LYMPHOMAS AND LEUKEMIAS
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Why don't cancer patients get entered into clinical trials?
Experience of the Sheffield Lymphoma Group's collaboration in British National Lymphoma Investigation studies.
Hancock, BW.
BMJ 1997;314:36 (4 January).This study looked into the reasons of the generally low rates of recruitment of cancer patients into clinical trials. The study was conducted on all patients that had been referred for participation in clinical trial to the Sheffield Lymphoma Group during a 12-year period from 1981 to 1992. Of the 1813 patients with a biopsy-proven diagnosis of lymphoma, only 822 (45%) were entered into clinical trials. Thirty-five percent of them (639 patients) were excluded from participation because they were old (274) or for medical reasons (365). An additional 7% of patients did not enter the trial due to physician's decision. Selecting which patient may enter a trial may lead to bias, since old and medically frail patients have an inherent survival disadvantage compared to fitter patients. A selection process may explain why patients entered into clinical trials have higher survival rates, compared to those who do not.
Augmented therapy of extensive Hodgkin's disease: radiation to known disease or prolongation of induction chemotherapy did not improve survival
Results of a Cancer and Leukemia Group B study.
Coleman M, et al.
Int J Radiat Oncol Biol Phys 1998 Jun 1;41(3):639-45.This study tested whether more aggressive treatment with more cycles of chemotherapy or with the addition of radiation therapy is associated with improved survival in patients with advanced-stage Hodgkin's disease. Two hundred fifty-eight patients were randomly assigned to four different protocols: 6 cycles of chemotherapy, 12 cycles of chemotherapy, or 6 cycles of chemo with the addition of radiation therapy at different points in time depending on the protocol. Tumor responses, time to progression of disease, and overall survival, were not significantly different among the four groups. These results indicate that the addition of radiotherapy or a prolonged chemotherapy treatment are not associated with improved outcome in patients with advanced Hodgkin's disease, compared to standard 6-months treatment.
Retrospective assessment of quality of life and treatment outcome in patients with Hodgkin's disease from 1969 to 1994.
Greil R, et al.
Eur J Cancer 1999 May;35(5):698-706.The results of this study show that the addition of radiotherapy to chemotherapy in patients with Hodgkin's disease is associated with a worsening of quality of life and no improvement in survival. The study was conducted on 126 patients treated for Hodgkin's disease between 1969 and 1994 at one institution. Those who received combination treatment with chemo- and radiotherapy had lowered rates of relapse, but no improvement in overall survival. Quality of life, as assessed through a questionnaire, was significantly worse in patients treated with combination regimens. The inclusion of radiotherapy as standard treatment in patients with Hodgkin's disease must be weighted against its negative impact on overall well being, especially in consideration of the fact that its use does not translate in survival advantage.
A randomized study comparing chemotherapy alone with chemotherapy followed by radiotherapy in patients with pathologically staged IIIA Hodgkin's disease.
Crowther D. et al.
J Clin Oncol 1984 Aug;2(8):892-7.
The results of this study show that the addition of radiotherapy to chemotherapy in patients with advanced stage (IIIA) Hodgkin's disease does not prolong time to progression of disease. These data indicate that chemotherapy alone can be used as a valid alternative in the management of these patients, especially in view of the increased rates of complications in patients treated with combination chemo- and radiotherapy.
Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkin's disease
A meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkin's Disease Collaborative Group.
Specht L; Gray RG; Clarke MJ; Peto R.
J Clin Oncol, 16(3):830-43 1998 Mar.This study evaluated the effects of increased doses of radiation therapy and of the addition of chemotherapy to radiation therapy in the management of patients with early stage Hodgkin's disease. Analysis of the results of 8 trials conducted on 1,974 patients who were randomized to receive more versus less extensive radiotherapy, revealed that more extensive radiotherapy decreases rates of tumor recurrence, but has no beneficial effect on overall 10-year survival. Tumor recurrences were generally brought to remission if patients had not received chemotherapy during initial treatment. Analysis of 1,688 patients from 13 trials revealed that the addition of chemotherapy to radiation therapy improved disease control, but not rates of survival. The authors conclude that less intensive treatment appears as valuable as more intensive treatment in patients with early stage Hodgkin's disease.
Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease.
International Database on Hodgkin's Disease Overview Study Group.
Loeffler M, et al.
J Clin Oncol 1998 Mar;16(3):818-29.This study evaluated the results of 14 clinical trials conducted on 1,740 patients to determine the impact of the addition of radiation therapy to chemotherapy in the management of patients with Hodgkin's disease. Overall, it was shown that the addition of radiotherapy to chemotherapy significantly increased long-term mortality in patients with Hodgkin's disease. Patients who received chemotherapy only, had significantly higher 10-year survival rates, than those who received chemotherapy plus radiation therapy. These data do not support routine use of radiotherapy in patients with Hodgkin's disease.
Management of early-stage Hodgkin's disease: a continuing evolution.
Golomb HM.
Semin Oncol 1998 Aug;25(4):476-82.This article illustrates how the management of Hodkin's disease has significantly evolved during the past 20 years. Extensive radiation has been replaced with more selective irradiation limited to the involved area only, and radiation therapy has been replaced by systemic chemotherapy. This evolution reflects the acquired knowledge of the high rate of short- and long-term complications associated with radiation therapy, and of the equivalent efficacy of chemotherapy, devoid of the high rates of adverse effects.
Long-term toxicity of the treatment of Hodgkin's disease.
Armitage JO.
Ann Oncol 1998;9 Suppl 5:S133-6.This article highlights that current treatment modalities of Hodgkin's disease are associated with rates of complications that rival mortality from the disease. Treatment is associated with significant long-term mortality, in particular from cardiovascular disease and cancer, and with adverse effects on the reproductive, endocrine, and skeletal system, which significantly affect the quality of life of the individuals. New treatment regimens should be designed to minimize the risks associated with current management of this condition.
Second cancer among long-term survivors from Hodgkin's disease.
Nyandoto P, Muhonen T, Joensuu H.
Int J Radiat Oncol Biol Phys 1998 Sep 1;42(2):373-8.The results of this study show that patients with Hodgkin's disease treated with radiotherapy are at high risk of developing secondary tumors later in life. The study was conducted on 202 patients treated with radiotherapy for Hodgkin's disease, and followed-up for an average of 20 years. The overall risk of developing a secondary tumor during that period was 17%. Three-quarters of solid cancers occurred within or around the area of the body that had been irradiated.
Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: the relation to age at treatment.
Swerdlow AJ, et al.
J Clin Oncol 2000 Feb;18(3):498-509.This study shows that treatment for Hodgkin's disease significantly increases the risk of secondary cancers. The study was conducted on 5,519 patients with Hodgkin's disease treated between 1963 and 1993. The incidence of cancers of the lung, of the breast and of the gastro-intestinal tract was 3 times higher in this cohort, compared to the general population. The incidence of leukemia was 30 times higher. Patients who received treatment at age younger than 25, were particularly at risk, and had a 19-fold increased risk of developing gastrointestinal cancers, a 14-fold increased risk of developing breast cancer, and an 85-fold increased risk of developing leukemia, compared to the general population.
Reduced health-related quality of life among Hodgkin's disease survivors: a comparative study with general population norms.
Loge JH, Abrahamsen AF, Ekeberg O, Kaasa S.
Ann Oncol 1999 Jan;10(1):71-7.This study evaluated the quality of life of 459 survivors of Hodgkin's disease aged 19-74 years, treated between 1971 and 1991 at a Norwegian Institution. Hodgkin's disease survivors scored significantly worse in general health, physical functioning and vitality, compared to controls from the general population. Of note, the worse quality of life was found in patients treated for early stage disease (IB-IIB). These findings underline the importance of considering quality of life when choosing treatment modalities in patients with Hodgkin's disease, especially since the disease is often diagnosed in young individuals who have a long life expectancy.
Modest decline in late mortality following Hodgkin's disease in the southeastern Netherlands since 1972.
van Spronsen DJ, Post PN, Crommelin MA, Breed WP, Coebergh JW.
