Therapeutic effects of surgical debulking of metastatic lymph nodes in cervical cancer IIICr: a trial protocol for a phase III, multicenter, randomized controlled study (KGOG1047/DEBULK trial).

BACKGROUND: Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, well-planned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests. METHODS: The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m²), 4-6 times administered intravenously. The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05421650; Clinical Research Information Service Identifier: KCT0007137.

Diagnostic assessments and treatment results of well-differentiated gastric-type adenocarcinoma of the uterine cervix (Adenoma malignum): A multicenter retrospective analysis of KROG 22-03 study.

OBJECTIVE: Among cervical adenocarcinomas, well-differentiated gastric adenocarcinoma of the uterine cervix (WD-GAS), previously termed adenoma malignum (minimal deviation adenocarcinoma) is not well understood. Because of its rarity and difficulty in diagnosis, there is no standard care for WD-GAS. Thus, we conducted the first multicenter retrospective study on WD-GAS to clarify prognostic factors for long-term survival and recurrence. METHODS: Patients diagnosed with WD-GAS at eight hospitals participated in this multi-center study. Overall survival (OS) and recurrence-free survival (RFS) were calculated with the Kaplan-Meier method. Additionally, OS between the early and advanced FIGO stage groups were compared with the log-rank test. Cox regression analysis was conducted to identify significant factors associated with recurrence-free survival (RFS). RESULTS: A total of 73 patients from eight hospitals in South Korea were included in the analysis. The median follow-up period was 44.8 months, and all patients underwent curative surgical intervention as the primary treatment. Recurrence was observed in 17 patients (23.3%). Ten patients had locoregional recurrence, four patients had distant metastasis, and three patients presented with both locoregional recurrence and distant metastasis. The Cox regression analysis identified several statistically significant factors associated with RFS, including vaginal invasion (VI), parametrial invasion (PMI), resection margin (RM), and nodal and lymphovascular invasion (LVI). When considering these five factors together, patients without any of the factors exhibited recurrence-free survival (RFS) of 97.0% at three years and those with more than one of these factors had a 3-year RFS of 65.4% (P < 0.001). CONCLUSION: WD-GAS showed relatively high locoregional recurrence rate. Positive PMI, VI, RM, nodal involvement, and LVI were associated with a significant increase in recurrence or distant metastasis rates.

Assessment of Bone Marrow Involvement in Extranodal NK/T-Cell Lymphoma: Positron Emission Tomography versus Bone Marrow Biopsy, and the Significance of Minimal Involvement by EBV+ Cells (KROG 18-09).

PURPOSE: This study aims to investigate the diagnostic significance of positron emission tomography/computed tomography (PET/CT) in assessing bone marrow (BM) involvement through a comparison of PET/CT findings with BM biopsy in extranodal natural killer/T-cell lymphoma. MATERIALS AND METHODS: The medical records of 193 patients were retrospectively reviewed. Patients were categorized as having early-stage (PET-ES) or advanced-stage (PET-AS) disease based on PET/CT results. The BM involvement was classified into three groups according to BM biopsy: gross BM involvement, minimal BM involvement (defined as the presence of a limited number of Epstein-Barr virus-positive cells in BM), and no involvement. Calculations of the accuracy of PET/CT in detecting BM involvement and analysis of the clinical outcomes (progression-free survival [PFS] and overall survival [OS]) according to the BM biopsy status were performed. RESULTS: PET/CT exhibited a sensitivity of 64.7% and a specificity of 96.0% in detecting gross BM involvement. For detecting any (both gross and minimal) BM involvement, the sensitivity was 30.4%, while the specificity was 99.0%. Only one patient (0.7%) demonstrated gross BM involvement among the PET-ES group. Survival outcomes of the PET-ES group with minimal BM involvement (3-year PFS, 55.6%; OS, 77.0%) were closer to those of the PET-ES group with no BM involvement (3-year PFS, 62.2%; OS, 80.6%) than to those of the PET-AS group (3-year PFS, 20.1%; OS, 29.9%). CONCLUSION: PET/CT exhibits high specificity, but moderate and low sensitivity in detecting gross and minimal BM involvement, respectively. The clinical significance of minimal BM involvement for patients in the PET-ES group may be limited.

