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Phase III Cancer Trials in Children
- Paul S Gaynon (11 January 2006)
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Re: Evaluating Treatment Success in Phase III Cancer Trials in Children
- Benjamin Djulbegovic, Ambuj Kumar, Heloisa P. Soares, Robert Wells, Gregory Reaman (14 January 2006)
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Paul S Gaynon, Professor of Pediatrics Childrens Hospital Los Angeles 90027
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To the Editor: I read the paper of Kumar and coworkers with interest and mounting unease (1). As the authors suggest, a substantial experience has been accumulated in pediatric clinical cancer trials and this experience may be instructive and helpful. Their thoughtful defense of “uncertainty” in an age of expert opinion is appreciated. However, I was puzzled their assertion that experimental treatments are as likely to be inferior as superior to standard treatments and by their exclusive use of survival and event free survival to assess randomization outcomes. The authors assert that “experimental treatments for childhood cancer assessed in phase III randomized trials are as likely to be inferior as they are to be superior to standard treatments.” Figure C purports to detail all included Children’s Oncology Group studies –but my casual eye quickly noted the apparent omission of several studies, which seem to fulfill the stated inclusion criteria. Several of these, CCG-123 (2), CCG -1882 (3), CCG-1891 (4), and CCG-1922 (5) showed an event free survival (EFS) advantage for an experimental arm. Despite these omissions, Figure B of their manuscript reports that 64% of trials found no statistically significant difference among treatments. In 8% of trials, the standard arm was found statistically superior and in 21%, outcomes favored the experimental arm. Thus, the experimental arm was superior 2.5-times more often than the standard arm. This seems different than chance. Joffe and coworkers reviewed 103 adult phase III randomizations and found that 3% favored the standard arm while 29% favored the experimental arm. Sixty-eight percent yielded similar results with either treatment (6). This also seems different than chance. All trials are begun with the hope that the experimental innovation may benefit patients. The authors seem to restrict benefit to improvement in EFS or survival. A number of successful trials have in fact improved EFS and survival (2-5). However, the desired benefit was not always survival or event free survival. Important studies have shown that treatments may be lessened, i.e., shortened in duration (7), more convenient drug administration chosen (8), or freed from unhelpful elements like whole brain irradiation therapy (9-10) with preservation of EFS. Elimination of a less-than-helpful interventions like induction daunomycin for standard risk children with acute lymphoblastic leukemia (11) facilitated later introduction of a more helpful intervention, namely, induction dexamethasone (5) without confounding and unnecessary morbidity (12, 13). These studies also benefit children, even though event free survival did not improve immediately. Despite the lumping of morbidity reduction trials with EFS advancing trials, the authors still find a 10% reduction in odds ratio in favor of experimental regimens. Given the authors’ observation that treatment mortality is 1.8-time more likely with experimental therapies than with conventional therapies and their assertion that “experimental” therapies are as likely to be “inferior as superior to conventional therapies,” one wonders at the motivation of any parent who might subject his child to a phase III trial and the logic of institutional ethics committees that allow such research to go forward. The authors seem to have omitted several important phase III trials, lumped morbidity reduction and EFS increasing trials, and perhaps contradicted their own data. One might argue to the contrary that the data show that trials that seek to reduce therapy and decrease morbidity are often – but not always - successful. Trials that make the “devil’s bargain” and accept greater acute toxicity in exchange for the possibility of a superior ultimate EFS, deliver superior EFS with some frequency. In childhood cancer, treatment morbidity has to be judged against the terrible morbidity of recurrent cancer and its usually unsuccessful treatment. Thank you. References 1. Kumar A, Soares H, Wells R et al. Are experimental treatments for cancer in children superior to established treatment? Observational study of randomised controlled trials by the children’s Oncology Group. BMJ 2005; 7528. 2. Steinherz P, Gaynon P, Breneman J, et al. Treatment of acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: randomized control trial from the Children’s Cancer Group. Cancer 1998; 82:600–12. 3. Nachman JB, Sather HN, Sensel MG, et al. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 1998; 338: 1663–71. 4. Lange B, Bostrom B, JM C, et al. Double-delayed intensification improves event free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood 2002; 99: 825–33. 5. Bostrom BC, Sensel MR (sic), Sather HN, et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous 6- mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood 2003; 101(10): 3809-17. 6. Joffe S, Harrington DP, George SL, et al. Satisfaction of the uncertainty principle in cancer clinical trials: retrospective cohort analysis. BMJ 2004; 328: 1463. 7. Green DM, Breslow NE, Beckwith JB, et al. Effect of duration of treatment on treatment outcome and cost of treatment for Wilms’ tumor: a report of the National Wilms’ Tumor Study Group. J Clin Oncol 1998; 16: 3744-3751. 8. Green DM, Breslow NE, Beckwith JB, et al. Comparison between single-dose and dividied-dose administration of dactinomycin and doxorubicin for patients with Wilms’ tumor: a report of the National Wilms’ Tumor Study Group. J Clin Oncol 1998; 16: 237-245. 9. Tubergen DG, Gilchrist GS, O’Brien RT, et al. Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Children’s Cancer Group report. J Clin Oncol 1993; 11: 520–6. 10. Nachman J, Sather HN, Cherlow JM, et al. Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children’s Cancer Group. J Clin Oncol 1998; 16: 920–930. 11. Tubergen D, Gilchrist G, O’Brien A, et al. Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features. J Clin Oncol 1993; 11: 527–37. 12. Hurwitz CA, Silverman LB, Schorin MA, et al. Substituting dexamethasone for prednisone complicates inductin in children with acute lymphoblastic leukemia. Cancer 2000; 88(8): 1964-9. 13. Belgaumi AF, Al-Bahrah M, al-Mahr M, et al. Dexamethasone- associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin. Cancer 2003; 97(11): 2898-903. Competing interests: None declared |
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Benjamin Djulbegovic, Professor of Medicine and Oncology H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL 33612, Ambuj Kumar, Heloisa P. Soares, Robert Wells, Gregory Reaman
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We are grateful for Dr. Gaynon’s interest in and thoughtful response to our paper, particularly in light of his contributions to cooperative group clinical trials in acute leukemia. He is concerned that we may have excluded eligible trials from our analysis, and mentions CCG-123, CCG- 1882, CCG-1891 and CCG-1922 specifically. In fact, all these trials were included in our analysis (Fig 2), but we would be happy to do a further analysis if he or others draw to our attention eligible trials that we have overlooked. Dr. Gaynon suggests that the question we addressed should have been approached by counting the number of statistically significant trials favoring experimental treatment and comparing that number with the number of trials favoring standard treatments. However, this “vote counting method” does not take into account effect sizes, number of patients or time to events, and “inconclusive” results whose results are consistent both with “no evidence of effect” and “evidence of no effect”[1]. As discussed in our paper, meta-analysis endeavors to take all these factors into account in summarizing data related to primary outcomes [1]. We agree with Dr. Gaynon that outcomes considered solely in terms of survival or event free survival may well not capture all subtleties in advances of treatments, such as more convenient or shorter administration of therapy. This is why we used a third method in evaluating treatment success, namely, investigators’ judgments whether new treatments were better than standard treatments. As our Figure B shows (supplement/extra www.bmj.com), experimental treatments were favored 43% of the time, and standard treatments 57% of the time. After taking into account these multi-dimensional aspects of treatment evaluation, we believe it is reasonable to conclude that investigators cannot predict the results randomized trials in advance, despite the fact that such “trials are begun with the hope that the experimental innovation will benefit patients”. As illustrated in Figure 4 of our paper, detection of moderate but important wanted and unwanted effects of treatments depends on the feasibility of randomized trials and the willingness of patients to take part in them, and they require assurances that they will not knowingly be offered inferior treatments. We believe that our data help to provide such assurance, and as noted in the accompanying editorial by Dr. Godlee, it is this uncertainty in results, which removes ethical dilemma in trials of cancer drugs [2]. REFERENCES 1. Hedges LV, Olkin I. Statistical Methods for Meta-Analysis. San Diego, California: Academic Press, 1985. 2. Godlee F. In praise of uncertainty. BMJ 10.1136/bmj.331.7528.0-f 2005;331(7528):0-f-. Competing interests: None declared |
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