Systemic Treatment Regimens Research Articles

Systemic therapies and primary tumour downsizing in renal cell carcinoma: a real-world comparison of anti-angiogenic and immune checkpoint inhibition regimens.

To investigate responses in the primary tumour to different systemic treatment regimens in patients with metastatic renal cell carcinoma (mRCC). A single-centre retrospective analysis of treatment-naive mRCC patients without prior nephrectomy receiving VEGF tyrosine kinase inhibitors (VEGF only), immune checkpoint inhibitors (IO only), or combinations thereof (IO + VEGF). The primary outcome was the rate of partial response in the primary tumour (primary tumour PR, ≥ 30% diameter reduction). Secondary outcomes were time to best primary tumour diameter change, overall survival (OS) and progression-free survival (PFS) by Kaplan-Meier analysis. Predictors of survival outcomes were explored by Cox proportional hazards regression analysis. The rate of primary tumour PR was 14% for VEGF only (4/28 patients), 22% for IO only (5/23) and 50% for IO + VEGF (7/14), with median best primary tumour diameter change of -8.0%, + 5.1%, and -31.1% respectively, and median time to best primary tumour diameter change of 3.2, 3.0 and 6.9months respectively. Median OS was significantly greater with IO + VEGF compared to VEGF only (HR 0.45, p = 0.04) and non-significantly greater compared to IO only (HR 0.46, p = 0.06). In multivariable analysis, primary tumour PR was the only response variable significantly associated with both OS (adjusted HR 0.32, p = 0.01) and PFS (adjusted HR 0.29, p < 0.01). mRCC patients without prior nephrectomy receiving first-line IO + VEGF regimens showed the greatest primary tumour responses, suggesting further prospective evaluation of this combination in the neoadjuvant and deferred cytoreductive nephrectomy settings.

Safety of first-line systemic therapy in patients with metastatic colorectal cancer: a network meta-analysis of randomized controlled trials

ObjectiveTo evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis.MethodsThe literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens.ResultsA total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs.ConclusionIn summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs.

Impact of autotransfusion on recurrence of colorectal cancer liver metastasis: Long-term follow-up of patients undergoing curative intent hepatectomy.

Colorectal cancer liver metastasis (CRLM) occurs in upto 50% of cases and drives patient outcomes. Up-front liver resection is the treatment of choice in resectable cases. There is no consensus yet established as to the safety of intraoperative autotransfusion in liver resection for CRLM. Patients undergoing curative-intent hepatectomy for CRLM at a single quaternary-care institution from 1999 to 2016 were included. Demographics, surgical variables, Fong Clinical Risk Score (FCRS), use of intraoperative auto and/or allotransfusion, and survival data were analyzed. Propensity score matching (PSM) was performed accounting for allotransfusion, extent of hepatectomy, FCRS, and systemic treatment regimens. Three-hundred sixteen patients were included. The median follow-up was 10.4 years (7.8-14.1 years). The median recurrence-freesurvival (RFS) and overall survival (OS) in all patients were 1.6 years (interquartile range: 0.63-6.6 years) and 4.4 years (2.1-8.7), respectively. Before PSM, there was a significantly reduced RFS in the autotransfusion group (0.96 vs. 1.73 years, p = 0.20). There was no difference in OS (4.11 vs. 4.44 years, p = 0.118). Patients in groups of FCRS 0-2 and 3-5 both had reduced RFS when autotransfusion was used (p = 0.005). This reduction in RFS was further found when comparing autotransfusion versus no autotransfusion within the FCRS 0-2 group and within the FCRS 3-5 group (p = 0.027). On Cox-regression analysis, autotransfusion (hazard ratio = 1.423, 1.028-2.182, p = 0.015) remained predictive of RFS. After PSM, there were no differences in FCRS (p = 0.601), preoperative hemoglobin (p = 0.880), allotransfusion (p = 0.130), adjuvant chemotherapy (p = 1.000), immunotherapy (p = 0.172), tumor grade (p = 1.000), use of platinum-based chemotherapy (p = 0.548), or type of hepatic resection (p = 0.967). After matching, there was a higher rate of recurrence with autotransfusion (69.0% vs. 47.6%, p = 0.046). There was also a reduced time to recurrence in the autotransfusion group compared with the group without (p = 0.006). There was no difference in OS after PSM (p = 0.262). Autotransfusion may adversely affect recurrence in liver resection for CRLM. Until further studies clarify this risk profile, the use of intraoperative autotransfusion should be critically assessed on a case-by-case basis only when other resuscitation options are not available.

