Autologous Bone Marrow Rescue Research Articles

High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma.

Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor; more than half of patients experience disease recurrence. High-dose chemotherapy and haematopoietic stem cell rescue (i.e. myeloablative therapy) might improve survival. This review is the second update of a previously published Cochrane review.Primary objectiveTo compare the efficacy, that is event-free and overall survival, of high-dose chemotherapy and autologous bone marrow or stem cell rescue with conventional therapy in children with high-risk neuroblastoma. Secondary objectivesTo determine adverse effects (e.g. veno-occlusive disease of the liver) and late effects (e.g. endocrine disorders or secondary malignancies) related to the procedure and possible effects of these procedures on quality of life.We searched the electronic databases The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, issue 11), MEDLINE/PubMed (1966 to December 2014) and EMBASE/Ovid (1980 to December 2014). In addition, we searched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2002 to 2014), American Society for Pediatric Hematology and Oncology (ASPHO) (from 2002 to 2014), Advances in Neuroblastoma Research (ANR) (from 2002 to 2014) and American Society for Clinical Oncology (ASCO) (from 2008 to 2014). We searched for ongoing trials by scanning the ISRCTN register (www.isrct.com) and the National Institute of Health Register (www.clinicaltrials.gov). Both registers were screened in April 2015.Randomised controlled trials (RCTs) comparing the efficacy of myeloablative therapy with conventional therapy in high-risk neuroblastoma patients.Two authors independently performed study selection, data extraction and risk of bias assessment. If appropriate, we pooled studies. The risk ratio (RR) and 95% confidence interval (CI) was calculated for dichotomous outcomes. For the assessment of survival data, we calculated the hazard ratio (HR) and 95% CI. We used Parmar's method if hazard ratios were not reported in the study. We used a random-effects model.We identified three RCTs including 739 children. They all used an age of one year as the cut-off point for pre-treatment risk stratification. The first updated search identified a manuscript reporting additional follow-up data for one of these RCTs, while the second update identified an erratum of this study. There was a significant statistical difference in event-free survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (three studies, 739 patients; HR 0.78, 95% CI 0.67 to 0.90). There was a significant statistical difference in overall survival in favour of myeloablative therapy over conventional chemotherapy or no further treatment (two studies, 360 patients; HR 0.74, 95% CI 0.57 to 0.98). However, when additional follow-up data were included in the analyses the difference in event-free survival remained statistically significant (three studies, 739 patients; HR 0.79, 95% CI 0.70 to 0.90), but the difference in overall survival was no longer statistically significant (two studies, 360 patients; HR 0.86, 95% CI 0.73 to 1.01). The meta-analysis of secondary malignant disease and treatment-related death did not show any significant statistical differences between the treatment groups. Data from one study (379 patients) showed a significantly higher incidence of renal effects, interstitial pneumonitis and veno-occlusive disease in the myeloablative group compared to conventional chemotherapy, whereas for serious infections and sepsis no significant difference between the treatment groups was identified. No information on quality of life was reported. In the individual studies we evaluated different subgroups, but the results were not univocal in all studies. All studies had some methodological limitations.Based on the currently available evidence, myeloablative therapy seems to work in terms of event-free survival. For overall survival there is currently no evidence of effect when additional follow-up data are included. No definitive conclusions can be made regarding adverse effects and quality of life, although possible higher levels of adverse effects should be kept in mind. A definitive conclusion regarding the effect of myeloablative therapy in different subgroups is not possible. This systematic review only allows a conclusion on the concept of myeloablative therapy; no conclusions can be made regarding the best treatment strategy. Future trials on the use of myeloablative therapy for high-risk neuroblastoma should focus on identifying the most optimal induction and/or myeloablative regimen. The best study design to answer these questions is a RCT. These RCTs should be performed in homogeneous study populations (e.g. stage of disease and patient age) and have a long-term follow-up. Different risk groups, using the most recent definitions, should be taken into account.It should be kept in mind that recently the age cut-off for high risk disease was changed from one year to 18 months. As a result it is possible that patients with what is now classified as intermediate-risk disease have been included in the high-risk groups. Consequently the relevance of the results of these studies to the current practice can be questioned. Survival rates may be overestimated due to the inclusion of patients with intermediate-risk disease.