Modulation of CD8+ T Cell Responses by Radiotherapy-Current Evidence and Rationale for Combination with Immune Checkpoint Inhibitors.

Radiotherapy for cancer has been known to affect the responses of immune cells, especially those of CD8+ T cells that play a pivotal role in anti-tumor immunity. Clinical success of immune checkpoint inhibitors led to an increasing interest in the ability of radiation to modulate CD8+ T cell responses. Recent studies that carefully analyzed CD8+ T cell responses following radiotherapy suggest the beneficial roles of radiotherapy on anti-tumor immunity. In addition, numerous clinical trials to evaluate the efficacy of combining radiotherapy with immune checkpoint inhibitors are currently undergoing. In this review, we summarize the current status of knowledge regarding the changes in CD8+ T cells following radiotherapy from various preclinical and clinical studies. Furthermore, key biological mechanisms that underlie such modulation, including both direct and indirect effects, are described. Lastly, we discuss the current evidence and essential considerations for harnessing radiotherapy as a combination partner for immune checkpoint inhibitors.

Pattern of practice for postoperative management of endometrial cancer in Korea: a survey by the Korean Gynecologic Oncology Group and the Korean Radiation Oncology Group (KGOG 2028-KROG 2104).

OBJECTIVE: This study aimed to investigate the current status of postoperative management of uterine endometrial cancer (EC) in Korea. METHODS: A mail survey was administered to members of the Korean Gynecologic Oncology Group and Korean Radiation Oncology Group. A total of 38 gynecologic cancer surgeons (GYNs) and 31 radiation oncologists (RO) in 43 institutions was responded. The questionnaire consisted of general questions for clinical decision and clinical case questions. The GYN and RO responses were compared using chi-square statistics. RESULTS: The 2 expert groups had similar responses for clinical decision based on the results of the Gynecologic Oncology Group (GOG)-249 and Postoperative Radiation Therapy for Endometrial Carcinoma-III trials in the early-stage EC. In contrast, the responses based on GOG-258 results differed, as GYNs most frequently opted for sequential chemotherapy (CTx) and radiotherapy (RT), while ROs preferred concurrent chemoradiotherapy in locally advanced stage (p<0.05). Based on the GOG-258, GYNs preferred CTx alone for adjuvant treatment of serous or clear cell adenocarcinoma histology, whereas ROs advocated for combined CTx and RT (sequential or concurrent). Among the clinical case questions, GYNs were more likely than ROs to choose CTx alone rather than the combination of CTx and RT (sequential or concurrent) as the answers to case questions representing patients with locally advanced stage or unfavorable histology (all p<0.05). CONCLUSION: The present study showed several different opinions of GYNs and ROs regarding adjuvant treatment for EC, particularly for adjuvant RT in advanced stage or unfavorable histology.

Adjuvant radiotherapy in node-negative salivary malignancies of the parotid gland: A multi-institutional analysis.

BACKGROUND AND PURPOSE: To determine the role of adjuvant radiotherapy (ART) in parotid gland cancer without nodal metastasis, we evaluated the survival outcomes, prognostic factors, and dose-response relationships in patients with node-negative parotid gland cancer patients. MATERIALS AND METHODS: Patients who underwent curative parotidectomy and were pathologically diagnosed with parotid gland cancer without regional or distant metastases between 2004 and 2019 were reviewed. The benefit of ART in terms of locoregional control (LRC) and progression-free survival (PFS) were evaluated. RESULTS: In total, 261 patients were included in the analysis. Of them, 45.2 % received ART. The median follow-up period was 66.8 months. Multivariate analysis revealed that histological grade and ART were independent prognostic factors for LRC and PFS (all p <.05). For patients with high-grade histology, ART was associated with a significant improvement in 5-year LRC (p =.005) and PFS (p =.009). Among patients with high-grade histology who completed RT, higher biologic effective dose (≥77 Gy10) significantly increased PFS (adjusted hazard ratio [HR], 0.10 per 1-Gy increase; 95 % confidence interval [CI], 0.02-0.58; p =.010). ART significantly improved LRC (p =.039) in patients with low-to-intermediate histological grade as well per multivariate analysis, and subgroup analyses revealed patients with T3-4 stage and close/positive resection margins (<1 mm) would benefit from ART. CONCLUSION: ART should be strongly recommended for patients with node-negative parotid gland cancer with high-grade histology in terms of disease control and survival. In patients with low-to-intermediate-grade disease, those with high T stage and incomplete resection margin benefit with ART.