Ann Hematol 1998 May;76(5):205-9.This study evaluated whether acquired clinician's awareness of the side effects of treatment in patients with Hodgkin's disease translated in a decreased rate of treatment-related complications during the period 1972 through 1993. Data on 345 patients were reviewed. In cured patients, 10-year survival rates increased from 84% in the 1970s to 90% in the 1980s. The risk of developing secondary cancers in patients cured from Hodgkin's disease was 4.3-times higher in the 1070s, and 3 times higher in the 1980s, compared to the general population. No significant change in radiation therapy-related cardiovascular mortality was observed. Severe treatment-induced morbidity was present in 34% of patients. These data indicate that although long-term mortality rates in patients cured from Hodgkin's disease decreased over a 20-year period, death rates, especially due to radiation-induced cardiovascular disease, are still high. Furthermore, serious morbidity due to radiation treatment still impairs the lives of one third of patients.
Hodgkin's disease: complications of therapy and excess mortality.
Hoppe RT.
Ann Oncol 1997;8 Suppl 1:115-8.This study emphasizes how treatment causes an excess risk of long-term mortality in patients with Hodgkin's disease, especially due to secondary cancers and cardiovascular disease. Fifteen years after diagnosis, patients with Hodgkin's disease have the same risk of dying from the disease itself than of dying from other causes, often as a consequence of treatment. After 15 years, the risk of dying from other, primarily treatment-related causes greatly surpasses that of dying from Hodgkin's disease. Although changes in treatment regimens resulted in a decreased risk of excess deaths in patients treated from 1980 to 1995, compared to those treated from 1962 to 1980, treatment regimens must be implemented in order to further reduce mortality in these patients.
Results of treatment of childhood localized non-Hodgkin's lymphoma with combination chemotherapy with or without radiotherapy.
Link MP, Donaldson SS, Berard CW, Shuster JJ, Murphy SB.
N Engl J Med 1990 Apr 26;322(17):1169-74.Treatment of children with early stage non-Hodgkin's lymphoma is associated with considerable toxicity limiting the benefits of therapy. This study was conducted to evaluate whether less toxic treatment, achieved by omitting radiation therapy and reducing the time and the dose of chemotherapy exposure, could achieve the same beneficial results of more aggressive regimens. One hundred twenty-nine patients were randomized to receive either chemotherapy and radiotherapy, or chemotherapy alone. No differences in time to progression of disease were observed between the two groups, during a median follow-up of 3 years. Toxicity was significantly more pronounced in patients who had been exposed to both chemo- and radio-therapy, compared to those who received chemotherapy only. These data indicate that less aggressive treatment with reduced time and length of exposure to chemotherapy and omission of radiotherapy is as beneficial, in terms of survival, of more aggressive treatment, and is associated with significantly less short- and long-term toxicity.
Treatment of children and young adults with early-stage non-Hodgkin's lymphoma.
Link MP, Shuster JJ, Donaldson SS, Berard CW, Murphy SB.
N Engl J Med 1997 Oct 30;337(18):1259-66.The results of this study show that children and young adults with non-Hodgkin's lymphoma who receive less intensive treatment consisting of a short course of chemotherapy fare as well, in terms of time to progression of disease, as those receiving more aggressive treatment with a long-course of chemotherapy, with or without the addition of radiotherapy. The study reports on the results of two trials, conducted on a total of 340 patients, who were randomly assigned to receive one of three treatment regimens: 9 weeks of chemotherapy, 8 months of chemotherapy, or 8 months of chemotherapy with radiation therapy. During a 5-year follow-up, no differences in rates of recurrences were observed between the three groups. These data indicate that less intense treatment is a valid alternative in young patients with non-Hodgkin's lymphoma. These results are important, since prolonged treatment is associated with significant toxicity.
Limiting Therapy for Limited Childhood Non-Hodgkin's Lymphoma. Editorial. Magrath, I.
