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24th March 2023
The use of neoadjuvant socazolimab with cisplatin chemotherapy appears to be a promising approach to the treatment of locally advanced oesophageal squamous cell carcinoma (OSCC) according to the findings of a phase 2, randomised trial by Chinese researchers.
Data from 2020 show that globally, there were 604,000 new cases of oesophageal cancer and which gave rise to 544,000 deaths. Survival from advanced oesophageal cancer is poor and following surgery, one study identified how 1-year survival was 29% and 5-year survival only 6%. Although programmed cell death protein 1 inhibitors such as pembrolizumab with chemotherapy significantly prolonged overall survival compared to placebo as a first-line treatment for advanced OSCC, much less is known about the value of programmed cell death ligand 1 (PD-L1) inhibitors for this cancer. Evidence to date, shows that one such PD-L1 inhibitor, socazolimab, demonstrated a durable safety and efficacy for the treatment of recurrent or metastatic cervical cancer. But whether neoadjuvant socazolimab in combination with nab-paclitaxel and cisplatin chemotherapy is of benefit to patients with locally advanced OSCC is uncertain and was examined in the current randomised, phase 2 trial.
The Chinese team randomised participants 1:1 to socazolimab plus nab-paclitaxel and cisplatin or the same regimen without PD-L1 inhibitor and which formed the placebo arm. The primary endpoint was a major pathological response (MPR) whereas the secondary endpoints were a pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety.
Neoadjuvant socazolimab associated outcomes
A total of 64 patients with a median age of 62 years (79.7% male) were enrolled and equally randomised between the two groups.
There were 29 patients in each arm who subsequently underwent surgery. The MPR rate was 69% in the socazolimab group and 62.1% in the placebo arm although this difference was not significant (p = 0.509). Similarly, whilst the pCR rate was higher with socazolimab (41.4%) than in the placebo group (27.6%), again this was not significant (p = 0.311).
However, there was a significantly higher incidence rate of ypT0 for socazolimab (37.9%) compared to placebo (3.5%, p = 0.001) and the rate of T down-staging was also higher (65.5% vs 62.1%). At the time of publication, the EFS and OS outcomes were not mature.
The authors concluded that neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T down-staging in locally advanced OSCC and without increasing surgical complication rates.
Li Y et al. Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: a randomized Phase II clinical trial : A randomized clinical trial of neoadjuvant therapy for ESCC. BMC Med 2023
23rd February 2023
In a phase 2 trial of adding talimogene laherparepvec (T-VEC) to neoadjuvant chemotherapy (NAC) in patients with triple negative breast cancer, researchers from the Moffitt Cancer Center, Florida, observed an improved estimated pathological complete response rate.
Triple negative breast cancer accounts for 10 to 15% of all breast cancers and chemotherapy has become the established treatment for both early and advanced disease. In a phase 1 trial reported in 2021 among 9 women with stage II to III triple negative breast cancer, use of T-VEC in combination with neoadjuvant chemotherapy, led to a complete response rate of 55%. The rational for T-VEC is based on the notion that the oncolytic virus selectively replicates within tumour cells and produces granulocyte-macrophage colony-stimulating factor which enhances both the local and systemic anti-tumour response. In fact, T-VEC (brand name Imlygic) is already licensed for the treatment of adult patients with unresectable melanoma which has become both regionally and distantly metastatic but without bone, brain, lung or other visceral disease.
Following the success of the phase 1 trial, the US researchers continued to explore the utility of this therapeutic approach by undertaking a phase 2 trial of T-VEC in patients with stage II to III triple negative breast cancer, followed by doxorubicin and cyclophosphamide chemotherapy prior to surgery, to assess residual the cancer burden index. Eligible patients received a total of five doses of intra-tumoral T-VEC injection, given initially at week 1, followed by four subsequent doses on weeks 4, 6, 8 and 10 concurrently with intravenous once-weekly paclitaxel. The primary outcome of interest was a pathological complete response (RCB0), defined as no residual invasive disease in the breast or sampled nodes after completion of NAC. The secondary endpoint was the RCB0-1 rate.
T-VEC and pathological complete response
A total of 37 women with a median age of 49 years, the majority of whom (84%) had stage II disease were included in the study.
A total of 16 women had a pathological complete response with an estimated RCB0 response of 45.9%. In addition, 8 patients had RCB1 minimal residual disease, giving a descriptive RCB0-1 rate of 65%. The authors added that the 2-year disease-free event rate was equal to 89% with no recurrence in RCB0-1 patients.
