Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and ...safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs.
Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over.
From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months 95% confidence interval (CI) 1.6-2.9 months with pimitespib versus 1.4 months (0.9-1.8 months) with placebo hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo HR 0.42 (0.21-0.85), one-sided P = 0.007. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients.
Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.
•Pimitespib improved PFS compared with placebo in patients with previously treated advanced GIST.•OS was improved with pimitespib compared with placebo using the RPSFT model.•Exploratory pharmacogenomic analysis showed a benefit of pimitespib irrespective of KIT mutation status.•The safety profile of pimitespib was acceptable, and quality of life was not deteriorated by pimitespib compared with placebo.
Summary
Recently, depletion of skeletal muscle mass (sarcopenia) has been linked to poor prognosis in several types of cancers, but has not been investigated in esophageal squamous cell carcinoma ...(ESCC). This retrospective study investigates the relationship between sarcopenia and clinical outcome in ESCC patients treated by surgical resection or definitive chemoradiation therapy (dCRT). The study was retrospectively conducted in a single academic hospital in Kumamoto, Japan, and involved 325 ESCC patients (256 surgical cases and 69 dCRT cases) treated between April 2005 and April 2011. Skeletal muscle mass was quantified by radiologic measures using standard computed tomography scans. The skeletal muscle tissue in the 325 ESCC patients was distributed as follows: mean: 47.10; median: 46.88; standard deviation (SD): 7.39; range: 31.48–71.11; interquartile range, 46.29–47.90. Skeletal muscle tissue was greater in male patients than in female patients (P < 0.0001), but was independent of other clinical and tumor features. Sarcopenia was not significantly associated with overall survival (log rank P = 0.54). Lymph node involvement significantly altered the relationship between sarcopenia and survival rate (P for interaction = 0.026). Sarcopenia significantly reduced the overall survival of patients without lymph node involvement (log rank P = 0.035), but was uncorrelated with overall survival in patients with lymph involvement (log rank, P = 0.31). The anastomosis leakage rate was significantly higher in the sarcopenia group than in the non‐sarcopenia group (P = 0.032), but other surgical complications did not significantly differ between the two groups. Sarcopenia in ESCC patients without lymph node involvement is associated with poor prognosis, indicating sarcopenia as a potential biomarker for identifying patients likely to experience an inferior outcome. Moreover, sarcopenia was associated with anastomosis leakage but no other short‐term surgical outcome.
Background
Immune checkpoint inhibitors, such as antibody against programmed cell death protein (PD‐1), have demonstrated antitumour effects in patients with malignancies, including oesophageal ...cancer. A lymphocytic reaction observed by pathological examination is a manifestation of the host immune response to tumour cells. It was hypothesized that a stronger lymphocytic reaction to tumours might be associated with favourable prognosis in oesophageal cancer.
Methods
Using a database of resected oesophageal cancers, four morphological components of lymphocytic reactions (peritumoral, intranest, lymphoid and stromal) to tumours were evaluated in relation to clinical outcome, PD‐1 expression by immunohistochemistry and total lymphocyte count in blood.
Results
Resected oesophageal cancer specimens from 436 patients were included in the study. Among the four morphological components, only peritumoral reaction was associated with patient prognosis (multivariable P for trend <0·001); patients with a higher peritumoral reaction had significantly longer overall survival than those with a lower reaction (multivariable hazard ratio 0·48, 95 per cent c.i. 0·34 to 0·67). The prognostic effect of peritumoral reaction was not significantly modified by other clinical variables (all P for interaction >0·050). Peritumoral reaction was associated with total lymphocyte count in the blood (P < 0·001), supporting the relationship between local immune response and systemic immune competence. In addition, higher morphological peritumoral reaction was associated with high PD‐1 expression on lymphocytes in tumours (P = 0·034).
Conclusion
These findings should help to improve risk‐adapted therapeutic strategies and help stratify patients in the future clinical setting of immunotherapy for oesophageal cancer.
Antecedentes
Los inhibidores de los puntos de control inmunitario (checkpoints) (p.ej. los anticuerpos anti‐PD‐1) han demostrado efectos antitumorales en pacientes con tumores malignos, incluido el cáncer de esófago. La reacción linfocítica detectada en estudios anatomopatológicos es una manifestación de la respuesta inmune del huésped a las células tumorales. Se estableció la hipótesis de que una mayor reacción linfocítica a los tumores podría asociarse con un mejor pronóstico en el cáncer de esófago.
