5-year Progression-free Survival Rates Research Articles

The Value of Progression-Free Survival at Three Years as a Primary Endpoint for Studies on Radiotherapy in Patients with Locally Advanced Cervical Cancer: Individual Patient Data and Validation From 27 Randomized Trials

A traditional endpoint for locally advanced cervical cancer (LACC) clinical trials is overall survival (OS) with five years of follow-up. At present, many clinical trials evaluating concurrent chemoradiotherapy combined with immunotherapy for LACC are underway in worldwide. The use of a shorter-term endpoint could significantly speed the translation of research findings into practice. The primary hypothesis was that PFS with three years of follow-up (PFS36) is an appropriate primary endpoint to replace OS with five years of follow-up (5-year OS). The primary hypothesis was developed from our individual data, was further investigated using phase III randomized controlled trials (RCTs), and then externally validated by phase II trials and retrospective studies up to 2022. Correlation analysis at the treatment-arm level was performed between 2-, 3-, 4-, and 5-year PFS rates and 5-year OS, using the Pearson correlation coefficient r in weighted linear regression, with weight equal to patient size. The MEDLINE, Embase, and PubMed databases, together with the Cochrane Central Register of Controlled Trials, were searched from January 1, 1999, to February 2, 2023. Articles eligible for inclusion contained complete survival data. A total of 613 patients with histologically confirmed, FIGO 2009 stage IB-IVA cervical cancer who underwent radiotherapy at our institute from January 2010 to December 2013 were eligible. Individual patient data were pooled to explore the correlation between PFS and the OS trend. The recurrence rates for years 1 through 5 were 12.9%, 7.3%, 3%, 2.3%, and 1.8%, respectively. The median recurrence time was 13 months and the median time from recurrence to death was 12.2 months. Within all the recurrence, 47.3% of recurrences occurred during the first year, 71.4% in the first two years, and 85% in the first three years. Patients who did not achieve PFS36 had a 5-year OS rate of 30.3%. In contrast, a 5-year OS rate of 98.2% was observed in patients who achieved PFS36. Further data were extracted from 27 RCTs on locally advanced cervical cancer. The trials included 57 arms, with a pooled sample size of 7,692 patients. Formal measures of surrogacy were satisfied. Quality control was performed, where studies with a high risk of bias were excluded. In trial-level surrogacy, PFS36 (r2, 0.778) was associated with 5-year OS. The correlation between PFS36 and OS was externally validated using independent phase II trials and retrospective data. In total, 23 studies representing 5,174 patients were included. PFS36 (r2, 0.719) was found to be associated with OS. The patients who achieved PFS36 had excellent outcomes, whereas patients that experienced earlier progression had poor survival. A significant correlation was found between PFS36 and 5-year OS in clinical trials on patients with locally advanced cervical cancer. These results suggest that PFS36 is an appropriate endpoint for LACC clinical trials of radiotherapy-based regimens.

Survival Analysis of Patients with Locally Advanced Non-Small Cell Lung Cancer Who Received Neoadjuvant Immunotherapy

In the PACIFIC study, immuno-consolidation therapy has a great survival benefit for patients with locally advanced non-small cell lung cancer who had no progression after concurrent chemoradiotherapy. However, there is no clear evidence that earlier immunotherapy intervention can obtain better survival benefits for patients with progression after concurrent or sequential chemoradiotherapy. The purpose of this retrospective study was to further explore impact of early intervention in immunotherapy on survival. All patients who were treated with concurrent or sequential chemoradiotherapy and immunotherapy for LA-NSCLC between September 2019 and December 2021 were eligible. Time-to-event data were assessed by using the Kaplan-Meier estimator, and the Cox proportional hazards model was used for prognostic factor analyses. According to the timing of immunotherapy use, 60 patients with LA non-small cell lung cancer were divided into neoadjuvant group and consolidation group, with 30 patients in each group. All patients completed concurrent or sequential chemoradiotherapy. The median follow-up time in the neoadjuvant and consolidation groups was 20 and 18 months. In the neoadjuvant group, 4 patients died, 15 patients developed tumor progression, and 5 patients had distant metastasis. In the consolidation group, 5 patients died, 15 patients developed tumor progression, and 4 patients had distant metastasis. The median PFS of the neoadjuvant group and the consolidation group were 19 months and 15 months (P = 0.703). Both groups did not reach the median OS. The 1-year and 2-year PFS rates were 72.9%, 63.3% and 41.0%, 48.1%. 1-year and 2-year OS rate were 93.0%, 93.3%, and 74.4%, 76.6%. Disease control rates (DCR) in the both neoadjuvant and consolidation groups were 90%. There was little difference in the incidence of adverse responses between the two groups. Earlier immune intervention may have resulted in treatment effects similar to those observed in the PACIFIC trial, which suggests that the benefits of immunotherapy could be extended to a broader population.

