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PubMed1996

Autologous Stem Cell Transplants Taking Breast and Ovarian Cancer Chemotherapy to New Heights.

Traditional chemotherapy regimens for advanced breast cancer have produced complete response (CR) rates of 5%-25% and remissions of 5-13 months. Autologous stem cell transplantation (ASCT), however, permits a 5- to 10-fold escalation of chemotherapy, which results in a substantial increase in tumor-cell killing relative to standard therapy. This technique involves protecting hematopoietic function by collecting stem cells from bone marrow or peripheral blood before subjecting the patient to high-dose chemotherapy. These stem cells are then reinfused in an autologous bone marrow transplant (ABMT) or autologous blood stem cell transplant (ABSCT) to quickly repopulate the patient's marrow and blood. The largest and most mature of phase II trials of ASCT for metastatic breast cancer reports rates of 35%-68% and 4-year survival rates of 19%-27%. Although most patients develop recurrent disease 6-12 months post-ASCT, it is encouraging that a few patients survive, disease-free, beyond 5 years. The Autologous Blood and Marrow Transplant Registry analyzed data on more than 800 patients with metastatic breast cancer who underwent ASCT. The Registry reported a 3-year progression-free survival rate of 20% and an overall survival rate of 37%, which compares favorably with an expected 17%-25% 3-year survival rate after conventional chemotherapy. Whether similar success can be achieved with ASCT in ovarian cancer is uncertain because few ovarian cancer patients are presently entered in high-dose studies using ASCT support.

Journal Article↗
PubMed2006

Prophylaxis of central venous catheter-related thrombosis with minidose warfarin in patients treated with high-dose chemotherapy and peripheral-blood stem-cell transplantation: retrospective analysis of 228 cancer patients.

Patients with a central venous catheter (CVC) undergoing high-dose chemotherapy (HDC) followed by peripheral-blood stem-cell transplantation (PBSCT) for malignancies are at high risk of thrombosis, but the use of anti-coagulant prophylaxis remains debatable in this setting of patients. We analyzed the efficacy and the safety of minidose warfarin in 228 patients in whom CVCs had been placed and who had received 292 HDC courses of therapy. The catheters remained in place for a mean of 173 (range 40-298) days. All patients received prophylactic oral warfarin in the fixed dose of 1 mg/day starting on the day of CVC insertion. Prophylaxis was interrupted during aplasia when platelet counts fell below 50,000/dL. There were no toxic deaths related to the prophylaxis. Overall there were 4 thrombotic events. Three occurrences were directly related to the catheter, while the remaining event was a deep saphenous-vein thrombosis. A number of potential predictive factors were analyzed for their impact on thrombotic events without finding any significant correlation. Four episodes of bleeding occurred, with each of these individuals having a normal INR but a platelet count below 50,000/dL. Minidose warfarin is effective and safe to use for preventing thrombotic events in this setting of patients.

Administration, Oral↗
PubMed2000

A phase I dose escalation study of multicyclic, dose-intensive chemotherapy with peripheral blood stem cell support for small cell lung cancer.

A phase I dose-escalation study of multicyclic, ifosfamide, carboplatin, and etoposide (ICE) with sequential reinfusion of peripheral blood stem cells (PBSCs) was conducted to determine the maximum-tolerated dose (MTD) of ICE. Twenty-four patients with SCLC (LD: 6, ED: 18) were treated with ifosfamide (3000-9000 mg/m2, 24-h infusion), carboplatin (300-400 mg/m2), and etoposide (300 mg/m2) followed by subcutaneous filgrastim (75 microg/day) from day 4 to the day of PBSC collection. PBSC were harvested when the WBC count reached >/=5 x 109/l. The leukapheresis product was cryopreserved and reinfused on day 4 of the next cycle, which was started 48 h after the last PBSC collection. The ifosfamide dose was escalated as follows: 3000 mg/m2 (level 1), 5000 mg/m2 (level 2), 7000 mg/m2 (level 3), 9000 mg/m2 (level 4). Patients with LD were treated with concurrent radiotherapy at 1.5 Gy twice daily for the initial 3 weeks to a total dose of 45 Gy and MTD, defined separately. Patients were evaluated for hematologic and non-hematologic toxicity, actual dose intensities, as well as response to therapy. The maximum-tolerated dose (MTD) was defined as the dose level at which more than 5 days of grade 4 myelo- suppression or non-hematologic toxicity greater than grade 3 developed in two thirds of the patients. For ED cases, MTD was level 4 and the recommended dose of ifosfamide was 7000 mg/m2. For LD cases, the recommended dose of ifosfamide was 5000 mg/m2. The dose limiting toxicity of multicyclic ICE was hemato- logic toxicity and CNS toxicity which manifested as ataxia. Tumor responses were seen in all patients, with 14 patients showing a complete response. The actual total dose-intensity at the recommended dose level was 2.2 and 1.74, for ED and LD, respectively, compared with previously reported ICE regimens. PBSC support for dose-intensive ICE regimen permitted dose escalation of ifosfamide with a mean interval of 16-17 days. We conclude that this regimen is well tolerated, with acceptable hematological and non-hematological toxicity. Bone Marrow Transplantation (2000) 25, 5-11.