Image-Guided Versus Conventional Brachytherapy for Locally Advanced Cervical Cancer: Experience of Single Institution with the Same Practitioner and Time Period.

PURPOSE: This study aimed to compare treatment outcomes and toxicity profile between imaged-guided brachytherapy (IGBT) versus conventional brachytherapy (CBT) performed by the same practitioner during the same time period. MATERIALS AND METHODS: Medical records of 104 eligible patients who underwent brachytherapy for locally advanced cervical cancer were retrospectively reviewed. Fifty patients (48.1%) underwent IGBT, and 54 (51.9%) patients underwent CBT. All patients underwent concurrent chemoradiation with cisplatin. High-dose-rate intracavitary brachytherapy with dose prescription of 25-30 Gy in 4-6 fractions was performed for all patients. Late lower gastrointestinal (GI) and urinary toxicities occurred more than 3 months after the end of brachytherapy were included for comparative and dosimetric analyses. RESULTS: The median follow-up period was 18.33 months (range, 3.25 to 38.43 months). There were no differences in oncologic outcomes between the two groups. The IGBT group had lower rate of actuarial grade ≥ 3 toxicity than the CBT group (2-year, 4.5% vs. 25.7%; p=0.030). Cumulative equieffective D2cc of sigmoid colon was significantly correlated with grade ≥ 2 lower GI toxicity (p=0.033), while equieffective D2cc of rectum (p=0.055) and bladder (p=0.069) showed marginal significance with corresponding grade ≥ 2 toxicities in the IGBT group. Half of grade ≥ 3 lower GI toxicities impacted GI tract above the rectum. Optimal thresholds of cumulative D2cc of sigmoid colon and rectum were 69.7 Gy and 70.8 Gy, respectively, for grade ≥ 2 lower GI toxicity. CONCLUSION: IGBT showed superior toxicity profile to CBT. Evaluating the dose to the GI tract above rectum by IGBT might prevent some toxicities.

Evaluation of Optimal Assessment Schedules for Surveillance After Definitive Locoregional Treatment of Locally Advanced Head and Neck Cancer: A Retrospective Cohort Study With Parametric Modeling of Event-Free Survival.

Importance: In clinical practice, assessment schedules are often arbitrarily determined after definitive treatment of head and neck cancer (HNC), producing heterogeneous and inconsistent surveillance plans. Objective: To establish an optimal assessment schedule for patients with definitively treated locally advanced HNC, stratified by the primary subsite and HPV status, using a parametric model of standardized event-free survival curves. Design, Setting, and Participants: This was a retrospective study including 2 tertiary referral hospitals and a total of 673 patients with definitive locoregional treatment of locally advanced HNC (227 patients with nasopharyngeal cancer [NPC]; 237 patients with human papillomavirus-positive oropharyngeal cancer [HPV+ OPC]; 47 patients with HPV-negative [HPV-] OPC; 65 patients with hypopharyngeal cancer [HPC]; and 97 patients with laryngeal cancer [LC]). Patients had received primary treatment in 2008 through 2019. The median (range) follow-up duration was 57.8 (6.4-158.1) months. Data analyses were performed from April to October 2021. Main Outcomes and Measures: Tumor recurrence and secondary malignant neoplasms. Event-free survival was defined as the period from the end of treatment to occurrence of any event. Event-free survival curves were estimated using a piecewise exponential model and divided into 3 phases of regular follow-up. A 5% event rate criterion determined optimal follow-up time point and interval. Results: The median (range) age of the 673 patients at HNC diagnosis was 58 (15-83) years; 555 (82.5%) were men; race and ethnicity were not considered. The event rates of NPC, HPV+ OPC, HPV- OPC, HPC, and LC were 18.9% (43 of 227), 14.8% (35 of 237), 36.2% (17 of 47), 44.6% (29 of 65), and 30.9% (30 of 97), respectively. Parametric modeling demonstrated optimal follow-up intervals for HPC, LC, and NPC, respectively, every 2.1, 3.2, and 6.1 months; 3.7, 5.6, and 10.8 months; and 9.1, 13.8, and 26.5 months until 16.5, 16.5 to 25.0, and 25.0 to 99.0 months posttreatment (open follow-up thereafter). For HPV- OPC, assessment was recommended every 2.7, 4.8, and 11.8 months until 16.5, 16.5 to 25.0, and 25 to 99 months posttreatment, respectively. In contrast, HPV+ OPC optimal intervals were every 7.7, 13.7, and 33.7 months until 16.5, 16.5 to 25.0, and 25 to 99 months posttreatment, respectively. Five, 4, 12, 15, and 10 follow-up visits were recommended for NPC, HPV+ OPC, HPV- OPC, HPC, and LC, respectively. Conclusions and Relevance: This retrospective cohort study using parametric modeling suggests that the HNC assessment schedules should be patient tailored and evidence based to consider primary subsites and HPV status. Given limited health care resources and rising detection rates and costs of HNC, the guidelines offered by these findings could benefit patients and health systems and aid in developing future consensus guidelines.