A 46‐year‐old woman with chin pain and a fainting spell

History of the present illness The patient had a history of primary central nervous system (CNS) lymphoma that had recurred in the past but had been in remission for 2 years. She was admitted to the hospital in August 2008, following a syncopal episode. For several weeks prior to her syncope, she had experienced generalized malaise and the sensation of total body weakness. On the day of admission, she was nauseated and had one episode of non-bloody emesis. As the day progressed, she felt lightheaded and eventually lost consciousness while walking to the bathroom. In the emergency department, she was suspected of dehydration. However, an electrocardiogram revealed complete heart block (CHB). A temporary transjugular pacing wire was placed, intravenous fluids were started, and she was admitted to the Cardiac Unit. The patient stated that she had been completely well until 2 months before admission, when she began to experience easy fatigability. One month before admission, she developed a series of episodes of myalgias that involved her shoulders and neck. These symptoms responded to acetaminophen. She had also experienced periodic night sweats during this time. Two weeks before admission, the patient presented to her oncologist with the symptom of chin pain that radiated bilaterally toward the angle of her mandible. The pain was described as “sharp and shooting.” It sometimes appeared to be worsened by jaw movement. The patient indicated that chewing exacerbated the pain, starting with the first bite. Her oncologist had obtained a brain magnetic resonance imaging (MRI) study to exclude a lymphoma recurrence. The MRI study was interpreted as showing no new lesions. The pain did not respond to nonsteroidal antiinflammatory drugs and had been present for 2 weeks at the time of her syncope.

Outcome of high‐risk stage 3 neuroblastoma with myeloablative therapy and 13‐cis‐retinoic acid: A report from the Children's Oncology Group

The components of therapy required for patients with INSS Stage 3 neuroblastoma and high-risk features remain controversial. A retrospective cohort design was used to determine if intensive chemoradiotherapy with purged autologous bone marrow rescue (ABMT) and/or 13-cis-retinoic acid (13-cis-RA) improved outcome for patients with high-risk neuroblastoma that was not metastatic to distant sites. We identified 72 patients with INSS Stage 3 neuroblastoma enrolled between 1991 and 1996 on the Phase 3 CCG-3891 randomized trial. Patients were analyzed on an intent-to-treat basis using a log-rank test. The 5-year event-free survival (EFS) and overall survival (OS) rates for patients with Stage 3 neuroblastoma were 55 +/- 6% and 59 +/- 6%, respectively (n = 72). Patients randomized to ABMT (n = 20) had 5-year EFS of 65 +/- 11% and OS of 65 +/- 11% compared to 41 +/- 11 (P = 0.21) and 46 +/- 11% (P = 0.23) for patients randomized to CC (n = 23), respectively. Patients randomized to 13-cis-RA (n = 23) had 5-year EFS of 70 +/- 10% and OS of 78 +/- 9% compared to 63 +/- 12% (P = 0.67) and 67 +/- 12% (P = 0.55) for those receiving no further therapy (n = 16), respectively. Patients randomized to both ABMT and 13-cis-RA (n = 6) had a 5-year EFS of 80 +/- 11% and OS of 100%. Patients with high-risk Stage 3 neuroblastoma have an overall poor prognosis despite aggressive chemoradiotherapy. Further studies are warranted to determine if myeloablative consolidation followed by 13-cis-RA maintenance therapy statistically significantly improves outcome.

