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Sjoerd Rodenhuis - One of the best experts on this subject based on the ideXlab platform.
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Is High-Dose Chemotherapy dead?
European Journal of Cancer, 2005Co-Authors: Sjoerd RodenhuisAbstract:The story of High-Dose Chemotherapy in breast cancer is a remarkable one and it contains a number of valuable lessons for all of us. Many oncologists believe that this story has come to an end and that the further study of this treatment modality is no longer worthwhile. However, such a belief could be just as premature and thoughtless as the uncritical use of High-Dose Chemotherapy that was so common 10 years ago. Small phase I and II studies in the 1980s had shown that High-Dose Chemotherapy in advanced breast cancer was associated with unusually High complete response rates, and that long-term disease-free survival was observed in a proportion of patients [1]. Similar findings were reported from the American and European bone marrow transplant registries. Approximately 20% of patients with stage IV disease appeared to be free of disease five years after the transplant and this finding raised hope that breast cancer could eventually take its place among the malignancies that are curable by Chemotherapy. In 1993, a Highly provocative study was published by Peters and colleagues, which showed that High-Dose Chemotherapy administered in the adjuvant setting to patients with High-risk primary breast cancer could achieve a 5-year disease-free survival of 70%. This appeared to be dramatically superior to conventional Chemotherapy in historical controls [2]. Supported by a strong rationale derived from laboratory studies [3], but in the absence of data from randomised trials, High-Dose Chemotherapy was adopted as a potentially curative treatment option. Particularly in the United States, randomised studies with a conventional control arm were difficult to conduct since patients and doctors alike believed in the concept. As a result, the number
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Palliative Chemotherapy after failure of High-Dose Chemotherapy in breast cancer--toxicity and efficacy.
Anticancer research, 2003Co-Authors: J. G. Schrama, M. M. D. De Boer, Joke W. Baars, Jan H. Schornagel, Sjoerd RodenhuisAbstract:We evaluated the toxicity and efficacy of the first palliative Chemotherapy regimen after failure of High-Dose Chemotherapy in 148 patients with primary or metastatic breast cancer treated with High-Dose Chemotherapy (one full Dose CTC, (cyclophosphamide 6000 mg/m2, thiotepa 480 mg/m2, carboplatin 1600 mg/m2) or multiple courses CTC or 'tiny' CTC (tCTC) (two-thirds of the agents of the full-Dose regimen), all divided over 4 days). After a median follow-up time of 46.8 (range 1-120) months, 79 patients had a relapse or progressive disease and 41 patients were treated with palliative Chemotherapy. The most commonly used regimens were classical CMF (n = 13), docetaxel (n = 16) and less frequently anthracycline (n = 4), paclitaxel (n = 5), capecitabine (n = 2) and vinorelbine (n = 2). In both the CMF and docetaxel group, 3 patients required a Dose reduction because of hematological toxicity. Objective responses were seen with CMF (23%) and docetaxel (69%) with a median duration of 161 (range 28-481) and 196 (range 62-437) days, respectively. We found no relationship of toxicity and response with treatment-free interval after High-Dose Chemotherapy. This report shows that conventional-Dose palliative Chemotherapy regimens may be safe and effective after failure of High-Dose Chemotherapy.
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High-Dose Chemotherapy in breast cancer--interpretation of the randomized trials.
Anti-Cancer Drugs, 2001Co-Authors: Sjoerd RodenhuisAbstract:High-Dose Chemotherapy was widely viewed as an effective treatment modality in breast cancer until the preliminary results of randomized trials proved disappointing. When it transpired that the author of the two unequivocally positive studies had fabricated data, many decided that High-Dose Chemotherapy in breast cancer was no longer worth studying. In fact, however, the reported results from randomized studies are consistent with a modest progression-free survival advantage of High-Dose Chemotherapy over conventional Dose. Several more years of data maturation and the results of additional randomized trials must be awaited.
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The clinical pharmacology of alkylating agents in High-Dose Chemotherapy.
