Catherine H. Han

Phase I drug-interaction study of effects of calcium and magnesium infusions on oxaliplatin pharmacokinetics and acute neurotoxicity in colorectal cancer patients

BackgroundCalcium and magnesium (Ca/Mg) infusions have been suggested as an effective intervention for preventing oxaliplatin-induced neurotoxicity, but the effects of Ca/Mg infusions on oxaliplatin pharmacokinetics, motor nerve hyperexcitability and acute neurotoxicity symptoms are unclear.MethodsIn this double blind crossover study, colorectal cancer patients undergoing oxaliplatin-based chemotherapy were randomised to receive Ca/Mg (1g Ca Gluconate plus 1g MgSO4) on cycle 1 and placebo (vehicle alone) on cycle 2, or to receive the same treatments in the opposite sequence. Study endpoints included plasma pharmacokinetics of intact oxaliplatin and free platinum; electromyography (EMG) detection of abnormal spontaneous high-frequency motor unit action potential discharges; and patient-reported acute neurotoxicity symptoms and their preferred study treatment for reducing these symptoms.ResultsNineteen of 20 enrolled patients completed the study. Plasma pharmacokinetics of intact oxaliplatin and free platinum were similar when oxaliplatin was given with Ca/Mg or placebo (ratio of geometric means of AUC0-t with Ca/Mg or placebo: intact oxaliplatin, 0.95 (90% CI, 0.90 – 1.01); free platinum, 0.99 (90% CI, 0.94 – 1.05)). EMG motor nerve hyperexcitability scores were similar with Ca/Mg and placebo (mean difference in EMG score between Ca/Mg and placebo: -0.3 (95% CI, -2.2 – 1.6)). Patient-reported acute neurotoxicity symptoms were similar in frequency with Ca/Mg and placebo. For reducing neurotoxic symptoms, fewer patients preferred Ca/Mg than placebo or neither treatment (26% versus 74%; P<0.01).ConclusionsCa/Mg infusions do not alter the clinical pharmacokinetics of oxaliplatin and do not seem to reduce its acute neurotoxicity.Trial registrationTrial registration identifier ACTRN12611000738921

Chemotherapy-induced reversible posterior leucoencephalopathy syndrome

Reversible posterior leucoencephalopathy syndrome is a neurological condition seen in various areas of acute medicine, including the administration of antineoplastic therapies used in haemato‐oncology patients. It is a rare complication that has been increasingly recognized. It is characterized by altered mental status, visual disturbance, headache and seizures. Magnetic resonance imaging typically shows vasogenic oedema in the posterior regions of the brain. Although its name suggests reversibility, it may result in an irreversible brain injury without prompt treatment. Therefore, it is vital for treating clinicians to recognize this syndrome. We describe the case of a 55‐year‐old woman with advanced pancreatic adenocarcinoma, who developed clinical and radiological manifestations consistent with this syndrome as a complication of gemcitabine monotherapy.

Muir-Torre syndrome-associated pleomorphic liposarcoma arising in a previous radiation field

Muir–Torre syndrome is a variant of Lynch syndrome, characterised by sebaceous neoplasia and/or keratoacanthomas associated with visceral malignancies. Muir–Torre syndrome is caused by germline mutations of one of the mismatch repair genes, frequently MSH2 and less frequently MLH1 and MSH6. Visceral malignancies associated with Muir–Torre syndrome and Lynch syndrome include colorectal, endometrial and other gastrointestinal, urological and gynaecological malignancies. Small numbers of Lynch syndrome-associated soft tissue sarcomas have been reported, but there are no reported cases of soft tissue sarcomas in Muir–Torre syndrome. In this study, we report a 74-year-old man with known Muir–Torre syndrome with confirmed MSH2 germline mutation, diagnosed with pleomorphic liposarcoma of the right buttock in a previous radiation field. The tumour showed loss of expression of MSH2 and MSH6 on immunohistochemistry. Immunohistochemistry on another pleomorphic liposarcoma in a different patient with no previous history of Muir–Torre syndrome or Lynch syndrome showed no loss of expression of mismatch repair proteins. This is the first report of Muir–Torre syndrome-associated sarcoma and the first case of post-radiation sarcoma in Lynch syndrome.

Predicting effects on oxaliplatin clearance: in vitro , kinetic and clinical studies of calcium- and magnesium-mediated oxaliplatin degradation

This study evaluated the impact of calcium and magnesium on the in vitro degradation and in vivo clearance of oxaliplatin. Intact oxaliplatin and Pt(DACH)Cl2 were measured in incubation solutions by HPLC-UV. A clinical study determined changes in plasma concentrations of calcium and magnesium in cancer patients and their impact on oxaliplatin clearance. Kinetic analyses modelled oxaliplatin degradation reactions in vitro and contributions to oxaliplatin clearance in vivo. Calcium and magnesium accelerated oxaliplatin degradation to Pt(DACH)Cl2 in chloride-containing solutions in vitro. Kinetic models based on calcium and magnesium binding to a monochloro-monooxalato ring-opened anionic oxaliplatin intermediate fitted the in vitro degradation time-course data. In cancer patients, calcium and magnesium plasma concentrations varied and were increased by giving calcium gluconate and magnesium sulfate infusions, but did not alter or correlate with oxaliplatin clearance. The intrinsic in vitro clearance of oxaliplatin attributed to chloride-, calcium- and magnesium-mediated degradation predicted contributions of <2.5% to the total in vivo clearance of oxaliplatin. In conclusion, calcium and magnesium accelerate the in vitro degradation of oxaliplatin by binding to a monochloro-monooxalato ring-opened anionic intermediate. Kinetic analysis of in vitro oxaliplatin stability data can be used for in vitro prediction of potential effects on oxaliplatin clearance in vivo.