High-dose chemotherapy for recurrent medulloblastoma

M ore than a decade ago, Finlay et al. published a landmark article in which they demonstrated that a subset of patients with recurrent brain tumors of diverse histologic diagnosis could be salvaged with high-dose chemotherapy followed by autologous stem cell rescue. The preparatory regimen included only 2 drugs: thiotepa and etoposide. Hematopoietic growth factors were used to enhance count recovery. Observations from this early series suggested that patients with minimal residual disease at the time of high-dose chemotherapy may be the appropriate candidates for this retrieval strategy. Patients with bulky, metastatic recurrent disease or disease that has not responded to retrieval chemotherapy may not be the best candidates for this intervention. The toxicity of this approach was also a concern in this early series. Overall, 5 of the 45 patients (11%) were long-term survivors and all of them had highgrade gliomas. Subsequent publications from these and other investigators have further defined the role of high-dose chemotherapy in patients with recurrent medulloblastoma. Dunkel et al. suggested that patients treated with prior combined modality therapy (ie, radiotherapy and chemotherapy) had a worse outcome compared with patients who were treated with chemotherapy only (25 6 15% vs 43 6 16%). In the series by Gururangan et al., 12 of the 20 patients (60%) were irradiated after high-dose chemotherapy and autologous bone marrow rescue and 7 of these 12 patients were long-term survivors. Taken together, these data suggest that a select group of patients may be able to achieve durable disease control; this subgroup consists of young patients treated with chemotherapy alone as initial therapy followed by high-dose chemotherapy and radiotherapy at the time of disease recurrence. In a large prospective French series, infants with local recurrences of medulloblastoma after initial treatment with surgical resection and chemotherapy alone could be salvaged with surgical resection, high-dose chemotherapy, and radiotherapy. In contrast, patients with metastatic recurrent disease had a much worse outcome. See referenced original article on pages 1805 11, this issue.

Morbidity After Total Body Irradiation.

High-dose chemotherapy and total body irradiation with either allogeneic or autologous bone-marrow rescue has been used successfully in the treatment of various hematologic malignancies. Total body irradiation, despite its acute and late side effects, combined with cyclophosphamide remains one of the best conditioning regimens before bone marrow transplantation. Interstitial pneumonitis and veno-occlusive disease are major and lethal complications following bone marrow transplantation. In this article, morbidity after total body irradiation will be discussed.

Outcome of high risk (HR) stage 3 neuroblastoma (NB) with myeloablative therapy and 13-cis-retinoic Acid

8503 Background: We assessed whether myeloablative chemotherapy with purged autologous bone marrow rescue (ABMT) compared to chemotherapy (CC) alone and whether subsequent treatment with 13-cis-retinoic acid (RA) compared to no RA therapy improved event-free survival (EFS) and survival (S) for patients with high risk (HR) stage 3 neuroblastoma (NB) defined as greater than 1 year of age with amplified MYCN copy number (MYCN-A), unfavorable Shimada histopathology or elevated serum ferritin level. Methods: Seventy-two of 539 patients enrolled onto CCG study 3891 had HR stage 3 NB. Patients were analyzed using a log-rank test. Results: The 5-yr EFS and S was 55 +/- 6% and 59% +/- 6%, respectively (n=72). MYCN-A (n=24) adversely effected prognosis with 5-yr EFS of 25% +/- 9% compared to 75% +/- 7% for patients without MYCN-A (n=38), p<0.0001. Partial response (PR) or less to induction chemotherapy (n=19) adversely effected prognosis with 5-year EFS of 26 +/- 11% compared to 66 +/- 8% for patients achieving com...

