Original Article
Leukemia Following Chemotherapy for Ovarian Cancer
N Engl J Med 1990; 322:1-6January 4, 1990
- Abstract
- Abstract
An international collaborative group of cancer registries and hospitals identified 114 cases of leukemia following ovarian cancer. We investigated the possible etiologic role of chemotherapy, radiotherapy, and other factors, using a case–control study design, with three controls matched to each case of leukemia.
Chemotherapy alone was associated with a relative risk of 12 (95 percent confidence interval, 4.4 to 32), as compared with surgery alone, and patients treated with both chemotherapy and radiotherapy had a relative risk of 10 (95 percent confidence interval, 3.4 to 28). Radiotherapy alone did not produce a significant increase in risk, as compared with surgery alone. The risk of leukemia was greatest four or five years after chemotherapy began, and the risk was elevated for at least eight years after the cessation of chemotherapy.
The drugs cyclophosphamide, chlorambucil, melphalan, thiotepa, and treosulfan were independently associated with significantly increased risks of leukemia, as was the combination of doxorubicin hydrochloride and cisplatin. Chlorambucil and melphalan were the most leukemogenic drugs, followed by thiotepa; cyclophosphamide and treosulfan were the weakest leukemogens, and the effect per gram was substantially lower at high doses than at lower doses. The extent to which the relative risks of leukemia are offset by differences in chemotherapeutic effectiveness is not known. (N Engl J Med 1990; 322:1–6.)
Media in This Article
Table 1
Distribution of Cases of Leukemia Following Ovarian Cancer, According to Study Center.Table 2
Distribution of Cases of Leukemia Following Ovarian Cancer, According to Type of Leukemia and Years since the Diagnosis of Ovarian Cancer.Article Activity
- Article
IT has been clearly demonstrated that patients who have received chemotherapy with alkylating agents for ovarian cancer have an increased risk of acute leukemia, particularly the myeloid type.1 2 3 4 5 6 Although the drugs treosulfan, melphalan, chlorambucil, and cyclophosphamide have all been identified as leukemogenic,7 most previous studies have not been large enough to permit detailed analyses of the risk and the time of occurrence of leukemia according to the amount and type of chemotherapy received. Since several different drugs and combinations of drugs currently used to treat ovarian cancer cannot be clearly distinguished in terms of their therapeutic effects (Tamar M: personal communication), it is particularly important to minimize the long-term side effects of treatment by identifying the regimens that have the lowest leukemogenic potential.
We present the results of a case–control study in which 114 patients with leukemia were identified among 99,113 survivors of ovarian cancer, and compared with matched controls.
Methods
The study was carried out by a collaborative group comprising 11 population-based cancer registries in Europe and Canada and two large oncology hospitals in Europe, both of which have maintained cancer registries for decades (Table 1Table 1
Distribution of Cases of Leukemia Following Ovarian Cancer, According to Study Center.).Study Subjects
The collaborating registries and hospitals all routinely carry out long-term follow-up of patients with ovarian cancer. The occurrence of second cancers was identified through a comparison of records (in the registries) or through active follow-up (in the hospitals) and was confirmed histologically whenever possible. The case patients, defined as patients who were given a diagnosis of leukemia at least one year after receiving a diagnosis of ovarian cancer, were identified from the records maintained by the participating institutions of patients given diagnoses of ovarian cancer on or after January 1, 1960. Women who received diagnoses of myelodysplastic syndrome8 at least one year after their diagnoses of ovarian cancer were also included as case patients.
For each case patient, three matched control subjects were sought (four in the case of the German Democratic Republic Cancer Registry, which began the study somewhat earlier with a slightly different protocol). First, all patients were identified who had received diagnoses of ovarian cancer in the same registry or hospital as the case patient and had survived free of a second cancer for at least as long as the interval between the diagnoses of ovarian cancer and of leukemia in the case patient. Among the patients in this group, those who were most similar to the case patient with respect to year of birth and then to year of diagnosis of ovarian cancer were chosen as controls. If the controls were equally well matched, a random choice was made. The maximal acceptable differences between case patients and their matched controls were three years for year of birth and five years for year of diagnosis of ovarian cancer, unless no patients satisfied the requirements, in which event the most similar available patient was chosen as a control.
The purpose of matching was to eliminate the potentially confounding effect of factors that are of little interest in themselves but that may be related to both the risk of leukemia and the type of treatment for ovarian cancer. The stage of ovarian cancer was not a matching factor, because its relation to the risk of leukemia has not been established.