Efficacy and Safety of Image-Guided Hypofractionated Radiotherapy for Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis

To evaluate the efficacy and safety of image-guided 10-fraction hypofractionated radiotherapy (RT) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). Between 2016 and March 2022, 69 HCC with PVTT patients received RT (40-50Gy/10fx) in our institutions. The median prescribed dose of 50 Gy (range, 40-50 Gy, BED10; 56-75 Gy10) was delivered in 10 fractions in all patients. Follow-up imaging was performed at three-month intervals after the completion of RT. The extent of PVTT was described according to the Liver Cancer Study Group of Japan classification: Vp0 = no PVTT, Vp1 = segmental portal vein branch, Vp2 = right/left anterior/posterior portal vein, Vp3 = right/left portal vein and Vp4 = main portal vein. Response evaluation was performed using response evaluation criteria in solid tumors, version 1.1. Freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) were calculated from the start date of RT. In this cohort, 4.3% of patients had Vp1 PVTT, 20.3% had Vp2, 37.7% had Vp3, and 37.7% had Vp4. The median PTV volume was 105.3 cc (interquartile range [IQR], 74.1-179.4 cc). Fifty-two (75.4%) patients received 50 Gy in 10 fractions. With a median follow-up of 10.2 months (IQR, 6-21 months), the median OS was 18.5 months, and 1-year FFLP, PFS, and OS rates were 84.8%, 26.9%, and 62.2% respectively. At 3 months after RT, 13.0% had a complete response, 36.2% had a partial response, 46.4% had a stable disease and 4.4% had a progressive disease. In the multivariate analysis, AFP ≥ 600 IU/ml (HR 2.06, p = 0.03), Child-Pugh Class B or C (HR 2.30, p = 0.02), and modified Union for International Cancer Control (mUICC) stage IVA or IVB (4.05, p = 0.02) were significantly related to OS. During the follow-up period, there were 2 (2.8%) cases of grade ≥3 toxicity: grade 3 AST/ALT elevation (n = 1), and acute cholangitis (n = 1). Hypofractionated RT demonstrated promising local PVTT control with acceptable toxicity. These data suggest that 10-fraction image-guided hypofractionated RT (BED10 = 56-75 Gy10) is a feasible treatment option for PVTT in HCC patients.

Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) for Patients with Pleural Metastases from Thymic Malignancies

Pleural metastases are common sites for recurrence and progression in patients with thymic malignancies. The management of pleural metastases typically involves surgical resection with or without neoadjuvant or adjuvant systemic therapy. After surgical resection of pleural metastases, the 5-year progression-free survival (PFS) rate is about 29-45%. While radiation therapy (RT) is standardly used in the management of locally-advanced thymic malignancies, the role of RT in patients with pleural metastases in unclear. Intensity-modulated pleural radiation therapy (IMPRINT) is a RT technique currently being used to treat malignant pleural mesothelioma (MPM) patients with 2 intact lungs at centers that specialize in MPM treatment. This IMPRINT technique can potentially be extrapolated to thymic patients with pleural metastases. Because the risk of toxicity is of greater concern for thymic patients given their overall relatively favorable prognosis, the rate of toxicity, particularly radiation pneumonitis, needs to be established in the thymic patient population. This is a single-arm, single institution Phase II study of hemithoracic IMPRINT for patients with pleural metastases from thymic malignancies. The primary endpoint of this study is grade 3 or higher radiation pneumonitis within 4 months of completing RT. Secondary endpoints include any toxicity, progression-free survival, patterns of failure and overall survival. Patients must have a pathologically confirmed diagnosis of a thymic malignancy with radiologic or pathologic evidence of pleural metastases. Thymoma or thymic carcinoma are allowed. Patients may have de novo stage IVA disease or recurrent disease in the pleura. There must be no evidence of extrathoracic metastatic disease or contralateral pleural/pericardial disease. Surgical resection of the pleural nodules (ex: pleurectomy/decortication, debulking/metastasectomy) are allowed. Extrapleural pneumonectomy is not allowed. Patients are excluded if they have undergone prior thoracic radiation therapy preventing hemithoracic pleural IMRT, whereas prior thymic bed radiation and/or prior pleural SBRT are allowed. RT will be administered to the ipsilateral pleura to 50.4 Gy in 28 fractions. An optional dose-painting boost to gross disease up to 60 Gy while respecting normal tissue constraints is allowed. Patients can be treated with photon or proton therapy. Simulation, contouring and RT planning guidelines have been developed. Patients will be followed per protocol at regular intervals for at least 12 months following RT. The expected accrual is 36 patients over 4 years. Further information can be found on clinicaltrials.gov (NCT05354570). To be determined. To be determined.

Outcomes and Failure Patterns after Chemoradiotherapy for Locally Advanced Rectal Cancer with Positive Lateral Pelvic Lymph Nodes: A Propensity Score-Matched Analysis

