Incidence of fistula occurrence in patients with cervical cancer treated with bevacizumab: data from real-world clinical practice.

BACKGROUND: This study aimed to determine the incidence of pelvic fistulas in cervical cancer patients treated with bevacizumab in Japanese clinical practice. METHODS: A post-marketing surveillance (PMS) study was conducted between June 2016 and February 2018 to survey physicians who treated advanced or recurrent cervical cancer patients with bevacizumab (according to the product label). The clinical/treatment status of patients with pelvic fistulas was assessed in an additional retrospective case series study. RESULTS: 142 patients were included in the PMS study (median age 51 years; 66.9% squamous cell carcinoma; 66.2% recurrent cervical cancer; 64.1% previous radiotherapy). Patients received a median of seven bevacizumab doses. Six patients, all of whom had a history of pelvic irradiation, developed seven fistulas (4.2%; 95% confidence interval, 1.56-8.96), and five patients had also undergone pelvic surgery. The case series study of the patients who developed fistulas indicated that three patients had high cumulative bladder and rectal doses of radiation, and two of them had undergone salvage re-irradiation for pelvic recurrence. The other three patients underwent both radical hysterectomy and adjuvant radiotherapy, but did not receive an excessive radiation dose to the bladder or rectum. CONCLUSIONS: This study found that the upper limit of the 95% confidence interval for pelvic fistula incidence did not exceed the incidence reported in the GOG 240 study. To ensure an adequate benefit-risk assessment of bevacizumab in cervical cancer patients, a comprehensive evaluation of prior treatment is essential and the possibility of unexpected fistulas, even after careful evaluation, should be considered.

Safety and effectiveness of bevacizumab in Japanese patients with malignant glioma: a post-marketing surveillance study.

OBJECTIVE: This surveillance study was conducted to verify the post-market safety and effectiveness of bevacizumab, which was approved in Japan in 2013 for the treatment of patients with newly diagnosed and or recurrent malignant glioma. METHODS: This was a prospective, observational, multicenter post-marketing surveillance study. Patients with newly diagnosed or recurrent malignant glioma scheduled for bevacizumab treatment were enrolled. The incidence and severity of adverse drug reactions were calculated. The effectiveness of bevacizumab was assessed by the 1-year survival rate and the overall survival rate. RESULTS: The safety analysis set and the effectiveness analysis set each comprised 258 of the 268 enrolled patients: tumours were newly diagnosed in 80 patients (31%) and recurrent in 178 patients (68.9%). The incidence of grade ≥ 3 adverse drug reactions was 15.1%. Adverse drug reactions of special interest included 14 cerebral bleeding events and 11 infections. Of the 80 patients with newly diagnosed malignant glioma, 44 (55%) were alive throughout the 18-month observation period. The 1-year survival rate for patients with newly diagnosed glioblastoma was 78%. Median overall survival was not calculated, but 51.2% of patients were alive at the last date of observation of the last observed patient. In patients with recurrent glioblastoma, the 1-year survival rate was 38.9%, and the median overall survival was 10.2 months. CONCLUSIONS: The results suggest no new safety concerns, and the effectiveness might be similar to previously reported data in clinical trials. Therefore, bevacizumab is considered as one of the treatment options for patients with malignant glioma in real-world clinical practice.

A water soluble prodrug of a novel camptothecin analog is efficacious against breast cancer resistance protein-expressing tumor xenografts.

PURPOSE: Identification of a novel topoisomerase I inhibitor which shows superior efficacy and less individual variation than irinotecan hydrochloride (CPT-11). METHODS: A novel camptothecin analog that is effective against breast cancer resistance protein (BCRP)-positive cells was screened, and a water soluble prodrug was generated. Antitumor activity of the prodrug was examined in BCRP-positive and -negative xenografts both as a single agent and in combination with other anti-cancer drugs. RESULTS: A novel camptothecin analog, CH0793076, was discovered. Because CH0793076 was found to be highly lipophilic, a water soluble prodrug (TP300) was generated. TP300 is stable in an acidic solution but is rapidly converted to CH0793076 under physiological pH conditions such as in sera. This efficient prodrug activation would minimize interpatient differences in pharmacokinetic and toxicity profiles. Unlike CPT-11, TP300 does not exhibit cholinergic interaction or cause acute diarrhea at effective doses. In mouse xenograft models, TP300 showed antitumor activity against both BCRP-positive and -negative xenografts, whereas CPT-11 was less active against BCRP-positive xenografts. In addition, the effective dose range (MTD/ED(50)) for TP300 was wider than for CPT-11 and TP300 showed additive or synergistic antitumor effects in combination with other anti-cancer drugs such as capecitabine, oxaliplatin, cisplatin, bevacizumab and cetuximab. CONCLUSION: It is therefore expected that TP300 will provide an additional treatment option for patients who will undergo chemotherapy with camptothecins.