Data Abstraction
For each case patient and the corresponding matched controls, the full medical record of the diagnosis and treatment of ovarian cancer was sought. For the case patients, the record of the leukemia diagnosis was also obtained. The records were abstracted on specially prepared forms that requested information on the patient's date of birth; the morphology, stage, and date of diagnosis of the ovarian cancer; and all cytotoxic chemotherapy and radiotherapy given for the ovarian cancer. For the case patients, the record of the diagnosis of leukemia was also obtained, including relevant pathology reports, and the morphologic features and date of diagnosis were recorded. For each course or cycle of chemotherapy, the details abstracted included the name and total dose of each drug used and the dates of the period during which it was administered. For each patient treated by radiotherapy, the most detailed record of radiotherapy available was obtained.
For each course of external-beam radiotherapy, the details abstracted included the size and location of the field, the energy level of the radiation, and the dose to the tumor. For brachytherapy, data on the anatomical site of the implant, the activity and type of the isotope, and the duration of implantation were abstracted.
Radiation Dose
To provide an average dose of radiation to the total active bone marrow, the bone marrow was partitioned and weighted according to the method of Cristy.9 In a region treated by external beams, the dose to the bone marrow was assumed to be the same as the tumor dose. Outside the treated region, the dose was estimated on the basis of measurements in a water phantom.10 In the case of brachytherapy, the dose to the bone marrow was calculated with a computer program in routine clinical use.11
Statistical Analysis
Standard conditional-likelihood methods for the analysis of matched case–control studies were used.12 These methods can provide estimates only of relative risk, not of absolute risk, and thus they require the choice of a reference category of treatment against which the risk of other types of therapy is to be compared. In this study, the comparisons were made either in relation to patients treated with surgery only or to those treated without chemotherapy — that is, with surgery or radiotherapy only.
The treatment of the case patients was considered only in the period between the diagnosis of ovarian cancer and the diagnosis of leukemia. For each control subject, therapy was considered only in an equivalent interval, starting with the date on which ovarian cancer was diagnosed.
Although chemotherapy with combinations of drugs has been widely used in the treatment of ovarian cancer over the past decade, the case patients and controls in this study were generally treated with single agents. Furthermore, the combinations of drugs used rarely involved more than one alkylating agent. Nevertheless, some patients were treated with multiple potentially leukemogenic agents in the same course of therapy, and we therefore defined two categories of combination therapy. The first was the combination of doxorubicin hydrochloride and cisplatin, and the second included all other combinations of two or more alkylating agents or drugs identified as carcinogenic to humans or laboratory animals.7 Combinations that included only one such drug were treated as single agents.
Most statistical analyses were restricted to leukemia that was acute, nonlymphocytic, or both and to the myelodysplastic syndrome — conditions that have all been associated previously with either chemotherapy involving alkylating agents or exposure to radiation. For simplicity, these conditions are referred to subsequently as acute or nonlymphocytic leukemia. There were not enough cases of chronic lymphocytic leukemia for analysis.
In the statistical analyses, all relative risks were estimated with the computer program PECAN,13 and P values and 95 percent confidence intervals were obtained with the likelihood-ratio test,14 unless otherwise specified.
Results
Table 1 shows the number of patients with ovarian cancer studied, the number of cases of leukemia identified in these patients, and the number of matched controls sampled, according to study center. Among the women in whom leukemia developed subsequently, the median age at diagnosis of ovarian cancer was 58 years. Most of the cases of leukemia (69 percent) occurred in women given the diagnosis of ovarian cancer in 1970 or later, and the last one entered in the study occurred in a woman whose leukemia was diagnosed in 1985. Of the controls, 74 percent were matched within two years of the case patient according to age at diagnosis of ovarian cancer, and 90 percent were matched within two years according to date of diagnosis. For 9 case patients, it was impossible to find 3 controls who satisfied the matching criteria, and a total of 12 controls were therefore missing.