Intensity Modulated High Dose Rate (HDR) Brachytherapy Using Patient Specific 3D Metal Printed Applicators: Proof of Concept.

Purpose: In high-dose-rate (HDR) brachytherapy, an anisotropic dose distribution may be desirable for achieving a higher therapeutic index, particularly when the anatomy imposes challenges. Several methods to deliver intensity-modulated brachytherapy (IMBT) have been proposed in the literature, however practical implementation is lacking due to issues of increased delivery times and complicated delivery mechanisms. This study presents the novel approach of designing a patient-specific inner shape of an applicator with 3D metal printing for IMBT using an inverse plan optimization model. Methods: The 3D printed patient-specific HDR applicator has an external shape that resembles the conventional brachytherapy applicator. However, at each dwell position of the HDR source, the shielding walls in the interior are divided into six equiangular sections with varying thicknesses. We developed a mathematical model to simultaneously optimize the shielding thicknesses and dwell times according to the patient's anatomical information to achieve the best possible target coverage. The model, which is a bi-convex optimization problem, is solved using alternating minimization. Finally, the applicator design parameters were input into 3D modeling software and saved in a 3D printable file. The applicator has been tested with both a digital phantom and a simulated clinical cervical cancer patient. Results: The proposed approach showed substantial improvements in the target coverage over the conventional method. For the phantom case, 99.18% of the target was covered by the prescribed dose using the proposed method, compared to only 58.32% coverage achieved by the conventional method. For the clinical case, the proposed method increased the coverage of the target from 56.21% to 99.92%. In each case, both methods satisfied the treatment constraints for neighboring OARs. Conclusion: The study simulates the concept of the IMBT with inverse planning using the 3D printed applicator design. The non-isotropic dose map can be produced with optimized shielding patterns and tailored to individual patient's anatomy, to plan a more conformal plan.

Evaluation of the dosimetric and radiobiological parameters in four radiotherapy regimens for synchronous bilateral breast cancer.