Anti-Cancer Drugs, 2000Co-Authors: Alwin D. R. Huitema, Sjoerd Rodenhuis, Karen Doesburg Smits, Ron A. A. Mathôt, Jan H.m. Schellens, Jos H. BeijnenAbstract:Alkylating agents are widely used in High-Dose Chemotherapy regimens in combination with hematological support. Knowledge about the pharmacokinetics and pharmacodynamics of these agents administered in High Doses is critical for the safe and efficient use of these regimens. The aim of this review is to summarize the clinical pharmacology of the alkylating agents (including the platinum compounds) in High-Dose Chemotherapy. Differences between conventional and High Doses will be discussed.
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The status of High-Dose Chemotherapy in breast cancer.
The Oncologist, 2000Co-Authors: Sjoerd RodenhuisAbstract:High-Dose Chemotherapy in breast cancer is a subject of considerable controversy. Preliminary results from several randomized trials have shown that it is certainly not the breakthrough hoped for in the early 1990s. The available data are, however, compatible with a modest but potentially important effect on relapse-free survival in the adjuvant treatment of High-risk breast cancer. To prove such an effect, several more years of maturation are required for a number of randomized studies. At this point in time, there is no justification for the use of HighDose Chemotherapy in breast cancer outside clinical studies. The Oncologist 2000;5:369-375
Edward A. Stadtmauer - One of the best experts on this subject based on the ideXlab platform.
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High Dose Chemotherapy and autologous stem cell transplantation for metastatic breast cancer: is there a place?
Breast Cancer Research and Treatment, 2003Co-Authors: Edward A. StadtmauerAbstract:Seven comparative trials with over 2000 patients enrolled show no definitive evidence that High Dose Chemotherapy with stem cell support offers a survival advantage for metastatic breast cancer over conventional Dose Chemotherapy. Though numbers are low and small differences may exist particularly in subsets of patients, the duration of follow-up is adequate to make the likelihood of a late benefit low. High Dose Chemotherapy with stem cell transplantation does not have a place in the treatment of metastatic breast cancer outside of clinical trials.
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High-Dose Chemotherapy and Stem Cell Support for Breast Cancer
Drugs & Aging, 2002Co-Authors: Renee M. Gerrero, Steven Stein, Edward A. StadtmauerAbstract:To date, there is no definitive evidence that High-Dose Chemotherapy and haematopoietic stem cell support offers a survival advantage over conventional-Dose Chemotherapy for metastatic or High-risk primary breast cancer. Studies of metastatic disease discussed in this review have an adequate duration of follow-up given the short natural history of metastatic breast cancer. Thus, the results of these studies are unlikely to change with a longer observation period. On the other hand, studies of High-Dose Chemotherapy in the treatment of High-risk primary breast cancer need longer follow-up in light of the longer natural history of this type of disease. Results of unpublished studies and longer follow-up of available studies may still demonstrate a survival advantage for High-Dose Chemotherapy in patients with metastatic or High-risk primary breast cancer. We continue to encourage participation in innovative clinical studies.
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High-Dose Chemotherapy and stem cell support for breast cancer: where are we now?
Drugs & Aging, 2002Co-Authors: Renee M. Gerrero, Steven Stein, Edward A. StadtmauerAbstract:To date, there is no definitive evidence that High-Dose Chemotherapy and haematopoietic stem cell support offers a survival advantage over conventional-Dose Chemotherapy for metastatic or High-risk primary breast cancer. Studies of metastatic disease discussed in this review have an adequate duration of follow-up given the short natural history of metastatic breast cancer. Thus, the results of these studies are unlikely to change with a longer observation period. On the other hand, studies of High-Dose Chemotherapy in the treatment of High-risk primary breast cancer need longer follow-up in light of the longer natural history of this type of disease. Results of unpublished studies and longer follow-up of available studies may still demonstrate a survival advantage for High-Dose Chemotherapy in patients with metastatic or High-risk primary breast cancer. We continue to encourage participation in innovative clinical studies.
E.g.e. De Vries - One of the best experts on this subject based on the ideXlab platform.