2023 updated MASCC/ESMO consensus recommendations: controlling nausea and vomiting with chemotherapy of low or minimal emetic potential.

Review the literature to update the MASCC guidelines from 2016 for controlling nausea and vomiting with systemic cancer treatment of low and minimal emetic potential. A working group performed a systematic literature review using Medline, Embase, and Scopus databases between June 2015 and January 2023 of the management of antiemetic prophylaxis for anticancer therapy of low or minimal emetic potential. A consensus committee reviewed recommendations and required a consensus of 67% or greater and a change in outcome of at least 10%. Of 293 papers identified, 15 had information about managing systemic cancer treatment regimens of low or minimal emetic potential and/or compliance with previous management recommendations. No new evidence was reported that would change the current MASCC recommendations. No antiemetic prophylaxis is recommended for minimal emetic potential therapy, and single agents recommended for low emetic potential chemotherapy for acute emesis, but no prophylaxis is recommended for delayed emesis. Commonly, rescue medication includes antiemetics prescribed for the next higher level of emesis. There is insufficient data to change the current guidelines. Future studies should seek to more accurately determine the risk of emesis with LEC beyond the emetogenicity of the chemotherapy to include patient-related risk assessment.

Estimating the Time Toxicity of Contemporary Systemic Treatment Regimens for Advanced Esophageal and Gastric Cancers

(1) Background: The purpose of this study was to evaluate the time toxicity, or time spent in health care, of immunotherapy- versus chemotherapy-based regimens for metastatic esophageal and gastric cancers. (2) Methods: A literature search was conducted, and 18 phase III clinical trials of immune checkpoint inhibitors were selected for analysis. Health care days were calculated based on the number of days associated with receiving therapy and the adverse events reported in the clinical trials. Both the number of health care days and the median overall survival were compared among chemotherapy-only, immunotherapy-only, and chemo-immunotherapy regimens across this cohort of drug registration trials. (3) Results: The estimated median number of health care days was 37 (range of 7–52) days, or 1.2 (range of 0.2–1.7) months, compared to a median survival of 10.2 months across these 18 studies. For the chemotherapy-only regimens, the median number of health care days was 39 (range of 21–51) days, and for chemo-immunotherapy, it was 39 (range of 30–52) days. The immunotherapy-only regimens had fewer days, a median of 28 (range of 24–41), p &lt; 0.05, compared to the other two arms. (4) Conclusions: The chemo-immunotherapy regimens did not add time toxicity compared to chemotherapy alone. The immunotherapy-only regimens had lower time toxicity compared to chemotherapy alone. In the setting of decreased time toxicity and improved overall survival, further development of immunotherapy-based regimens could improve outcomes in advanced esophageal and gastric cancers.

Aggressive Local Ablative Radiotherapy Mitigates Progression Risk in Oligometastatic Lung Adenocarcinoma.

This study aimed to determine the role of local ablative radiotherapy (LART) in oligometastatic/oligoprogressive lung adenocarcinoma. Patients (n=176) with oligometastatic lung adenocarcinoma treated with LART were identified, and those treated with LART at the initial diagnosis of synchronous oligometastatic disease (OMD group) or treated with LART when they presented with repeat oligoprogression (OPD group) were included. In the OMD group (n=54), the 1- and 3-year progression-free survival (PFS) were 50.9% and 22.5%, respectively, whereas the 1- and 3-year overall survival in the OPD group were 75.9% and 58.1%, respectively. Forty-one patients (75.9%) received LART at all gross disease sites. Tyrosine kinase inhibitor (TKI) use and all-metastatic site LART were significant predictors of higher PFS (p=0.018 and p=0.046, respectively). In patients treated with TKIs at the time of LART (n=23) and those treated with all-metastatic site LART, the 1-year PFS was 86.7%, while that of patients not treated with all-metastatic site LART was 37.5% (p=0.006). In the OPD group (n=122), 67.2% of the patients (n=82) maintained a systemic therapy regimen after LART. The cumulative incidence of changing systemic therapy was 39.6%, 62.9%, and 78.5% at 6 months, 1 year, and 2 years after LART, respectively. Aggressive LART can be an option to improve survival in patients with oligometastatic disease. Patients with synchronous oligometastatic disease receiving TKI and all-metastatic site LART may have improved PFS. In patients with repeat oligoprogression, LART might potentially extend survival by delaying the need to change the systemic treatment regimen.

