To our knowledge, this study is the first to show down-regulation of CTLA4 in clinical cervical cancer tissues after treatment with radiotherapy.

Patient-Derived Training Simulator for Image-Guided Adaptive Brachytherapy of Locally Advanced Cervical Cancers: Development and Initial Use.

Image-guided adaptive brachytherapy (IGABT) using intracavitary and interstitial (IC/IS) techniques plays a pivotal role in definitive radiotherapy for locally advanced cervical cancers. However, the training opportunities for interstitial needle application are limited, preventing this technique from becoming widespread. This study aimed to develop a training simulator for IC/IS brachytherapy. The simulator consists of a soft silicone tumor phantom and acrylic tube mimicking the vagina; it has high visibility because of translucent materials and is compatible with computed tomography (CT) and magnetic resonance imaging (MRI). A patient harboring a typical bulky and irregular-shaped cervical tumor was selected from 495 in-house IGABT-treated candidates, and a tumor phantom (68 × 49 × 45 mm) modeled on this patient was produced from three-dimensional real-scale measurements of the MRI-based high-risk clinical target volume at first brachytherapy. In trial use by two physicians with different levels of IGABT skills, a Fletcher-Suit Asian Pacific applicator, and a Venezia applicator with interstitial needles were nicely applied to the simulator, facilitating successful creation of CT-based treatment plans consistent with clinical practice. Thus, the training simulator can be useful for the training of IC/IS brachytherapy, and warrants further research employing a greater number of phantoms and practitioners to verify its educational value.

Large volume was associated with increased risk of acute non-hematologic adverse events in the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer: preliminary results of prospective phase I/II clinical trial.

OBJECTIVE: This is the preliminary results of a multi-center prospective clinical trial evaluating the feasibility of the hybrid of intracavitary and interstitial brachytherapy for locally advanced cervical cancer. METHODS: Patients with FIGO stage IB2, IIA2, IIB, IIIA, IIIB and IVA uterine cervical cancer pretreatment width of which was ≥5 cm measured by MRI were eligible. Protocol therapy consisted of 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP, followed by 24 Gy in 4 fractions of hybrid of intracavitary and interstitial and pelvic radiotherapy with central shield up to 50-50.4 Gy in 25-28 fractions. The primary endpoint of phase I part was that the rate of grade ≥ 3 acute non-hematologic adverse events related to hybrid of intracavitary and interstitial would be <10%. RESULTS: Between October 2015 and October 2019, 74 patients underwent primary registration, with 52 patients eventually proceeding to the secondary registration. The median pretreatment tumor width was 5.7 cm, and FIGO Stages were IB2 10, IIA2 2, IIB 20 and IIIB 20, respectively. The median high-risk clinical target volume D90 was 72.0 Gy (54.8-86.6 Gy, EQD2), rectum D2cc was 53.7 Gy (29.3-80.3 Gy) and bladder D2cc was 69.8 Gy (38.9-84.8 Gy). The rate of grade ≥ 3 non-hematologic adverse events related to hybrid of intracavitary and interstitial was 1.9% (1/52), and 17.3% (9/52) of patients experienced non-hematologic adverse events related to hybrid of intracavitary and interstitial of any grade. In multivariate analysis, high-risk clinical target volume ≥ 35 ml was associated with an increased risk of any grade of acute non-hematologic adverse events related to hybrid of intracavitary and interstitial (P = 0.036). CONCLUSION: The feasibility and reproducibility of hybrid of intracavitary and interstitial were demonstrated from a multi-center prospective clinical trial.

An Asian multi-national multi-institutional retrospective study comparing intracavitary versus the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical carcinoma.

