- Pixantrone -- Benefit Assessment According to §35a Social Code Book V [BOOK]
- BOOKInstitute for Quality and Efficiency in Health Care (IQWiG): Cologne, Germany
- The assessment of the added benefit of pixantrone was conducted according to the approval status for the following therapeutic indication: monotherapy for the treatment of adult patients with multipl...
The assessment of the added benefit of pixantrone was conducted according to the approval status for the following therapeutic indication: monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma (B-cell NHL). The approval is limited to third- and fourth-line therapy. The appropriate comparator therapy (ACT) specified by the Federal Joint Committee (G-BA) is the individual therapy assigned by the treating physician, particularly treatment containing bleomycin, cyclophosphamide, etoposide, ifosfamide, methotrexate, mitoxantrone, rituximab, trofosfamide, vinblastine, vincristine, or vindesine, provided that prior therapy allows further treatment with these drugs, and under consideration of the respective German approval status and the approved dosages. The company cited the ACT specified by the G-BA, but did not state explicitly whether it concurred with this specification. On the basis of the study called PIX301, presented by the company for a direct comparison, it became clear that the company deviated from the G-BA's specifications. This deviation particularly concerns the approval status of the comparator therapy. The randomized controlled trial (RCT) PIX301 compared pixantrone monotherapy with the individual monotherapy specified by the investigator, using one of 7 antineoplastic drugs specified in the protocol, in patients with aggressive non-Hodgkin's lymphoma (NHL) who had received at least 2 prior chemotherapeutic treatments (total population of 140 patients). The study included patients with both T-cell NHL and B-cell NHL, and patients with subsequent treatments after fourth-line therapy. Pixantrone, however, is only approved for the treatment of B-cell NHL in third- and fourth-line therapy. In its dossier, the company therefore presented an analysis of those patients for whom pixantrone is approved (subpopulation of 99 patients; pixantrone group: 50 patients; comparator treatment group: 49 patients). 4 of the 7 possible comparator therapies specified in the protocol of the study PIX301 comprise NHL in their approved therapeutic indication in Germany (etoposide, ifosfamide, mitoxantrone, and rituximab). In its dossier, the company therefore presented a further evaluation of the subpopulation for whom pixantrone is approved, considering only those patients in the comparator group who had received one of the 4 substances mentioned (subpopulation: 73 patients; pixantrone group: 50 patients; comparator treatment group: 23 patients). Only 2 of these 4 drugs are approved for monotherapy in NHL, however (mitoxantrone and rituximab). In the study PIX301, rituximab was not used in any patients, mitoxantrone was only used in of 4 patients in the total population. Hence the vast majority of patients in the comparator arm, both of the entire study PIX301 and of the subpopulation described above, were not treated according to the German approval status. According to the G-BA's specification on the ACT, however, the German approval status including the approved dosages is to be considered for the treatments chosen in the comparator group. Compliance with the approval status constitutes a necessary precondition for the ACT, pursuant to the G-BA's code of procedure. This precondition (benefit assessment strictly within the German approval status) does not inevitably mean that studies in which patients were treated outside the valid approval status are not relevant for the assessment. It has to be examined for these studies whether the study results are applicable to a treatment situation within the German approval status, i.e. whether the effects of a treatment that is not approval-compliant are sufficiently comparable to treatment within the approval status. In such a case, it would therefore be conceivable that conclusions on the added benefit of a new drug in comparison with an (approval-compliant) ACT are based on data outside the German approval status. This requires plausible, data-based considerations on why the therapy chosen in the study is an adequate option for the patients, and is at least not inferior to the ACT. For the benefit assessment of pixantrone, the company did not present any explanation for the applicability of the PIX301 study results to an approval-compliant treatment. Hence the study PIX301 presented by the company is unsuitable for answering the research question on the added benefit of pixantrone versus the ACT specified by the G-BA. For the reasons stated above, the implementation of the ACT by the company was inadequate. For the benefit assessment, the ACT specified by the G-BA was used without reservation.