Adult↗
PubMed1996

The toxicity of radiotherapy following high-dose chemotherapy with peripheral blood stem cell support in high-risk breast cancer: a preliminary analysis.

High-dose chemotherapy with autologous bone marrow and/or peripheral blood stem cell (PBSC) support is increasingly employed in the adjuvant treatment of high-risk breast cancer. Subsequent radiotherapy has been reported to be associated with morbidity and mortality resulting from pulmonary toxicity. In addition, the course of radiation therapy may be hampered by excess myelosuppression. The aim of this study was to investigate the contribution to radiation-induced toxicity of a high-dose chemotherapy regimen (CTC) that incorporates cyclophosphamide, thiotepa and carboplatin, in patients with high-risk breast cancer. In two randomised single institution studies, 70 consecutive patients received anthracycline-containing adjuvant chemotherapy (FEC: 5-fluorouracil, epirubicin and cyclophosphamide) followed by radiotherapy to achieve maximal local control. Of these patients, 34 received high-dose CTC with autologous PBSC support. All patients tolerated the full radiation dose in the planned time schedule. Radiation pneumonitis was observed in 5 patients (7%), 4 of whom had undergone high-dose chemotherapy (P = 0.38). All 5 responded favourably to prednisone. Fatal toxicities were not observed. Myelosuppression did not require interruption or untimely discontinuation of the radiotherapy, although significant reductions in median nadir platelet counts and haemoglobin levels were observed in patients who had received high-dose chemotherapy (P = 0.0001). The median nadir of WBC counts was mildly but significantly decreased during radiotherapy (P = 0.01). Red blood cell or platelet transfusions were rarely indicated. Adequate radiotherapy for breast cancer can be safely administered after high-dose CTC with autologous PBSC support. Radiation-induced myelotoxicity is clearly enhanced following CTC, but this is of little clinical significance. Radiation pneumonitis after high-dose therapy may occur more often in patients with a history of lung disease or after a relatively high radiation dose to the chest wall. Other high-dose regimens, particularly those incorporating drugs with known pulmonary toxicity (such as BCNU), may predispose patients to radiation pneumonitis.

Adenocarcinoma↗
PubMed1995

Immunocytochemical detection of tumor cells in bone marrow and peripheral blood stem cell collections from patients with ovarian cancer.

High-dose chemotherapy (HDC) followed by autologous hematopoietic reconstitution is an experimental treatment option for patients with epithelial ovarian cancer. However, the incidence of occult ovarian tumor cell involvement in autologous bone marrow (BM) or peripheral blood stem cell (PBSC) autografts has not been widely investigated. We used a highly sensitive immunocytochemical (ICC) procedure that detects occult blood-borne tumor micrometastases. We analyzed 24 BM specimens (15 obtained during therapy and 9 harvest samples) and seven PBSC specimens from 22 patients with ovarian cancer. Overall, ICC analysis detected immunostained tumor cells in 10 of 23 evaluable BM specimens (43%) from 9 of 19 patients (47%). One of 9 (11%) harvest samples contained tumor cells. Only one of the 10 ICC-positive BM specimens had tumor cells detected by routine histopathological analysis. ICC-detectable tumor cells were cleared from the marrow of two patients during chemotherapy. None of the seven PBSC specimens contained tumor cells. We conclude that ovarian cancer micrometastases have the potential to contaminate BM, as is also the case in patients with other epithelial malignancies. In the limited number of specimens analyzed, PBSC harvests appeared to provide a less tumor-contaminated source of hematopoietic stem cells for autologous transplantation.