E-45. Small cell lung cancer: Targeting minimal residual disease

The outcome for patients with small cell lung cancer has improved marginally over the last 20 years. Standard chemotherapy regimens yield high response rates and some cures when combined with thoracic irradiation in limited stage patients. Nonetheless, SCLC has a high relapse rate due to drug resistance. This has resulted in continued poor survival for most patients. Developing ways to maintain response after induction chemotherapy or chemoradiotherapy has been a major research focus. The lack of an assay capable of measuring residual disease limits our ability to gauge the risk for relapse or to assess the efficacy of therapy in this setting. At this time all patients are considered at high risk and the challenge is to maintain their remission status. The chemosensitivity of SCLC logically supports the use of maintenance chemotherapy or high dose treatments as a way to attack residual metastatic disease. However, trials using more chemotherapy have generally resulted in more toxicity with no improvement in survival. In 13 randomized trials of maintenance chemotherapy, only one showed an overall survival advantage, five showed improvements only in subgroups of patients, and one showed a shorter survival with continued treatment [ 11. At least 36 studies of high dose chemotherapy with autologous bone marrow or stem cell rescue have been reported [2,3]. In these trials, only a small fraction of patients can complete the high dose chemotherapy due to co-morbid illnesses or toxicity, treatment related mortality is significant, and survival remains poor. In order to change outcomes in SCLC substantially, new approaches are needed. The matrix metalloproteinase (MMP) inhibitors are a novel class of drugs that were tested in SCLC patients as a potential therapy aimed at maintaining remission, but unfortunately yielded disappointing results in phase III trials. MMPs are a class of over 30 extracellular enzymes that degrade connective tissue and play an important role in bone development, wound healing, and vascular remodeling. Several inhibitors of these enzymes have been developed to decrease the cell migration responsible for metastatic spread. Dr. Shepherd reported the results of a phase III NCICEORTC trial in which 532 patients with small cell lung cancer who completed initial therapy were randomized to receive marimastat, a broad-spectrum MMP inhibitor, or placebo [4]. There was no difference between the marimastat and placebo groups with regards to overall survival or progression free survival. Furthermore, myalgias and arthralgias necessitated dose reduction or drug discontinuation in 33% and 32% of the patients receiving marimastat. The results of this trial, as well as the early discontinuation of a similar trial with BAY 12-9566, raise doubts as to the efficacy of this class of agents in SCLC, though specific inhibition of other MMPs could be explored. At Memorial Sloan-Kettering, we are attempting to take advantage of unique epitopes present on SCLC to develop vaccines. One potential target identified is the ganglioside GD3 expressed on cells of neuroectodermal origin. Using an anti-idiotype approach, the mouse monoclonal antibody BEC2 was developed against the binding region of the mouse monoclonal antibody R24 which binds to GD3. A pilot study was performed in which 1.5 patients with SCLC who had a major response to induction chemotherapy were immunized with BEC2. BCG was also added as an immunologic adjuvant [5]. Of the 13 evaluable patients, all developed anti-BEC2 antibodies (HAMA). Five patients had measurable anti-GD3 IgM antibody and 3 of those patients developed IgG antibodies. Median overall survival was 21 months; median time to relapse was 11 months in the extensive stage group and had not been reached in the limited stage group (>47 months). These results were a significant improvement when compared to two historical control groups treated at our center, and prompted an international phase III trial in SCLC patients with limited disease and a complete or partial response after initial therapy (the SILVA trial, lead by the EORTC). This trial completed accrual in October, 2002. Currently, we are also testing the immunogenicity of vaccines against other targets in SCLC such as GM2, Fucosyl GM1 [6,7], Globo H, and polysialic acid [S]. In order to optimize the likelihood of immunologic effect, we plan to combine the vaccines into a polyvalent vaccine. Only new strategies will improve outcomes for SCLC patients. Eligible individuals should enroll in clinical trials after chemotherapy and irradiation.

Autotransplants for histologically transformed follicular non-Hodgkin's lymphoma.

Histological transformation from a follicular non-Hodgkin's lymphoma (NHL) to a higher grade lymphoma carries a poor prognosis despite treatment with aggressive anthracycline-based chemotherapy. We retrospectively analysed 35 patients with histologically transformed NHL who underwent high-dose therapy and autotransplantation at our centre. Patients up to 65 years old were eligible for autotransplant at the time of transformation or with subsequent relapses, provided that chemosensitivity to a salvage regimen could be demonstrated. All patients received high-dose therapy [etoposide 60 mg/kg, melphalan 160 mg/m2 and fractionated total body irradiation (TBI) 12 Gy] followed by unpurged autologous bone marrow or blood stem cell rescue. Most patients (69%) had advanced stage disease (stages 3--4) at transformation and bone marrow involvement was common (49%). Twenty-six (74%) patients were in partial remission (PR) and nine (26%) in complete remission (CR) at the time of transplant. Median duration from transformation to transplant was 10.9 months (range, 5.2 months--4.6 years). At a median follow up of 52 months after autotransplant, 19 (54%) patients had died. Causes of death were progressive lymphoma in nine patients (26%), treatment-related mortality (TRM) in seven (20%) and myelodysplasia in three (8%). Only five patients in our cohort were > 60 years old, but all died as a result of treatment-related causes (mostly pulmonary infections). Five-year overall survival and progression-free survival from time of transplant were 37% and 36% respectively. Using multivariate analysis of factors including gender, age, stage, extranodal disease, disease bulk, B symptoms, number of prior therapies, relapse status and CR/PR status at transplant, only advanced age significantly predicted for survival from autotransplant (P = 0.002). Our survival data are comparable to previous reports of autotransplantation for transformed NHL and suggest a benefit over standard chemotherapy alone in selected patients. However, our high TRM cautions the use of aggressive therapy, including TBI, in patients over 60 years old.