- Small cell ovarian carcinoma: Long term survival in juvenile case with poor prognostic features. [Journal Article]
- GOGynecol Oncol Rep 2016; 18:45-48
- CONCLUSIONS: This is the first long-term juvenile survivor managed with both fertility-sparing surgery and BEP (bleomycin, etoposide, cisplatin).
- In vitro evaluation of a combination treatment involving anticancer agents and an aurora kinase B inhibitor. [Journal Article]
- OLOncol Lett 2016; 12(5):4263-4269
- Aurora kinase B (AURKB) inhibitors are regarded as potential molecular-targeting drugs for cancer therapy. The present study evaluated the cytotoxic effect of a combination of AZD1152-hQPA, an AURKB ...
Aurora kinase B (AURKB) inhibitors are regarded as potential molecular-targeting drugs for cancer therapy. The present study evaluated the cytotoxic effect of a combination of AZD1152-hQPA, an AURKB inhibitor, and various anticancer agents on the HeLa human cervical cancer cell line, as well as its cisplatin-resistant equivalent HCP4 cell line. It was demonstrated that AZD1152-hQPA had an antagonistic effect on the cytotoxicity of cisplatin, etoposide and doxorubicin, but had a synergistic effect on that of all-trans-retinoic acid (ATRA), Am80 and TAC-101, when tested on HeLa cells. Cisplatin, etoposide and doxorubicin were shown to increase the cellular expression of AURKB, while ATRA, Am80 and TAC-101 downregulated its expression. These results suggested that AURKB expression is regulated by these anticancer agents at the transcriptional level, and that the level of expression of AURKB may influence the cytotoxic effect of AZD1152-hQPA. Therefore, when using anticancer agents, decreasing the expression of AURKB using a molecular-targeting drug may be an optimal therapeutic strategy.
- Weakening Impact of Excessive Human Serum Albumin (eHSA) on Cisplatin and Etoposide Anticancer Effect in C57BL/6 Mice with Tumor and in Human NSCLC A549 Cells. [Journal Article]
- FPFront Pharmacol 2016; 7:434
- Excessive human serum albumin (eHSA) impact on anticancer effects is inconsistent. We explored the outcome of cisplatin (DDP)/etoposide (VP-16) plus eHSA in vivo and in vitro. C57BL/6 mice with tumor...
Excessive human serum albumin (eHSA) impact on anticancer effects is inconsistent. We explored the outcome of cisplatin (DDP)/etoposide (VP-16) plus eHSA in vivo and in vitro. C57BL/6 mice with tumor were used to compare the efficacy of DDP/VP-16 alone and DDP/VP-16+eHSA. Blood albumin was measured to confirm whether eHSA elevate its level. Western blotting assay were used to measure the expression of ERCC1/TOP2A in tumor tissues. Cell proliferation, mRNA, and protein expression of ERCC1/TOP2A were also assayed to compare two groups in A549 cells. Furthermore we evaluated eHSA impact on cell proliferation in RNAi targeting ERCC1/TOP2A in A549 cells, respectively. eHSA reduced the anticancer effect of DDP/VP-16 without altering albumin level, increased protein expression of ERCC1/TOP2A, respectively in mice. Similarly, eHSA increased mRNA and proteins expression of ERCC1/TOP2A in A549 cells. In RNAi A549 cells, however, eHSA no longer weakened but enhanced the anticancer effect of DDP, while no longer altered the effect of VP-16. Our findings suggested that eHSA weaken the anticancer effect of DDP/VP-16 via up-regulating ERCC1/TOP2A expression, respectively. Further molecular mechanism studies are warranted to investigate whether eHSA is not conducive to lung cancer chemotherapy.
- Collision tumor of hepatocellular carcinoma and neuroendocrine carcinoma involving the liver: Case report and review of the literature. [Journal Article]
- WJWorld J Gastroenterol 2016 Nov 7; 22(41):9229-9234
- Primary hepatic neuroendocrine carcinoma (NEC) with concurrent occurrence of hepatocellular carcinoma (HCC) of the liver is very rare. Only 8 cases have been reported in the literature. Concurrent oc...