This study is to investigate the optimal treatment option for synchronous bilateral breast cancer (SBBC) by comparing dosimetric and radiobiological parameters of intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans using single and dual isocenters. Twenty patients with SBBC without lymph node involvement were selected retrospectively. Four treatment plans were generated for each patient using the Eclipse treatment planning system (Varian Medical System, Palo Alto, CA, USA) following two delivery techniques with two isocenter conditions-IMRT using a single isocenter (IMRT_Iso1), VMAT using a single isocenter (VMAT_Iso1), IMRT using dual isocenters (IMRT_Iso2), and VMAT using dual isocenters (VMAT_Iso2). A dose of 42.56 Gy in 16 fractions was prescribed for the planning target volume (PTV). All plans were calculated using the Acuros XB algorithm and a photon optimizer for a 6-MV beam of a Vital Beam linear accelerator. PTV-related dosimetric parameters were analyzed. Further, the homogeneity index, conformity index, and conformation number were computed to evaluate plan quality. Dosimetric parameters were also measured for the organs at risk (OARs). In addition, the equivalent uniform dose corresponding to an equivalent dose related to a reference of 2 Gy per fraction, the tumor control probability, and the normal tissue complication probability were calculated based on the dose-volume histogram to investigate the radiobiological impact on PTV and OARs. IMRT_Iso1 exhibited similar target coverage and a certain degree of dosimetric improvement in OAR sparing compared to the other techniques. It also exhibited some radiobiological improvement, albeit insignificant. Although IMRT_Iso1 significantly increased monitor unit compared to VMAT_Iso1, which is the best option in terms of delivery efficiency, there was only a 22% increase in delivery time. Therefore, in conclusion, IMRT_Iso1, the complete treatment of which can be completed using a single setup, is the most effective method for treating SBBC.

Effect of National Oral Health Screening Program on the Risk of Head and Neck Cancer: A Korean National Population-Based Study.

PURPOSE: Poor oral health is associated with head and neck cancer (HNC). We evaluated whether a national oral health screening program (OHSP) could reduce the risk of HNC. MATERIALS AND METHODS: Data from 408,247 healthy individuals aged ≥ 40 years from the National Health Insurance System-National Health Screening program during 2003 and 2004 in Korea were analyzed. The risk of HNC was compared between subjects who underwent OHSP (HEALS-Dental+, n=165,292) and routine health check-ups only (HEALS-Dental‒, n=242,955). The impact of individual oral health-related factors on HNC risk was evaluated in HEALS-Dental+. RESULTS: A total of 1,650 HNC cases were diagnosed. The 10-year HNC-free rate was 99.684% with a median follow-up of 11 years. The risk of all HNC (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.03 to 1.29; p=0.011) and oropharyngeal cancer (HR, 1.48; 95% CI, 1.13 to 1.94; p=0.005) was significantly higher in HEALS-Dental‒ than in HEALS-Dental+. In HEALS-Dental+, oral cavity cancer was marginally reduced (p=0.085), and missing teeth was a significant factor for HNC (HR, 1.24; 95% CI, 1.02 to 1.50; p=0.032). Toothbrushing was a significant factor in univariate analysis (p=0.028), but not in multivariate analysis (p=0.877). CONCLUSION: The National OHSP significantly reduced the long-term HNC risk, particularly the incidence of oropharyngeal cancer. Routine OHSP should be considered at the population level.

Radiotherapy versus Surgery in Early-Stage HPV-Positive Oropharyngeal Cancer.

PURPOSE: This study aimed to compare the outcomes of primary radiotherapy (RT) versus surgery in early-stage human papilloma virus-positive oropharyngeal squamous cell carcinoma (hpv+OPC), and investigate the preoperative clinical factors that can predict the requirement for postoperative adjuvant treatment. MATERIALS AND METHODS: This multicenter study included 166 patients with American Joint Committee on Cancer 8th edition-Stages I-II hpv+OPC. Sixty (36.1%) and 106 (63.9%) patients underwent primary (concurrent chemo)radiotherapy [(CC)RT] and surgery, respectively. Seventy-eight patients (73.6%) in the surgery group received postoperative (CC)RT. RESULTS: With a median follow-up of 45.6 months for survivors, the 2-year overall survival (OS), progression-free survival (PFS), and locoregional control (LC) for RT/surgery were 97.8%/96.4%, 91.1%/92.0%, and 92.9%/93.3%, respectively. In multivariate analyses, patients with synchronous radiologic extranodal extension and conglomeration (ENEcong) of metastatic lymph nodes (LNs) showed significantly poorer OS (p=0.047), PFS (p=0.001), and LC (p=0.003). In patients undergoing primary surgery, two or more clinically positive LN metastases (odds ratio [OR], 5.15; p=0.004) and LN metastases with ENEcong (OR, 3.75; p=0.009) were predictors of postoperative chemoradiotherapy. No patient in the primary RT group demonstrated late severe toxicity whereas three (2.8%), one (0.9%), and one (0.9%) patient in the surgery group showed grade 3 dysphagia, grade 3 xerostomia, and fatal oral cavity bleeding. CONCLUSION: We found no differences in OS, PFS, and LC between upfront RT and surgery in stage I-II hpv+OPC which warrants comparison through a prospective trial in the treatment de-escalation era. However, most early-stage hpv+OPC patients undergoing surgery received adjuvant (CC)RT. Pretreatment LN findings were prognostic and predictive for adjuvant treatment.

