Gemcitabine plus cisplatin versus docetaxel plus cisplatin and fluorouracil induction chemotherapy combined with locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma: A single center prospective phase II clinical trial.

This prospective clinical trial aims to compare the efficacy and safety of gemcitabine plus cisplatin (GP) versus docetaxel plus cisplatin and fluorouracil (TPF) as induction chemotherapy combined with locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma (dmNPC). 146 dmNPC patients were randomly assigned in a 1:1 ratio to receive 4-6 cycles of GP (GP group) or TPF induction chemotherapy (TPF group) followed by locoregional radiotherapy (LRRT). The primary endpoint was overall survival (OS). Secondary endpoints consisted of progression-free survival（PFS）, objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (AEs). As of data cutoff (May 31, 2024), the median follow-up time was 60.0 months (IQR 40.3-68.1). There is no significant difference in median OS (35.4 vs. 34.8 months, p = 0.2609) and PFS (15.8 vs. 14.3 months, p = 0.2318) between the GP and TPF groups. No significant differences in ORR (65.8 % vs. 71.2 %, p = 0.476) and DCR (79.5 % vs. 82.2 %, p = 0.674) were observed between GP and TPF group too. Furthermore, the 5-year OS was 40.1 % (95 % CI, 29.6 %-54.2 %) in the GP group, compared with 27.2 % (95 % CI, 17.9 %-41.3 %) in the TPF group（HR = 0.79, 95 % CI, 0.53-1.20). However, the TPF group had higher incidences of grade 3-4 AEs such as neutropenia, leukopenia, nausea, and diarrhea. The study indicates that 4-6 cycles of TPF induction chemotherapy combined with LRRT achieves a therapeutic effect comparable to the GP regimen with controllable safety.

Shang K ，Li T ，Chen Y ，Luo X ，Wu H ，Zhou Y ，Song J ，Wu W ，Li Y ，Luo X ，Chen X ，Gong X ，Zhao C ，Li Z ，Liu L ，He Q ，Long J ，Jin F ... -  《-》

HAEMATOLOGICAL TOXICITIES OF GEMCITABINE PLUS CISPLATIN VERSUS FLUOROURACIL, CISPLATIN, PLUS DOCETAXEL FOLLOWED BY CONCURRENT CHEMORADIOTHERAPY IN LOCOREGIONALLY ADVANCED NASOPHARYNGEAL CARCINOMA.

Rehman A ，Haider G ，Ramchand A ，Khan SN ，Sehar S ，Mahmood R ，Khattak YR ，Anaum ，Siddiqa A ，Aqeel MA ... -  《-》

Chemotherapy and radiotherapy for advanced pancreatic cancer.