The cases of leukemia following ovarian cancer were classified according to the subtype of leukemia and the length of the interval between the diagnoses of ovarian cancer and leukemia (Table 2Table 2
Distribution of Cases of Leukemia Following Ovarian Cancer, According to Type of Leukemia and Years since the Diagnosis of Ovarian Cancer.). When a specific subtype was assigned, the designation was based on a histologically confirmed diagnosis. Most cases (74 percent) occurred between two and nine years after ovarian cancer, and acute or nonlymphocytic leukemias represented 89 percent of the total. Nine of the 11 cases of myelodysplastic syndrome were reported from the Karolinska Hospital, Stockholm. Subsequent analyses involved only the restricted group of 101 case patients referred to as having acute or nonlymphocytic leukemia (Table 2) and their matched controls. Because of the small number of cases, no separate statistical analyses were attempted for other subtypes of leukemia or for the myelodysplastic syndrome.Table 3Table 3
Distribution of Case Patients and Controls with Acute or Nonlymphocytic Leukemia, with Relative Risks According to Overall Treatment Category. shows the number of case patients and controls who were treated with surgery, chemotherapy, radiotherapy, or both chemotherapy and radiotherapy. The relative risks, P values, and 95 percent confidence intervals for each category (with the surgery-only category as the base line) are also shown. The relative risk for chemotherapy alone (12) was slightly higher than the risk for radiotherapy and chemotherapy combined (10), although the difference was not significant (P = 0.41). Almost identical estimates of relative risk (12 and 9.3, respectively) were obtained when the case patients and controls from the participating hospitals were excluded. Because of the small and nonsignificant increase in risk associated with radiotherapy alone and the limited number of case patients treated with surgery alone, the groups of patients treated with surgery or radiotherapy only were combined to provide a larger reference group for the estimation of relative risk. The resulting estimates may thus be slightly conservative (biased toward 1.0) but will have narrower confidence intervals than those using surgery alone as a reference category.For each drug recorded as having been used by itself to treat ovarian cancer and for the two categories of combination therapy, Table 4Table 4
Distribution of Case Patients and Controls with Acute or Nonlymphocytic Leukemia, According to Type of Chemotherapy.* gives the number of patients who were ever treated, according to their status as case patients or controls. The alkylating agents chlorambucil, cyclophosphamide, melphalan, thiotepa, and treosulfan were the most frequently recorded chemotherapeutic agents. Combinations of drugs were used far less often during the observation period of the study.In the case of several drugs and combinations, there were enough case patients and controls who had received no other chemotherapy to allow a separate estimation of the relative risks, without the need to adjust for other types of chemotherapy. The results of these analyses are shown in Table 5Table 5
Distribution of Case Patients and Controls with Acute or Nonlymphocytic Leukemia, with Relative Risks According to Type and Dose of Chemotherapy among Patients Who Received Only One Type.*. The median dose in the controls was used as a cutoff point to create high-dose and low-dose groups for each drug. In addition to the relative risks (with treatment with surgery and radiotherapy only as the base line), the table shows the number of case patients and controls in each group and the median dose among the controls in the low-dose and high-dose groups. For five drugs used as single agents, there was a clear and dramatic increase in risk between the two dosages. The increase was comparable in magnitude for four of the drugs. Cyclophosphamide appeared substantially less leukemogenic, the difference being statistically significant when cyclophosphamide was compared with the other four agents (P = 0.02). There were also two case patients and two controls who were treated only with the combination of doxorubicin hydrochloride and cisplatin, resulting in a relative risk of 6.5 (P = 0.05).Among the patients who had been treated with radiotherapy only, the relative risks were 1.9 (P = 0.34) and 1.2 (P = 0.80) for estimated doses to the active bone marrow of less than 10 Gy and 10 Gy or more, respectively. In general, the patients treated with both chemotherapy and radiotherapy received less chemotherapy overall than those whose only treatment was chemotherapy (results not shown).
Of the 101 case patients, 39 received diagnoses of Stage III or IV ovarian cancer, as compared with only 38 of 304 controls. However, after allowance by multiple logistic regression for the leukemogenic effect of the categories of chemotherapy listed in Table 5, the estimated relative risks were 0.80, 4.9, and 1.5 for Stages II, III, and IV, respectively, as compared with Stage I. The relative risk for Stage III differed significantly from 1.0 (P = 0.004), but the risks for the other two stages were not significant at the 0.05 level. No attempt was made to evaluate the risk according to subtype of ovarian cancer.
Table 6Table 6
Relative Risk of Chemotherapy among Case Patients and Controls with Acute or Nonlymphocytic Leukemia, According to Time since First and Last Treatments. shows the relative risks of chemotherapy as broken down according to the time since the first and last episodes of treatment. After the initial chemotherapy, the relative risk as compared with that in patients who received no chemotherapy increased steadily for about six years, and although it decreased when chemotherapy ceased, it remained elevated for at least eight years.Finally, the effect of age at the time of diagnosis of ovarian cancer on the risk associated with chemotherapy was considered by estimating the relative risk separately for patients above and below the median age at diagnosis (57 years). For patients taking cyclophosphamide, there was little difference in relative risk, but the patients in the older group taking melphalan or chlorambucil had a relative risk that was nearly 10 times higher than that in the younger group.
The results in Tables 3, 5, and 6 remained essentially unchanged when the case patients with myelodysplastic syndrome and their matched controls were excluded. For example, the relative risks in Table 3 became 1.0, 1.7, 11, and 8.8, respectively, for the categories of surgery, radiotherapy only, chemotherapy only, and radiotherapy and chemotherapy combined.