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Relevance of High-Dose Chemotherapy in solid tumours
Cancer Treatment Reviews, 2005Co-Authors: P Nieboer, E.g.e. De Vries, Nanno Mulder, W.t.a. Van Der GraafAbstract:Summary Drug resistance is a major problem in the treatment of solid tumours. Based on a steep Dose–response relationship for especially alkylating agents on tumour cell survival, High-Dose Chemotherapy was considered of interest for the treatment of solid tumours. Results of phase 1 and 2 studies with High-Dose Chemotherapy in a variety of tumour types showed good response rates. Nowadays, several phase 3 studies are available especially in metastatic and High-risk breast cancer patients. The High expectations of High-Dose Chemotherapy did not come true. This review analyses results of randomised studies and comments on the discrepancy between findings in patients versus those in tissue culture. Potential factors involved are the presence of tumour stem cells with different characteristics from more mature tumour cells, limitations in drug escalation in the clinic, transplant mortality, trial design and tumour cell contamination of the haematopoietic stem cell transplant. Maturation of the results from recent studies indicating a more modest benefit in, e.g., adjuvant breast cancer balanced versus long-term side effects will ultimately determine the role of High-Dose Chemotherapy in certain solid tumours. In case of well-defined indications for High-Dose Chemotherapy, further selection of patients based on patient and tumour characteristics as well as the introduction of new agents will most likely play a role.
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High-Dose Chemotherapy with stem cell support for solid tumors in adults
Nederlands tijdschrift voor geneeskunde, 1999Co-Authors: Sjoerd Rodenhuis, E.g.e. De VriesAbstract:High-Dose Chemotherapy for advanced solid malignancies has been the subject of many clinical studies. The replacement of autologous bone marrow transplantation by peripheral blood haematopoietic progenitor cell transplantation and other advances in supportive care have led to a considerable reduction of therapy-related mortality and morbidity. In certain rare disorders, such as germ cell tumours or pediatric sarcomas in adults, High-Dose therapy is currently considered the therapeutic standard. It is likely that a subgroup of patients with High-risk or disseminated breast cancer can also benefit in terms of survival from this treatment modality, but final proof from randomized studies remains to be generated. On theoretical grounds, High-Dose Chemotherapy could also be effective in small cell lung cancer and ovarian cancer, and randomized studies to answer this question are in progress. Many investigators concur that High-Dose Chemotherapy often leads to dramatic cytoreduction in solid tumours, but only rarely achieves cure. Novel therapeutic modalities are required to control the residual microscopic disease.
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Constrictive pericarditis after High-Dose Chemotherapy
The Lancet, 1997Co-Authors: J. E. Tulleken, Cghm Kooiman, T. S. Van Der Werf, Jan G. Zijlstra, E.g.e. De VriesAbstract:High-Dose Chemotherapy with autologous stem-cell support for the adjuvant treatment of breast cancer and metastatic breast cancer has become common. This approach may offer a survival advantage over standard-Dose therapy in women with earlier stage disease and in those who respond to pretransplant Chemotherapy. We describe a patient who developed life-threatening constrictive pericarditis 8 weeks after High-Dose Chemotherapy. A 52-year-old woman presented with progressive dyspnoea and fatigue. Her past history revealed a mastectomy plus lymph-node dissection for breast cancer. Thereafter she participated in a trial comparing High-Dose with standardDose Chemotherapy as adjuvant treatment for breast cancer patients with four or more positive axillary lymph nodes. Treatment consisted of four courses of fluorouracil 500 mg/m, epirubicin 90 mg/m, and cyclophosphamide 500 mg/m daily every 3 weeks, followed by High-Dose Chemotherapy with cyclophosphamide (6 g/m), carboplatin (1600 mg/m), and thiotepa (480 mg/m) (CTC regimen) divided over 4 days. On day 7, peripheral stem-cell reinfusion was administered. 