Pancreatic cancer (PC) is a lethal disease with few effective treatment options. Many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review synthesises all the randomised data available to help better inform patient and clinician decision-making. It updates the previous version of the review, published in 2018. To assess the effects of chemotherapy, radiotherapy, or both on overall survival, severe or life-threatening adverse events, and quality of life in people undergoing first-line treatment of advanced pancreatic cancer. We searched for published and unpublished studies in CENTRAL, MEDLINE, Embase, and CANCERLIT, and handsearched various sources for additional studies. The latest search dates were in March and July 2023. We included randomised controlled trials comparing chemotherapy, radiotherapy, or both with another intervention or best supportive care. Participants were required to have locally advanced, unresectable pancreatic cancer or metastatic pancreatic cancer not amenable to curative intent treatment. Histological confirmation was required. Trials were required to report overall survival. We used standard methodological procedures expected by Cochrane. We included 75 studies in the review and 51 in the meta-analysis (11,333 participants). We divided the studies into seven categories: any anti-cancer treatment versus best supportive care; various chemotherapy types versus gemcitabine; gemcitabine-based combinations versus gemcitabine alone; various chemotherapy combinations versus gemcitabine plus nab-paclitaxel; fluoropyrimidine-based studies; miscellaneous studies; and radiotherapy studies. In general, the included studies were at low risk for random sequence generation, detection bias, attrition bias, and reporting bias, at unclear risk for allocation concealment, and high risk for performance bias. Compared to best supportive care, chemotherapy likely results in little to no difference in overall survival (OS) (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.88 to 1.33; absolute risk of death at 12 months of 971 per 1000 versus 962 per 1000; 4 studies, 298 participants; moderate-certainty evidence). The adverse effects of chemotherapy and impacts on quality of life (QoL) were uncertain. Many of the chemotherapy regimens were outdated. Eight studies compared non-gemcitabine-based chemotherapy regimens to gemcitabine. These showed that 5-fluorouracil (5FU) likely reduces OS (HR 1.69, 95% CI 1.26 to 2.27; risk of death at 12 months of 914 per 1000 versus 767 per 1000; 1 study, 126 participants; moderate certainty), and grade 3/4 adverse events (QoL not reported). Fixed dose rate gemcitabine likely improves OS (HR 0.79, 95% CI 0.66 to 0.94; risk of death at 12 months of 683 per 1000 versus 767 per 1000; 2 studies, 644 participants; moderate certainty), and likely increase grade 3/4 adverse events (QoL not reported). FOLFIRINOX improves OS (HR 0.51, 95% CI 0.43 to 0.60; risk of death at 12 months of 524 per 1000 versus 767 per 1000; P < 0.001; 2 studies, 652 participants; high certainty), and delays deterioration in QoL, but increases grade 3/4 adverse events. Twenty-eight studies compared gemcitabine-based combinations to gemcitabine. Gemcitabine plus platinum may result in little to no difference in OS (HR 0.94, 95% CI 0.81 to 1.08; risk of death at 12 months of 745 per 1000 versus 767 per 1000; 6 studies, 1140 participants; low certainty), may increase grade 3/4 adverse events, and likely worsens QoL. Gemcitabine plus fluoropyrimidine improves OS (HR 0.88, 95% CI 0.81 to 0.95; risk of death at 12 months of 722 per 1000 versus 767 per 1000; 10 studies, 2718 participants; high certainty), likely increases grade 3/4 adverse events, and likely improves QoL. Gemcitabine plus topoisomerase inhibitors result in little to no difference in OS (HR 1.01, 95% CI 0.87 to 1.16; risk of death at 12 months of 770 per 1000 versus 767 per 1000; 3 studies, 839 participants; high certainty), likely increases grade 3/4 adverse events, and likely does not alter QoL. Gemcitabine plus taxane result in a large improvement in OS (HR 0.71, 95% CI 0.62 to 0.81; risk of death at 12 months of 644 per 1000 versus 767 per 1000; 2 studies, 986 participants; high certainty), and likely increases grade 3/4 adverse events and improves QoL. Nine studies compared chemotherapy combinations to gemcitabine plus nab-paclitaxel. Fluoropyrimidine-based combination regimens improve OS (HR 0.79, 95% CI 0.70 to 0.89; risk of death at 12 months of 542 per 1000 versus 628 per 1000; 6 studies, 1285 participants; high certainty). The treatment arms had distinct toxicity profiles, and there was little to no difference in QoL. Alternative schedules of gemcitabine plus nab-paclitaxel likely result in little to no difference in OS (HR 1.10, 95% CI 0.82 to 1.47; risk of death at 12 months of 663 per 1000 versus 628 per 1000; 2 studies, 367 participants; moderate certainty) or QoL, but may increase grade 3/4 adverse events. Four studies compared fluoropyrimidine-based combinations to fluoropyrimidines alone, with poor quality evidence. Fluoropyrimidine-based combinations are likely to result in little to no impact on OS (HR 0.84, 95% CI 0.61 to 1.15; risk of death at 12 months of 765 per 1000 versus 704 per 1000; P = 0.27; 4 studies, 491 participants; moderate certainty) versus fluoropyrimidines alone. The evidence suggests that there was little to no difference in grade 3/4 adverse events or QoL between the two groups. We included only one radiotherapy (iodine-125 brachytherapy) study with 165 participants. The evidence is very uncertain about the effect of radiotherapy on outcomes. Combination chemotherapy remains standard of care for metastatic pancreatic cancer. Both FOLFIRINOX and gemcitabine plus a taxane improve OS compared to gemcitabine alone. Furthermore, the evidence suggests that fluoropyrimidine-based combination chemotherapy regimens improve OS compared to gemcitabine plus nab-paclitaxel. The effects of radiotherapy were uncertain as only one low-quality trial was included. Selection of the most appropriate chemotherapy for individuals still remains unpersonalised, with clinicopathological stratification remaining elusive. Biomarker development is essential to assist in rationalising treatment selection for patients.