N Engl J Med 1997 Oct 30;337(18).This letter presents the results of several trials indicating that radiation therapy has no role in the management of children and young adults with non-Hodgkin's lymphoma. Radiation therapy, used as standard treatment for this form of disease, causes several severe side effects including skeletal deformities, stunted growth, intellectual deficits, and breast cancer. Chemotherapy, mainly used in combination with radiotherapy, has also serious side effects such as secondary cancer, cardiac failure, and infertility, and its toxicity is proportional to the dose and time of exposure. The findings of the aforementioned study published in the October 1997 issue of the NEJM, indicate that short-course chemotherapy is as effective as long-course chemotherapy in the management of patients with this disease. Therefore, switching to less intensive treatment could avoid some of the complications associated with therapy. These findings, however, are not new. Thirty years ago it was shown that one or two doses of chemotherapy could cure some patients with Burkitt's lymphoma, and the value of radiotherapy was questioned as early as 1970. In 1990 a study by Link and colleagues revealed that radiotherapy was unnecessary in patients with non-Hodgkin's lymphoma. Furthermore, results from several trials conducted in Europe on over 900 patients have shown that chemotherapy alone is as effective as combination treatment with chemo- and radiation therapy. All these data conclusively indicate that radiation therapy can be eliminated from the treatment of young patients with non-Hodgkin's lymphoma.
Treatment of localized primary non-Hodgkin's lymphoma of bone in children
A Pediatric Oncology Group study.
Suryanarayan K, et al.
J Clin Oncol 1999 Feb;17(2):456-9.In this study, analysis of the results of 3 trials conducted on children and adolescents with
early-stage primary lymphoma of bone showed that the addition of radiotherapy to chemotherapy is not associated with improved survival, and is therefore unnecessary.
Long-term follow-up and analysis for prognostic factors for patients with limited-stage diffuse large-cell lymphoma treated with initial chemotherapy with or without adjuvant radiotherapy.
Jones SE, Miller TP, Connors JM.
J Clin Oncol 1989 Sep;7(9):1186-91.The results of this study show that the addition of radiotherapy to chemotherapy in patients with early-stage diffuse large-cell lymphoma is not associated with improved time to disease progression.
Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials.
CLL Trialists' Collaborative Group.
J Natl Cancer Inst 1999 May 19;91(10):861-8.This study analyzed the results of 16 trials to determine the impact that different chemotherapy regimens have on survival in patients with chronic lymphocytic leukemia (CLL). In 6 trials, conducted on a total of 2,048 patients with early stage CLL, the effects of immediate versus postponed treatment with chemotherapy were compared. Ten-year survival of patients who had been treated immediately with chemotherapy was slightly worse, compared to that of patients in whom treatment had been delayed until progression of disease (44% vs. 47%), although not significantly. Analysis of the results of 10 trials conducted on 2,022 patients revealed that those who were treated with combination chemotherapy fared not better in terms of survival, than those treated with single-agent chemotherapy. These data indicate that immediate treatment in patients with early stage CLL is unnecessary, and patients with advanced disease should receive single agent chemotherapy rather than combination treatment, since more aggressive management does not improve survival while increasing the risk of toxicity.
Chlorambucil in indolent chronic lymphocytic leukemia.
French Cooperative Group on Chronic Lymphocytic Leukemia.
Dighiero G, et al.
N Engl J Med 1998 May 21;338(21):1506-14.The results of this study show that treatment in patients with early stage chronic lymphocytic leukemia (CLL) is unnecessary. These data came from the analysis of the results of two trials conducted on a total of 1,535 patients with CLL. In the first trial, patients were randomly assigned to receive either daily administration of the anti-cancer drug chlorambucil, or no treatment. In the second trial, patients were randomly assigned to receive alternate treatment with chlorambucil and prednisone, or no treatment. No improvement in survival was observed among treated patients. Patients receiving chlorambucil had a 14% increased risk of death, compared to those who received no treatment. Patients receiving combination regimen of chlorambucil and prednisone had a 4% decreased risk of death, compared to those who were untreated. These differences were not significant. The results of this study indicate that in patients with early stage CLL, treatment can be safely postponed until the disease progresses to more advanced stages.