Discussion
The case–control design used in the present study has only recently been applied to the investigation of second cancers.6 , 15 , 16 Although the method does not readily produce estimates of absolute risk, approximate estimates could be obtained by applying the estimated relative risks to leukemia rates in the general population, taking into account the survival curve for patients with ovarian cancer.
This investigation was carried out after a previous cohort study17 in which the risk of a second cancer following ovarian cancer was estimated from the records of 11 population-based cancer registries listing more than 87,000 survivors of ovarian cancer. In that study, there were about four times as many cases of acute or nonlymphocytic leukemia following ovarian cancer as would have been expected in a population of healthy women of the same age during the same time.
On the basis of the percentages shown for the controls in Table 3, about 26 percent of the survivors of ovarian cancer were treated with surgery alone; 36 percent received radiotherapy only, with a relative risk of leukemia of 1.6, as compared with those receiving surgery alone; 17 percent received chemotherapy only, with a relative risk of 12; and 21 percent received both chemotherapy and radiotherapy, with a relative risk of 9.8. Thus, if the patients with ovarian cancer who were treated with surgery alone had no increased risk of leukemia as compared with the general population and if the same relative risks can be applied throughout the follow-up period, the predicted relative risk of leukemia in the cohort study would have been 0.26 + (1.6)(0.36) + (12)(0.17) + (9.8)(0.21) = 4.9, which is rather close to the fourfold increase seen in that study.17 It thus seems reasonable to attribute the excess risk of leukemia among survivors of ovarian cancer overwhelmingly to their chemotherapy, either alone or in conjunction with radiotherapy, rather than to the disease itself or to some related factor.
By restricting our analysis to patients who received only one type of chemotherapy, we have been able to identify five single drugs as clearly leukemogenic —chlorambucil, cyclophosphamide, melphalan, thiotepa, and treosulfan. All these agents except thiotepa have been classified elsewhere as human leukemogens,7 but only in a few earlier studies has it been possible to demonstrate the leukemogenicity of more than one alkylating agent. In these studies, melphalan emerged as a far more potent leukemogen than cyclophosphamide.18 , 19 For all five agents, there was clear evidence of a dose–response relation with respect to leukemogenicity in our study when the patients were classified according to those who had received less or more than the median total dose of each drug or combination. In fact, the risks in the study may have been somewhat underestimated, if the matching according to registry and time of diagnosis resulted in a greater similarity between the case patients and the controls with regard to treatment than would otherwise have been observed. The possibility of overmatching cannot be evaluated in this study, but it was considered to be preferable to unadjusted confounding.
The leukemogenic effect of radiation in this study was close to that observed for radiotherapy in patients with cervical cancer,15 and the downturn in risk at doses to the bone marrow above 10 Gy supports the hypothesis that at high levels of exposure cell killing overwhelms the leukemogenic effect of radiation. The slightly lower risk in patients treated with both chemotherapy and radiotherapy than in those receiving chemotherapy alone can probably be attributed to differences in the amount of chemotherapy administered in the two groups. There was no suggestion of a multiplicative or synergistic joint effect of the two methods of treatment.
The relative leukemogenic potency of alkylating agents is difficult to characterize on the basis of data in humans.20 Comparisons can be made in terms of either absolute drug dose (in grams, for example) or units of equal therapeutic or clinical effect. In the treatment of ovarian cancer, there is still no clear consensus on the relative effectiveness of different drugs, and it is therefore difficult to define standard doses. Risk per unit of weight of drug is thus a more generally useful measure of potency, since it can be used to calculate the predicted risk at any given dose level.
In crude comparisons of the risks associated with the administration of total doses of each agent below and above the median dose, only cyclophosphamide can be clearly distinguished as being far less potent than all the other drugs. However, when the dose is taken into account by dividing the excess relative risks (the relative risk minus 1.0) shown in Table 5 by the corresponding median doses (data not shown), melphalan was the most leukemogenic drug per gram at high doses, followed by thiotepa and chlorambucil. At low doses, thiotepa was the most potent. Treosulfan was the least leukemogenic drug at either dose level.
Four of the five drugs were substantially more potent at low doses than at high doses, implying that the increase in relative risk was less than linear with respect to dose. Several explanations could be put forward for this finding. One possibility is that for patients treated orally over long periods, the recorded doses were an overestimation of the true doses, simply because the patients stopped taking their tablets. Alternatively, the phenomenon may have been due to the effect of cell killing or saturation of metabolic activation at higher dosages, differences in dose rate, or lower sensitivity to leukemogenesis among patients tolerant of high doses.