Locally advanced rectal cancer (LARC) combined with positive lateral pelvic lymph nodes (LPLN) tends to present worse prognosis. However, for those patients it remains unclear whether other combination high-risk factors affect the prognosis. This study aimed to use propensity score matching (PSM) to examine long-term outcomes and failure patterns in patients with positive vs. negative LPLN. Patients with LARC were retrospectively divided into LPLN-positive and LPLN-negative groups. LPLN-positivity was defined as lymph node short diameter greater than or equal to 7 mm with specific morphological features. Clinical characteristics were compared between the groups using the chi-square test. PSM was applied to balance these differences. Progression-free survival (PFS) and overall survival (OS), and local-regional recurrence (LRR) and distant metastasis (DM) rates were compared between the groups using the Kaplan-Meier method and log-rank tests. Prior to PSM, a total of 651 LARC patients were included. The LPLN-positive group had higher rates of lower location (53.1% vs. 43.0%, P = 0.025), mesorectal fascia (MRF)-positive (53.9% vs. 35.4%, P<0.001) and extramural venous invasion (EMVI)-positive (51.2% vs. 27.2%, P<0.001) disease than the LPLN-negative group. After PSM, there were 114 patients for each group along with the balanced clinical factors, and both groups had comparable surgery, pathologic complete response (pCR), and ypN stage rates. The median follow-up time was 45.9 months, 3-year OS (88.3% vs. 92.1%, P = 0.276) and LRR (5.7% vs. 2.8%, P = 0.172) rates were comparable between LPLN-positive and LPLN-negative groups. Meanwhile, despite no statistical difference, 3-year PFS (78.8% vs. 85.9%, P = 0.065) and DM (20.4% vs. 13.3%, P = 0.061) rates slightly differed between the groups. Among 10 patients with LRR, seven (70.0%) had lateral pelvic recurrence, among them, five patients were LPLN-positive, and four (80.0%) of these patients did not receive simultaneous integrated boost intensity-modulated radiotherapy (SIB- IMRT).45 patients were diagnosed with DM, 11 (40.7%) LPLN-positive and 3 (17.6%) LPLN-negative patients were diagnosed with oligometastases (P = 0.109). Our study shows there is a tendency of worse PFS and DM in LPLN-positive than LPLN-negative patients, for LPLN-positive patients, oligometastases account for a large proportion of all distant metastases.

Radiotherapy Alone vs. Concurrent or Adjuvant Chemoradiotherapy for Nasopharyngeal Carcinoma Patients with Negative Epstein-Barr Virus DNA Post-Induction Chemotherapy

Induction chemotherapy (IC) plus concurrent chemoradiotherapy has been recommended as the standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). However, concurrent chemotherapy was associated with increased toxicities, poor tolerance, and low completion rates. The aim of this study was to compare the efficacy and toxicity of IC+ radiotherapy (RT) and IC+ concurrent or adjuvant chemoradiotherapy (IC+CCRT/AC) in patients with negative post-IC EBV DNA. A total of 547 NPC patients with negative plasma EBV DNA post-IC were included. Patients were classified into the IC+RT group and the IC+ concurrent or adjuvant chemoradiotherapy (IC+CCRT/AC) group. Locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS) were estimated and compared using the Kaplan-Meier method. Propensity-score matching (PSM) was performed to balance the variables. The median follow-up time was 37 months. The 3-year LRFS, DMFS, OS, and PFS rates for the whole group were 92.2%, 92.4%, 96.4%, and 84.4%, respectively. There was no significant difference in LRFS, DMFS, OS, and PFS between the IC+RT and the IC+CCRT/AC group both before PSM (3-year rates of 91.1% vs. 92.6%, p = 0.94; 95.6% vs. 91.5%, p = 0.08; 95.2% vs. 96.8%, p = 0.80; 85.9% vs. 84.0%, p = 0.38) and after PSM (90.7% vs. 92.7%, p = 0.77; 96.8% vs. 93.7%, p = 0.29; 94.5% vs. 93.9%, p = 0.57; 84.7% vs. 85.6%, p = 0.96). Multivariate analysis demonstrated that treatment schedule was not an independent predictor for survival rates. Patients in the IC+RT group had fewer treatment-related acute toxicities and better tolerance. IC+RT displayed similar survival outcomes as IC+CCRT/AC for NPC patients with negative post-IC EBV DNA. Our current data seems not to support the routine use of concurrent or adjuvant chemotherapy after IC for unselected patients.

Safety and Efficacy of Hypofractionated Radiotherapy Combined with Tyrosine Kinase Inhibitors in Patients with Lung Metastases after Liver Transplantation for Hepatocellular Carcinoma

We evaluated the safety and efficacy of hypofractionated radiotherapy (HFRT) combined with tyrosine kinase inhibitors (TKIs) in patients with pulmonary metastases after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). Twenty-five patients with lung metastases after OLT for HCC who underwent HFRT using helical tomotherapy concomitantly with TKIs (sorafenib or lenvatinib) were retrospectively. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), local control rate (LCR), objective response rate (ORR), and treatment-related side effects. The median follow-up time was 35.5 months, with a median interval from OLT to lung metastasis of 15.3 months. The median PFS and OS were 9.9 and 32.7 months, respectively. The 1-, 2-, and 3-year PFS and OS rates were 36.0%, 16.0%, and 12.0%, and 84.0%, 52.0%, and 20.0%, respectively. The LCR of pulmonary metastases at 1 year was 100%, whereas the two-year LCR was 76.9%. The 1- and 2- year ORRs were 95.2% and 69.2%, respectively, with no grade > 2 adverse events. Radiation pneumonitis was observed in 17 patients (68.0%). Grade 1 pneumonitis occurred in 15 patients (60.0%), and grade 2 pneumonitis occurred in 2 patients (8.0%). The combination therapy of HFRT with TKIs is a feasible, safe, and promising approach in the treatment of pulmonary metastases for HCC after OLT.