The researchers concluded that the use of T-VEC when added to NAC may increase RCB0-1 rates and called for continued investigation of this strategic approach in women with triple negative breast cancer.
Soliman H et al. Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial. Nat Med 2023
14th February 2023
The provision of neoadjuvant chemotherapy (NAC) for patients with operable colon cancer lead to histopathologic down-staging and better 2-year disease control according to the findings of study by Swedish and UK researchers.
Colorectal cancer is the 3rd most common cancer globally with 1.9 million new cases in 2020 and 935,173 deaths. The use of neoadjuvant chemotherapy has been shown to be of value at reducing tumour size and stage in patients with other operable cancers such as gastric and lower oesophageal adenocarcinomas but this approach has not been explored in the treatment of patients with colon cancer, possibly due to risk that treatment toxicities may compromise patient’s fitness for subsequent surgery.
However, despite the potential concerns, in the current study, researchers randomised patients 2:1 with radiologically staged T3-4, NO-2, MO colon cancer to either 6 weeks of preoperative oxaliplatin-fluoropyrimidine therapy followed by 18 weeks of postoperative adjuvant therapy (the intervention group) or postoperative chemotherapy only and which served as the control arm. They set the primary outcome as residual or recurrent disease within 2 years of randomisation, defined as no resection or macroscopic incomplete resection, that is, residual tumour or metastases following surgery. For the secondary outcomes, the team looked at several measures including surgical morbidity, histopathologic stage and cause-specific mortality.
Neoadjuvant chemotherapy and cancer surgery outcomes\
A total of 686 patients assigned to NAC and 351 control patients were included in the analysis.
The primary outcome occurred significantly less frequently in those assigned to NAC (rate ratio, RR = 0.72, 95% CI 0.54 – 0.98, p = 0.037). Moreover, there was also a reduction, albeit non-significant, in colon-cancer specific mortality (RR = 0.74, 95% CI 0.52 – 1.05, p = 0.095).
In addition, the researchers observed substantial reductions in T stage (21% vs 31%, NAC vs control, p < 0.001) and a higher proportion of NAC patients had histopathologically complete resections (94% vs 89%, p < 0.001).
Based on these findings, the authors concluded that NAC should be considered as a treatment option for patients with locally advanced colon cancer.
Morton D et al. Preoperative Chemotherapy for Operable Colon Cancer: Mature Results of an International Randomized Controlled Trial. J Clin Oncol 2023
13th December 2021
An MRI radiomics model based on deep learning has shown good predictive accuracy at identifying whether patients with triple negative breast cancer (TNBC) would have systemic recurrence within three years of neoadjuvant chemotherapy, according to researchers from the Department of Radiology, Peking University, Beijing, China.
A triple negative breast cancer describes an aggressive tumour which lacks expression of oestrogen receptor, progesterone receptor and HER2 and accounts for around 15% of all breast cancers. Moreover, TNBC has been found to have the lowest 4-year survival rate at 77%.
Neoadjuvant chemotherapy is seen as the mainstay of treatment for early stage TNBC followed by definitive surgery although relapse within 3 years has been found to occur in up to 97% of patients. Magnetic resonance imaging (MRI) has been used to enable prediction of disease recurrence although these MRI radiomics models have required a radiologist to manually draw regions of interest (ROIs) as the input which is very time-consuming.
In the present study, the Chinese team used radiomics based on deep learning models and which utilised automated segmented ROIs of breast tumours from MRI images to predict whether patients with TNBC who had received neoadjuvant chemotherapy, would experience disease recurrence within three years of treatment. The team undertook a retrospective analysis of consecutive female patients with unilateral primary TNBC and for whom pre- and post-neoadjuvant MRI imaging was available. The researchers also collected clinico-pathologic factors from the patient medical records, e.g., menopausal status, the histological type of cancer, the clinical T and N stages. They developed a MRI radiomics model based on three separate features; pre-treatment features (model 1), post-treatment features (model 2) and a combination of pre and post-treatment MRI features (model 3). Multivariate analysis was used to assess associations between clinical factors and disease recurrence and the predictive performance of the models was assessed using the receiver operating characteristic curves and the area under the curves (AUC).
A total of 147 women with a median age of 49.5 years were included in the analysis, 104 (22 with disease recurrence) were used for the training cohort and 43 for the testing cohort (9 with disease recurrence) and the median time to disease recurrence was 17 months.