An important new finding in the present study concerns the leukemogenicity of the combination of doxorubicin hydrochloride and cisplatin. Both drugs are used widely and effectively to treat a number of malignant diseases, and both have been recognized as carcinogens in animals.7 It thus appears that at least one of them is also a human leukemogen. Several of the drugs studied here are no longer in use. Although estimates of their leukemogenic effect have limited clinical importance, they are of interest to scientists studying aspects of the structure and activity of carcinogens.
Analyses of the temporal pattern of these leukemia cases show that the risk was at its highest four to six years after treatment for ovarian cancer. It dropped substantially after the cessation of therapy with alkylating agents, from a 13-fold increase immediately after cessation to about 6-fold five to eight years later. Increasing age at diagnosis of ovarian cancer seemed to increase substantially the relative risk due to certain types of chemotherapy in this study. This finding should be viewed with caution, in view of the small number of cases on which it is based.
The trend in treatment for ovarian cancer is toward more use of chemotherapy and in particular an increasing reliance on combinations of drugs. Despite some promising recent findings,21 there is limited evidence so far that the effectiveness of such chemotherapy improves with the intensity or number of agents, and our study clearly shows dramatic increases in the long-term risk of leukemia at high dosages. In the case of Hodgkin's disease, a substantial risk of leukemia following combination chemotherapy is clearly offset by enormous gains in survival.22 However, after ovarian cancer, the extent to which the increased risk of leukemia is offset is still unclear.
Source Information
From the International Agency for Research on Cancer, Lyon, France (J.M.K., A.A.); Medical Research Council Biostatistics Unit, Cambridge, United Kingdom (N.E.D.); Department of Gynecological Oncology, Karolinska Hospital, Stockholm, Sweden (F.P., B.Z.); Ontario Cancer Treatment and Research Foundation, Toronto (E.A.C.); Radiumstationen, Aarhus Kommune Hospital, Aarhus, Denmark (D.P.); National Cancer Registry of the German Democratic Republic, Berlin (W.M., B.K.); Thames Cancer Registry, Surrey, United Kingdom (J.B.); Norwegian Cancer Registry, Oslo (H.H.); Cancer Epidemiology Research Unit, University of Birmingham, United Kingdom (P.P.); Finnish Cancer Registry, Helsinki (S.K.); Weston Park Hospital, Sheffield, United Kingdom (F.N.); Alberta Cancer Registry, Edmonton, Alb., Canada (M.K.); Cancer Control Agency of British Columbia, Vancouver, B.C., Canada (P.B.); Manitoba Cancer Treatment and Research Foundation, Winnipeg, Man., Canada (W.C.); Cancer Registry of Slovenia, Ljubljana, Yugoslavia (V.P.K.); University of Alberta, Edmonton, Alb., Canada (A.R.B.); Danish Cancer Registry, Copenhagen (H.S.); Division of Medical Statistics and Epidemiology of the London School of Hygiene and Tropical Medicine, London (P.F.); and Department of Radiation Physics, M.D. Anderson Cancer Center, Houston (M.S.). Address reprint requests to Dr. Kaldor at the International Agency for Research on Cancer, 150 cours Albert-Thomas, 69372 Lyon Cédex 08, France.
- References
References
1
Reimer
Full Text | Web of Science | Medline2
Einhorn
CrossRef | Web of Science | Medline3
Pedersen-Bjergaard
CrossRef | Web of Science | Medline4
Einhorn
CrossRef | Web of Science | Medline5
De Gramont
CrossRef | Web of Science | Medline6
Haas
CrossRef | Web of Science | Medline7
IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans: overall evaluations of carcinogenicity: an update of IARC monographs from Volumes 1 to 42. Suppl. no. 7. Lyon, France: International Agency for Research on Cancer, 1987.
8
Bennett
CrossRef | Web of Science | Medline9
Cristy
CrossRef | Web of Science | Medline10
Stovall
Web of Science11
Stovall
Web of Science12
Breslow NE, Day NE. Statistical methods in cancer research. Vol. 1: The analysis of case–control studies. Lyon, France: International Agency for Research on Cancer, 1980. (IARC scientific publications no. 32.)
13
Storer
CrossRef | Web of Science14
Cox DR, Hinkley DV. Theoretical statistics. London: Chapman & Hall, 1974.