Clinical Outcomes of Carbon-Ion Radiotherapy for Large-Sized (≥4cm) Hepatocellular Carcinoma

Radical treatment options for bulky unresectable locally advanced hepatocellular carcinoma (HCC) are limited. The purpose of this study is to evaluate the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for bulky (≥4cm) locally advanced HCC. We performed a retrospective cohort study of patients with bulky (≥4cm) locally advanced HCC treated by C-ion RT between April 2000 and March 2020 in our institution. The eligibility criteria for this study were: (1) the treatment protocols of 45.0-48.0 Gy/2 fractions or 52.8-60.0 Gy/4 fractions, which proven the safety and efficacy in the past clinical trials; (2) Tumors within 3 intrahepatic lesions and with a maximum tumor diameter of 4 cm or greater; (3) N0M0 status; (4) an Eastern Cooperative Oncology Group performance status of 0 to 2; (5) controllable ascites; (6) Child-Pugh grade was A or B. Overall survival (OS), progression-free survival (PFS), and local control rate (LC) were calculated by the Kaplan-Meier method, and Cox regression analysis was used for multivariate analysis. Adverse events were evaluated by CTCAE ver. 5.0. JMP® 12 (SAS Institute Inc., Cary, NC, USA) was used for all analyses. We defined p < 0.05 as statistically significant. A total of 187 patients met the criteria and were evaluated. The median patient age was 73 years (range, 37-90), and 139 of 187 patients were male. Child-Pugh grade was A in 163 patients and B in 24. Modified albumin-bilirubin (mALBI) grade was 1 in 96 patients, 2a in 50, and 2b in 41. The number of HCV-related HCC cases was in 80, HBV in 32 and non-B and non-C in 75. In 51 patients, identification of vascular invasion to the first-order branch of the portal vein and/or major hepatic vein was confirmed. The median maximum tumor diameter was 5.1 cm (4.0-13.5 cm). In 76 patients, C-ion RT were treated for recurrence. With a median follow-up period of 25.9 months (range, 1.1-215.1), 2-year overall survival, progression-free survival and local control rates were 68.3% (95% confidence interval [CI], 64.7-72.0%), 39.0% (95% CI, 35.2 - 42.8%) and 86.7% (95% CI, 84.7 - 89.7%), respectively. Late adverse events were observed in 3 patients (1.6%) with Grade 3 liver dysfunction and in 3 patients (1.6%) with Grade 3 skin disorders, but there were no cases of Grade 4 or higher. Multivariate analysis of prognostic factors for overall survival revealed that mALBI grade in 2b(HR:3.13, 1.97-4.78, p<0.0001), tumor status in recurrent treatment (HR:1.50, 1.02-2.21, p = 0.039), the number of tumors in 2 or more (HR:2.16, 1.01-2.17, p = 0.045), and maximum tumor diameter in larger than 6 cm (HR:2.34, 1.50-3.61, p = 0.0001) were the predominant prognostic factors, while age, presence of vascular invasion, AFP and DCP were not. The safety and efficacy of C-ion RT for bulky (≥4cm) locally advanced HCC was demonstrated. These results suggested that C-ion RT may be a new treatment option for locally advanced bulky HCC with no curative treatment options.

Induction Chemotherapy and Toripalimab for Larynx Preservation in Resectable Locally Advanced Laryngeal/Hypopharyngeal Carcinoma: Preliminary Results of INSIGHT Study

Previous studies have demonstrated excellent pathological response of induction PD-1 inhibitor with chemotherapy for locally advanced head and neck cancer. To our knowledge, there is scarce evidence on induction chemotherapy (ICT) and PD-1 inhibitor in organ preservation for patients (pts) with laryngeal/hypopharyngeal carcinoma. Hence, the aim of this study is to evaluate the efficacy and toxicities of ICT and PD-1inhibitor (Toripalimab) followed by radiotherapy or surgery, for pts with resectable locally advanced laryngeal/hypopharyngeal carcinoma. This isa single-arm phase II study. Pts with histopathologic confirmed, resectable locally advanced laryngeal/hypopharyngeal squamous cell carcinoma and ECOG PS 0-1 were eligible. Three cycles of ICT (paclitaxel 175 mg/m d1, cisplatin 25 mg/m d1-3) combined with PD-1 inhibitor (Toripalimab 240 mg d0) were given. Response assessment (RECIST 1.1) was performed post-ICT. Patients with complete response (CR)/partial response (PR) of primary tumor received concurrent chemoradiation, followed by maintenance therapy of Toripalimab for eight cycles. Otherwise, patients were referred to surgery, followed by adjuvant radiation (RT)/chemoradiation (CRT), and then maintenance therapy of Toripalimab. The primary endpoint is larynx-preservation (LP) rate at 3 months post-RT. Forty-two patients were planned. Based on a two-stage Fleming design (one-sided α:10%, power: 80%), if at least 22 patients attained LP of the first 27 patients in stage I or at least thirty-two pts attained LP of the 42 patients at the end of stage II, the null hypothesis would be rejected. The cohort would enroll 15 more pts in stage II if 19-21 pts in stage I observed LP, and the study would be terminated if the number of pts with LP were less than 18 in stage I. A total of 27 pts were enrolled. By the cut-off date Feb 8, 2023, all reached at least 3 months of follow-up post-RT. Median age was 63 (53-74) years with 92.6% male. Hypopharyngeal cancer accounted for 66.7%. There were 74.1% who were T3 to T4, and 77.7% were N2 to N3. Six cases had primary invasion of esophagus and five pts underwent pretreatment tracheostomy. ORR of ICT was 85.2%. Afterward, 21 pts were treated with concurrent CRT, while 6 pts received surgery of primary tumor. At 3 months post-RT, 23 pts attained organ preservation and the LP rate was 85.2%. With a median follow-up of 13.5 months, 1-year OS rate, PFS rate and LP survival rate was 83.1%, 79.5% and 79.4%, respectively. During ICT, 22.2% of pts experienced grade 3-4 treatment-related AEs (TRAEs). The most common grade 3-4 TRAEs were nausea and neutrophil count decreased. The primary endpoint LP rate was met. In this cohort of extensive locally advanced laryngeal/hypopharyngeal carcinoma, ICT and Toripalimab followed by radiotherapy or surgery resulted in satisfactory short-term LP rate and encouraging survival.