Mirvetuximab soravtansine in ovarian cancer therapy: expert opinion on pharmacological considerations.

ImmunoGen developed mirvetuximab soravtansine as an antibody-drug conjugate comprising of a humanized anti-folate receptor-α (FRα) monoclonal antibody of IgG1k subtype, a cleavable linker, and a cytotoxic payload, DM4. Mirvetuximab soravtansine was granted accelerated approval by the US FDA on November 14, 2022, for the treatment of adult patients with FRα positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have received 1-3 prior systemic treatment regimens. The approval of mirvetuximab soravtansine represents a breakthrough for addressing the unmet medical needs of ovarian cancer, especially for up to 80% of patients who relapse and become resistant to platinum-based chemotherapy, resulting in poor prognosis and limited treatment options. However, it is my impression that addressing several pharmacological factors could improve the safety and efficacy of mirvetuximab soravtansine. This article summarizes the current pharmacological profile of mirvetuximab soravtansine and provides an expert opinion on pharmacological strategies for optimizing its safety and efficacy profile for the treatment of platinum-resistant ovarian cancer.

Radiotherapy in Pancreatic Cancer: To Whom, When, and How?

The diagnosis rate of pancreatic cancer is steadily increasing. The average age of onset is close to 70 years. In most cases, the disease is diagnosed at an advanced stage. The indications for and techniques of radiotherapy are changing over time. The aim of this thesis is to present the role and possibilities of radiotherapy from the perspective of radiation oncologist. The most common cause of treatment failure in pancreatic cancer remains generalisation. The implementation of new systemic treatment regimens contributes to improved treatment outcomes regardless of the stage of the disease. With improved treatment outcomes in terms of the incidence of distant metastases, the impact of local curability on the length and quality of life of patients increases. Modern radiotherapy offers the opportunity to achieve high local cure rates. Postoperative radiotherapy in combination with chemotherapy seems justified in the group of postoperative pancreatic cancer patients with pT3 and pN+ features. In the group of patients with borderline resectable pancreatic cancer, the impact of radiotherapy in combination with the latest chemotherapy regimens is difficult to define clearly. In the setting of a diagnosis of advanced pancreatic cancer, radiotherapy, especially stereotactic radiotherapy, in combination with chemotherapy, contributes to improved local curability and allows to achieve a significantly reduced level of pain.

“Conversion surgery” for locally advanced pancreatic cancer: A position paper by the study group at the joint meeting of the International Association of Pancreatology (IAP) & Japan Pancreas Society (JPS) 2022

Locally advanced pancreatic cancer (LAPC), which progresses locally and surrounds major vessels, has historically been deemed unresectable. Surgery alone failed to provide curative resection and improve overall survival. With the advancements in treatment, reports have shown favorable results in LAPC after undergoing successful chemotherapy therapy or chemoradiation therapy followed by surgical resection, so-called “conversion surgery”, at experienced high-volume centers. However, recognizing significant regional and institutional disparities in the management of LAPC, an international consensus meeting on conversion surgery for LAPC was held during the Joint Congress of the 26th Meeting of the International Association of Pancreatology (IAP) and the 53rd Annual Meeting of Japan Pancreas Society (JPS) in Kyoto in July 2022. During the meeting, presenters reported the current best multidisciplinary practices for LAPC, including preoperative modalities, best systemic treatment regimens and durations, procedures of conversion surgery with or without vascular resections, biomarkers, and genetic studies. It was unanimously agreed among the experts in this meeting that “cancer biology is surpassing locoregional anatomical resectability” in the era of effective multiagent treatment. The biology of pancreatic cancer has yet to be further elucidated, and we believe it is essential to improve the treatment outcomes of LAPC patients through continued efforts from each institution and more international collaboration. This article summarizes the agreement during the discussion amongst the experts in the meeting. We hope that this will serve as a foundation for future international collaboration and recommendations for future guidelines.