This study is an international multi-institutional retrospective study comparing the clinical outcomes between intracavitary brachytherapy (ICBT) and the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced cervical cancer patients treated with definitive radiation therapy. Locally advanced cervical cancer, the initial size of which is larger than 4 cm and treated by concurrent chemoradiotherapy and image-guided adaptive brachytherapy, were eligible for this retrospective study. Patients who received HBT at least once were included in the HBT group, and patients who received only ICBT were included in the ICBT group. Anonymized data from 469 patients from 13 institutions in Japan, one from Korea and one from Thailand, were analyzed. Two hundred eighty and 189 patients were included in the ICBT group and the HBT group, respectively. Patients in the HBT group had more advanced stage, non-Scc histopathology, a higher rate of uterine body involvement, larger tumor at diagnosis, larger tumor before brachytherapy and a lower tumor reduction ratio. With a median follow-up of 51.3 months (2.1-139.9 months), 4-y local control (LC), progression-free survival (PFS) and overall survival (OS) for the entire patient population were 88.2%, 64.2% and 83%, respectively. The HBT group received a higher HR-CTV D90 than that of the ICBT group (68.8 Gy vs 65.6 Gy, P = 0.001). In multivariate analysis, the non-Scc histological subtype, HR-CTV D95 ≤ 60 Gy, reduction ratio ≤ 29% and total treatment time (TTT) ≥ 9 weeks were identified as the independent adverse prognostic factors for LC. Regarding LC, no difference was found between ICBT and HBT (4-y LC 89.3% vs 86.8%, P = 0.314). After adjustment for confounding factors by propensity score matching, no advantage of applying HBT was demonstrated regarding LC, PFS, or OS. Despite the fact that HBT patients had more adverse clinical factors than ICBT patients, HBT delivered a higher dose to HR-CTV and resulted in comparable LC.

Japanese Society for Radiation Oncology Consensus Guidelines of combined intracavitary and interstitial brachytherapy for gynecological cancers.

It has been postulated that the combination of intracavitary and interstitial brachytherapy (IC/IS) is effective and safe for large and irregularly shaped uterine cervical cancer patients. However, due to its invasiveness compared to conventional intracavitary brachytherapy (ICBT), it has to be said that the implementation speed of IC/IS is slow. Until now, there have been no guidelines for required equipment, human resources, and procedural guide focusing solely on IC/IS. The purpose of this guideline is to provide radiation oncologists and medical physicists who wish to start IC/IS with practical and comprehensive guidance for a safe IC/IS introduction and to help accelerate the spread of the utilization of IC/IS nationwide. This is the English translation of the Japanese IC/IS Guidelines, and it was created in an effort to share the Japanese approach to the management of locally advanced uterine cervical cancer worldwide.

A retrospective study of small-pelvis radiotherapy plus image-guided brachytherapy in stage I-II non-bulky cervical squamous cell carcinoma.

We herein report a retrospective analysis of the efficacy of a combination therapy of pelvic irradiation that excluded the common iliac lymph nodes region and image-guided brachytherapy (IGBT) for non-bulky (≤4 cm) cervical cancer. Thirty-three patients with stage I-II cervical squamous cell carcinoma (≤4 cm) and without pelvic/para-aortic lymphadenopathy who were treated with definitive radiotherapy alone between February 2009 and September 2016 were included. The radiotherapy consisted of CT-based small-pelvis irradiation (whole pelvis minus common iliac lymph node area) of 20 Gy/10 fractions followed by pelvic irradiation with a midline block of 30 Gy/15 fractions and IGBT of 24 Gy/4 fractions (6 Gy/fraction for high-risk [HR] clinical target volume [CTV] D90%). In-room computed tomography (CT) imaging with applicator insertion was used for brachytherapy planning, with physical examinations and diagnostic magnetic resonance imaging (MRI) also being referred to for determination of HR CTV. Over a median follow-up of 60.5 months (range, 7-89), two patients developed distant recurrence and one developed local and distant recurrence. Two patients died from cervical cancer, one from hepatocellular carcinoma and one from non-cancerous disease. The 2/5-year local control (LC), progression-free survival (PFS) and overall survival (OS) rates were 100%/96.7%, 93.8%/90.6% and 93.9%/93.9%, respectively. No pelvic/para-aortic lymph node recurrence was observed. There were no late complications of grade 3 or higher in the small bowel, large bowel/rectum, or bladder. Our results suggest that a combination therapy of IGBT plus small-pelvis irradiation excluding common iliac lymph nodes provides reasonable clinical outcomes and can be a treatment option in non-bulky (≤4 cm) cervical squamous cell carcinoma.