Treatment Outcomes of Concurrent Nimotuzumab with Intensity Modulated Radiotherapy in Advanced Nasopharyngeal Carcinoma Patients Unfit for Concurrent Chemoradiotherapy: A Single Institute Experience

To assess the safety and efficacy of intensity-modulated radiotherapy (IMRT) combined with nimotuzumab for patients with locally advanced nasopharyngeal carcinoma (LA-NPC) medically unfit to receive concomitant chemotherapy. From 2016.6 to 2020.9, 34 newly diagnosed patients with local-regional advanced NPC medically unfit for concurrent chemoradiation had undergone definitive radiotherapy and were retrospectively evaluated. All patients were treated with IMRT combined treatment modality of nimotuzumab with or without cisplatin-based induction chemotherapy. Nimotuzumab was administered concurrently with IMRT at a weekly dose of 200 mg. Acute and late radiation-related toxicities were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 during and after IMRT. The Kaplan-Meier method was used for survival analysis. Univariate and multivariate prognostic analyses were performed by using the Cox proportional hazard model. The median follow-up time for the entire group was 15 months (range 5 to 55 months). At the time of this analysis, a total of 2 cases developed loco-regional recurrence. In addition, 4 patients developed distant metastasis. There was a total of 5 deaths: 3 patients died from distant metastasis, 1 patient died from the progression of loco-regional disease after recurrence, and the causes of death for the additional 1 case was a nasopharyngeal ulcer and deadly bleeding. The 1-year OS rate of the whole cohort was 87.9%, and the 1-year LFFR, DFFR, and PFS rates were 100%, 91.0%, and 91.0%, respectively. During the period of concurrent nimotuzumab and IMRT, no grade 3-4 hematologic toxicities and dermatitis were observed. Grade 3-4 radiotherapy-related oral mucositis was reported in 7 patients (20.6%). No infusion reaction was observed. No acneiform eruptions were found among these patients. The most commonly observed late complication was xerostomia. The degree of dry mouth in most patients was mild-to-moderate at the time of the last follow-up. Finally, 7 patients developed either unilateral or bilateral hearing impairment. One female patient experienced a nasopharyngeal ulcer and deadly bleeding after 5 months of completion of radiotherapy. Concurrent nimotuzumab with IMRT for the treatment of LA-NPC was well tolerated, with encouraging survival data, and it could be an effective treatment alternative for patients with LA-NPC medically unfit for concomitant chemotherapy. Further clinical trials are needed to confirm these findings.

Radiotherapy for Postoperative Vaginal Recurrences of Cervical Cancer Patients: Analysis of Recurrent Causes and Prognosis

Vagina is the most common site of cervical cancer recurrence, and salvage radiotherapy (RT) is recommended owing to its effectiveness and tolerable adverse events. Several studies have focused on prognostic factors of RT treatment for postoperative recurrent cervical cancer patients. However, few researches identified different recurrent causes as a prognostic factor and studied the relationship between recurrent causes and survival. The aim of this study was to identify the recurrent causes affecting prognosis of vaginal recurrent patients treated with salvage RT. One hundred and twenty-six female patients with vaginal recurrent cervical cancer, treated with salvage RT between July 2011 and January 2020, were reviewed in this study. Among these patients, a combination of EBRT and BRT was delivered to 94 patients, EBRT alone was delivered to 20 patients. Causes of recurrence were distributed into five groups: (1) selection of surgical indication (n = 15): included ①surgery beyond indication (n = 8) and ②neoadjuvant therapy (n = 7);(2) Positive surgical margin (n = 18); (3) nonstandard RT (n = 20): include ④no RT, despite indications of postoperative RT (n = 15), and ⑤insufficient postoperative RT dose (n = 5); (4) with risk factors but no indication for RT according to the Sedlis criteria (n = 29): include ⑥non-squamous carcinoma (n = 7) and ⑦only one intermediate risk factor in Sedlis criteria (n = 22); (5) HPV infection (n = 44). Log-rank tests and Cox proportional hazards regression methods were used to identify prognostic factors. The median follow-up time of the 126 cervical cancer patients was 39.1 months with estimated 5-year OS, PFS and LC rates of 79%, 75% and 86%, respectively. In multivariate analysis, recurrence pattern (including endovaginal recurrence, paravaginal recurrence, invasion of surrounding organs and distant metastasis, p < 0.05) and causes of recurrence were independent prognostic factors for OS. Recurrence because of "(1) the selection of surgical indication" (p < 0.05) was associated with poor OS, while recurrence because of "(2) positive surgical margin" was associated with prolonged OS. Multivariate analysis also revealed that recurrence pattern, causes of recurrence (p < 0.05) and re-irradiation were independently factors for PFS. Majority of patients with recurrence causes of HPV infection (79.5%) and positive surgical margin (77.8%) experienced endovaginal recurrence. Patients with recurrence cause of selection of surgical indication had the highest proportion (26.7%) of recurrence with invasion of surrounding organs, and 53.3% experienced re-irradiation. The results this research suggest that salvage RT is an effective treatment for vaginal recurrences in postoperative patients with cervical cancer. Causes of recurrence was an independently factor for OS and PFS, and recurrence caused by selection of surgical indication was associated poor survival.