Antibodies, Monoclonal↗
PubMed2002

Autologous stem cell transplantation for small cell lung cancer.

Small cell lung cancer usually responds to radiation and chemotherapy, but cures are infrequent. Autotransplantation attempts to increase cures by intensifying the effects of chemotherapy. We studied 103 patients receiving high-dose chemotherapy with autologous hematopoietic stem cell transplantation (SCT) for small cell lung cancer in 1989-1997 at 22 centers participating in the Autologous Blood and Marrow Transplant Registry. Median age at transplantation was 50 years (range, 30-74 years). Fifty-five percent of patients were men. Forty-seven percent of patients underwent transplantation in 1989-1993 and 53% in 1994-1997. Most patients received peripheral blood stem cells alone (39%) or with bone marrow (44%); 18% received bone marrow alone. The 2 most common preparative regimens were cyclophosphamide/carmustine/cisplatin (CBP) (60%) and ifosfamide/carboplatin/etoposide (ICE) (28%). Median time from diagnosis to transplantation was 6 months (range, 1-34 months). Most patients underwent transplantation after partial response (66%) or complete response (27%) to combination therapy. The 100-day mortality was 11% (95% confidence interval [CI], 6%-18%). Three-year probabilities of survival and progression-free survival (PFS) were 33% (95% CI, 24%-44%) and 26% (95% CI, 17%-36%), respectively, for all patients. Factors negatively associated with outcome in multivariate analysis were age greater than 50 years, extensive-stage disease at presentation, and preparative regimens other than CBP or ICE. Three-year survival and PFS rates were higher in patients with limited versus extensive disease, 43% versus 10% (P < .001) and 35% versus 4% (P < .001), respectively. Patients older than 50 years had nearly twice the risk of death or progression as younger patients (relative risk, 1.7; 95% CI, 1.1-2.8). Autologous SCT produces long-term survival in some patients with small cell lung cancer; SCT outcomes appear better in young patients with limited-stage disease. Transplantation for patients with extensive disease does not appear to produce substantial benefit.

Adult↗
PubMed2006

[Clinical practice guideline on peritoneal carcinomatosis treatment using surgical cytoreduction and hyperthermic intraoperative intraperitoneal chemotherapy].

In 2005, the Comité de l'évolution des pratiques en oncologie (CEPO) took it upon itself to develop a clinical practice guideline to determine the clinical value of surgical cytoreduction followed by hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) for treating peritoneal carcinomatosis stemming from colorectal cancer, cancers of the appendix and stomach, pseudomyxoma peritonei, and mesothelioma of the peritoneum. A review of the scientific literature was performed using the PubMed search engine. The period covered extended from January 1990 to January 2006, inclusively. The scientific literature search was limited to clinical trials (minimum phase II) and organizations elaborating clinical practice recommendations. Twenty-six studies were identified. Of these, only one was phase III. Although some of these studies have demonstrated a benefit from this treatment in terms of patient survival, HIPEC remains a complex procedure whose optimal use is uncertain. Given the morbidity and mortality associated with this treatment, this procedure requires a high level of expertise. Considering the evidence available, the CEPO recommends: 1) that complete cytoreduction followed by HIPEC be used in a clinical research context only, preferably in the presence of an isolated peritoneal carcinomatosis stemming from colorectal cancer, cancer of the appendix, peritoneal pseudomyxoma, or mesothelioma of the peritoneum; 2) that studies be conducted only in specialized centers with the necessary expertise and technical resources.

Antineoplastic Agents↗
PubMed2002

Radiation therapy after high-dose chemotherapy with peripheral blood stem cell support for high-risk breast cancer.