2 months after CTC a pericardial effusion developed without signs of tamponade. Transthoracic echocardiogram showed normal right and left ventricular function and a pericardial effusion of 2 cm but no evidence of right ventricular inflow limitation. No increase in viral antibody titres was noted and cultures taken from the blood, sputum, and urine were negative. The symptomless pericardial effusion was ascribed to the use of cyclophosphamide and consequently no pericardial tap was done. She was treated with furosemide. Short term followup was uneventful. After 2 weeks she was admitted because of exertional dyspnoea. Distended neck veins, pulsus paradoxus of 30 mm Hg, a decrease voltage in the electrocardiogram, and liver function disturbances were found. Transthoracic echocardiogram suggested normal left and right ventricular function and in particular no pericardial effusion. Swan-Ganz catheterisation showed, however, equalisation of right and left ventricular filling pressures compatible with constrictive pericarditis. She had a midsternal thoracotomy. Dense pericardial adhesions were seen at the right ventricular entry and pericardial stripping was performed. Cardiac performance strongly improved after surgery. Histologically, the surgical specimen revealed pericardial thickening due to proliferation of myofibroblasts. Specimens of pleural fluid and pericardial tissue were examined for microorganisms including mycobacteria, fungi, and viruses; all direct stains and cultures were negative. In addition, there was no evidence of connective-tissue diseases, mechanical trauma, myocardial infarction, or infiltration with malignant cells. The patient’s condition improved; 2 weeks later she was discharged in an excellent cardiopulmonary condition. After 3 months she fully resumed her domestic duties and job. Our patient developed a life-threatening but potentially reversible complication within 3 months of High-Dose Chemotherapy. The cause of this constrictive pericarditis was not established but it may be associated with High-Dose Chemotherapy. The CTC regimen is the most frequently used High-Dose treatment schedule for breast cancer. When more frequent causes of dyspnoea such as pleural effusion, left ventricular failure, and malignancy have been excluded the clinician should be alerted to this potential complication of High-Dose Chemotherapy. 1 Gradishar WJ, Tallman MS, Abrams JS. High-Dose Chemotherapy for breast cancer. Ann Intern Med 1996; 125: 599–604. 2 Antman KH, Rowlings PA, Vaughan WP, et al. High-Dose Chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America. J Clin Oncol 1997; 15: 1870–79. 3 de Vries EGE, ten Vergert EM, Mastenbroek CG, Dalieso O, Rodenhuis S. Breast cancer studies in the Netherlands. Lancet 1996; 348: 407–08. 4 Braverman AC, Antin JH, Plappert MT, Cook EF, Lee RT. Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens. J Clin Oncol 1991; 9: 1215–23.
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High-Dose Chemotherapy with stem cell reinfusion and growth factor support for solid tumors.
Stem Cells, 1995Co-Authors: E.g.e. De Vries, W.t.a. Van Der Graaf, H. De Graaf, A. Boonstra, Nh MulderAbstract:With the help of stem cell reinfusion and hematopoietic growth factors, it is possible to get up to a ten-fold Dose increase for certain chemotherapeutic drugs, A number of reasons may have made High-Dose Chemotherapy less dangerous and the fore more acceptable in a more upfront treatment setting, One of these is the addition of peripheral stem cell harvest obtained after mobilization,vith a hematopoietic growth factor alone or after Chemotherapy followed by a hematopoietic growth factor, which seems to result in a faster recovery of neutrophils and platelets compared to bone marrow reinfusion alone, The combination of various hematopoietic growth factors could potentially improve hematopoietic recovery of the High-Dose Chemotherapy regimen, The relevance of tumor cells sometimes present in the reinfused hematopoietic stem cells is as yet unknown. High-Dose Chemotherapy may be interesting for a number of solid tumors such as nonseminomatous testicular carcinoma, breast carcinoma in the metastatic and adjuvant setting, ovarian carcinoma, tumors of young adults such as Ewing sarcoma and small cell lung carcinoma, In patients with refractory nonseminomatous testicular cancer there have been a number of studies performed with High-Dose Chemotherapy showing a 15% complete and prolonged remission, For other tumor types and settings it will be necessary to perform randomized studies before firm conclusions can be drawn, For example, this is especially important for patients with breast carcinoma with more than three positive axillary lymph nodes, Preliminary data from various groups compared to historical controls treated with standard adjuvant Chemotherapy show favorable results of adjuvant Chemotherapy containing High-Dose Chemotherapy, Many relatively small nonrandomized studies are performed in various stages of disease for ovarian carcinoma, Although there are long-term survivors reported it is currently difficult to draw firm conclusions, The potentially safer therapy of High-Dose Chemotherapy may reveal in the near future the role of High-Dose Chemotherapy in solid tumors.
Renee M. Gerrero - One of the best experts on this subject based on the ideXlab platform.