Radiotherapy (RT) for Cutaneous Adnexal Carcinoma (CAC): 49 Patients Treated at a Single Institution Over 2 Decades

Cutaneous adnexal carcinomas (CACs) are a heterogenous group of rare skin cancers. Management strategies are extrapolated from the treatment of more common skin cancers, and case series describing patients treated with radiotherapy (RT) for CAC are limited to <15 patients. We reviewed our institutional experience to better understand the characteristics and outcomes of patients with CAC treated with RT. Patients diagnosed with CAC and treated RT from 2000-2020 were identified using the following keywords: adnexal, microcystic, apocrine, eccrine, sebaceous, sweat gland, syringoma, mucinous, tubular, porocarcinoma, hidradenocarcinoma, and cylindrocarcinoma. Patient, cancer, and treatment characteristics were assessed by retrospective record review. Time to overall survival (OS), locoregional recurrence (LRR), distant metastasis (DM), and progression free survival (PFS) were evaluated using Kaplan-Meier methods. Forty-nine patients with a median age of 65 years (IQR 53-82) were identified. Most were white (90%) men (59%) harboring tumors on the head and neck (80%). The most common subtypes of CAC were adnexal adenocarcinoma (39%), sebaceous carcinoma (35%) and microcystic adnexal carcinoma (10%). Patients were treated for de novo cancer (n = 35) or after recurrence (n = 14). Among de novo cases, 9 (26%) were treated with definitive RT, 22 (63%) were treated with surgery and adjuvant RT, and 4 (11%) with palliative RT. Per UICC system, de novo stage at time of RT was I in 2 (6%), II in 9 (26%), III in 12 (34%), IVA in 10 (29%), and IVB in 2 (6%). Median OS was 44 months and median follow-up of surviving patients was 41 months (IQR 17-75). De novo patients treated with definitive RT received a median dose of 70 Gy (IQR 60-73 Gy) and experienced 2-year rates of PFS, LRR, and DM of 30%, 55%, and 40%, respectively. All LRR events occurred within the irradiated volume. De novo patients treated with surgery and adjuvant RT received a median dose of 60 Gy (IQR 60-64 Gy) and experienced 2-year rates of PFS, LRR, and DM of 77%, 13%, and 10%, respectively. All LRR events occurred outside the irradiated volume. Among patients treated at recurrence, most (93%) underwent surgery and adjuvant RT. Per UICC system, their stage at time of RT was II in 2 (15.4%), III in 4 (30.8%), and IVA in 7 (53.8%). Recurrent patients treated with surgery and adjuvant RT received a median dose of 60 Gy (IQR 60-66 Gy) and experienced 2-year rates of PFS, LRR, and DM of 30%, 58%, and 29%, respectively. Three of 4 evaluable patients treated with palliative RT exhibited stable disease or tumor response. In the largest single institution analysis to date, RT was primarily used for CAC patients as an adjuvant treatment. LRR was less frequent and less likely to occur within irradiated volume in patients selected for surgery and adjuvant RT than those selected for definitive RT or at time of recurrence.

Ibrutinib maintenance after frontline treatment in patients with mantle cell lymphoma

AbstractMaintenance rituximab in mantle cell lymphoma (MCL) has improved survival and supports exploration of maintenance with novel agents. We evaluated the safety and efficacy of ibrutinib maintenance (I-M) after induction in patients with treatment-naive MCL. Patients with MCL with complete response (CR) or partial response to frontline chemoimmunotherapy ± autologous stem cell transplantation (auto-SCT) received I-M 560 mg daily for up to 4 years. Primary objective was 3-year progression-free survival (PFS) rate from initiation of I-M. Minimal residual disease (MRD) assessments by next-generation sequencing (NGS) on peripheral blood were measured before I-M initiation and at 1, 6, and 18 to 24 months after initiation. Among 36 patients, the median age was 60 years (range, 46-90). For frontline treatment, 18 patients (50%) had consolidation with auto-SCT in CR1 before I-M. At median follow-up of 55.7 months, 17 patients (47%) completed full course I-M (median, 37.5 cycles; range, 2-52). The 3-year PFS and overall survival (OS) rates were 94% and 97%, respectively. With prior auto-SCT, 3-year PFS and OS rates were both 100%. The most common treatment–related adverse event with I-M was infection (n = 31; 86%), typically low grade; the most common grade 3/4 toxicities were hematologic. In 22 patients with MRD assessments, all were MRD negative after induction. Six became MRD positive on I-M, with 2 reverting to MRD-negative status with continued I-M, and all maintain radiographic CR with the exception of 1 with disease progression. I-M is feasible in MCL after frontline chemoimmunotherapy with manageable toxicities although significant. Changes in NGS-MRD were noted in limited patients during maintenance with few progression and survival events. This trial was registered at www.clinicaltrials.gov as #NCT02242097.