Th Balance-Related Host Genetic Background Affects the Therapeutic Effects of Combining Carbon-Ion Radiation Therapy With Dendritic Cell Immunotherapy.

PURPOSE: The goal of this study is to clarify the underlying mechanisms of metastasis suppression by carbon-ion radiotherapy combined with immature dendritic cell immunotherapy (CiDC), which was shown previously to suppress pulmonary metastasis in an NR-S1-bearing C3H/He mouse model. METHODS AND MATERIALS: Mouse carcinoma cell lines (LLC, LM8, Colon-26, and Colon-26MGS) were grafted into the right hind paw of syngeneic mice (C57BL/6J, C3H/He, and BALB/c). Seven days later, the tumors on the mice were locally irradiated with carbon ions (290 MeV/n, 6 cm spread-out Bragg peak, 1 or 2 Gy). At 1.5 days after irradiation, bone marrow-derived immature dendritic cells (iDCs) were administrated intravenously into a subset of the mice. The number of lung metastases was evaluated within 3 weeks after irradiation. In vitro-cultured cancer cells were irradiated with carbon ions (290 MeV/n, mono-energy, LET approximately 70-80 keV/µm), and then cocultured with iDCs for 3 days to determine the DC maturation. RESULTS: CiDC effectively repressed distant lung metastases in cancer cell (LLC and LM8)-bearing C57BL/6J and C3H/He mouse models. However, Colon-26- and Colon-26MGS-bearing BALB/c models did not show enhancement of metastasis suppression by combination treatment. This result was evaluated further by comparing LM8-bearing C3H/He and LLC-bearing C57BL/6J models with a Colon-26-bearing BALB/c model. In vitro coculture assays demonstrated that all irradiated cell lines were able to activate C3H/He- or C57BL/6J-derived iDCs into mature DCs, but not BALB/c-derived iDCs. CONCLUSIONS: The genetic background of the host could have a strong effect on the potency of combination therapy. Future animal and clinical testing should evaluate host genetic factors when evaluating treatment efficacy.

High tumor mutational burden predicts worse prognosis for cervical cancer treated with radiotherapy.

PURPOSE: Tumor mutational burden (TMB) is a surrogate biomarker of neo-antigens and high TMB status is associated with favorable response to immune-checkpoint inhibitors (ICIs). This study aimed to elucidate the association between TMB and the outcome of definitive radiotherapy in patients with cervical cancer. MATERIALS AND METHODS: TMB and treatment outcome were retrospectively analyzed in patients with newly diagnosed cervical cancer treated with definitive radiotherapy available with somatic mutation data of pre-treatment tumors obtained using a commercially available gene panel. RESULTS: The study enrolled 98 patients (median follow-up period, 61 months). The median TMB was 9.5 mutations per megabase (range, 3.0-35.5 mutations per megabase). After dichotomization based on this median value, the 5-year overall survival (OS) for TMB-high patients was significantly worse than that of TMB-low patients (61.1% vs. 82.2%). Multivariate analysis identified high TMB status as a significant prognostic factor for worse OS, along with advanced stage, para-aortic lymph node involvement, and absence of concurrent chemotherapy. CONCLUSION: These data indicate that TMB is a potential prognostic factor for worse survival in patients with cervical cancer treated with definitive radiotherapy, thereby providing a rationale for treatment of TMB-high cervical cancers with a combination of ICIs plus radiotherapy. This retrospective study of 98 patients demonstrates for the first time that tumor mutational burden (TMB) is an independent prognostic factor for worse overall survival of patients treated with definitive radiotherapy, providing a rationale for treatment of TMB-high cervical cancers with a combination of immune-checkpoint inhibitors plus radiotherapy.

Prediction of out-of-field recurrence after chemoradiotherapy for cervical cancer using a combination model of clinical parameters and magnetic resonance imaging radiomics: a multi-institutional study of the Japanese Radiation Oncology Study Group.