Primary hepatic neuroendocrine carcinoma (NEC) with concurrent occurrence of hepatocellular carcinoma (HCC) of the liver is very rare. Only 8 cases have been reported in the literature. Concurrent occurrence of HCC and NEC in the liver is classified as combined type or collision type by histological distributional patterns; only 2 cases have been reported. Herein, we report a case of collision type concurrent occurrence of HCC and NEC, in which primary hepatic NEC was in only a small portion of the nodule, which is different from the 2 previously reported cases. A 72-year-old male with chronic hepatitis C was admitted to our hospital for a hepatic mass detected by liver computed tomography (CT) at another clinic. Because the nodule was in hepatic segment 3 and had proper radiologic findings for diagnosis of HCC, including enhancement in the arterial phase and wash-out in the portal and delay phases, the patient was treated with laparoscopic left lateral sectionectomy. The pathology demonstrated that the nodule was 2.5 cm and was moderately differentiated HCC. However, a 3 mm-sized focal neuroendocrine carcinoma was also detected on the capsule of the nodule. The tumor was concluded to be a collision type with HCC and primary hepatic NEC. After the surgery, for follow-up, the patient underwent a liver CT every 3 mo. Five multiple nodules were found in the right hepatic lobe on the follow-up liver CT 6 mo post-operatively. As the features of the nodules in the liver CT and MRI were different from that of HCC, a liver biopsy was performed. Intrahepatic recurrent NEC was proven after the liver biopsy, which showed the same pathologic features with the specimen obtained 6 mo ago. Palliative chemotherapy with a combination of etoposide and cisplatin has been administered for 4 months, showing partial response.
- Cyclic AMP (cAMP) confers drug resistance against DNA damaging agents via PKAIA in CML cells. [Journal Article]
- EJEur J Pharmacol 2016 Nov 25; 794:201-208
- Cyclic adenosine monophosphate (cAMP) regulates many vital functions such as metabolism, proliferation, differentiation and death. Depending on cell types and stimulators, cAMP could either promote o...
Cyclic adenosine monophosphate (cAMP) regulates many vital functions such as metabolism, proliferation, differentiation and death. Depending on cell types and stimulators, cAMP could either promote or attenuate cell death. cAMP signal can be transduced by protein kinase A (PKA) and/or exchange protein directly activated by cAMP (EPAC). In CML cells, cAMP may suppress their proliferation and enhance their differentiation. However, the role of cAMP on DNA damaging agent toxicity and the mechanism involved has not been studied. In this study, we studied the effect of cAMP on the sensitivity of CML cells to DNA damaging agents. We observed that forskolin (FSK) and dibutyryl-cAMP (DBcAMP) decreased cisplatin and etoposide-induced cell death in K562 cells. Moreover, PKA activator prevented K562 cells from DNA damaging agent-induced cell death while EPAC activator had no effect. Furthermore, we found that the PKA subtype, PKAIA, was involved in cAMP-attenuated resistance in K562 cells. Taken together, our results suggest that increased cAMP level confers CML cells to acquire a novel mechanism against DNA damaging agent toxicity via PKAIA. Thus, PKAIA inhibitor may be helpful in overcoming the resistance to DNA damaging agents in CML cells.
- Acute liver failure caused by hemophagocytic lymphohistiocytosis in adults: A case report and review of the literature. [Journal Article]
- MMedicine (Baltimore) 2016; 95(47):e5431
- CONCLUSIONS: Reports of adult patients with ALF caused by HLH have increased, and HLH should be suspected in patients with ALF of indeterminate cause. Although the efficacy of the treatment strategy recommended by the HLH 2004 remains to be confirmed in adult patients with ALF caused by HLH, early diagnosis and prompt combined treatment with steroids and cyclosporin A or etoposide should be emphasized.
- Whole-body MRI reveals high incidence of osteonecrosis in children treated for Hodgkin lymphoma. [Journal Article]
- BJBr J Haematol 2016 Nov 28
- Osteonecrosis is a well-recognized complication in patients treated with corticosteroids. The incidence of osteonecrosis in children treated for Hodgkin lymphoma is unknown because prospective whole-...