Disialoganglioside GD2 loss following monoclonal antibody therapy is rare in neuroblastoma

Ganglioside GD2 is abundant on human neuroblastoma (NB). Monoclonal antibody 3F8 targeted to GD2 may have imaging and therapeutic potential. Antigen-negative clones can escape immune-mediated attack, leading to clinical resistance or recurrence. Among 95 evaluable patients treated i.v. with 3F8 (94 stage 4 and 1 stage 3), 66 received nonradiolabeled 3F8, 11 received 131I-labeled 3F8 (8-28 mCi/kg) with autologous bone marrow rescue, and 18 received both forms of treatment. Prior to treatment, 91 patients tested positive for GD2 reactivity by bone marrow immunofluorescence (n = 68), tumor immunohistochemistry (n = 20), or diagnostic radioimmunoscintigraphy only (n = 3). Of 62 patients who had refractory or recurrent NB following 3F8 treatment, 61 (98%) tested positive for GD2 reactivity by bone marrow immunofluorescence (n = 51) or tumor immunohistochemistry (n = 10). The sole tumor that lost GD2 expression underwent phenotypic transformation into a pheochromocytoma-like tumor. The persistence of GD2 expression in refractory or recurrent NB suggests that complete antigen loss is an uncommon event and cannot account for treatment failure.

Classical chemotherapy for metastatic melanoma

Despite a major effort in clinical research scrutinizing various treatment regimens for patients suffering from metastatic melanoma the prognosis for these patients still remains poor. The treatment options tested have ranged from monochemotherapy, polychemotherapeutic approaches including highly toxic regimens requiring autologous bone marrow rescue, immuno-modulatory therapies, e.g. defined cytokines such as interferon-alpha and interleukin-2 as well as vaccination therapy with dendritic cells or genetically modified tumour cells, and bio-chemotherapy. Although immuno-modulatory approaches are currently regarded as the most promising, to date no improved overall survival has been achieved by any of these measures especially if tested in large multicentre trials. The focus of this review will be on classical chemotherapy with emphasis on both cutaneous and uveal melanoma.

High-dose carmustine, thiotepa and etoposide followed by autologous bone marrow rescue for the treatment of high risk central nervous system tumors.

Forty-two patients (29 newly diagnosed) with high grade gliomas (n = 37), medulloblastoma (n = 2) or non-biopsied tumors (n = 3) with supratentorial (n = 24), brain stem (n = 11), posterior fossa (n = 5) or spinal (n = 2) location were eligible for this study with adequate organ function and no bone marrow tumor infiltration. Median patient age was 12.2 years (range, 0.7-46.8). A total of 600 mg/m2 BCNU, 900 mg/m2 thiotepa and 1500 or 750 mg/m2 etoposide (VP-16) was administered followed by autologous bone marrow reinfusion (ABMR). Twenty-one newly diagnosed patients received local irradiation (RT) post ABMR. Nine early deaths were observed (21%), as well as one secondary graft failure. Half of the patients aged 18 years or older experienced toxic deaths, whereas only 15% of patients younger than 18 years experienced toxic death (P = 0.05). Of 25 evaluable newly diagnosed patients, 20% achieved complete remission (CR) and 4% partial remission (PR), while 28% remained in continuing complete remission (CCR) and 44% remained with stable disease prior to RT. Of eight evaluable patients with recurrent disease, one achieved CR and two PR, while one remained in CCR and four with stable disease for 1 to 110.2 months. Overall survival was 36%, 24% and 17% at 1, 2 and 3 years following ABMR, with three newly diagnosed patients and one patient treated for recurrent disease being alive, without disease progression 64.4, 67.0, 86.3 and 110.2 months after ABMR, respectively. The combination of high-dose BCNU/ thiotepa/VP-16 has substantial toxicity but definite activity for high risk CNS tumors. Similar protocols with lower toxicity merit further evaluation in both newly diagnosed and recurrent CNS tumors.