Synthesis and biological activities of a pH-dependently activated water-soluble prodrug of a novel hexacyclic camptothecin analog.

CH0793076 (1) is a novel hexacyclic camptothecin analog showing potent antitumor activity in various human caner xenograft models. To improve the water solubility of 1, water-soluble prodrugs were designed to generate an active drug 1 nonenzymatically, thus expected to show less interpatient PK variability than CPT-11. Among the prodrugs synthesized, 4c (TP300, hydrochloride) having a glycylsarcosyl ester at the C-20 position of 1 is highly water-soluble (>10mg/ml), stable below pH 4 and rapidly generates 1 at physiological pH in vitro. The rapid (ca. <1min) generation of 1 after incubation of TP300 with plasma (mouse, rat, dog and monkey) was also demonstrated. TP300 showed a broader antitumor spectrum and more potent antitumor activity than CPT-11 in various human cancer xenograft models.

Synthesis of new camptothecin analogs with improved antitumor activities.

Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.

Involvement of cyclooxygenase-2 in the tumor site-dependent production of parathyroid hormone-related protein in colon 26 carcinoma.

It has been shown that in the mouse colon 26 tumor model, tumors grown in the subcutis (subcutis colon 26) caused early onset of cachectic syndromes, whereas those in the liver (liver colon 26) did not. Both interleukin (IL)-6 and parathyroid hormone-related protein (PTHrP) were involved in the development of cachectic syndromes in this tumor model. However, whether expression of PTHrP and IL-6 is differently regulated in the tumor microenvironment is unclear. In the present study, culturing the colon 26 cells under different conditions in vitro revealed that IL-6 production was increased by monolayer culture under a low-glucose condition but not by spheroid culture. In contrast, PTHrP production was increased by spheroid culture but not by monolayer culture, even under a low-glucose condition. Gene expression profiling revealed that the expression of cyclooxygenase (COX)-2 was up-regulated in both subcutis colon 26 and spheroid cultures, and that COX-2 inhibitor NS-398 suppressed PTHrP production in spheroid cultures. Furthermore, administration of NS-398 decreased the PTHrP level without affecting the tumor growth in mice bearing subcutis colon 26. These results demonstrate that production of PTHrP and IL-6 largely depends on the microenvironments in which tumors are developed or metastasized and that up-regulation of COX-2 in a necrobiotic environment leads to PTHrP production, thereby causing cachectic syndromes.

Design and synthesis of novel prodrugs of 2'-deoxy-2'-methylidenecytidine activated by membrane dipeptidase overexpressed in tumor tissues.

DNA microarray analysis comparing human tumor tissues with normal tissues including hematopoietic progenitor cells resulted in identification of membrane dipeptidase as a prodrug activation enzyme. Novel prodrugs of 2'-deoxy-2'-methylidenecytidine (DMDC) including compound 23 that are activated by membrane dipeptidase (MDP) preferentially in tumor tissue were designed and synthesized to generate the active drug, DMDC, after hydrolysis of the dipeptide bond followed by spontaneous cyclization of the promoiety.

Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889.

Capecitabine is an orally available fluoropyrimidine and is finally converted to 5-FU selectively in tumor tissues. In our study, we examined whether the antitumor activity of capecitabine is directly affected by a modulation of dihydropyrimidine dehydrogenase (DPD). The modulations were carried out by the overexpression of DPD in tumor cells and by tumor selective DPD inhibition. The DPD-overexpressing cells were obtained by transfection of human DPD cDNA into HCT116 human colorectal cancer cells. The HCT116 cells bearing DPD cDNA expressed about 13 times higher DPD activities than the parental HCT116 cells, and they became significantly less susceptible to capecitabine than the parental cells when transplanted into nude mice. Administration of RO0094889 that is converted to a DPD inhibitor 5-vinyluracil selectively in tumor tissues restored the antitumor activity of capecitabine against the tumor of the HCT116 cells carrying DPD cDNA and various tumors expressing DPD. As compared to 5-ethynyluracil or 5-vinyluracil, which inhibited DPD not only in tumor tissues but also in other non-cancerous tissues, the effective dose range of RO0094889 in augmenting the efficacy of capecitabine was much broader. These results indicate that the antitumor activity of capecitabine is directly affected by DPD activities in tumor tissues and therefore, the combination of capecitabine and a tumor selective DPD inhibitor, RO0094889, will be beneficial to patients who have tumors with high levels of DPD.

Design and synthesis of the tumor-activated prodrug of dihydropyrimidine dehydrogenase (DPD) inhibitor, RO0094889 for combination therapy with capecitabine.

A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known DPD inhibitor, and was designed to generate 4c selectively in tumor tissues by sequential conversion of 11c by three enzymes: esterase, cytidine deaminase and thymidine phosphorylase, the latter two of which are known to be highly expressed in various tumor tissues. When capecitabine (1), a tumor-activated prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor tissues was significantly increased with only a slight increase of 5-FU in plasma as compared with oral capecitabine alone.