Osteonecrosis is a well-recognized complication in patients treated with corticosteroids. The incidence of osteonecrosis in children treated for Hodgkin lymphoma is unknown because prospective whole-body magnetic resonance imaging (MRI) studies are lacking in this patient population. Paediatric patients with newly diagnosed Hodgkin lymphoma who were treated according to a uniform paediatric Hodgkin protocol were eligible for inclusion in this prospective study. Whole-body MRI was performed in all 24 included patients (mean age 15·1 years, 12 girls) both before treatment and after 2 cycles of chemotherapy, and in 16 patients after completion of chemotherapy. Osteonecrosis was identified in 10 patients (41·7%, 95% confidence interval: 22·0-61·4%), with a total of 56 osteonecrotic sites. Osteonecrosis was detected in 8 patients after 2 cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin), and in 2 additional patients after completion of chemotherapy. Epiphyseal involvement of long bones was seen in 4 of 10 children. None of the patients with osteonecrosis had any signs of bone collapse at the times of scanning. Whole-body MRI demonstrates osteonecrosis to be a common finding occurring during therapy response assessment of paediatric Hodgkin lymphoma. Detection of early epiphyseal osteonecrosis could allow for treatment before bone collapse and joint damage may occur.
- Histone deacetylase inhibitors interrupt HSP90 RASGRP1 and HSP90 CRAF interactions to upregulate BIM and circumvent drug resistance in lymphoma cells. [Journal Article]
- LLeukemia 2016 Nov 28
- Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill sus...
Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here we show that trichostatin A, romidepsin, and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine, and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo. Importantly, these pro-apoptotic effects are mimicked by RASGRP1 siRNA or HSP90 inhibition and reversed by overexpression of constitutively active MEK1 or siRNA-mediated downregulation of BIM. Collectively, these observations not only identify a new HSP90 client protein, RASGRP1, but also delineate a complete signaling pathway from HSP90 acetylation through RASGRP1 and CRAF degradation to BIM upregulation that contributes to selective cytotoxicity of HDAC inhibitors in lymphoid malignancies.Leukemia accepted article preview online, 28 November 2016. doi:10.1038/leu.2016.357.
Previous New Search Next
- Dysgerminoma developing from an ectopic ovary in a patient with WAGR syndrome: A case report. [Journal Article]
- MCMol Clin Oncol 2016; 5(5):503-506
- WAGR syndrome is caused by an 11p13 deletion and includes Wilms' tumor, aniridia, genitourinary anomalies and mental retardation. We encountered a case of a dysgerminoma originating in an ectopic ova...
WAGR syndrome is caused by an 11p13 deletion and includes Wilms' tumor, aniridia, genitourinary anomalies and mental retardation. We encountered a case of a dysgerminoma originating in an ectopic ovary in a woman with WAGR syndrome. Our patient was a 24-year-old nulliparous woman who was diagnosed with WAGR syndrome. The patient had undergone left nephrectomy for a Wilms' tumor and postoperative chemotherapy at the age of 7 months. She also had a history of glaucoma surgery in both eyes, and was followed up at the Department of Pediatrics for diabetes mellitus, hypertension, liver dysfunction and hyperuricemia. The patient was investigated for oliguria and had elevated levels of blood urea nitrogen (45 mg/dl) and creatinine (5.4 mg/dl); she was admitted to the hospital with acute renal failure and a computed tomography scan revealed a pelvic tumor with a long axis of 10 cm that was obstructing the right ureter. Following insertion of a ureteral stent, the tumor was removed. The tumor had developed in the retroperitoneal space independent of the ovaries. The right adnexa were normal. The tumor was histopathologically diagnosed as dysgerminoma. Follicles were found in part of the tumor; it was thus hypothesized that the tumor developed from an ectopic ovary. The patient was administered etoposide after surgery, and has been recurrence-free for 4 years since treatment.