Chemotherapy of Testis Cancer.

BACKGROUND: Prior to the use of cisplatin, durable complete remissions of metastatic testis cancer were rare. In 1977, a treatment program including a chemotherapy program of cisplatin, vinblastine, and bleomycin (PVB) led to high response rates and acceptable toxicities in patients with disseminated testis cancer. Since then, the BEP (bleomycin, etoposide, and cisplatin) regimen has been established as standard therapy for good- and poor-risk disease and ifosfamide-based regimens or high-dose chemotherapy with stem cell rescue as salvage therapy. METHODS: The results of those prospective, randomized clinical trials that have markedly improved the outlook of patients with this type of cancer have been reviewed. RESULTS: Categories of risk have been defined. Standard therapy for both good-risk and poor-risk disease remains BEP therapy. High-dose chemotherapy with autologous bone marrow or peripheral stem cell rescue transplantation is being investigated to overcome chemotherapy resistance. CONCLUSIONS: While the present state of the art for treating metastatic testicular cancer is promising, approximately one third of patients with "poor-risk" disease will not achieve a remission. Trials of new agents and approaches are needed to increase patient survival.

Studies on health-related quality of life in childhood cancer in the European setting: An overview

Since the beginning of the 1990s there has been a growing interest, in the European setting, in evaluating health-related quality of life (HRQL) in clinical studies. Assessing HRQL in childhood cancer survivors, in particular, is a new field of research. Studies of survivors of leukemia and brain tumors are of special interest since these are the commonest groups of survivors of cancer in childhood. Initial reports suggest that most of the survivors of childhood cancer are in good health with a normal psychosocial status, social life and capacity to cope with activities of daily living. More discriminative evaluations identify a number of subtle problems, such as cognitive deficits in brain tumor survivors or anxiety about a recurrence (especially) in children who have had megatherapy and autologous bone marrow rescue. In this group, pain is also a lasting problem in about one-third of patients. The main problem in these studies is comparability as the study designs vary widely. Little information is available with respect to inter-observer agreement, which is important since it is known that proxy respondents will under- or over-estimate components of the HRQL of the child. The most important base for further development of HRQL research is communication between researchers, in order to exchange experience and to avoid duplication of effort. Communication is necessary also for combining interests and forces in developing a standardized methodology as well as for conducting collaborative studies using equivalent measures.

A risk-benefit assessment of amifostine in cytoprotection.