Haggstrom L ，Chan WY ，Nagrial A ，Chantrill LA ，Sim HW ，Yip D ，Chin V ... -  《Cochrane Database of Systematic Reviews》

Efficacy and safety of prostate radiotherapy in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design.

The 2 × 2 PEACE-1 study showed that combining androgen-deprivation therapy with docetaxel and abiraterone improved overall and radiographic progression-free survival in patients with de novo metastatic castration-sensitive prostate cancer. We aimed to examine the efficacy and safety of adding radiotherapy in this population. We conducted an open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Europe. Eligible participants were male patients (aged ≥18 years) with de novo metastatic castration-sensitive prostate cancer confirmed by bone scan, CT, or MRI, and an Eastern Cooperative Oncology Group performance status of 0-1 (or 2 in the case of bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen-deprivation therapy alone or with six cycles of intravenous docetaxel 75 mg/m2 every 3 weeks), standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), standard of care plus radiotherapy (74 Gy in 37 fractions to the prostate), or standard of care plus radiotherapy and abiraterone. Participants and investigators were not masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival, analysed by intention to treat in patients with low-volume metastatic disease and in the overall study population. This ongoing study is registered with EudraCT, 2012-000142-35. Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled and 1172 were randomly assigned to receive standard of care (n=296 [25·3%]), standard of care plus abiraterone (n=292 [24·9%]), standard of care plus radiotherapy (n=293 [25·0%]), and standard of care plus abiraterone and radiotherapy (n=291 [24·8%]). Median follow-up was 6·0 years (IQR 5·1-7·0) at the time of radiographic progression-free survival and overall survival analysis. A qualitative interaction between radiotherapy and abiraterone for radiographic progression-free survival in the population of patients with low-volume disease prevented the pooling of intervention groups for analysis (p=0·026). Adding radiotherapy to standard of care improved radiographic progression-free survival in patients with low-volume disease treated with abiraterone (median 4·4 years [99·9% CI 2·5-7·3] in the standard of care plus abiraterone group vs 7·5 years [4·0-not reached] in the standard of care plus abiraterone and radiotherapy group; adjusted hazard ratio [HR] 0·65 [99·9% CI 0·36-1·19]; p=0·019), but not in patients not treated with abiraterone (median 3·0 years [99·9% CI 2·3-4·8] in the standard of care group vs 2·6 years [1·7-4·6] in the standard of care plus radiotherapy group; 1·08 [0·65-1·80]; p=0·61). For overall survival, the predefined threshold for a statistical interaction was not reached (p=0·12); therefore, the two intervention groups receiving radiotherapy were pooled together for analysis. In patients with low-volume disease, the overall survival was not influenced by radiotherapy (median 6·9 years [95·1% CI 5·9-7·5] for standard of care with or without abiraterone vs 7·5 years [6·0-not reached] for standard of care plus radiotherapy with or without abiraterone; HR 0·98 [95·1% CI 0·74-1·28]; p=0·86). In the overall safety population, 339 (56·1%) of 604 patients who did not receive radiotherapy and 329 (58·8%) of 560 patients who received radiotherapy developed at least one severe adverse event (grade ≥3), the most common being hypertension (110 [18·2%] patients in the standard of care with or without abiraterone group and 127 [22·7%] in the standard of care plus radiotherapy with or without abiraterone group) and neutropenia (40 [6·6%] and 29 [5·2%]). Combining radiotherapy with standard of care plus abiraterone improves radiographic progression-free survival and castration resistance-free survival, but not overall survival in patients with low-volume de novo metastatic castration-sensitive prostate cancer. Radiotherapy reduces the occurrence of serious genitourinary events, regardless of metastatic burden and without increasing the overall toxicity, and could become a component of standard of care in patients with both high-volume and low-volume de novo metastatic castration-sensitive prostate cancer. Janssen-Cilag, Ipsen, Sanofi, and Institut National du Cancer.