Genetic Characterization of Brain Metastases in the Era of Targeted Therapy

In the current era of molecularly targeted therapies and precision medicine, choice of cancer treatment has been increasingly tailored according to the molecular or genomic characterization of the cancer the individual has. Previously, the clinical observation of inadequate control of brain metastases was widely attributed to a lack of central nervous system (CNS) penetration of the anticancer drugs. However, more recent data have suggested that there are genetic explanations for such observations. Genomic analyses of brain metastases and matching primary tumor and other extracranial metastases have revealed that brain metastases can harbor potentially actionable driver mutations that are unique to them. Identification of genomic alterations specific to brain metastases and targeted therapies against these mutations represent an important research area to potentially improve survival outcomes for patients who develop brain metastases. Novel approaches in genomic testing such as that using cell-free circulating tumor DNA (ctDNA) in the cerebrospinal fluid (CSF) facilitate advancing our understanding of the genomics of brain metastases, which is critical for precision medicine. CSF-derived ctDNA sequencing may be particularly useful in patients who are unfit for surgical resection or have multiple brain metastases, which can harbor mutations that are distinct from their primary tumors. Compared to the traditional chemotherapeutics, novel targeted agents appear to be more effective in controlling the CNS disease with better safety profiles. Several brain metastases-dedicated trials of various targeted therapies are currently underway to address the role of these agents in the treatment of CNS disease. This review focuses on recent advances in genomic profiling of brain metastases and current knowledge of targeted therapies in the management of brain metastases from cancers of the breast, lung, colorectum, kidneys, and ovaries as well as melanoma.

Diagnosis and management of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non‐Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole‐brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High‐dose methotrexate (HD‐MTX)–based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced‐dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD‐MTX–based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced‐dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patients age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017;123:4314‐24.

Primary Central Nervous System Lymphoma

ABSTRACT Purpose of Review: Primary central nervous system (CNS) lymphoma is a rare and aggressive extranodal non-Hodgkin lymphoma confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. This article provides an overview of the clinical features, diagnosis, and management of primary CNS lymphoma in patients who are immunocompetent, focusing on recent advances in treatment. Recent Findings: Primary CNS lymphoma is sensitive to radiation therapy; however, whole-brain radiation therapy inadequately controls the disease when used alone and causes delayed neurotoxicity with significant neurocognitive impairment, especially in patients who are elderly. A number of clinical trials have demonstrated durable disease control and less neurotoxicity with methotrexate-based induction chemotherapy with or without autologous stem cell transplantation or reduced-dose whole-brain radiation therapy. Summary: Prompt diagnosis and initiation of treatment are vital to improving clinical outcomes in patients with primary CNS lymphoma. The optimal treatment has yet to be defined, but high-dose methotrexate-based induction chemotherapy is considered standard for newly diagnosed primary CNS lymphoma. Ongoing randomized trials will attempt to address the roles of rituximab and consolidative treatment using autologous stem cell transplantation or reduced-dose whole-brain radiation therapy. Despite high tumor response rates to initial treatment, many patients will relapse. The choice of salvage treatment will depend on age, previous treatment and response, performance status, and comorbidities at the time of relapse.

Primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL), confined to the brain, eyes, spinal cord or leptomeninges without systemic involvement. Overall prognosis, diagnosis and management of PCNSL differ from other types of NHL. Prompt diagnosis and initiation of treatment are vital to improving clinical outcomes. PCNSL is responsive to radiation therapy, however whole-brain radiotherapy (WBRT) inadequately controls the disease when used alone and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined, however HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials address the role of rituximab, and of consolidative treatment using ASCT or reduced-dose WBRT. Despite high tumor response rates to initial treatment, many patients have relapsing disease with very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on age, previous treatment and response, performance status and comorbidities at the time of relapse. Novel therapeutics targeting underlying tumor biology include small molecule inhibitors of B-cell receptor, cereblon, and mammalian target of rapamycin signaling, and immunotherapy programmed cell death 1 receptor inhibitors and chimeric antigen receptor T cells.

