Three-year Failure-free Survival Research Articles

Efficacy of off-the-shelf bone marrow mesenchymal stem cells for pediatric steroid-refractory acute graft-versus-host disease.

Temcell is a mesenchymal stem cell (MSC) product approved for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in Japan. However, reports regarding Temcell's efficacy in pediatric patients have been scarce, and the appropriate use of MSC therapy against pediatric SR-aGVHD also remains to be determined. We retrospectively assessed a cohort of pediatric patients treated with Temcell for SR-aGVHD following allogeneic hematopoietic transplantation. MSCs were infused intravenously at a dose of 2 × 106 cells/kg according to the manufacturer's instructions. Twelve patients received eighteen cycles of MSC therapy (median age, 10.3 [1.7-17.8] years), with four receiving additional cycles (one cycle: n = 3, three cycles: n = 1). The severity of aGVHD before MSC therapy was grade I-II in three patients and grade III-IV in nine patients (gut stage 3-4, n= 7; liver stage 3-4; n =2). The median number of immunosuppressive therapy regimens received prior to MSC administration was two (range: 1-5). The first MSC cycle displayed the best overall response rate of 83%, including six patients with a complete response (CR) and with a 49% reduction in the mean daily dose of prednisone after eight weeks. The median time to first response was 3.5 days (range: 2-15 days). Two of the four patients who were re-administered MSCs for recurrent or persistent GVHD achieved a CR. The three-year overall survival rate was 69.4%, while the three-year failure free survival (FFS) rate was 22.2%, with a median FFS of 4.9 months. There were no observable side effects of MSC therapy. MSC therapy appears to be an effective and safe treatment for pediatric SR-aGVHD, with a steroid-sparing effect and satisfactory efficacy upon re-administration. Further studies are needed to determine its appropriate combination with additional treatments and the optimal use of re-administration of MSCs.

Effect of Radiotherapy Alone vs Radiotherapy With Concurrent Chemoradiotherapy on Survival Without Disease Relapse in Patients With Low-risk Nasopharyngeal Carcinoma

Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the role of chemotherapy with use of intensity-modulated radiation therapy (IMRT). To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT. This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. The final date of follow-up was March 15, 2022. Patients were randomly assigned to receive IMRT alone (n = 172) or concurrent chemoradiotherapy (IMRT with cisplatin, 100 mg/m2 every 3 weeks for 3 cycles [n = 169]). The primary end point was 3-year failure-free survival (time from randomization to any disease relapse or death), with a noninferiority margin of 10%. Secondary end points comprised overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life (QOL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference ≥10 for physical function, symptom control, or health-related QOL; higher score indicates better functioning and global health status or worse symptoms). Among 341 randomized patients (mean [SD] age, 48 [10] years; 30% women), 334 (98.0%) completed the trial. Median follow-up was 46 months (IQR, 34-58). Three-year failure-free survival was 90.5% for the IMRT-alone group vs 91.9% for the concurrent chemoradiotherapy group (difference, -1.4%; 1-sided 95% CI, -7.4% to ∞; P value for noninferiority, <.001). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. The IMRT-alone group experienced a significantly lower incidence of grade 3 to 4 adverse events (17% vs 46%; difference, -29% [95% CI, -39% to -20%]), including hematologic toxicities (leukopenia, neutropenia) and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had significantly better QOL scores during radiotherapy including the domains of global health status, social functioning, fatigue, nausea and vomiting, pain, insomnia, appetite loss, and constipation. Among patients with low-risk NPC, treatment with IMRT alone resulted in 3-year failure-free survival that was not inferior to concurrent chemoradiotherapy. ClinicalTrials.gov Identifier: NCT02633202.

A prospective phase II study of prostate-specific antigen-guided salvage radiotherapy and 68Ga-PSMA-PET for biochemical relapse after radical prostatectomy – The PROPER 1 trial