Bossi A ，Foulon S ，Maldonado X ，Sargos P ，MacDermott R ，Kelly P ，Fléchon A ，Tombal B ，Supiot S ，Berthold D ，Ronchin P ，Kacso G ，Salem N ，Calabro F ，Berdah JF ，Hasbini A ，Silva M ，Boustani J ，Ribault H ，Fizazi K ，PEACE-1 investigators ... -  《-》

Chemotherapy alone versus chemotherapy plus radiotherapy for adults with early-stage Hodgkin's lymphoma.

Early-stage Hodgkin's lymphoma in adults is commonly treated with combined modality treatment of chemotherapy followed by radiotherapy. The role of radiotherapy has been questioned due to potential long-term adverse effects. To assess the effects of chemotherapy compared to chemotherapy plus radiotherapy in adults with early-stage Hodgkin's lymphoma. We updated all previous searches for randomised controlled trials (RCTs) on the databases Cochrane Central Register of Controlled Trial, MEDLINE and Embase, in trial registries and in relevant conference proceedings until November 2023. We included RCTs comparing chemotherapy alone with chemotherapy plus radiotherapy in adults with early-stage Hodgkin's lymphoma and excluded trials with more than 20% of participants with advanced Hodgkin's lymphoma. We considered immunotherapy in addition to chemotherapy eligible if both were applied similarly in the comparator groups, but did not identify such trials. For our comparisons, we separated RCTs with the same number of chemotherapy cycles in both arms and RCTs with a different number of cycles, when the chemotherapy regimens were the same. We separated RCTs which compared participants with a favourable, mixed or unfavourable risk profile. Two review authors independently screened search results, extracted data and assessed the quality of included trials. A third review author resolved discrepancies. We analysed time-to-event outcomes (overall survival, progression-free survival) as hazard ratios (HR) and binary outcomes (adverse events) as risk ratios (RR). We assessed the certainty of evidence using the GRADE approach. We included nine comparisons of eight RCTs involving 3840 participants in this updated review. Same number of chemotherapy cycles in both trial arms Favourable disease For overall survival in individuals with favourable Hodgkin's lymphoma, the evidence is uncertain and inconclusive (HR 0.92, 95% confidence interval (CI) 0.11 to 7.92; 2 RCTs, 1245 participants; very low-certainty evidence due to study limitations, inconsistency and imprecision). Additional radiotherapy to chemotherapy is likely to improve progression-free survival (HR 0.36, 95% CI 0.20 to 0.68; 2 RCTs, 1245 participants; moderate-certainty evidence due to study limitations). The evidence was uncertain and inconclusive for second-cancer-related mortality (RR 0.93, 95% CI 0.01 to 74.24; 2 RCTs, 1245 participants; very low-certainty evidence due to study limitations, inconsistency and substantial imprecision) and suggests little to no difference in cardiac disease-related mortality (RR 0.89, 95% CI 0.06 to 14.16; 1 RCT, 667 participants; low-certainty evidence due to substantial imprecision). There were no data on infection-related mortality or infertility. Mixed population For a population of mixed risk profile, the evidence on overall survival is uncertain and inconclusive (HR 0.79, 95% CI 0.13 to 4.80; 2 RCTs, 572 participants; very low-certainty evidence due to study limitations, inconsistency and imprecision). It indicates that additional radiotherapy may lead to an improvement in progression-free survival (HR 0.71, 95% CI 0.43 to 1.17; 2 RCTs, 572 participants; low-certainty evidence due to study limitations and imprecision). The evidence is uncertain and inconclusive for infection-related mortality (RR 1.35, 95% CI 