Long-term survivors (LTSs) population of metastatic colorectal cancer (mCRC): A Northern Italian comprehensive cancer center experience.

e15590 Background: mCRC patients (pts) have a median survival of 13-24 months with a 5-year survival rate of about 1%. LTSs are defined as pts with survival greater than or equal to 36 months after diagnosis of mCRC. Mutational status, new treatments, and surgery resection advances led to improved survival outcomes. Methods: This is a single-center retrospective analysis of 106 consecutive CRC pts with synchronous or metachronous metastases diagnosed from the AUSL-IRCCS of Reggio Emilia Comprehensive Cancer Center between January 1st, 2017, and November 30, 2019. Clinical and pathological characteristics of pts were obtained from clinical records. Long-term survivors were defined as pts with survival &gt; 36 months. Results: Out of 106 mCRC, 33 (31.1%) were LTSs with a median survival of 53 months (range, 36-129 months). At the data cut-off of November 30, 2022, 24 (72.7%) were still alive. Among all, 18 (54.5%) were men, the median age was 65 years (47-83), and 14 (42.4%) had a right tumor primary site. Synchronous metastases were found in 20 (60.6%), while 13 (39.4%) developed metachronous metastases; the most frequent site of metastases was the liver (63.6%), peritoneum and lymph nodes (21.2%), respectively. Surgical resections and systemic treatment regimens based on fluorouracil, oxaliplatin, and/or irinotecan, cetuximab, bevacizumab, TAS-102, regorafenib, and others are listed in Table 1. Regarding biological status, 28 (84.8%) had an MSS, 18 (54.5%) RAS wild type, and 3 (9.1%) BRAF V600E mutated of which 2 (66.7%) underwent surgical resection of primary tumor and metastases, receiving up to 2 lines of systemic treatments. Conclusions: This study confirms that long-term survivors of mCRC pts are the results of intrinsic tumor biology, appropriate treatment timing including surgery, and the available pharmacological opportunities beyond chemotherapy. Further analysis including the role of liquid biopsy is under investigation to identify prognostic and predictive biomarkers in order to improve survival outcomes. [Table: see text]

Safety of locally administered large surface area microparticle paclitaxel and docetaxel in combination with standard of care cancer therapies.

e15187 Background: The safety of local delivery of large surface area microparticle paclitaxel (LSAM-PTX) or docetaxel (LSAM-DTX) to solid tumors has been evaluated in Phase 1/2 trials across 156 subjects with 43% (67/156) on various concurrent standard of care (SOC) therapies. Local administration of LSAM-PTX or LSAM-DTX leads to a reduction in systemic drug exposure and drug-related adverse events (AE) and may reduce toxicities encountered in combination systemic treatment regimens. This report summarizes safety findings in subjects co-administered LSAM-PTX or LSAM-DTX and common SOC therapies for treatment of carcinomas. Methods: During the study follow-up periods, AE and serious AE (SAE) were coded (MedDRA 16.1 -23.1) and assessed (NCI CTCAE 3 - 5). Results: In 7 studies (median age 69 years (range 37-96), 61% male, 88% white) (Table), LSAM-PTX administrations occurred as follows: intraperitoneal (n = 31 subjects), intraprostatic (n = 17), and intratumoral (n = 72). A median of 1 cycle (range 1-6) of LSAM-PTX was administered. LSAM-DTX was injected once into bladder tissue after tumor resection followed by a median of 10 cycles (range 7-10) of intravesical instillation in 36 subjects. 59 subjects (median age 65 (range 48-86), 53% male, 88% white) received local LSAM-PTX and concomitant chemotherapy, immunotherapy, or radiation. Rates of subjects who had Grade 3 SAE possibly related to LSAM-PTX were 29%, 24%, 16%, 6.7% and 5.0% in paclitaxel, carboplatin, 5-FU, nab-paclitaxel, and gemcitabine combinations, respectively. Grade 4 SAE possibly related to LSAM-PTX were found in 1 subject each co-administered pembrolizumab (13%), carboplatin (5.9%), and paclitaxel (7.1%). Subjects treated with 5-FU, gemcitabine, and nab-paclitaxel reported no related Grade 4 SAE. No Grade 5 SAE were deemed possibly related to LSAM-PTX. 8 subjects (median age 78 (range 54-89), 100% male, 88% white) received local LSAM-DTX therapy in combination with SOC therapies. No Grade 3-5 AE were reported with LSAM-DTX in combination with gemcitabine, carboplatin, pembrolizumab, avelumab or radiation. Conclusions: Local treatment of solid tumors with LSAM-PTX or LSAM-DTX has the potential to overcome some limitations of SOC therapies by increasing tumor dwell time and reducing systemic toxicities which are often exacerbated in combinatorial treatment regimens. Clinical trial information: NCT00666991 , NCT03636256 , NCT03077659 , NCT04221828 , NCT03029585 , NCT03077685 , NCT04314895 . [Table: see text]

Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study.

Few treatment options are available for patients with advanced renal cell carcinoma who have received previous anti-PD-1-based or anti-PD-L1-based immunotherapy. Combining belzutifan, an HIF-2α inhibitor, with cabozantinib, a multitargeted tyrosine-kinase inhibitor of VEGFR, c-MET, and AXL, might provide more antitumoural effects than either agent alone. We aimed to investigate the antitumour activity and safety of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma that was previously treated with immunotherapy. This open-label, single-arm, phase 2 study was conducted at ten hospitals and cancer centres in the USA. Patients were enrolled into two cohorts. Patients in cohort 1 had treatment-naive disease (results will be reported separately). In cohort 2, eligible patients were aged 18 years or older with locally advanced or metastatic clear cell renal cell carcinoma, measurable disease according to Response Evaluation Criteria in Solid Tumours version 1.1, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had previously received immunotherapy and up to two systemic treatment regimens. Patients were given belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was confirmed objective response assessed by the investigator. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03634540, and is ongoing. Between Sept 27, 2018, and July 14, 2020, 117 patients were screened for eligibility, 52 (44%) of whom were enrolled in cohort 2 and received at least one dose of study treatment. Median age was 63·0 years (IQR 57·5-68·5), 38 (73%) of 52 patients were male, 14 (27%) were female, 48 (92%) were White, two (4%) were Black or African American, and two were Asian (4%). As of data cutoff (Feb 1, 2022), median follow-up was 24·6 months (IQR 22·1-32·2). 16 (30·8% [95% CI 18·7-45·1]) of 52 patients had a confirmed objective response, including one (2%) who had a complete response and 15 (29%) who had partial responses. The most common grade 3-4 treatment-related adverse event was hypertension (14 [27%] of 52 patients). Serious treatment-related adverse events occurred in 15 (29%) patients. One death was considered treatment related by the investigator (respiratory failure). Belzutifan plus cabozantinib has promising antitumour activity in patients with pretreated clear cell renal cell carcinoma and our findings provide rationale for further randomised trials with belzutifan in combination with a VEGFR tyrosine-kinase inhibitor. Merck Sharp & Dohme (a subsidiary of Merck & Co) and the National Cancer Institute.

Prognostic effect of CD73 in pancreatic ductal adenocarcinoma for disease-free survival after radical surgery.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a high potency of metastasis or recurrence after radical resection. Effective predictors for metastasis and recurrence postoperatively were dominant for the development of systemic adjuvant treatment regimens. The ATP hydrolase correlated gene CD73 was described as a promoter in tumor growth and immune escape of PDAC. However, there lacked research focused on the role of CD73 in PDAC metastasis. This study aimed to investigate the expression of CD73 in PDAC patients with different outcomes as well as the prognostic effect of CD73 for disease-free survival (DFS). The expression level of CD73 in cancerous samples from 301 PDAC patients was evaluated by immunohistochemistry (IHC) and translated into a histochemistry score (H-score) by the HALO analysis system. Then, the CD73 H-score was involved in multivariate Cox regression along with other clinicopathological characteristics to find independent prognostic factors for DFS. Finally, a nomogram was constructed based on those independent prognostic factors for DFS prediction. Higher CD73 expression was found in PDAC patients with tumor metastasis postoperatively. Meanwhile, higher CD73 expressions were also investigated in PDAC patients diagnosed with advanced N stage and T stage. Furthermore, CD73 H-score along with tumor margin status, CA19-9, 8th N stage, and adjuvant chemotherapy was indicated as independent prognostic factors for DFS in PDAC patients. The nomogram based on these factors predicted DFS in a good manner. CD73 was associated with PDAC metastasis and served as an effective prognostic factor for DFS in PDAC patients after radical surgery.

