Cyclophosphamide, Vincristine And Dacarbazine Research Articles

Phase II clinical trial of axitinib in metastatic pheochromocytomas and paraganlgiomas (P/PG): Preliminary results.

457 Background: Malignant pheochromocytoma/paraganglioma (P/PG) is a rare malignancy. Management of metastatic disease includes surgery, external radiation, 131I-MIBG and systemic chemotherapy. CVD (cyclophosphamide, vincristine and dacarbazine) is the only chemotherapy commonly used to treat metastatic disease. Putative anti-angiogenic agents such as the tyrosine kinase inhibitor (TKI) axitinib target a well-recognized pathway thought to be active in many tumors. Methods: Patients with histologically confirmed P/PG previously treated or naive to treatment received axitinib at initial dose of 5 mg BID. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival, response rate and safety. Results: Between January and September 2014 nine patients have been enrolled. The median age was 54.7 years, (range 42.5 – 70.5); median number of previous systemic treatments was one (range 0 – 3). Three of the nine patients achieved a partial response. An additional 5 patients have had tumor shrinkage insufficient to qualify as a partial response with only one patient response scored as progression. Tumor shrinkage has been observed in lymph node, soft tissue and lung metastases; and has been associated with reductions in circulating cathecholamines. Median time to progression has not been reached. A total of 50 cycles have been administered. Toxicity has led to a reduction of the dose of axitinib from a starting dose of 5 mg BID to 3 mg BID in six and 2 mg BID in two patients. The axitinib dose could be increased to 7 mg BID in only one patient Principal grade 3-4 toxicities included hypertension (6 patients), fatigue (4 patients), diarrhea (1 patient) and mucositis (1 patient). Conclusions: Preliminary data shows axitinib can result in tumor shrinkage in patients with a diagnosis of malignant P/PG. The high rate of dose reduction related to toxicity may reflect a different pharmacokinetic profile of the drug in these patients a possibility now under investigation. Clinical trial information: NCT01967576.

P3-30-4 - A Case of Metastatic Paraganglioma with Good Response to Combination of Cyclophosphamide, Vincristine and Dacarbazine

Sympathetic paragangliomas are rare neuroendocrine tumors.Patients with progressive metastatic tumors are currently treated with systemic chemotherapy. We had a metastatic paraganglioma with good response to combination of cyclophosphamide, vincristine and dacarbazine(CVD).A 53-year-old woman underwent tumor resection of retroperitoneal paraganglioma in 2005. She had a repeat surgery of recurrence lesion in 2008. 2012, she had back pain, and computated tomography and MRI showed multiple bone metastasis.Radiation and CVD chemotherapy resulted in tumor regression and marked improvement of clinical symptoms.The combined chemotherapy with CVD appears to be effective for progressive metastatic paragangliomas.

Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis.

Chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD) can be used for palliative treatment of malignant pheochromocytoma and paraganglioma. However, the precise effect of this chemotherapeutic regimen on tumour volume is unclear. The main objective of this study was to perform a systematic review and meta-analysis assessing the effect of chemotherapy with CVD on tumour volume in patients with malignant paraganglioma/pheochromocytoma. A literature search was performed in October 2013 to identify potentially relevant studies. Main outcomes were the pooled percentages of complete response, partial response and stable disease after chemotherapy with CVD. A meta-analysis was performed with an exact likelihood approach using a logistic regression. Pooled percentages with 95% confidence intervals (CI) were reported. Four studies concerning a total of 50 patients with malignant paraganglioma/pheochromocytoma reported on treatment with a combination of CVD chemotherapy. A meta-analysis of the effect of chemotherapy on tumour volume showed pooled percentages of complete response, partial response and stable disease of, respectively, 4% (95% CI: 1%-15%), 37%(95% CI: 25%-51%) and 14% (95% CI: 7%-27%). Only two studies concerning a total of 35 patients assessed the response on catecholamine excess; pooled percentages for complete, partial and stable hormonal response were 14% (95% CI: 6%-30%), 40% (95% CI: 25%-57%) and 20% (95% CI: 10%-36%), respectively. Duration of response was also reported in only two studies with a median duration of response of 20months and 40months. Data on the effects of a combination of CVD chemotherapy on malignant paraganglioma/pheochromocytoma suggest that a partial response concerning tumour volume can be achieved in about 37% of patients and a partial response on catecholamine excess in about 40% of patients. However, in the included studies, the protocol when to initiate treatment was not well described. Therefore, it cannot be excluded that the reported effect of chemotherapy on tumour volume reflects the natural course of the disease, at least partially.

Metastatic paraganglioma: management of orthostatic hypotension – a case report

Paragangliomas, also referred to as extra-adrenal phaeochromocytomas, are neoplasms of extra-adrenal chromaffin tissue which synthesise cathecholamines.1 The increased production and release of catecholamines causes symptoms as a result of excess alpha- and beta-adrenoceptor stimulation. These may include headaches, palpitations and profuse sweating. On examination hypertension and tachycardia may be present, although these can be paroxysmal.2 Chromaffin cell tumours are extremely rare, and about 5–10% of these comprise paragangliomas located in the para-aortic sympathetic chains or the urinary bladder; least commonly, paragangliomas are found in the thoracic or head and neck regions.3 Although most commonly benign, they can occasionally (approximately 3% of paragangliomas) be malignant, with either local invasion (gross or microscopic), seen at the time of primary resection, or distant metastatic spread, which is usually only recognised at tumour recurrence.4 Malignant disease can often be successfully managed with high-dose radiolabelled metaiodobenzylguanidine (MIBG)5 with or without combination chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD).6 The rarity of the disease means the evidence base of management is currently relatively poor. Orthostatic hypotension can also be present with cathecholamine-secreting tumours. 7 It can be defined as more than 20mmHg fall in systolic blood pressure (BP) and/or more than 10mmHg fall in diastolic BP, over a 2 minute period after standing.8 The aetiological basis of orthostatic hypotension in this context remains unclear. For some time it has been postulated that the increase in circulating catecholamines leads to depression of sympathetic vascular response, due to alpha-adrenoceptor down-regulation; reduced blood volume is also thought to be involved, as a consequence of pressure-induced natriuresis especially when hypertension is severe and paroxysmal.9,10 It has also been proposed that sympathetic vascular modulation is involved in the aetiology.11 The existing literature contains reports of orthostatic hypotension in benign disease, where measures such as increased fluid and salt intake have been used with some success. However, in the rare cases of malignant disease, with or without distant metastases, very little has been described as regards how best to manage this debilitating and poorly understood symptom. Here we describe a case of in- and out-patient management of orthostatic hypotension in a patient with metastatic paraganglioma.