15
Boice
Web of Science | Medline16
van der Velden
CrossRef | Web of Science | Medline17
Kaldor
CrossRef | Web of Science | Medline18
Greene
Web of Science | Medline19
Cuzick
CrossRef | Web of Science | Medline20
Kaldor
CrossRef | Medline21
Tropé
Web of Science | Medline22
Kaldor
Full Text | Web of Science | Medline
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B Rachet, E Mitry, A Shah, N Cooper, M P Coleman. (2008) Survival from adult leukaemia in England and Wales up to 2001. British Journal of Cancer 99, S116-S118
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CrossRef29
C. Ferrari, T. Bohling, M. S. Benassi, A. Ferraro, G. Gamberi, G. Bacci, A. brach del prever, L. Sangiorgi, P. Ragazzini, M. R. Sollazzo, A. Balladelli, P. Picci. (1999) Secondary Tumors in Bone Sarcomas After Treatment with Chemotherapy. Cancer Detection <html_ent glyph="@amp;" ascii="&"/> Prevention 23:5, 368-374
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Schueler, Trimbos, Hermans, Fleuren. (1998) The yield of surgical staging in presumed early stage ovarian cancer: Benefits or doubts?. International Journal of Gynecological Cancer 8:2, 95-102
CrossRef34
Lewis B. Silverman, Thomas W. McLean, Richard D. Gelber, Mia J. Donnelly, D. Gary Gilliland, Nancy J. Tarbell, Stephen E. Sallan. (1997) Intensified therapy for infants with acute lymphoblastic leukemia. Cancer 80:12, 2285-2295
CrossRef35
D.S. Richardson, S.A. Johnson. (1997) Anthracyclines in haematology: preclinical studies, toxicity and delivery systems. Blood Reviews 11:4, 201-223
CrossRef36
Jolanda Cibere, John Sibley, May Haga. (1997) Rheumatoid arthritis and the risk of malignancy. Arthritis & Rheumatism 40:9, 1580-1586
CrossRef37
Christopher S. George, Alan E. Lichtin. (1997) HEMATOLOGIC COMPLICATIONS OF RHEUMATIC DISEASE THERAPIES. Rheumatic Disease Clinics of North America 23:2, 425-437
CrossRef38
Günter Emons, Olaf Ortmann, Hanns-Martin Teichert, Horst Fassl, Udo Löhrs, Stig Kullander, Antti Kauppila, Daniel Ayalon, Andrew Schally, Friedhelm Oberheuser, . (1996) Luteinizing hormone-releasing hormone agonist triptorelin in combination with cytotoxic chemotherapy in patients with advanced ovarian carcinoma: A prospective double blind randomized trial. Cancer 78:7, 1452-1460
CrossRef39
Raymond M. Lowenthal, Kristine Eaton. (1996) TOXICITY OF CHEMOTHERAPY. Hematology/Oncology Clinics of North America 10:4, 967-990
CrossRef40
Barbara J.S. Sanderson, Alison J. Shield. (1996) Mutagenic damage to mammalian cells by therapeutic alkylating agents. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 355:1-2, 41-57
CrossRef41
M Hawkins. (1996) Multiple primary cancers in population-based cancer registries. European Journal of Cancer 32:8, 1279-1280
CrossRef42
Daniel M. Green, Norman E. Breslow, Ilonka Evans, Jami Moksness, Giulio J. D'Angio. (1996) Treatment of children with stage IV favorable histology Wilms tumor: A report from the National Wilms Tumor Study Group. Medical and Pediatric Oncology 26:3, 147-152
CrossRef43
Claudio Ponticelli, Pietro Zucchelli, Patrizia Passerini, Bruno Cesana, Francesco Locatelli, Sonia Pasquali, Mauro Sasdelli, Bruno Redaelli, Claudio Grassi, Claudio Pozzi, Daniela Bizzarri, Giovanni Banfi. (1995) A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney International 48:5, 1600-1604
CrossRef44
John M. Kaldor, Nicholas E. Day, Berndt Kittelmann, Folke Pettersson, Froydis Langmark, Dorthe Pedersen, Patricia Prior, Frank Neal, Sakari Karjalainen, Janine Bell, Won Choi, Maria Koch, Pierre Band, Vera Pompe-Kirn, Catherine Garton, Wolfhardt Staneczek, Birgitta Zarén, Marilyn Stovall, Paolo Boffetta. (1995) Bladder tumours following chemotherapy and radiotherapy for ovarian cancer: A case—control study. International Journal of Cancer 63:1, 1-6
CrossRef45