Recent advances in chemotherapy have focused on the benefit of high dose regimens, increasing the dose intensity of conventional chemotherapy and using intensified chemotherapy with or without autologous bone marrow rescue. Dose intensity usually increases objective response rates of antineoplastic drugs and might, in some circumstances, improves survival. However, unacceptable acute and/or cumulative toxicity often impairs the proper management of patients, leading to dose reduction or treatment delay, thus reducing the efficacy and potentially the quality of life of patients. Therefore, considerable efforts have been made to manage, to prevent, and to delay many acute and cumulative treatment-related toxicities. Amifostine (WR-2721 ) is a multiorgan cytoprotector which has demonstrated cytoprotective effects, in vitro and in vivo, against the most common cytotoxic drug-related toxicities and against radiation-induced adverse effects in healthy tissues. In vitro and in vivo, cytoprotection was observed in several organs including kidney, haematopoietic stem cells, myocardial cells, neural cells, and mucosa, without detectable protection of malignant cells. In addition, in preclinical studies, amifostine appeared to be able to reduce the risk of radiation-induced secondary neoplasms. Phase I studies showed that nausea/vomiting and hypotension are the dose-limiting toxicities of amifostine and these may be controlled by reducing the duration of injection of amifostine. Phase II and randomised studies have confirmed the efficacy of amifostine in protecting against radiotherapy-induced mucositis, cisplatin-induced nephrotoxicity, cyclophosphamide-induced neutropenia and carboplatin-induced thrombocytopenia. Importantly, the cytoprotection of healthy tissues occurred without any significant deleterious effect on response rate, time to progression, and survival of patients receiving amifostine. However, in addition to the potential quality of life benefit, the most important question of whether the use of a cytoprotective agent might translate into the possibility of maintaining the dose intensity of anticancer therapies has still to be answered. The real benefit of amifostine in the overall management of patients with cancer requires additional studies to determine whether this chemoprotective approach can be of benefit to patients by increasing response rate, time to progression, and long term survival in patients receiving the more recent combination therapies involving new drugs such as the taxanes and oxaliplatin.

Advances in the biology and treatment of multiple myeloma.

Advances in the understanding of the cellular and molecular derangements involved in the initiation and progression of multiple myeloma are beginning to be translated into novel therapeutic approaches. The myeloma stem cell has been under intense scrutiny regarding its normal B-cell counterpart. Oncogenes, tumor-suppressor genes, and cell-survival genes have all been found to be dysregulated in some myeloma patients. Growth factors, especially interleukin-6, appear to be critical for disease progression, and interruption of autocrine and paracrine loops has been achieved with resultant inhibition of myeloma cell growth. Mechanisms of drug resistance and the implications of the multidrug resistance phenotype are just beginning to be understood. High-dose therapeutic regimens with autologous peripheral blood stem cell or allogeneic bone marrow rescue are rigorously being studied with an emphasis on exploiting the graft-versus-myeloma effect. Pamidronate, a second-generation bisphosponate, has been shown to be effective at decreasing adverse skeletal events in patients with advanced myeloma. The topoisomerase 1 inhibitor, topotecan, has shown activity in an initial study.

Treatment of non-Hodgkin's lymphoma.

Non-Hodgkin's lymphoma (NHL) is the most common type of lymphoid malignancy that affects over 40000 people in North American alone. The difficulty associated with NHL is correctly assigning patients into homogenous histologic subtypes. Appropriate classification is of paramount importance because the multiple subgroups are associated with distinct clinical outcomes. Current anticancer therapy for this heterogenous disease includes chemotherapy, radiation, cytokine administration and dose-intensive myeloablative antineoplastic treatments followed by autologous bone marrow rescue. With the optimal management strategy, approximately 50% of patients with aggressive NHL can achieve prolonged disease-free survival and even clinical cures. This article will review current therapies for NHL, and discuss some recent advances in the clinical application of prognostic factors, cytokines and the role of transplantation.

Much ado about not...enough data: high-dose chemotherapy with autologous stem cell rescue for breast cancer.

High-dose chemotherapy with autologous bone marrow or stem cell rescue (HDC/ASCR) has been proposed as a promising treatment strategy for breast cancer. Despite the frequency with which this procedure is performed, the role of HDC/ASCR in the treatment of breast cancer remains undefined. The purpose of this review is to examine the rationale for the procedure, the research progress to date, and the limitations of available data. A literature search of Medline from January 1966 through May 1997, CancerLit from January 1983 through May 1997, and Current Contents through May 1997 identified more than 600 English language papers or abstracts on this topic. Our review focuses on the preclinical and clinical data that explore the concept of chemotherapy dose intensity and the role of dose intensity in treating breast cancer. HDC/ASCR is based on the hypothesis that high-dose chemotherapy will overcome drug resistance, eradicate metastatic disease, and increase the proportion of women with breast cancer who are "cured." To date, results from only one phase 3 trial of HDC/ASCR compared with more conventional therapy have been published. Phase 2 and some phase 3 data on HDC/ASCR in the treatment of high-risk primary breast cancer and metastatic breast cancer are discussed. However, the results are inconclusive. The completion of national and international randomized trials is urgently needed to establish definitively the role of HDC/ASCR in the treatment of breast cancer.