0.17 to 10.87; 2 RCTs, 572 participants) and second-cancer-related mortality (RR 0.52, 95% CI 0.09 to 2.98; 2 RCTs, 572 participants) (both very low-certainty evidence due to study limitations and substantial imprecision), but suggests that additional radiotherapy may increase cardiac disease-related mortality (RR 3.03, 95% CI 0.12 to 73.92; 1 RCT, 420 participants; low-certainty evidence due to substantial imprecision). There were no data on infertility. Unfavourable disease For individuals with unfavourable disease, the evidence on overall survival is uncertain and inconclusive (HR 0.69, 95% CI 0.20 to 2.44; 2 RCTs, 688 participants; very low-certainty evidence due to study limitations and substantial imprecision), but additional radiotherapy probably improves progression-free survival (HR 0.55, 95% CI 0.19 to 1.60; 1 RCT, 651 participants; moderate-certainty evidence due to imprecision). The evidence was uncertain and inconclusive for cardiac disease-related mortality (RR 2.85, 95% CI 0.12 to 65.74; 1 RCT, 37 participants; very low-certainty evidence due to study limitations and substantial imprecision). There were no data on infection-related mortality, second-cancer related mortality or infertility. Different number of chemotherapy cycles in both trial arms Favourable disease The evidence for overall survival in individuals with favourable disease treated with different numbers of chemotherapy cycles in both arms is uncertain and inclusive (HR 0.36, 95% CI 0.04 to 3.38; 1 RCT, 357 participants; very low-certainty evidence due to study limitations and substantial imprecision), yet it suggests a likely improvement in progression-free survival with additional radiotherapy (HR 0.08, 95% CI 0.02 to 0.32; 1 RCT, 357 participants; moderate-certainty evidence due to study limitations). For second-cancer-related mortality, the evidence is uncertain and inconclusive (RR 0.21, 95% CI 0.01 to 4.34; 1 RCT, 465 participants; very low-certainty evidence due to study limitations and substantial imprecision). There were no data on infection-related mortality and infertility and data for cardiac disease-related mortality were not estimable (no events in either group). Unfavourable disease For individuals with an unfavourable risk profile, additional radiotherapy may decrease overall survival slightly (HR 1.66, 95% CI 0.95 to 2.90; 2 RCTs, 698 participants; low-certainty evidence due to study limitations and imprecision), but may slightly improve progression-free survival (HR 0.84, 95% CI 0.53 to 1.33; 2 RCTs, 698 participants; low-certainty evidence due to study limitations and imprecision). The evidence is uncertain and inconclusive for infection-related mortality (RR 6.90, 95% CI 0.36 to 132.34; 1 RCT, 276 participants), second-cancer-related mortality (RR 2.19, 95% CI 0.77 to 6.19; 2 RCTs, 870 participants) and cardiac disease-related mortality (RR 1.60, 95% CI 0.31 to 8.22; 2 RCTs, 870 participants) (all very low-certainty evidence due to study limitations and substantial imprecision). There were no data on infertility. The chemotherapy regimens in the trials differed and data for regimens commonly used today were limited. Additional radiotherapy may slightly improve progression-free survival. The available data for overall survival and adverse events were of low and very low certainty, and we were unable to draw conclusions about the effects of additional radiotherapy on these outcomes. No studies evaluated infertility. High-quality, longer-term follow-up data are required and data on fertility are needed.

Goldkuhle M ，Kreuzberger N ，von Tresckow B ，Eichenauer DA ，Specht L ，Monsef I ，Skoetz N ... -  《Cochrane Database of Systematic Reviews》