Background and purposeThe treatment of biochemical recurrence (BCR) after prostatectomy is challenging as the site of the recurrence is often undetectable. Our aim was to test a personalised treatment concept for BCR based on PSA kinetics during salvage radiotherapy (SRT) combined with prostate-specific membrane antigen positron emission tomography (PSMA-PET). Materials and methodsThis phase II trial included 100 patients with BCR. PSMA-PET was performed at baseline. PSA was measured weekly during SRT. Initially, 70 Gy in 35 fractions was prescribed to the prostate bed. Radiotherapy was adapted after 50 Gy. Non-responders (PSA still ≥ 0.15 ng/mL) received sequential lymph node irradiation with a boost to PSMA-PET positive lesions, while responders (PSA < 0.15 ng/mL) continued SRT as planned. PET-findings were only taken into consideration for treatment planning in case of PSA non-response after 50 Gy. ResultsData from 97 patients were eligible for analysis. Thirty-four patients were classified as responders and 63 as non-responders. PSMA-PET was positive in 3 patients (9%) in the responder group and in 22 (35%) in the non-responder group (p = 0.007). The three-year failure-free survival was 94% for responders and 68% for non-responders (median follow-up 38 months). There were no significant differences in physician-reported urinary and bowel toxicity. Patient-reported diarrhoea at end of SRT was more common among non-responders. ConclusionThis new personalised treatment concept with intensified SRT based on PSA response demonstrated a high tumour control rate in both responders and non-responders. These results suggest a clinically significant effect with moderate side effects in a patient group with otherwise poor prognosis. PSMA-PET added limited value. The treatment approach is now being evaluated in a phase III trial.Clinical trial registration numbers: NCT02699424&ISRCTN45905321.

Final results of the international randomized PORTEC-3 trial of adjuvant chemotherapy and radiation therapy (RT) versus RT alone for women with high-risk endometrial cancer.

5502 Background: Women with high-risk endometrial cancer (HREC) are at increased risk of distant metastasis and endometrial cancer-related death. The randomized PORTEC-3 intergroup trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (CTRT) versus pelvic radiotherapy (RT) alone for women with HREC. Methods: Women with HREC (FIGO stage I grade 3 with deep myometrial invasion and/or LVSI; stage II or III; or serous/clear cell histology) were randomly allocated (1:1) to RT (48.6 Gy in 1.8 Gy fractions) or CTRT (two cycles of cisplatin 50 mg/m² in week 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m² at 3-week intervals) with stratification for participating center, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival (OS) and failure-free survival (FFS). The Kaplan-Meier method, log-rank test and Cox regression analysis were used for final analysis according to intention-to-treat. PORTEC-3 is registered with ISRCTN (ISRCTN14387080) and ClinicalTrials.gov (NCT00411138). Results: 686 women were enrolled between 2006 and 2013. 26 women were excluded; 13 withdrew consent early and 13 were ineligible, which left 660 patients in the analysis, with a median follow up time of 60.2 months (IQR 47.1–72.9): 330 CTRT and 330 RT. Three- and five-year OS for CTRT vs. RT was 84.4% versus 83.9%, and 81.8% versus 76.7%; overall HR 0.79 [95% CI 0.57-1.12, p=0.183]. Three-year FFS was 79.7% (CTRT) versus 71.8% (RT), and at 5 years 75.5% versus 68.9%, overall HR for FFS 0.77 [0.58-1.03, p=0.078]. Patients with stage III EC had lower 5-year FFS and OS compared to stage I-II (FFS 63.9% vs 78.9%, p&lt;0.001, and OS 74.3% vs 83.1%, p=0.003). They also had greatest benefit of CTRT: 5-year FFS for stage III was 69.3% for CTRT vs 58.0% for RT [95% CI 0.45-0.97, p=0.032], and 5-year OS for stage III was 78.7 % vs 69.8% (p=0.114). Conclusions: Adjuvant chemotherapy given during and after pelvic radiotherapy for treatment of HREC did not significantly improve 5-year FFS and OS, compared with RT alone. For women with stage III EC FFS was however significantly improved with CTRT by 11% at 5 years. Follow-up will continue to evaluate long-term outcomes. Clinical trial information: NCT00411138.

Rituximab-CHOP Versus CHOP Alone or With Maintenance Rituximab in Older Patients With Diffuse Large B-Cell Lymphoma

To address early and late treatment failures in older patients with diffuse large B-cell lymphoma (DLBCL), we designed a two-stage randomized trial of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus rituximab plus CHOP (R-CHOP), with a second random assignment to maintenance rituximab (MR) or observation in responding patients. Untreated DLBCL patients who were 60 years or older were randomly assigned to R-CHOP (n = 318) or CHOP (n = 314); 415 responders were randomly assigned to MR (n = 207) or observation (n = 208). The primary end point was failure-free survival (FFS). All P values were two sided. Three-year FFS rate was 53% for R-CHOP patients and 46% for CHOP patients (P = .04) at a median follow-up time of 3.5 years. Two-year FFS rate from second random assignment was 76% for MR compared with 61% for observation (P = .009). No significant differences in survival were seen according to induction or maintenance therapy. FFS was prolonged with MR after CHOP (P = .0004) but not after R-CHOP (P = .81) with 2-year FFS rates from second random assignment of 77%, 79%, 74%, and 45% for R-CHOP, R-CHOP + MR, CHOP + MR, and CHOP, respectively. In a secondary analysis excluding MR patients, R-CHOP alone reduced the risks of treatment failure (P = .003) and death (P = .05) compared with CHOP alone. Rituximab administered as induction or maintenance with CHOP chemotherapy significantly prolonged FFS in older DLBCL patients. After R-CHOP, no benefit was provided by MR. These results, which are consistent with an additive effect of rituximab, suggest that future studies could focus on maintenance strategies with novel agents as well as new induction therapies.