Survival of Patients with Metastatic Malignant Pheochromocytoma and Efficacy of Combined Cyclophosphamide, Vincristine, and Dacarbazine Chemotherapy

About 10% of pheochromocytomas are malignant. Exact survival has not been reported, nor has an analysis of the efficacy of chemotherapy on survival time. The aim of this study was to analyze the survival curves and survival times of patients with malignant pheochromocytoma and to determine the efficacy of chemotherapy on prolongation of life. An inception cohort and Kaplan-Meier survival analysis was conducted. Thirty-two patients with metastasized malignant pheochromocytoma were analyzed for survival. Twenty-five patients had undergone excision of their primary tumors. Survival curves were compared among the 16 patients in this group treated with combined chemotherapy using cyclophosphamide, vincristine and dacarbazine (CVD) and the nine patients not treated with chemotherapy. The survival curve of the 32 patients declined continuously and linearly to at least 20 yr after the diagnosis of pheochromocytoma. The 50% survival rate was estimated to be 14.7 yr. In the 25 patients whose primary tumor was excised, patients who already had metastases at the time of pheochromocytoma diagnosis had better survival than those whose metastases were found later. The survival rate after diagnosis of metastasis was worse in the CVD group than in controls. When the effects of CVD were examined after stratifying several factors, female gender and adrenal origin of tumor were found to be negative prognostic factors for CVD chemotherapy. The present study revealed a long survival time. CVD chemotherapy was not shown to extend survival, especially for women and patients with adrenal gland-derived primary tumors.

The management of benign and malignant pheochromocytoma and abdominal paraganglioma

Aims: To report treatment and outcome in patients with malignant and benign pheochromocytoma and abdominal paraganglioma.Methods: Review of clinical and therapeutic features in 85 patients with pheochromocytoma or abdominal paraganglioma between 1976 and 1999.Results: Thirty-nine of 85 patients presented with symptoms other than classical paroxysmal attacks. Paragangliomas were more often malignant (7/15) than pheochromocytomas (7/70). No recurrences have occurred in 71 patients with tumours initially classified as benign after a median follow-up time of 144 months (range 7–287). Nine of 14 patients with tumours classified as malignant have developed metastasis and/or local recurrence. Treatment of malignant tumours with cyclophosphamide, vincristine and dacarbazine (CVD) improved or stabilised the disease in three of four patients.Conclusion: Life long follow-up of patients with benign pheochromocytoma is not necessary. Combination chemotherapy (CVD) is a valid option in the treatment of malignant pheochromocytomas and abdominal paragangliomas.

The role of chemotherapy in the nonsurgical management of malignant neuroendocrine tumours.

1993). The initial management of NET comprises surgical excision of the primary tumour (aimed at reducing as much as possible of the tumour mass); additionally, in patients who are not cured by surgery alone, medical therapy is used for the control of symptoms and humoral syndromes with agents such as somatostatin analogues and/or a-interferon. Specific therapy with radiopharmaceuticals using radio-labelled substances such as meta-iodobenzylguanidine (MIBG) or somatostatin analogues appears promising for some tumours which show diagnostic uptake, and is the first-line systemic management for sensitive cases. Hepatic artery ligation and/or chemoembolization is also used in patients with excessive hepatic tumour load and uncontrollable symptoms. The control of tumour growth with chemotherapeutic agents is currently mainly reserved for patients with recurrent and/or progressive disease and where other therapeutic modalities have failed. Chemotherapy may be particularly helpful for selected cases of advanced NET, especially pancreatic or poorly differentiated NET. This review deals with the general role of chemotherapy in the management of malignant NET, its integration with other modes of therapy, and the specific protocols which have been used. Histological classification and differentiation of NET

悪性褐色細胞腫に対するCVD療法と選択的動脈塞栓療法による治療

We performed combination therapy with cyclophosphamide, Vincristine and Dacarbazine (CVD) regimen and transarterial embolization (TAE) in 2 cases of malignant pheochromocytoma with metastases. Case 1: 59-year-old female. After primary left adrenal lesion had been removed, recurrence at the left renal hilar region and metastases to the right iliac bone and 5th cervical vertebra occurred. We took 3 courses of CVD regimen after TAE for the lesions in the right iliac bone. Her endocrinological data has been normal for more than 1 year after treatment. Case 2: 29-year-old male. Total cystectomy, ileal conduit and pelvic lymphadenectomy had been performed for the primary lesion of the urinary bladder. 2 years after the 1st operation, metastases to the right obturator nodes and multiple bones occurred. We gave 3 courses of CVD regimen followed by TAE for the lesions in the right obturator nodes. Just after treatment, we could stop insulin and reduce anti-hypertension drugs, but the effect of treatment was temporary. In conclusion, combination of CVD regimen and TAE is effective for malignant pheochromocytoma with metastases.