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High-Dose Chemotherapy and Stem Cell Support for Breast Cancer
Drugs & Aging, 2002Co-Authors: Renee M. Gerrero, Steven Stein, Edward A. StadtmauerAbstract:To date, there is no definitive evidence that High-Dose Chemotherapy and haematopoietic stem cell support offers a survival advantage over conventional-Dose Chemotherapy for metastatic or High-risk primary breast cancer. Studies of metastatic disease discussed in this review have an adequate duration of follow-up given the short natural history of metastatic breast cancer. Thus, the results of these studies are unlikely to change with a longer observation period. On the other hand, studies of High-Dose Chemotherapy in the treatment of High-risk primary breast cancer need longer follow-up in light of the longer natural history of this type of disease. Results of unpublished studies and longer follow-up of available studies may still demonstrate a survival advantage for High-Dose Chemotherapy in patients with metastatic or High-risk primary breast cancer. We continue to encourage participation in innovative clinical studies.
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High-Dose Chemotherapy and stem cell support for breast cancer: where are we now?
Drugs & Aging, 2002Co-Authors: Renee M. Gerrero, Steven Stein, Edward A. StadtmauerAbstract:To date, there is no definitive evidence that High-Dose Chemotherapy and haematopoietic stem cell support offers a survival advantage over conventional-Dose Chemotherapy for metastatic or High-risk primary breast cancer. Studies of metastatic disease discussed in this review have an adequate duration of follow-up given the short natural history of metastatic breast cancer. Thus, the results of these studies are unlikely to change with a longer observation period. On the other hand, studies of High-Dose Chemotherapy in the treatment of High-risk primary breast cancer need longer follow-up in light of the longer natural history of this type of disease. Results of unpublished studies and longer follow-up of available studies may still demonstrate a survival advantage for High-Dose Chemotherapy in patients with metastatic or High-risk primary breast cancer. We continue to encourage participation in innovative clinical studies.
Borje S Andersson - One of the best experts on this subject based on the ideXlab platform.
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randomized trial of High Dose Chemotherapy and blood cell autografts for High risk primary breast carcinoma
Journal of the National Cancer Institute, 2000Co-Authors: Gabriel N. Hortobagyi, Aman U Buzdar, Richard L Theriault, Vicente Valero, Debra Frye, Daniel J Booser, F A Holmes, Sergio Giralt, Issa F Khouri, Borje S AnderssonAbstract:Background: Uncontrolled studies have reported encouraging outcomes for patients with High-risk primary breast cancer treated with High-Dose Chemotherapy and autologous hematopoietic stem cell support. We conducted a prospective randomized trial to compare standard-Dose Chemotherapy with the same therapy followed by High-Dose Chemotherapy. Patients and Methods: Patients with 10 or more positive axillary lymph nodes after primary breast surgery or patients with four or more positive lymph nodes after four cycles of primary (neoadjuvant) Chemotherapy were eligible. All patients were to receive eight cycles of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC). Patients were stratified by stage and randomly assigned to receive two cycles of High-Dose cyclophosphamide, etoposide, and cisplatin with autologous hematopoietic stem cell support or no additional Chemotherapy. Tamoxifen was planned for postmenopausal patients with estrogen receptor-positive tumors and chest wall radiotherapy was planned for all. All P values are from two-sided tests. Results: Seventy-eight patients (48 after primary surgery and 30 after primary Chemotherapy) were registered. Thirty-nine patients were randomly assigned to FAC and 39 to FAC followed by High-Dose Chemotherapy. After a median follow-up of 6.5 years, there have been 41 relapses. In intention-to-treat analyses, estimated 3-year relapse-free survival rates were 62% and 48% for FAC and FAC/High-Dose Chemotherapy, respectively (P = .35), and 3-year survival rates were 77% and 58%, respectively (P = .23). Overall, there was greater and more frequent morbidity associated with High-Dose Chemotherapy than with FAC; there was one septic death associated with HighDose Chemotherapy. Conclusions: No relapse-free or overall survival advantage was associated with the use of High-Dose Chemotherapy, and morbidity was increased with its use. Thus, High-Dose Chemotherapy is not indicated outside a clinical trial. [J Natl Cancer Inst 2000;92:225‐33] Patients with stage III breast cancer or patients with stage II breast cancer and multiple positive axillary lymph nodes have an approximately 80% relapse rate at 5 years if treated only with locoregional therapy (1‐3). With optimal combined modality therapies, approximately 30% of the patients with stage IIIB breast cancer, 50% of those with stage IIIA breast cancer, and