In both the univariate and multivariate analysis the clinical T stage and pathological T stage were significantly associated with systemic disease recurrence within three years of treatment (p < 0.05). Using these two variables in a clinical model yielded AUCs of 0.75 for the training cohort and 0.74 in the testing cohort. In comparison, the AUCs for each of the MRI radiomics model was 0.88 (model 1), 0.91 (model 2) and 0.96 (model 3).
Model 3 had a perfect sensitivity (i.e., 1) and a specificity of 0.85 compared to a sensitivity of 0.67 and specificity of 0.82 for the clinical model and this difference was statistically significant (p < 0.05). However, neither model 1 or 2 were significantly better than the clinical model.
Commenting on their findings, the authors speculated that the predictive ability of the third MRI radiomics model was likely to have a greater prognostic value by inclusion of post-neoadjuvant chemotherapy features that were reflective of treatment-induced changes.
They concluded that the value of their non-invasive model was in being able to more easily identify those at risk of disease recurrence and to therefore strengthen the treatment of these patients after surgery to improve their prognosis.
Ma M et al. Radiomics features based on automatic segmented MRI images: Prognostic biomarkers for triple-negative breast cancer treated with neoadjuvant chemotherapy Eur J Radiol 2021
15th July 2021
Internationally, data from 2018 reveal how there were just over 1 million cases of gastric cancer, leading to 782,000 deaths. Fortunately, early treatment of gastric cancer either through endoscopic resection or surgery, provides a cure rate of over 90%. In contrast, in patients with locally advanced gastric cancer, prognosis is poor, with a 5-year overall survival rate of 20–30% for surgery-only patients. Among those with advanced gastric cancer, systemic chemotherapy has become the standard treatment, in particular, the combination of S-1, which is an oral fluoropyrimidine derivative and oxaliplatin (SOX) and this regime has been shown to be effective. Another therapeutic approach involves treatments targeting vascular endothelial growth factor (VEGF), which has been shown to have an important role in promoting tumour angiogenesis. Apatinib is a small molecule tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor 2 and which inhibits the action of VEGF. In fact, early data suggest that apatinib can improve overall survival in advanced gastric cancer.
In a review of 14 trials, the use of neoadjuvant chemotherapy, has been shown to improve tumour stage and survival in patients with advanced gastric cancer. However, little is known about the value of Apatinib in combination with neoadjuvant chemotherapy. This led a team from the Department of Gastric Surgery, Fujian Medical University Union Hospital, Fujian Province, China, to examine the effectiveness of this combination in patients with locally advanced gastric cancer. They conducted a multi-centre, open-label phase II, non-randomised controlled trial, in patients with confirmed primary gastric adenocarcinoma, without previous surgery, chemotherapy, radiotherapy or targeted therapy and no evidence of metastases. Patients with MO (i.e., no metastases) and either T2 to T4 (where the tumour has spread through the layers of the muscle into the connective tissue outside the stomach. All enrolled participants received 2 to 5 preoperative and 6 postoperative cycles of apatinib plus SOX every three weeks. Apatinib was given at a dose of 500 mg daily for 21 days and S1 twice daily on days 1 to 14 and intravenous oxaliplatin 130mg/square metre on day 1. Patients achieving a good response underwent surgery whereas those with a poor response received two further courses of adjuvant chemotherapy. The primary endpoint was the RO section rate (i.e., margin-negative resection with no tumour in the primary tumour bed) and which is the goal of surgery. The radiologic response was assessed using contrast-enhanced CT or magnetic resonance imaging.
A total of 48 patients with a mean age of 63.2 years (77.1% male) were included. All participants received 156 preoperative cycles neoadjuvant chemotherapy. The majority of patients (39.5%) had stage T3 cancer and nearly a third (36.9%) had stage T4 disease. Overall, 40 underwent surgery (38 radical gastrectomy and 2 exploratory laparotomy), with an R0 section rate of 75%. The radiological response rate was 75% and the pathological response rate, 54.2%.
Commenting on these early findings, the authors stated how the data indicated the effectiveness of apatinib and SOX chemotherapy as a neoadjuvant therapy for locally advanced gastric cancer. They concluded that apatinib plus SOX appeared to be an effective and well-tolerated regime and called for more studies to confirm this preliminary conclusion.
Lin JX et al. Effectiveness and Safety of Apatinib Plus Chemotherapy
as Neoadjuvant Treatment for Locally Advanced Gastric Cancer A Nonrandomised Controlled Trial. JAMA Oncol 2021