Survival following intensive chemotherapy with bone marrow reconstitution for children with recurrent intracranial ependymoma--a report of the Children's Cancer Group.

Recurrent intracranial ependymoma is rarely cured by surgery, radiotherapy, and chemotherapy in conventional doses. This study was designed to determine the toxicity, radiographic response rate and outcome following intensive chemotherapy with ThioTEPA, etoposide, carboplatinum and autologous bone marrow rescue (ABMR) for young children with recurrent central nervous system ependymoma. ThioTEPA 300 mg/m2/day (total 900 mg/m2) and etoposide 250 to 500 mg/m2/day (total 750 to 1500 mg/m2) were administered for three consecutive days with or without the addition of carboplatinum 500 mg/m2/day (total 1500 mg/m2) for an additional three consecutive days, and autologous bone marrow was reinfused 72 hours following chemotherapy. Eligibility criteria required adequate renal, hepatic and pulmonary function, and no tumor infiltration of bone marrow. Fifteen children with recurrent intracranial ependymoma, aged 5 months to 12 years (median 22 months), were treated. Five patients died of treatment related toxicities within 62 days of marrow reinfusion. Eight have expired from progressive disease a median of six months post-ABMR, and one has died from unrelated causes. One child remains alive 25 months post-ABMR, following further disease recurrence. No partial or complete responses were observed. This regimen of high-dose ThioTEPA and etoposide with or without additional carboplatinum with ABMR is not an effective strategy for retrieving heavily pre-treated children with recurrent ependymoma.

Ongoing Assessment of Nutritional Status in Children with Malignant Disease

The nutritional status of a child on cancer therapy influences both tolerance of and response to treatment. However, it is difficult to assess nutritional status on a daily basis because an accurate quantitation of the calorie intake is difficult. Anthropometric and biochemical parameters are prone to error and often reflect past rather than current nutritional status. In practice, a subjective clinical assessment is usually relied upon. This study objectively appraises the value of such an assessment. Based on clinical symptoms that alter oral intake and absorption of food, a scoring system was designed to assess nutritional status on a day to day basis. A symptom score (SS) of 10 implied “normality”; 0 indicated maximum debility. Over a 2-year period 511 daily scores were recorded in 30 patients aged 0.7-17.5 years. Patients were studied at presentation and during treatment for acute lymphoblastic leukemia (ALL, n = 14; solid tumors receiving megatherapy with autologous bone marrow rescue (ABMR, n = 8), and chemotherapy for different tumors (miscellaneous, n = 8). The SS was compared with other nutritional parameters, including sequential anthropometric indices, serum albumin, insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), and whole-body protein turnover (WBPT) using [1-13C]leucine. The mean SS was reduced at diagnosis for all leukemic patients (median score = 8), improved during first remission (p < 0.002), fell to a minimum during febrile neutropenia (p = 0.0009), and improved with clinical and hematological recovery (p = 0.0009). A reduction in SS was related to fever (p < 0.001) and a fall in neutrophil count (p < 0.001). There was no correlation with anthropometric indices or IGF-I and IGFBP-3 levels. Paired WBPT studies in 9 patients showed that SS correlated well with protein breakdown (p = 0.026). The results suggest that the ongoing nutritional status of children with malignancy undergoing chemotherapy is best assessed using simple clinical parameters.

The Monitoring of Potential Long-Term Complications in Treated Adult Cancer Patients

A wide variety of long-term complications may be noted following conventional cancer treatment. These include overwhelming postsplenectomy sepsis syndrome, central and peripheral nervous system toxicity, cardiovascular complications, chronic liver damage, and secondary malignancy. Follow-up monitoring usually incorporates both physical examination and the result of radiological and laboratory investigations. Primary care physicians will often be responsible for the majority of the follow-up monitoring involving cured cancer patients and need to be aware of possible long-term therapy-related problems, especially those that present years after successful treatment of the original malignancy.