Métodos
Usando una base de datos de 436 cánceres de esófago resecados, se evaluaron cuatro componentes morfológicos (peritumoral, intra‐epitelial, linfoide y estromal) de las reacciones linfocíticas a tumores en relación con los resultados clínicos, la expresión inmunohistoquímica de PD‐1 y el recuento total de linfocitos en sangre.
Resultados
De los cuatro componentes, solamente la reacción peritumoral se asoció con el pronóstico del paciente (P multivariable para tendencia < 0,001): los pacientes con mayor reacción peritumoral presentaron una supervivencia global significativamente más prolongada que aquellos pacientes con menor reacción peritumoral (cociente de riesgos instantáneos multivariable, hazard ratio, HR: 0,48; i.c. del 95%: 0,34 –0,67; P <0,001). El efecto pronóstico de la reacción peritumoral no se modificó significativamente por otras variables clínicas (todas las P para la interacción > 0,05). La reacción peritumoral se asoció con el recuento total de linfocitos en la sangre (P < 0,001), lo que respalda la relación entre la respuesta inmune local y la competencia inmune sistémica. Además, una elevada reacción morfológica peritumoral se asoció con una alta expresión de PD‐1 en linfocitos tumorales (P = 0,034).
Conclusión
Estos hallazgos deberían ayudar a mejorar las estrategias terapéuticas adaptadas al riesgo y contribuir a estratificar a los pacientes en el entorno clínico futuro de la inmunoterapia para los pacientes con cáncer de esófago.
Among four components of lymphocytic reactions, only peritumoral reaction was associated with patient prognosis in 436 patients with oesophageal cancer, suggesting higher peritumoral reaction as a prognostic marker. Peritumoral reaction was associated with total lymphocytes in the blood and programmed cell death protein 1 (PD‐1) expression on lymphocytes in tumours.
Will guide future immunotherapy
LINE-1 methylation level is a surrogate marker of global DNA methylation. LINE-1 methylation in primary colorectal cancers (CRCs) is highly variable and strongly associated with a poor prognosis. ...However, no study has examined LINE-1 methylation levels of metastatic CRCs in relation to prognosis or assessed the heterogeneity of LINE-1 methylation level within the primary CRCs.
Pyrosequencing was used to quantify LINE-1 methylation level in 42 liver metastases, 26 matched primary tumours, and 6 matched lymph node (LN) metastases. KRAS, BRAF, and PIK3CA mutation status and microsatellite instability (MSI) status were also examined.
The distribution of LINE-1 methylation level in liver metastases was as follows: mean, 67.3; range, 37.1-90.1. Primary tumours showed LINE-1 methylation levels similar to those of matched liver and LN metastases. The difference in LINE-1 methylation level between superficial areas and invasive front areas was within 7.0 in all six cases evaluated. Prognostic impact of LINE-1 hypomethylation in liver metastases on overall survival was not observed. The concordance rate was 94% for KRAS, 100% for BRAF, 88% for PIK3CA, and 97% for MSI.
Alteration of LINE-1 methylation level may occur in early CRC tumorigenesis, and the LINE-1 methylation level is relatively stable during CRC progression.
The clinical significance of circulating tumour cell (CTC) detection in gastrointestinal (GI) cancer remains controversial and the molecular biological characteristics of CTCs are poorly understood.
...A total of 87 patients with metastatic or recurrent GI cancer were prospectively enrolled. Circulating tumour cells and their HER2 status were assessed using the CellSearch System.
Among the 62 CTC-positive cases, we found 22 discordant cases (35.5%). Among the HER2-negative primary tumours, 17 of 54 developed HER2-positive CTCs. Five of eight had HER2-negative CTCs among the HER2-positive primary tumours.
The findings in the current study suggest that it is critical to evaluate the HER2 status of not only the primary tumour but also the CTCs because the metastasising tumour cells are the primary target of systemic therapy.
Summary
A limited number of patients with resectable advanced esophageal cancer can be cured by surgery alone. Although a regimen that consists of docetaxel, cisplatin, and 5‐fluorouracil (DCF) is a ...potential preoperative chemotherapy (PCT) option for squamous cell carcinoma of the esophagus, the influence of DCF on subsequent esophagectomies remains unclear. A total of 80 patients who received preoperative DCF chemotherapy, and 174 patients who did not receive any preoperative treatment were retrospectively analyzed. There were no treatment‐related deaths. No delays in surgery due to adverse events related to DCF were reported. Although patients who received PCT had significantly more advanced cancers and worse preoperative conditions, the incidence rates of complications did not increase. Although the frequency of severe complications was significantly higher in patients who received PCT, this treatment was not an independent factor for the occurrence of severe complications. PCT with DCF did not negatively affect subsequent esophagectomies with regard to the frequency of complications.
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