Multidisciplinary treatment in high-risk breast cancer improves survival and local control. The feasibility and patterns of failure after several induction and high-dose consolidation regimens of chemotherapy were evaluated in this study. Between November 1990 and January 1997, 65 patients with histologically proven breast cancer American Joint Committee on Cancer stages II-III with four or more axillary lymph nodes positive or locally advanced breast cancer underwent high-dose chemotherapy (HDC) with peripheral stem cell support after surgery and induction chemotherapy. All patients were subsequently treated with radiotherapy (up to total doses of 50-60 Gy), which included the ipsilateral axilla and supraclavicular fossa and the chest wall or breast. A minimum follow-up period of 2 years from the completion of radiotherapy was required for analysis. Local control (LC), disease-free survival (DFS), overall survival (OS), and toxicity were evaluated. With a median follow-up of 62 months (range: 32-107 months), LC was 89%, and 5-year OS and DFS were 78% and 63%, respectively. Symptomatic pneumonitis developed in six patients (9%); only one patient had her radiotherapy interrupted because of hematologic toxicity. No treatment-related mortality was observed. Radiation therapy after HDC provides excellent local control rates without excessive toxicity. Delaying the start of irradiation until recovery from HDC does not seem to increase local failure rates.

Adult↗
PubMed1997

Immunomagnetic selection of CD34+ peripheral blood stem cells for autografting in patients with breast cancer.

Contamination of transplants with tumour cells may contribute to relapse after peripheral blood stem cell transplantation (PBSCT). We studied the feasibility of CD34+ cell selection from blood-derived autografts obtained following G-CSF-supported cytotoxic chemotherapy in a group of 25 patients with breast cancer (10 with high-risk stage II/III and 15 with stage IV without bone or bone marrow involvement). Using immunomagnetic beads (Isolex 300 SA. Baxter) CD34+ cells were enriched and released by chymopapain resulting in a median purity of 95% (range 82-99%) and a median recovery of 80% (range 27-132%). The enrichment procedure did not change the proportion of CD34+ subsets coexpressing HLA-DR, CD38 and Thy-1, while L-selectin was removed from the cell surface following selection. Using a sensitive immunocytological technique with a cocktail of epithelial-specific antibodies (anti-cytokeratin 8, 18 and 19; HEA125; BM7 and BM8), five leukaphereses products contained epithelial cells, whereas the selected CD34+ cell fraction was free of tumour cells. A neutrophil count of 0.5 x 10(9)/l and a platelet count of 20 x 10(9)/l was reached after a median time of 14 and 10d following 40 high-dose chemotherapy (HDC) cycles. Our results indicate that immunomagnetic selection of CD34+ cells yields highly purified autografts devoid of tumour cells whereas the engraftment ability of the progenitor and stem cells is fully retained.

Adult↗
PubMed2006

Aging at the interface of stem cell renewal, apoptosis, senescence, and cancer.

The aging-related research field has focused on the detection of genetic factors that affect the aging process, but more recently scientists have started to shift their attention to novel and more integrative ways of studying cellular and organismal function. Such approaches allow them to uncover and explore unexpected patterns and themes, resulting in a more comprehensive knowledge of the complex regulatory pathways and networks involved in aging and age-related diseases. Eventually, this knowledge will lead to a systems-level understanding of aging. The third "Functional Genomics of Aging" conference held in Palermo, Italy, in March/April 2006 highlighted some of the more exciting work in this area.

Aging↗
PubMed1995

Prognostic factors for prolonged progression-free survival with high-dose chemotherapy with autologous stem-cell support for advanced breast cancer.