Clinical characteristics and outcome of patients with combined hepatocellular-cholangiocarcinoma—a European multicenter cohort

There is no clear consensus on the optimal systemic treatment regimen in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) patients. We describe clinical characteristics and outcome of cHCC-CCA patients, with a special focus on patients receiving palliative systemic therapy, including immune checkpoint inhibitors (ICIs). In this European retrospective, multicenter study, patients with histologically proven cHCC-CCA treated at four institutions between April 2003 and June 2022 were included. In patients receiving palliative systemic therapy, outcome was compared between cytotoxic chemotherapy (CHT)- and non-cytotoxic CHT (nCHT)-treated patients. Of 101 patients, the majority were male (n= 70, 69%) with a mean age of 64.6 ± 10.6 years. Only type of first-line treatment was independently associated with overall survival (OS). Palliative systemic therapy was administered to 44 (44%) patients. Of those, 25 (57%) patients received CHT and 19 (43%) had nCHT (n= 16 of them sorafenib) in systemic first line. Although there was no significant difference in overall response rate (ORR; CHT versus nCHT: 8% versus 5%), disease control rate (24% versus 21%), and median progression-free survival {3.0 months [95% confidence interval (CI) 1.4-4.6 months] versus 3.2 months (95% CI 2.8-3.6 months), P= 0.725}, there was a trend towards longer median OS in the CHT group [15.5 months (95% CI 8.0-23.0 months) versus 5.3 months (95% CI 0-12.5 months), P= 0.052]. However, in multivariable analysis, type of first-line regimen (CHT versus sorafenib) was not associated with OS. ORR in patients receiving ICIs (n= 7) was 29%. In patients with cHCC-CCA, OS, progression-free survival, ORR, and disease control rate were not significantly different between individuals receiving CHT and patients receiving nCHT. Immunotherapy may be effective in a subset of patients. Prospective studies are needed to identify optimal systemic treatment regimens in cHCC-CCA.

Mirvetuximab Soravtansine: First Approval.

Mirvetuximab soravtansine (mirvetuximab soravtansine-gynx; Elahere™) is an antibody-drug conjugate (ADC), which is comprised of a folate receptor α (FRα) directed antibody conjugated to a microtubule inhibitor via a cleavable linker. The ADC is being developed by ImmunoGen for the treatment of FRα expressing cancers. In November 2022, mirvetuximab soravtansine was approved in the USA for the treatment of adult patients with FRα positive, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have received 1-3 prior systemic treatment regimens. This article summarizes the milestones in the development of mirvetuximab soravtansine leading to this first approval.

Does neoadjuvant treatment in resectable pancreatic cancer improve overall survival? A systematic review and meta-analysis of randomized controlled trials

Neoadjuvant chemotherapy may improve overall survival (OS) in 'borderline' resectable pancreatic cancer (RPC). Whether the results are the same in upfront RPC is unknown. To evaluate the association of neoadjuvant treatment and survival outcomes in RPC, a systematic literature review was carried out including prospective randomized trials of neoadjuvant treatment versus upfront surgery. Articles indexed in PubMed, Embase and Scopus were evaluated. Data regarding systemic treatment regimens, R0 resection rates, disease-free survival (DFS) and OS were extracted. The outcomes were compared using a random-effects model. The index I2 and the graphs of funnel plot were used for the interpretation of the data. Of 3229 abstracts, 6 randomized controlled trials were considered eligible with a combined sample size of 805 RPC patients. Among the trials, PACT-15, PREP-02/JSAP-05 and updated long-term results from PREOPANC and NEONAX trials were included. Combining the studies with meta-analysis, we could see that neoadjuvant treatment in RPC does not improve DFS [hazard ratio (HR) 0.71 (0.46-1.09)] or OS [HR 0.76 (0.52-1.11)], without significant heterogeneity. Interestingly, R0 rates improved ∼20% with the neoadjuvant approach [HR 1.2 (1.04-1.37)]. It is important to note that most studies evaluated gemcitabine-based regimens in the neoadjuvant setting. Neoadjuvant chemotherapy or chemoradiation does not improve DFS or OS in RPC compared to upfront surgery followed by adjuvant treatment. Neoadjuvant treatment improves R0 rates by ∼20%. Randomized ongoing trials are eagerly awaited with more active combined regimens including modified FOLFIRINOX.