Interleukin-10 levels are often elevated in serum of adults with Hodgkin's disease and are associated with inferior failure-free survival

Interleukin-10 (IL-10) is a pleiotropic cytokine that protects B- or T-lymphocytes and hemopoietic progenitors from apoptosis induced by doxorubicin, glucocorticoids, or deprivation of growth factors. IL-10 is also immunosupressive, and tumor cells secreting IL-10 can grow in syngeneic or allogeneic hosts, and can inhibit the generation of tumor-specific cytotoxic T cells. Hodgkin-Reed-Sternberg cells are derived from follicular center B cells and they may be latently infected by EBV. When this occurs they often express IL-10. Based on these considerations we investigated the relationship between pretreatment serum IL-10 levels and failure-free survival (FFS) in Hodgkin's disease (HD). Untreated patients, older than 16 years, with biopsy-proven HD, were included if treated with ABVD or equivalent regimens, and if pretreatment serum was available. IL-10 levels were determined with a capture enzyme-linked immunoassay specific for cellular IL-10. Among healthy adult volunteers serum IL-10 levels ranged from 4.8-9.8 pg/ml (mean 7.1, standard deviation 1.5 pg/ml). Therefore levels > or = 10 pg/ml were considered elevated. We identified 101 patients with available serum. Their median age was 32 years, and 60% had B-symptoms. Ann Arbor stage was I in 4, II in 21, III in 35, and IV in 41 patients. Histology was nodular sclerosis in 74, mixed cellularity in 12, lymphocyte predominance in six, lymphocyte depletion in one, and unclassified in eight patients. Pretreatment serum IL-10 levels were elevated in 51 patients, and were higher in those with serum albumin < 3.5 g/dl, B symptoms, serum beta 2-microglobulin > or = 2.5 mg/l, anemia, and AAS III or IV. After a median follow-up of 32 months for survivors, 20 patients have progressed, and the three-year FFS of those with high vs. normal serum IL-10 was 60% +/- 9 vs. 91 +/- 9% (50% vs. 50% of the population; P = 0.004 by log-rank). Among patients with Ann Arbor stage III or IV the three-year FFS for those with high vs. normal serum IL-10 (58 vs. 42% of the population) was 57 +/- 9% vs. 92 +/- 6% (P = 0.008 by log-rank). Multivariate analysis using Cox's proportional hazards model confirmed that IL-10 was an independent variable associated with inferior FFS in this population. Elevation of serum IL-10 levels is frequent and is associated with inferior FFS in adults with ABVD-treated HD. This observation should be verified in other patient populations. In addition, the source and the role of IL-10 in the biology of HD should be further investigated.

Preliminary results of the EORTC-GPMC controlled clinical trial H7 in early-stage Hodgkin's disease

In this phase III trial, 770 patients with clinical stage I-II Hodgkin's disease (HD) have been enrolled since November 1988. Preliminary results are given for the 605 (79%) patients who have completed their initial therapy. Patients were grouped according to 6 pretreatment prognostic characteristics. In the very favourable (VF) group, treatment consisted of mantle field alone. In the favourable (F) group, patients were randomized to either subtotal nodal irradiation (STNI), or 6 cycles of EBVP (epirubicin, bleomycin, vinblastine, prednisone) followed by involved-field irradiation (IF-RT). Unfavourable (U) patients were randomized to either 6 cycles of EBVP plus IF-RT, or to 6 cycles of MOPP/ABV hybrid plus IF-RT. Of the 35 VF patients, none have progressed during radiotherapy. Four patients relapsed and were salvaged. Three-year failure-free survival (FFS) was 82%; overall survival (OS) was 100%. Of the 254 F patients, 130 were treated with STNI and 124 with EBVP plus IF-RT. At 3 years, FFS rates were 81% (1 progression, 14 relapses) and 79% (5 progressions, 8 relapses), respectively. Corresponding OS rates were 99% and 100%. Of the 316 U patients, 160 received EBVP and 156 MOPP/ABV. At 3 years, FFS rates were 72% (18 progressions, 20 relapses) and 88% (7 progressions, 6 relapses), respectively (p < 0.001). Although OS rates were identical (92%), the entry in the U-EBVP arm was stopped in November 1992. We conclude that a treatment strategy based on prognostic factors allows the use of less aggressive treatment in favourable patients.(ABSTRACT TRUNCATED AT 250 WORDS)