PURPOSE: With a median observation time of 50 months from transplant, 13 (22%) of 62 women with metastatic breast cancer treated with high-dose chemotherapy at the Dana-Farber Cancer Institute (DFCI)/Beth Israel Hospital (BIH) remain progression-free. This study determined factors prognostic for prolonged progression-free survival (PFS). METHODS: From June 1988 to January 1992, women who responded to standard chemotherapy received high-dose cyclophosphamide, thiotepa, and carboplatin with autotransplantation. Data encompassing initial breast cancer diagnosis, metastatic presentation, and response to induction treatment were examined for correlations with improved PFS. RESULTS: The 5-year PFS rate for the entire group is estimated to be 21% (95% confidence interval [CI], 10% to 32%). For those patients who attained a complete response (CR) to induction therapy, the 5-year PFS rate is estimated to be 31% (95% CI, 0% to 63%). In univariate analyses, a single metastatic site, CR to induction therapy, prolonged interval from primary diagnosis to first metastases, estrogen receptor (ER)-negative tumors, and older age (> or = 40 years) were associated with prolonged PFS. In multivariate analyses, single metastatic site (P = .002) and attainment of a CR to induction chemotherapy (P = .04) were the most significant predictors for PFS, with a strong trend observed for an interval from primary diagnosis to onset of metastatic disease of 24+ months (P = .066). CONCLUSION: We and others have shown that 10% to 25% of women with metastatic breast cancer are progression-free after high-dose chemotherapy with autotransplantation. Those with chemosensitive disease, minimal tumor bulk, and a prolonged disease-free interval appear to benefit most. Emphasis should continue to focus on the development of more effective cytotoxic regimens and biologic approaches to increase the percentage of patients who may benefit from this approach.

Adolescent↗
PubMed1993

Peripheral blood stem cell autografts for the treatment of childhood cancer: a review of the Japanese experience. Japanese Cooperative Study Group of PBSCT (JCSG/PBSCT).

Harvesting peripheral blood stem cells (PBSC) for autografts (PBSCT) in children with active cancers is a safe and reliable procedure with a low incidence of serious morbidity. A significant correlation between the number of infused CFU-GM and the time to both granulocyte and platelet engraftment was found. Cells induced by G-CSF could speed the recovery of granulocyte or platelet counts after PBSCT. In terms of preserving engraftment potential, cryopreservation of PBSC by a simplified uncontrolled-rate method is at least as effective as the traditional controlled-rate freezing procedure with a programmed freezer. As the serum G-CSF level increases immediately following infusion of PBSC graft, therapy with G-CSF may have only a limited ability to further enhance hematopoietic recovery after PBSCT. Preliminary results of high-dose chemotherapy without TBI and PBSCT for the treatment of children with relapsed ALL are encouraging.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Neoadjuvant intraarterial high-dose chemotherapy and autologous peripheral blood stem cell transplantation for advanced breast cancer.

Eight locally advanced breast cancer patients were treated with neoadjuvant intraarterial high-dose chemotherapy (epirubicin) plus MPA combined with autologous PBSCT. All patients completed the scheduled treatment, and there were no toxic deaths. Patients were treated with an escalating dose of epirubicin (370-480 mg) and cyclophosphamide (0-6000 mg). The rate of clinical response was 100%. The rate of good histologic response was 87.5% in the main tumor and 75% in diseased lymph nodes. The 2-year survival rate was 100%. Six patients were disease-free at the time of writing. This treatment resulted in higher rates of clinical and histologic response when compared with standard-dose intraarterial chemotherapy.

Adult↗
PubMed1999

Hematopoietic stem cell transplantation for small cell lung cancer.

Treatment for small cell lung cancer has not improved substantially in the past 15 years. Some advances are being made in supportive care and by use of more intense concurrent thoracic radiotherapy. New agents such as the taxanes and the topoisomerase I inhibitors hold promise and are currently in phase III evaluation. The question whether dose intensity can improve the outcome of patients with small cell lung cancer has been raised for many years. Improving supportive care enhances our ability to test this question more thoroughly. This paper reviews the historical and current experience using high-dose therapy with hematopoietic stem cell support for the treatment of small lung cancer. Future directions are identified.

Antineoplastic Agents↗
PubMed2003

Liver transplantation followed by adjuvant nonmyeloablative hemopoietic stem cell transplantation for advanced primary liver cancer in humans.