Retropharyngeal lymph node-sparing radiotherapy in patients with oropharyngeal carcinoma.

PURPOSE: In radiotherapy for head and neck cancer, it is crucial to define the appropriate treatment volume to determine treatment outcome and toxicity. We examined the feasibility of omitting elective high retropharyngeal lymph node (RPLN) irradiation in patients with oropharyngeal cancer. MATERIALS AND METHODS: We performed a retrospective review of 189 patients with oropharyngeal squamous cell carcinoma who were treated with definitive or postoperative radiation therapy between 2009 and 2016. Of them, 144 (76.2%) underwent ipsilateral RPLN irradiation up to the superior border of the C1 vertebral body, while the other 45 (23.8%) were irradiated up to the transverse process of the C1 vertebra. High RPLN-treated and spared group were propensity matched based on key clinical variables. RESULTS: During the follow-up period, only three patients (one in the high RPLN-treated group and two in the high RPLN-spared group) developed RPLN recurrence. There were no significant between-group differences in 5-year locoregional failure-free survival (82.8% vs. 90.6%; p = 0.14), distant metastasis-free survival (93.1% vs. 93.3%; p = 0.98) and RPLN failure-free survival (99.3% vs. 95.0%; p = 0.09). In the matched groups, high RPLN-spared patients received a lower mean ipsilateral parotid gland dose (mean, 20.8 Gy vs. 29.9 Gy; p < 0.001) and had a lower incidence of chronic xerostomia (grade 0, 43.5% vs. 13.0%; p = 0.023) at 1 year after radiotherapy compared with high RPLN-treated patients. CONCLUSION: Omission of ipsilateral high RPLN irradiation seems safe, and reduces the incidence of chronic xerostomia in patients with oropharyngeal squamous cell carcinoma.

Stereotactic ablative body radiotherapy boost for cervical cancer when brachytherapy boost is not feasible.

BACKGROUND: The purpose of this study was to analyze the treatment efficacy and safety of stereotactic ablative body radiotherapy (SABR) boost for cervical cancer patients not amenable to brachytherapy. METHODS: A retrospective review of the medical records from single institution of 25 eligible patients was performed. The patients underwent pelvic radiotherapy (RT) in 25 or 28 fractions with a median dose of 45 Gy (range 44-50.4 Gy). SABR boost was delivered after pelvic RT, with a median dose of 25 Gy (range 20-33 Gy), and a median fraction number of 5 (range 4-6). 21 patients with a follow-up period of more than one year were included in the toxicity analysis, and hematuria and hematochezia that occurred later than 3 months after the RT were graded. RESULTS: The median follow-up period after radiotherapy was 2.85 years (range 0.33-6.60). The 3-year local control, locoregional control, disease-free survival, and overall survival rates were 80.9%, 75.8%, 40.9%, and 77.1%, respectively. 5 patients experienced grade 3 toxicity (3 genitourinary, 3 gastrointestinal), and no grade 4-5 toxicity was reported. Univariate analysis showed that cumulative D2cc in equivalent dose in 2 Gy fractions (EQD2) of rectum was marginally predictive for any grade of hematochezia (P = 0.051). Cumulative D2cc EQD2 of bladder was not predictive for hematuria. In the receiver operating characteristic (ROC) curve analysis, the optimal threshold of cumulative rectal D2cc EQD2 was 81.2 Gy for any grade of hematochezia. CONCLUSION: SABR boost for cervical cancer was effective and tolerable. Although it cannot substitute brachytherapy, it can be a treatment option when brachytherapy is not possible.