Approaches to the Management of Metastatic Adenoid Cystic Carcinoma.

High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents - cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR - in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.

Outcome of Transformed Marginal Zone Lymphoma: A Population Based Study

Introduction: Marginal zone lymphomas (MZL) represent 6-9% of non-Hodgkin lymphomas and can be subclassified into extranodal MZL (EMZL), nodal MZL (NMZL) and splenic MZL (SMZL). Although the majority of MZL cases are characterized by an indolent clinical course, 4-15% of patients experience histological transformation, most commonly into diffuse large B-cell lymphoma (DLBCL). Risk stratification of transformed MZL (tMZL) remains difficult given the paucity of data. The aim of this study was to identify characteristics associated with outcome of tMZL in a large nationwide population-based study. Methods: Patients with MZL aged ≥18 years, diagnosed between 2014 and 2018 were identified from the Netherlands Cancer Registry (NCR). Transformations to DLBCL occurring between 2014 and 2020 among the MZL patients were identified by cross-linkage within the NCR, resulting in a follow-up of >2 years for each patient. Data on patient characteristics at time of MZL diagnosis and transformation were collected. Risk factors associated with transformation and overall survival (OS) were analyzed using competing-risk analyses with death of any cause as competing risk and Cox regression analyses, respectively. The following variables at MZL diagnosis (1) and at histological transformation (2) were included in the univariable analyses for risk factors associated with transformation (1) and OS after transformation (2): age, gender, MZL subtype, Ann Arbor Stage, LDH, >2 extranodal sites and International Prognostic Index (IPI) score. In addition, time to transformation < 2 years, prior treatment yes/no and R-CHOP versus other systemic treatment regimens were included in the univariable analysis for OS after transformation. Multivariable models were derived using backwards stepwise regression among variables with a p<0.25 in the univariable analysis to enter and p<0.05 to stay in the model. Results: In total, 1830 patients with MZL were identified including 1089 (59.5%) EMZL, 481 (26.3%) NMZL and 260 (14.2%) SMZL. In 1774/1930 (96.9%) cases, MZL diagnosis was histologically confirmed. In the other cases, cytology was used to confirm MZL diagnosis. Among the 1830 MZL patients, 1287 (70.3%) were aged >60 years, 899 (49.1%) had a limited Ann Arbor stage and 1280 (69.9%) had an IPI-score ≤2. The 5-year OS of the whole cohort was 78% (95%CI 0.76 - 0.80). Transformation to DLBCL was observed in 77 patients (4,2%). Transformation was most frequently observed in NMZL in 33/481 (6.8%), followed by 13/260 (5.0%) SMZL, and 31/1,089 (2.8%) EMZL (p<0.01). Median time to transformation was 1.6 years (range 0.25 - 6.0 years). The estimated annual incidence rate (IR) of histological transformation was 11.01 events per 1000 patients per year (95% CI 8.81 - 13.77). No significant difference was observed in the IR between the first year (IR 13.05) and second year (IR 14.54) of follow-up. Considering the entire MZL cohort, elevated LDH at diagnosis of MZL and NMZL subtype were associated with risk of transformation (subdistribution hazard ratio (SHR) 2.29, p<0.01 and SHR 2.08, p<0.01, respectively). The median OS from the time of histological transformation was 62 months (Figure 1). In 6 out of 77 tMZL patients, no treatment was initiated at transformation. In a multivariable analysis including the 71 patients who received treatment for tMZL, age >60 years (hazard ratio (HR) 3.92, p<0.01), time to transformation <2 years (HR 3.23, p=0.01) and Ann Arbor stage III-IV at transformation (HR 8.04, p=0.04) were significantly associated with a lower OS. R-CHOP versus other systemic treatment regimens (e.g. R-DHAP, BR, R-PECC, R-CVP) was associated with a higher OS (HR 0.36, p=0.02) (Figure 2). Conclusion: In this population-based study, histological transformation was observed in 4.2% of patients with MZL. Outcome was poor, especially for patients aged >60 years and with an advanced stage. Thus, there is a need for a better understanding of the molecular events underlying histological transformation in these patients to optimize and develop new treatment strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Management of Recurrent Glioblastomas: What Can We Learn from the French Glioblastoma Biobank?