BACKGROUND: Tumor recurrence after orthotopic liver transplantation (OLT) in patients with advanced primary liver cancer is common. To achieve an adjuvant graft-versus-tumor effect, the authors investigated whether transplantation of allogeneic peripheral blood stem cells (PSCT) after OLT can induce sustained complete donor chimerism. METHODS: Five patients with advanced primary liver cancer were included in the trial. None of the patients had signs of extrahepatic tumor before OLT. However, overall, the extent of surgery, as judged by morphologic examination of the explanted liver, was considered inadequate. A nonmyeloablative preparative regimen of fludarabine combined with total-body irradiation or cyclophosphamide preceded the allogeneic PSCT, which was then performed 16 to 135 days after OLT with human leukocyte antigen-matched donors. Mixed chimerism was monitored weekly by polymerase chain reaction of variable number tandem repeats after PSCT. RESULTS: In two patients, no engraftment of donor cells was seen, whereas one rejected the cells 2 months after PSCT. In two of the patients, a stable mixed donor chimerism was established. A mild transient graft-versus-host reaction was also noted in two patients. Three of the patients died of progressive disease 7 to 9 months after OLT. The other two are presently alive without recurrence at a follow-up of 26 and 10 months, respectively. CONCLUSIONS: These data suggest that PSCT after OLT is feasible, with low transplant-related morbidity. The rate of nonengraftment or rejection of the transplanted stem cells in this group of patients was three of five. An augmented pretreatment to prevent donor T-cell rejection seems to be necessary in this setting.

Adult↗
PubMed2005

Neosis--a paradigm of self-renewal in cancer.

We recently described a novel form of cell division termed neosis, which appears to be the mode of escape of cells from senescence and is involved in the neoplastic transformation and progression of tumors (Cancer Biol & Therap 2004;3:207-18). Neosis is a parasexual somatic reduction division and is characterized by (1) DNA damage-induced senescence/mitotic crisis and polyploidization, (2) followed by production of aneuploid daughter cells via nuclear budding, (3) asymmetric cytokinesis and cellularization conferring extended, but, limited mitotic life span to the offspring, and (4) is repeated several times during tumor growth. The immediate neotic progeny are termed the Raju cells, which seem to transiently display stem cell properties. The Raju cells immediately undergo symmetric mitotic division and become mature tumor cells. Exposure of tumor cells to genotoxic agents yields neosis-derived Raju cell progenies that are resistant to genotoxins, thus contributing to the recurrence of drug-resistant tumor growth. Similar events have been described in the literature under different names through several decades, but have been neglected due to the lack of appreciation of the significance of this process in cancer biology. Here we review and interpret the literature in the light of our observations and the recent advances in self-renewal in cancer. Neosis paradigm of self-renewal of cancer growth is consistent with the telomere attrition, aging and origin of cancer cells after reactivation of telomerase, and constitutes an alternative to the cancer stem cell hypothesis. We summarize the arguments favoring Raju cells and not cancer stem cells, as the source of self-renewal in cancer and present a comprehensive hypothesis of carcinogenesis, encompassing various aspects of cancer biology including senescence, tumor suppressor genes, oncogenes, cell cycle checkpoints, genomic instability, polyploidy and aneuploidy, natural selection, apoptosis, endoapoptosis, development of resistance to radiotherapy and chemotherapy leading tumor progression into malignancy.

Cell Death↗
PubMed2004

Hedgehog--Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer.

The Hedgehog-Gli signaling pathway is involved in the regulation of the proliferation of precursors in different organs of the normal vertebrate embryo. These cells express Gli1 and may be the target of cancer-causing agents. Many tumor types derived from organs that contain Gli1+ precursors appear to consistently express Gli1, indicating their origin and/or the presence of an active pathway. Inappropriate pathway activation in a variety of precursor cells in model organisms leads to tumor formation while inhibition of the pathway in human tumor cells leads to a decrease in their proliferation. In the brain we have documented the expression of Gli1 in germinative zones, and a variety of brain tumors express GLI1, including medulloblastomas of the cerebellum and a number of gliomas of the cerebral cortex. The requirement for SHH-Gli signaling in the growth of the mouse brain, together with the ability of inappropriate pathway activation in the cerebellum to cause medulloblastomas, and the inhibition of the growth of a number of brain tumors with cyclopamine, a SHH signaling inhibitor, underscores the critical role of the SHH-GLI pathway in brain growth and tumor formation. Moreover, they highlight the components of this pathway as prime targets for drug development, with special emphasis on the GLI proteins. Such reagents would allow a rational therapeutic approach to highly intractable diseases.

Brain↗