A. Corso, M. Lazzarino, E. Morra, S. Merante, C. Astori, P. Bernasconi, M. Boni, C. Bernasconi. (1995) Chronic myelogenous leukemia and exposure to ionizing radiation — a retrospective study of 443 patients. Annals of Hematology 70:2, 79-82
CrossRef46
Kjell Bergfeldt, Stefan Einhorn, Ingvar Rosendahl, Per Hall. (1995) Increased Risk of Second Primary Malignancies in Patients with Gynecological Cancer: A Swedish record-linkage study. Acta Oncologica 34:6, 771-777
CrossRef47
Peter H. Wiernik, Nancy T. Sklarin, Janice P. Dutcher, Joseph A. Sparano, Edward S. Greenwald. (1994) Adjuvant radiotherapy for breast cancer as a risk factor for the development of lung cancer. Medical Oncology 11:3-4, 121-125
CrossRef48
Paolo Boffetta, John M. Kaldor. (1994) Secondary Malignancies Following Cancer Chemotherapy. Acta Oncologica 33:6, 591-598
CrossRef49
Malcolm A. Smith, Lawrence Rubinstein, Richard S. Ungerleider. (1994) Therapy-related acute myeloid leukemia following treatment with epipodophyllotoxins: Estimating the risks. Medical and Pediatric Oncology 23:2, 86-98
CrossRef50
Daniel M. Green, Michael A. Zevon, Peter A. Reese, Geoffrey S. Lowrie, John F. Gaeta, John I. Pearce, Arthur M. Michalek, Elizabeth A. Stephens. (1994) Second malignant tumors following treatment during childhood and adolescence for cancer. Medical and Pediatric Oncology 22:1, 1-10
CrossRef51
Ruth Heyn, Fareed Khan, Lisa G. Ensign, Sarah S. Donaldson, Frederick Ruymann, Malcolm A. Smith, Teresa Vietti, Harold M. Maurer. (1994) Acute myeloid leukemia in patients treated for rhabdomyosarcoma with cyclophosphamide and low-dose etoposide on intergroup rhabdomyosarcoma study III: An interim report. Medical and Pediatric Oncology 23:2, 99-106
CrossRef52
R. Cheruku, M. Hussain, M. Tyrkus, M. Edelstein. (1993) Myelodysplastic syndrome after cisplatin therapy. Cancer 72:1, 213-218
CrossRef53
Figueroa, MichaelGehlsen, JaneHammond, DenisOndreyco, SharonPiro, LawrencePomeroy, TalismanWilliams, FrederickMcMillan, Robert. (1993) Combination Chemotherapy in Refractory Immune Thrombocytopenic Purpura. New England Journal of Medicine 328:17, 1226-1229
Full Text54
Hermann Brenner, Sabine Siegle, Christa Stegmaier, Hartwig Ziegler. (1993) Second primary malignancies following gynecological tumours in Saarland, Germany, 1968?1987. Journal of Cancer Research and Clinical Oncology 119:3, 179-183
CrossRef55
D.J. Straus. (1993) Treatment of early Stage Hodgkin's disease. Blood Reviews 7:1, 34-42
CrossRef56
A. K. Saraya, P. S. Dhot, R. Saxena. (1993) Refractory anaemias. The Indian Journal of Pediatrics 60:2, 187-192
CrossRef57
David M. Gershenson. (1993) Update on malignant ovarian germ cell tumors. Cancer 71:S4, 1581-1590
CrossRef58
Marco Treskes, Wim J. F. Vijgh. (1993) WR2721 as a modulator of cisplatin-and carboplatin-induced side effects in comparison with other chemoprotective agents: a molecular approach. Cancer Chemotherapy and Pharmacology 33:2, 93-106
CrossRef59
David M. Gershenson, Michele F. Mitchell, Neely Atkinson, Elvio G. Silva, John J. Kavanagh, Mitchell Morris, Thomas W. Burke, Donna Warner, J.Taylor Wharton. (1992) The effect of prolonged cisplatin-based chemotherapy on progression-free survival in patients with optimal epithelial ovarian cancer: “Maintenance” therapy reconsidered. Gynecologic Oncology 47:1, 7-13
CrossRef60
Curtis, Rochelle E., Boice, John D. Jr., Stovall, Marilyn, Bernstein, Leslie, Greenberg, Raymond S., Flannery, John T., Schwartz, Ann G., Weyer, PeterMoloney, William C., Hoover, Robert N., . (1992) Risk of Leukemia after Chemotherapy and Radiation Treatment for Breast Cancer. New England Journal of Medicine 326:26, 1745-1751
Full Text61
Robert F. Ozols. (1992) Ovarian cancer, Part II: Treatment. Current Problems in Cancer 16:2, 67-126
CrossRef62
R.A. Cartwright. (1992) Leukaemia epidemiology and radiation risks. Blood Reviews 6:1, 10-14
CrossRef63