The association between diarrhea and serum cytokines in patients with gynecologic cancer treated with surgery and pelvic chemoradiotherapy.

PURPOSE: We investigated whether serum cytokines including Interleukin (IL)-1ß, IL-6 and tumor necrosis factor alpha (TNFα) are increased during pelvic chemoradiotherapy (CRT) in patients with gynecologic malignancies, and sought to identify prognostic factors for the development of diarrhea during pelvic CRT. MATERIALS AND METHODS: Patients with cervical or endometrial cancer receiving postoperative pelvic CRT were eligible for this prospective study. Patients were evaluated weekly during CRT for symptoms, including diarrhea and constipation. Serum cytokine levels were measured using immunoassays 1 week before CRT, and at week 3 and 5-6 during CRT. Radiotherapy-related parameters such as mean dose, minimum dose, and maximum dose to the small bowel were also analyzed. Multivariate logistic regression analysis was used to assess factors associated with development of enteritis symptoms. RESULTS: Twenty-six patients were enrolled, all of whom were eligible for symptom and dosimetric parameter evaluation; 24 were eligible for cytokine level measurement. Cytokine levels did not differ between patients with and without diarrhea before CRT. IL-6 levels increased during CRT, and were significantly higher in patients with diarrhea ≥grade 2 than in those with grade 0-1 at week 5-6 (6.771 ± 2.657 pg/mL vs. 3.396 ± 0.499 pg/mL, p = 0.046). Serum IL-1ß and TNFα levels did not change during CRT. Diarrhea before CRT and the maximum dose to the small bowel were independent prognostic factors for CRT-induced diarrhea in the multivariate analysis. CONCLUSIONS: There was an increase of serum IL-6 levels in patients with ≥grade 2 diarrhea during pelvic CRT. Serum IL-1ß and TNFα levels did not change during CRT. Radiotherapy-related and clinical factors affect the development of diarrhea during pelvic CRT.

Optimal treatment strategies for small cell carcinoma of the uterine cervix: A retrospective multi-center study (KROG 19-03).

OBJECTIVE: This multi-institutional study aimed to identify the optimal treatment strategy for small cell carcinoma of the cervix. STUDY DESIGN: We retrospectively collected the medical records of 166 patients diagnosed with small cell carcinoma of the uterine cervix from January 2000 to December 2015 from 13 institutions of the Korean Radiation Oncology Group. After excluding 18 (10.8 %) patients who initially had distant metastasis, the treatment outcomes of 148 patients were analyzed. RESULTS: After a median 46.4 (1.4-231.9) months of follow-up, the 5-year progression-free survival (PFS) and overall survival (OS) rates of all patients were 45.9 % and 63.5 %, respectively. Distant metastasis was the dominant pattern of failure occurring in 67 patients (45.3 %). We stratified the patients according to the primary local treatment: primary surgery (n = 119), primary radiotherapy (RT) (n = 26), and no local treatment group (n = 3). Although the primary RT group had advanced disease (FIGO stage ≧ IIB) more frequently than the primary surgery group (80.8 % vs. 47.9 %), the PFS and OS did not differ between the groups in multivariate analysis. CONCLUSION: Definitive RT is a reasonable local treatment option for small cell cervical cancer, particularly for advanced cases. Given the high rates of distant relapse, an effective systemic therapy protocol is warranted for small cell cervical cancer patients.

Long-Term Outcomes and Sequelae Analysis of Intracranial Germinoma: Need to Reduce the Extended-Field Radiotherapy Volume and Dose to Minimize Late Sequelae.