We retrospectively assessed whether magnetic resonance imaging (MRI) radiomics combined with clinical parameters can improve the predictability of out-of-field recurrence (OFR) of cervical cancer after chemoradiotherapy. The data set was collected from 204 patients with stage IIB (FIGO: International Federation of Gynecology and Obstetrics 2008) cervical cancer who underwent chemoradiotherapy at 14 Japanese institutes. Of these, 180 patients were finally included for analysis. OFR-free survival was calculated using the Kaplan-Meier method, and the statistical significance of clinicopathological parameters for the OFR-free survival was evaluated using the log-rank test and Cox proportional-hazards model. Prediction of OFR from the analysis of diffusion-weighted images (DWI) and T2-weighted images of pretreatment MRI was done using the least absolute shrinkage and selection operator (LASSO) model for engineering image feature extraction. The accuracy of prediction was evaluated by 5-fold cross-validation of the receiver operating characteristic (ROC) analysis. Para-aortic lymph node metastasis (p = 0.003) was a significant prognostic factor in univariate and multivariate analyses. ROC analysis showed an area under the curve (AUC) of 0.709 in predicting OFR using the pretreatment status of para-aortic lymph node metastasis, 0.667 using the LASSO model for DWIs and 0.602 using T2 weighted images. The AUC improved to 0.734 upon combining the pretreatment status of para-aortic lymph node metastasis with that from the LASSO model for DWIs. Combining MRI radiomics with clinical parameters improved the accuracy of predicting OFR after chemoradiotherapy for locally advanced cervical cancer.

The Non-Cancer Specific Elevation of the Serum Squamous Cell Carcinoma Antigen during the Post-Radiotherapy Follow-Up of Cervical Cancer Patients.

The elevation of the serum squamous cell carcinoma (SCC) antigen unrelated to disease progression occurs during the follow-up of patients with cervical cancer treated with radiotherapy. Although known empirically, the incidence and characteristics of this non-cancer specific elevation in SCC remain unclear. Here, we examined the post-treatment kinetics of SCC in 143 consecutive patients with squamous cell carcinoma of the cervix treated with definitive radiotherapy; in all patients, progression-free disease status was confirmed by periodic monitoring for at least 36 months (median, 61 months). We found that the 5-year cumulative incidence of post-treatment SCC elevation was unexpectedly high at 37.3% (59/143 patients), and that 59.3% (35/59) of event-positive patients experienced multiple events. The median peak SCC level for a given event was 2.0 ng/mL (interquartile range, 1.7-2.9 ng/mL). The multivariate analysis showed that renal dysfunction was associated significantly with a greater incidence of SCC elevation (p = 0.046). In addition, the 5-year cumulative incidence of SCC elevation was significantly greater in patients with renal dysfunction than in those without (54.8% vs. 32.9%, respectively; hazard ratio, 2.1 [95% confidence interval, 1.1-4.2]; p = 0.028). These data will be useful for monitoring cervical cancer patients treated with radiotherapy.

Why not de-intensification for uterine cervical cancer?

OBJECTIVE: The majority of uterine cervical cancer is known to be related to human papillomavirus (HPV), and HPV-related tumors are known to be radio-sensitive. In the management of HPV-related oropharyngeal cancer, de-intensification of treatment has been attempted; however, no such attempt is performed in the management of cervical cancer. The aim of this study was to identify a group of patients who can safely be treated by de-escalated treatment intensity. METHODS: From the Asian international multi-institutional retrospective study involving 13 Japanese, one Thailand, and one Korean institutions based on 469 patients, squamous cell carcinoma (Scc), tumor reduction ratio ≥29%, tumor size before brachytherapy ≤4 cm, and total treatment time (TTT) <9 weeks were identified as factors having an influence on local control. Based on these findings, low-risk patients having these four factors were extracted, and treatment outcomes categorized in 10 Gy increment of CTVHR D90 were compared. RESULTS: Among 469 patients, 162 patients (34.5%) met the criteria of low-risk group, and 63, 41, 43, and 15 patients were categorized in CTVHR D90 50-60 Gy, 60-70 Gy, 70-80 Gy, and >80 Gy, respectively. While 4-y progression-free survival ranged from 66 to 80%, 4-y local control was consistently over 90% in every dose group. Rectum and bladder D2cc and incidence of late adverse events decreased as CTVHR D90 decreased. CONCLUSIONS: The low-risk patients achieved favorable local control with CTVHR D90 <80 Gy. A personalized treatment strategy based on tumor response could also be adopted for cervical cancer.