David J. Straus, Joachim Yahalom, Jeffrey Gaynor, Jane Myers, Benjamin Koziner, James Caravelli, Burton J. Lee, Lourdes Z. Nisce, Beryl McCormick, Daiva Bajorunas, John Redman, Janice Kirsch, Bayard D. Clarkson. (1992) Four cycles of chemotherapy and regional radiation therapy for clinical early-stage and intermediate-stage Hodgkin's disease. Cancer 69:4, 1052-1060
CrossRef64
Ignace B. Vergote, Laure N. Vergote-De Vos, Vera M. Abeler, Magne Aas, Mette W. Lindegaard, Kjell E. Kjørstad, Claes G. Tropé. (1992) Randomized trial comparing cisplatin with radioactive phosphorus or whole-abdomen irradiation as adjuvant treatment of Ovarian cancer. Cancer 69:3, 741-749
CrossRef65
Chaim Kaplinsky, Amos Frisch, Ian J. Cohen, Yacov Goshen, Lutfi Jaber, Isaar Yaniv, Batia Stark, Hanah Tamary, Rina Zaizov. (1992) T-cell acute lymphoblastic leukemia following therapy of rhabdomyosarcoma. Medical and Pediatric Oncology 20:3, 229-231
CrossRef66
Dana R. Crawford, Joel S. Greenberger. (1991) Active oxygen transforms murine myeloid progenitor cellsin vitro. International Journal of Cancer 49:5, 744-749
CrossRef67
Adriano Paccagnella, Vanna Chiarion-Sileni, Marcel Soesan, Giovannella Baggio, Sandro Bolzonella, Pietro De Besi, Dario Casara, Michela Frizzarin, Luigi Salvagno, Adolfo Favaretto, Mario V. Fiorentino. (1991) Second and third responses to the same induction regimen in relapsing patients with multiple myeloma. Cancer 68:5, 975-980
CrossRef68
Bengt B. Arnetz, Lawrence W. Raymond, Mark J. Nicolich, Lisa Vargo. (1991) Mortality among Petrochemical Science and Engineering Employees. Archives of Environmental Health: An International Journal 46:4, 237-248
CrossRef69
Lisa M. Deangelis. (1991) Primary central nervous system lymphoma as a secondary malignancy. Cancer 67:5, 1431-1435
CrossRef70
Marie-Hélène Moser, Walter R. Paukovits. (1991) Haemoprotection against cytostatic drugs by stem cell inhibition. Trends in Pharmacological Sciences 12, 304-310
CrossRef71
Glenn J. Bubley, Brian P. Ashburner, Beverly A. Teicher. (1991) Spectrum ofcis-diamminedichloroplatinum(II)-induced mutations in a shuttle vector propagated in human cells. Molecular Carcinogenesis 4:5, 397-406
CrossRef72
Susanne Osanto, Joyphi C. P. Thijssen, Viola M. Woldering, Jaap L. S. Van Rijn, Adayapalam T. Natarajan, Ad D. Tates, A. V. Carrano. (1991) Increased frequency of chromosomal damage in peripheral blood lymphocytes up to nine years following curative chemotherapy of patients with testicular carcinoma. Environmental and Molecular Mutagenesis 17:2, 71-78
CrossRef73
Aaron Sulkes, Rose Ruchlemer, Suzzanne Ben Neria, Rachel Leizerowitz, Dvora Abeliovich, Aaron Polliack. (1991) Acute Monoblastic Leukemia with t(9;11) in a Patient Receiving Chemotherapy for Ovarian Cancer: Secondary Leukemia or Fortuitous Association of Two Neoplasias?. Leukemia & Lymphoma 4:5-6, 405-409
CrossRef74
A. Horwich. (1990) The management of early Hodgkin's disease. Blood Reviews 4:3, 181-186
CrossRef75
C.-H. Pui, E. Thompson, J. Wilimas, L.C. Bowman, W.M. Crist, C.B. Pratt, C.-H. Pui, S.C. Raimondi, D.R. Head, L.E. Kun, M.L. Hancock, C.-H. Pui, E. Thompson, J. Wilimas, L.C. Bowman, W.M. Crist, C.B. Pratt. (1990) Myeloid neoplasia in children treated for solid tumours. The Lancet 336:8712, 417-421
CrossRef76
(1990) Leukemia after Treatment of Ovarian Cancer or Hodgkin's Disease. New England Journal of Medicine 322:25, 1818-1820
Full Text77
Friedman, Jaime B., Weiss, Noel S., . (1990) Second Thoughts about Second-Look Laparotomy in Advanced Ovarian Cancer. New England Journal of Medicine 322:15, 1079-1082
Full Text78
Berek, Jonathan S., . (1990) Adjuvant Therapy for Early-Stage Ovarian Cancer. New England Journal of Medicine 322:15, 1076-1078
Full Text79
Coltman, Charles A. Jr., , Dahlberg, Steve, . (1990) Treatment-Related Leukemia. New England Journal of Medicine 322:1, 52-53
Full Text80
J. Kaldor. (1990) Second Cancer Following Chemotherapy and Radiotherapy: An epidemiological perspective. Acta Oncologica 29:5, 647-655
CrossRef