Muir–torre syndrome-associated pleomorphic liposarcoma arising in a previous radiation field

Background: Muir–Torre syndrome is a variant of Lynch syndrome, characterised by sebaceous neoplasia and/or keratoacanthomas associated with visceral malignancies. Muir–Torre syndrome is caused by germline mutations of one of the mismatch repair genes, frequently MSH2 and less frequently MLH1 and MSH6. Visceral malignancies associated with Muir–Torre syndrome and Lynch syndrome include colorectal, endometrial and other gastrointestinal, urological and gynaecological malignancies. Small numbers of Lynch syndrome-associated soft tissue sarcomas have been reported but there are no reported cases of soft tissue sarcomas in Muir–Torre syndrome. Aim and Methods: In this study, we report a 74-year-old man with known Muir–Torre syndrome with confirmed MSH2 germline mutation, diagnosed with pleomorphic liposarcoma of the right buttock in a previous radiation field. The tumour showed loss of expression of MSH2 and MSH6 on immunohistochemistry. Results: Immunohistochemistry on another pleomorphic liposarcoma in a different patient with no previous history of Muir–Torre syndrome or Lynch syndrome showed no loss of expression of mismatch repair proteins. Discussion: This is the first report of Muir–Torre syndrome-associated sarcoma and the first case of post-radiation sarcoma in Lynch syndrome.

Neuropathies associated with oxaliplatin therapy

This issue of the Asia-Pacific Journal of Clinical Oncology reports two cases of rare neurological complications following oxaliplatin-based chemotherapy. Two recent reports in other issues of the journal highlight efforts to predict and prevent neurological side-effects of oxaliplatin. These reports are discussed in this editorial in the broader context of neuropathies associated with oxaliplatin therapy. Combination chemotherapy regimens based on oxaliplatin plus a fluoropyrimidine have become important treatment options for colorectal and other gastrointestinal cancers in both the adjuvant and palliative settings. Three pivotal adjuvant trials (MOSAIC, NSABP C-07 and NO 16968/XELOXA) showed significant improvements in disease-free and overall survival, with relative risk reductions of about 20 and 15%, respectively, when oxaliplatin was added to either 5-fluorouracil (5-FU) or capecitabine as adjuvant treatment after resection of stage III colorectal cancer. In metastatic colorectal cancer, phase III trials demonstrated that the addition of oxaliplatin to a fluoropyrimidine significantly prolonged progression-free survival and increased tumor response rates compared to a fluoropyrimidine alone, as both first-line and second-line treatment. In patients with previously untreated advanced esophagogastric cancer, a phase III trial (REAL-2) showed that oxaliplatin was at least as effective as cisplatin with respect to overall survival. A more recent analysis suggested that an epirubicin-oxaliplatin-capecitabine regimen was superior to an epirubicin-cisplatin-5-FU regimen with respect to overall survival in metastatic esophagogastric cancer. In advanced pancreatic cancer, a recent phase III trial (PRODIGE 4/ACOORD 11) showed significant improvements in tumor response rates, progression-free and overall survival with a regimen consisting of oxaliplatin, 5-FU and irinotecan (FOLFIRINOX) compared to single-agent gemcitabine, as first-line treatment. Together, these clinical studies provide strong evidence for the use of oxaliplatin as a standard treatment for colorectal and other gastrointestinal cancers. In this issue of the Asia-Pacific Journal of Clinical Oncology, Yoon et al. report a case of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) in a patient with advanced cholangiocarcinoma after receiving the biweekly infusional 5-FU plus oxaliplatin FOLFOX6 chemotherapy regimen. The clinical presentation of this case was consistent with AIDP and its diagnosis was supported by the results of nerve conduction studies and cerebrospinal fluid analysis. To our knowledge, this is the second case of AIDP reported in a cancer patient after oxaliplatin-based chemotherapy. In addition to oxaliplatin both patients received concurrent 5-FU therapy that may have been the main causative agent or contributed to the development of this neuropathy. Markedly abnormal sensory nerve conduction study findings in the Yoon et al. patient were not typical of AIDP, but may be explained by superimposed peripheral sensory neuropathy associated with oxaliplatin therapy as this patient had received a cumulative dose of 780 mg/m of oxaliplatin. AIDP is the commonest variant of Guillain-Barré syndrome and a demyelinating neuropathy characterized by rapidly ascending paralysis involving the extremities in a symmetrical pattern and in some cases, also the cranial nerves and respiratory musculature. Autonomic dysfunction is common that may affect orthostatic blood pressure control, bladder and bowel function. Recovery is incomplete in up to 20% of patients. I.v. immunoglobulin, when given early, may reduce the maximum functional deficit and accelerate recovery. Pathogenesis of GuillainBarré syndrome/AIDP associated with cancer therapy is poorly understood, but immune reaction associated with anticancer treatment may enhance immunologically mediated myelin sheath damage catalyzed by the tumor epitope. It has been suggested that elevation of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, induced by oxaliplatin may lead to the immune-mediated demyelination resulting in Guillain-Barré syndrome. It is important for oncologists to be aware of the possibility of AIDP complicating oxaliplatin therapy for its earlier recognition and management. Also in this issue, Femia et al. report a case of another rare neurological complication following oxaliplatinbased chemotherapy. The patient presented with symptoms that were consistent with posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leucoencephalopathy syndrome. bs_bs_banner