Definitive irradiation as a first treatment strategy for primary and metastatic sites of newly diagnosed IVB cervical cancer that presented with synchronous oligometastases

BackgroundThe present study identified survival and progression-free rates and evaluated prognostic factors for IVB stage cervical cancer in patients that presented with synchronous oligometastases (sync-oligometastases) who received definitive irradiation for primary and metastatic sites.MethodsThe study retrospectively included 60 patients with newly diagnosed stage IVB cervical cancer. Patients received definitive radiation for both primary and metastatic sites through Volumetric Modulated Arc Therapy (VMAT) or intensity modulated radiation therapy (IMRT) followed by three dimensional-intracavitary/interstitial brachytherapy at our institution between July 2014 to December 2020. All patients were staged based on the International Federation of Gynecology and Obstetrics (FIGO) 2018 guidelines. Overall survival (OS), progression-free survival (PFS), and patient prognostic factors were analyzed.ResultsThe 60 patients who received curative-intent irradiation for primary and metastatic sites showed a 5-year OS rate of 51.4% and a 5-year PFS rate of 25.9%. The median PFS was 52.3 months, and the median OS had not been reached. Lymphatic metastases had a better OS compared with hematogenous metastases (3-year OS rates: 57.2% vs. 20%, p = 0.017). Patients with one metastasis site showed a more favorable prognosis than patients with ≥ 2 metastases sites (3-year OS rates: 60.4% vs. 20.6%, p = 0.003). Patients that presented with tumors larger than 4 cm in diameter before treatment demonstrated a poorer prognosis (5-year OS rates: 41.2% vs. 65.2%, p = 0.029; 5-year PFS rates: 10.4% vs. 53.7%, p = 0.021).ConclusionDefinitive irradiation for both primary and oligo-metastatic sites for selected IVB patients is a feasible treatment strategy. Metastatic type, number of metastatic sites, and pre-treatment tumor diameter were significant prognostic factors. Neoadjuvant chemotherapy, the lymph nodal metastatic type (supraclavicular or inguinal), and number of lymphatic metastatic sites failed to reach statistical significance as prognostic factors.

Salvage radiotherapy strategy and its prognostic significance for patients with locoregional recurrent cervical cancer after radical hysterectomy: a multicenter retrospective 10-year analysis

ObjectiveWe aimed to evaluate the clinical efficacy and prognostic significance of intensity-modulated radiotherapy (IMRT)-based salvage concurrent chemoradiotherapy (CCRT) for patients with locoregional recurrence cervical cancer after radical hysterectomy and evaluated two salvage radiotherapy modes—regional RT (involved-field RT combined with regional lymph nodes) and local RT (involved-field RT).MethodsPatients were enrolled retrospectively from January 2011 to January 2022 in three medical centers. Clinical outcomes were analyzed using the Kaplan–Meier method and a Cox proportional hazards model. Propensity score (PS) matching analysis was used to compare the two RT groups.ResultsThere were 72 patients underwent IMRT-based salvage CCRT. The 5-year overall survival and progression-free survival rates were 65.9% and 57.6%, respectively. Univariate analysis showed that patients with stump recurrence, a lower systemic inflammation response index (SIRI), only one metastatic lesion, and received regional RT had better prognosis than their counterparts. In multivariate analysis, recurrence site was the independent prognostic factor of OS, and SIRI was that of PFS. After PS matching, there were 15 patients each in the regional RT group and local RT group. The 5-year OS rate of regional RT group was better than that of local RT group (90.9 vs. 42.4, p = 0.021). However, there was no significant difference between them in terms of PFS rate (47.1 vs. 38.1, p = 0.195).ConclusionLocoregional recurrent cervical cancer treated with IMRT-based salvage therapy has a good prognosis. Recurrence site and SIRI were independent prognostic factors. Regional RT may be a better option for patients with locoregional recurrent.

Clinical and cytogenetic characteristics of primary and secondary plasma cell leukemia under the new IMWG definition criteria: a retrospective study

ABSTRACTBackgroundPlasma cell leukemia (PCL) is a rare and aggressive plasma cell disorder, exhibiting a more unfavorable prognosis than multiple myeloma. PCL is classified into pPCL and sPCL. Recently, the IMWG has recommended new PCL definition criteria, which require the presence of ≥5% circulating plasma cells in peripheral blood smears. Due to its low incidence, research on pPCL and sPCL is limited.MethodsWe conducted a retrospective study and analyzed clinical and cytogenetic data of pPCL and sPCL patients. Overall survival (OS) and progression-free survival (PFS) were assessed by the Kaplan-Meier method, and survival distributions were compared using the log-rank test.ResultsThis is a small cohort comprising 23 pPCL and 9 sPCL patients. Notably, sPCL patients showed a higher incidence of extramedullary infiltration and a higher percentage of bone marrow plasma cells (p = 0.015 and 0.025, respectively). Although no significant difference was found between the two groups in OS and PFS, a trend emerged suggesting a superior survival outcome for pPCL patients, with a higher cumulative 1-year PFS rate (38.3% vs. 13.3%) and a lower early mortality rate (mortality rate at 3 months: 15% vs. 33%). We also suggested that pPCL patients carrying t(11;14) may have a longer median survival time than individuals with other cytogenetic abnormalities, but this was not confirmed due to the small sample size.ConclusionOur study revealed clinical and cytogenetic features of pPCL and sPCL patients according to the new diagnostic criteria. The findings suggested a generally better prognosis for pPCL than sPCL and the likelihood of t(11;14) translocation acting as a favorable prognostic factor in pPCL. It is important to note that our study had a limited sample size, which may lead to bias. We hope well-designed studies can be conducted to provide more results.