PURPOSE: We aimed to refine the radiotherapy (RT) volume and dose for intracranial germinoma considering recurrences and long-term toxicities. MATERIALS AND METHODS: Total 189 patients with intracranial germinoma were treated with RT alone (n=50) and RT with upfront chemotherapy (CRT) (n=139). All cases were confirmed histologically. RT fields comprised the extended-field and involved-field only for primary site. The extended-field, including craniospinal, whole brain (WB), and whole ventricle (WV) for cranial field, is followed by involved-field boost. The median follow-up duration was 115 months. RESULTS: The relapses developed in 13 patients (6.9%). For the extended-field, cranial RT dose down to 18 Gy exhibited no cranial recurrence in 34 patients. In CRT, 74 patients (56.5%) showed complete response to chemotherapy and no involved-field recurrence with low-dose RT of 30 Gy. WV RT with chemotherapy for the basal ganglia or thalamus germinoma showed no recurrence. Secondary malignancy developed in 10 patients (5.3%) with a latency of 20 years (range, 4 to 26 years) and caused mortalities in six. WB or craniospinal field rather than WV or involved-field significantly increased the rate of hormone deficiencies, and secondary malignancy. RT dose for extended-field correlated significantly with the rate of hormone deficiencies, secondary malignancy, and neurocognitive dysfunction. CONCLUSION: De-intensifying extended-field rather than involved-field or total scheme of RT will be critical to decrease the late toxicities. Upfront chemotherapy could be beneficial for the patients with complete response to minimize the RT dose down to 30 Gy. Prospective trials focused on de-intensification of the extended-field RT are warranted.

Re-irradiation for recurrent or second primary head and neck cancer.

PURPOSE: To investigate the efficacy and safety of intensity-modulated radiotherapy (IMRT)-based re-irradiation (reRT) for recurrent or second primary head and neck cancer (HNC). MATERIALS AND METHODS: Patients who underwent IMRT-based reRT for recurrent or second primary HNC between 2007 and 2019 at two institutions were included. Medical records and dosimetric data were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), severe late toxicities, and clinicopathological prognostic factors were analyzed. RESULTS: A total of 42 patients were analyzed. With a median follow-up of 15.1 months (range, 3.7 to 85.8 months), the median OS was 28.9 months with a 2-year OS rate of 54.6%. The median PFS and 2-year PFS rates were 10.0 months and 30.9%, respectively. Multivariate analysis showed that good performance (Eastern Cooperative Oncology Group [ECOG] 0 or 1), a longer time interval (≥24 months) between radiotherapy courses, and higher reRT dose (>60 Gy) were significantly favorable factors for OS (all p < 0.05). Higher reRT dose and salvage surgery were significantly associated with improved PFS (all p < 0.05). Regarding the Multi-Institution Reirradiation (MIRI) Collaborative RPA classification, the 2-year OS rates of each class were 87.5% in class I, 51.8% in class II, and 0% in class III (p = 0.008). Grade ≥3 late toxicity was reported in 10 (23.8%) patients. There was no significant factor associated with increased late toxicities. CONCLUSION: IMRT-based reRT should be considered as a treatment option for patients with recurrent or second primary HNC. Further trials are needed to establish a subset of patients who may benefit from reRT without severe late toxicity.

The predictive value of serum myeloma protein in solitary plasmacytoma.

PURPOSE: To identify the clinical usefulness of serum M protein and to establish a rationale for regular follow-up with serum protein electrophoresis in solitary plasmacytoma. MATERIALS AND METHODS: Sixty-nine patients with solitary plasmacytoma and solitary plasmacytoma with minimal marrow involvement according to the International Myeloma Working Group criteria were retrospectively reviewed. RESULTS: At a median follow-up of 6.2 years, 5-year local control (LC), 5-year multiple myeloma-free survival (MMFS), 5-year failure-free survival (FFS), and 5-year overall survival (OS) were 82.6%, 44.1%, 41.8%, and 85.1%, respectively. Among the patients whose initial serum M protein was present or not evaluated, 37.3% of patients showed disappearance of serum M protein after various treatment. MMFS of these patients were comparable to non-secretory plasmacytoma with undetectable levels of M protein, and significantly better than patients with persistent M protein. Increase of serum M protein ≥0.1 g/dL was most predictive of treatment failure with area under the curve of 0.731. CONCLUSION: Patients who eventually showed persistence of serum M protein after treatment showed worse MMFS and FFS compared to those whose serum M protein disappeared or who had initially non-secretory disease. The increase of serum M protein level ≥0.1 g/dL from current nadir was predictive of treatment failure. Therefore, regular follow-up with serum M protein is highly recommended especially unless the patient had initially non-secretory disease.