Incidence and risk factors of hyperprogressive disease caused by PD-1 inhibitors for treatment of digestive system malignancies

  Background  Immunocheckpoint inhibitors (ICIs) have been approved for treatment of many types of tumors and have shown promising antitumor activity. In clinical practice, some patients show an accelerated progression of the disease instead of benefiting from ICIs, which is called hyperprogressive disease (HPD).

  Objective  To describe the incidence of HPD in patients with various digestive system malignancies treated with PD-1 inhibitors and explore its related factors.

  Methods  The medical records of patients with digestive system malignancies treated with PD-1 inhibitors (Nivolumab or Pembrolizumab) in the First Medical Center of Chinese PLA General Hospital from April 2015 to April 2019 were retrospectively reviewed. Tumor growth rate (TGR) were calculated before and during treatment. HPD was defined as the increase between TGR at the first evaluation within 6-8 weeks after immunotherapy and TGR in previous treatment was more than 50%. The incidence and risk factors of HPD were analyzed.

  Results  Twenty-two patients (16.3%) were identified with HPD from 135 patients with evaluable digestive system malignancies, including 7 cases with pancreatic cancer, 2 cases with esophageal cancer, 5 cases with colorectal cancer, 3 cases with cholangiocarcinoma, 2 cases with liver cancer, 1 case with ampullary carcinoma, and 2 cases with gastric cancer. Univariate analysis showed that the proportion of patients associated with more than two metastatic sites was significantly higher in the HPD group before immunotherapy (54.5% vs 18.6% , P＜0.01), so did patients with liver metastasis (77.3% vs 52.2%, P＜0.01) and higher level of lactate dehydrogenase (LDH) (45.5% vs 18.6%, P＜0.01). Compared with the patients without HPD, those with HPD had a lower overall survival (OS) (3.6 months vs 6.2 months, P＜0.01). ROC curve analysis showed that in patients with pancreatic cancer, the amplitude of CA199>166.84% within 1 month after PD-1 treatment predicted the occurrence of HPD (specificity, 85.70%; sensitivity, 94.10%).

  Conclusion  Among patients with digestive system malignancies treated with ICIs, it is observed that HPD occurs in some patients, which may be related to some clinicopathological characteristics, including the number of metastatic sites, liver metastasis, and elevated LDH level, causing poor prognosis. The amplitude of CA199>166.84% within one month after immunotherapy may indicate the occurrence of HPD.