Long-term survival benefit of anti-PD-1 therapy in patients with relapsed or refractory classical Hodgkin lymphoma

Anti-programmed cell death-1 (anti-PD-1) therapies have shown a favorable efficacy and good tolerance for relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL). However, there are limited data on long-term outcomes among patients with r/r cHL who achieve an objective response to anti-PD-1 therapies. A total of 260 responders from four, phase 2 clinical trials were included in this study. The median age was 32 years with a male/female ratio of 1.3:1. After a median follow-up period of 31.1 months, 116 (44.6%) responders experienced disease progression and 18 (6.9%) died. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 55.1% and 89.7% overall. Patients with partial remission (PR) had inferior outcomes compared with those who achieved complete remission (3-year PFS, 29.5% vs. 72.3%, P < 0.001; 3-year OS, 81.5% vs. 94.4%, P = 0.017). Moreover, the survival outcome was inferior for patients with refractory disease compared with those with relapsed disease. Multivariate Cox regression analysis showed PR and refractory disease were independent risk factors for PFS. In conclusion, PR and refractory disease have a negative impact on the survival benefit of anti-PD-1 therapeutics in patients with r/r cHL, which highlights the need for multimodal treatment strategies.

Definitive carbon ion re-irradiation with pencil beam scanning in the treatment of unresectable locally recurrent rectal cancer.

This study aimed to evaluate the oncological outcomes and safety of carbon ion re-irradiation with pencil beam scanning (PBS) delivery technique for previously irradiated and unresectable locally recurrent rectal cancer (LRRC). Between June 2017 and September 2021, 24 patients of unresectable LRRC with prior pelvic photon radiotherapy who underwent carbon ion re-irradiation at our institute were retrospectively analyzed. Carbon ion radiotherapy was delivered by raster scanning with a median relative biological effectiveness-weighted dose of 72Gy in 20 fractions. Weekly CT reviews were carried out, and offline adaptive replanning was performed whenever required. The median follow-up duration was 23.8months (range, 6.2-47.1months). At the last follow-up, two patients had a local disease progression, and 11 patients developed distant metastases. The 1- and 2-year local control, progression-free survival and overall survival rates were 100 and 93.3%, 70.8 and 45.0% and 86.7 and 81.3%, respectively. There were no Grade 3 or higher acute toxicities observed. Three patients developed Grade 3 late toxicities, one each with gastrointestinal toxicity, skin reaction and pelvic infection. In conclusion, definitive carbon ion re-irradiation with PBS provided superior oncologic results with tolerable toxicities and may be served as a curative treatment strategy in unresectable LRRC.

In-class transition (iCT) of proteasome inhibitor-based therapy: a community approach to multiple myeloma management

Long-term proteasome inhibitor (PI) treatment can improve multiple myeloma (MM) outcomes, but this can be difficult to achieve in clinical practice due to toxicity, comorbidities, and the burden of repeated parenteral administration. US MM-6 (NCT03173092) enrolled transplant-ineligible patients with newly diagnosed MM to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd; ≤39 cycles or until progression or toxicity) following three cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS). Key secondary/exploratory endpoints included overall response rate (ORR), overall survival (OS), safety, quality of life (QoL), treatment satisfaction, and actigraphy. At datacut, in the fully accrued cohort of 140 patients, median age was 73 years with 42% aged ≥75 and 61% deemed frail; 10% of patients were ongoing on treatment. After a median follow-up of 27 months, the 2-year PFS rate was 71% (95% confidence interval: 61–78). ORR increased from 62% at the end of induction to 80% following in-class transition (iCT) to IRd for a median of 11 months. The 2-year OS rate was 86%. The overall safety profile/actigraphy levels were consistent with previous reports; QoL/treatment satisfaction scores were stable with ongoing therapy. iCT to IRd may allow prolonged PI-based therapy with promising efficacy and a tolerable safety profile, while maintaining QoL.

Induction immunochemotherapy followed by radiotherapy for patients with unresectable locally advanced or metastatic esophageal cancer: A propensity score-matched analysis

BackgroundThe study aimed to investigate the efficacy of induction immunochemotherapy before radiotherapy (RT) for patients with locally advanced or metastatic esophageal cancer. MethodsPatients with unresectable locally advanced or metastatic esophageal cancer who received induction immunochemotherapy followed by RT (ICIs + RT group) and RT alone (RT group) were retrospectively identified in two cancer centers, respectively. Propensity score matching (PSM) was used to balance the potential confounders between the two groups. Overall survival (OS), progression-free survival (PFS), and recurrence patterns were evaluated. ResultsA total of 467 patients were reviewed, and 66 were matched in each group. After PSM, the 1- and 2-year OS rates were 84.6% and 57.9% in ICIs + RT group, and 71.1% and 43.0% in RT group (HR 0.60, 95% CI 0.36–1.00, p = 0.050). The absolute increase of restricted mean survival time (RMST) for OS in ICIs + RT group compared with RT group were 0.89 years (p = 0.023) at one year and 2.59 years at two years (p = 0.030). The median PFS time, 1- and 2-year PFS rates were 20.3 months, 69.3%, and 45.7% in ICIs + RT group, and 12.2 months, 51.4%, and 35.8% in RT group (HR 0.64, 95% CI 0.41–0.99, p = 0.045). The cumulative locoregional recurrence (LRR) rate was significantly lower in ICIs + RT group (1-year rate, 17.4% vs. 38.8%, p = 0.011), and distant metastasis (DM) rates were comparable (p = 0.755). Consolidation ICIs was associated with a trend of improved 1-year OS and PFS. ConclusionInduction immunochemotherapy followed by RT might improve locoregional control and survival outcomes for patients with unresectable locally advanced or metastatic esophageal cancer.