Safe maximal resection followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ) is universally accepted as the first-line treatment for glioblastoma (GB), but no standard of care has yet been defined for managing recurrent GB (rGB). We used the French GB biobank (FGB) to evaluate the second-line options currently used, with a view to defining the optimal approach and future directions in GB research. We retrospectively analyzed data for 338 patients with de novo isocitrate dehydrogenase (IDH)-wildtype GB recurring after TMZ chemoradiotherapy. Cox proportional hazards models and Kaplan-Meier analyses were used to investigate survival outcomes. Median overall survival after first surgery (OS1) was 19.8 months (95% CI: 18.5-22.0) and median OS after first progression (OS2) was 9.9 months (95% CI: 8.8-10.8). Two second-line options were noted for rGB patients in the FGB: supportive care and treatments, with systemic treatment being the treatment most frequently used. The supportive care option was independently associated with a shorter OS2 (p < 0.001). None of the systemic treatment regimens was unequivocally better than the others for rGB patients. An analysis of survival outcomes based on time to first recurrence (TFR) after chemoradiotherapy indicated that survival was best for patients with a long TFR (≥18 months; median OS1: 44.3 months (95% CI: 41.7-56.4) and median OS2: 13.0 months (95% CI: 11.2-17.7), but that such patients constituted only a small proportion of the total patient population (13.0%). This better survival appeared to be more strongly associated with response to first-line treatment than with response to second-line treatment, indicating that the recurring tumors were more aggressive and/or resistant than the initial tumors in these patients. In the face of high rates of treatment failure for GB, the establishment of well-designed large cohorts of primary and rGB samples, with the help of biobanks, such as the FGB, taking into account the TFR and survival outcomes of GB patients, is urgently required for solid comparative biological analyses to drive the discovery of novel prognostic and/or therapeutic clinical markers for GB.

Endometrial cancer: news from ASCO

SummaryAt ASCO 2022 important abstracts were presented. The programmed death1 (PD1) inhibitor dostarlimab was investigated in the phase III GARNET study in advanced or metastatic endometrial cancer after failure of previous platinum-based combination chemotherapy. In the first group of patients with tumors with dMMR (mismatch repair-deficiency) or MSI‑H (microsatellite-high; group A), the median progression-free survival (PFS) was significantly higher than in the group with pMMR (mismatch repair-proficiency) or those with MSS (microsatellite-stable) tumors (group B), i.e., 6.0 months in group A and 2.7 months in group B. Overall survival was &gt; 50 months and 17 months, respectively. Immunotherapy-related adverse events were seen in 23% of patients, including grade 3 or 4 events in 8% of women. In all, 9% of patients discontinued treatment due to adverse events. Another important regimen is the combination of lenvatinib and pembrolizumab. In a randomized study of lenvatinib + pembrolizumab versus monotherapy with doxorubicin or paclitaxel in the second-line therapy of metastatic endometrial cancer, the chemotherapy-free regimen was superior. PFS2 was significantly higher in patients in the pMMR group and the all comer group if they received lenvatinib and pembrolizumab, compared to those receiving standard chemotherapy (p &lt; 0.0001). In conclusion, checkpoint inhibitors ± lenvatinib are now established in the second-line treatment of advanced endometrial cancer. Overall, the inclusion of PD1 or PDL1 inhibitors in systemic treatment regimens offers a significant opportunity for patients whose treatment options in the past only included conventional chemotherapy, radiotherapy or hormonal therapy.