Long-Term Results of a Randomized Trial on Extended Use of High Dose L-Asparaginase for Standard Risk Childhood Acute Lymphoblastic Leukemia
http://www.100md.com
《临床肿瘤学》
the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP)
Department of Pediatrics, University of Bologna, Bologna
Medical Statistics Unit, University of Milano-Bicocca, Italy
Department of Pediatrics, University of Milano, Milano
Ospedale San Gerardo, Monza
Center of Pediatric Hematology-Oncology, Università di Catania, Catania
Pediatric Hematology-Oncology, Policlinico San Matteo, Pavia
Department of Pediatrics, University of Padova, Padova
Pediatric Hematology-Oncology, Ospedale dei Bambini G. Di Cristina, Palermo, Italy
the Hungarian Pediatric Hematology Oncology Group (HPOG)
Heim Pal Children Hospital, Budapest, Hungary
the Dutch Childhood Oncology Group, the Hague
Beatrix Children's Hospital, Department of Pediatric Oncology, Groningen, the Netherlands
ABSTRACT
PURPOSE: Between September 1991 and May 1997, within the International Berlin-Frankfurt-Muenster Study Group (I-BFM-SG), a randomized study was performed aimed at assessing the efficacy of prolonged use of high-dose L-asparaginase (HD-L-ASP) during continuation therapy in children with standard risk (SR) acute lymphoblastic leukemia (ALL), treated with a reduced BFM-type chemotherapy.
PATIENTS AND METHODS: The Italian, Dutch, and Hungarian groups participated in this study denominated IDH-ALL-91, and 494 children were enrolled. Treatment consisted of a BFM-type modified backbone with omission of the IB part in induction and elimination of two doses of anthracyclines during reinduction in both arms at the beginning of continuation therapy. Patients were randomly assigned to receive (YES-ASP) or not (NO-ASP) 20 weekly HD-L-ASP (25,000 IU/m2).
RESULTS: The event-free-survival and overall survival probabilities at 10 years for the entire group were 82.5% (1.8) and 90.3% (1.3), respectively. Of the 490 patients eligible for random assignment, 355 (72.4%) were randomly assigned (178 YES-ASP and 177 NO-ASP). After a median follow-up of 9 years, the probability of disease-free survival at 10 years was 87.5% (SE, 2.5) for YES-ASP arm versus 78.7% (SE, 3.3) for NO-ASP arm (P = .03). In multivariate analysis, NO-ASP arm (P = .03), male sex (P = .004), and age older than 10 years (P = .0003) had a significantly adverse impact on outcome.
CONCLUSION: In this subset of patients, selected with criteria not including monitoring of minimal residual disease, application of extended HD-L-ASP may improve prognosis, compensating reduced leukemia control that results from adoption of a reduced-intensity BFM-backbone for treatment of children with SR ALL.
INTRODUCTION
Several cooperative groups or large single institutions worldwide have demonstrated that acute lymphoblastic leukemia (ALL), the most common type of cancer in children, is highly responsive to chemotherapy, with more than 75% of patients cured with current chemotherapy regimens.1-7
The outcome of children with standard risk (SR) childhood ALL is even better. Further improvement of treatment results for this subset of patients may be difficult to obtain because the degree of improvement to be expected with any modification of treatment is small and the number of patients needed to test relevant questions in a reasonable length of time is proportionally high.
The enzyme L-asparaginase has been used in the treatment of lymphoblastic malignancies in children since 1970 and its antileukemia effect is believed to result from the depletion of circulating asparagine, which is essential for most malignant lymphoblasts.8-10 At the Dana-Farber Cancer Institute (Boston, MA), weekly administration of high-dose (HD) Escherichia coli L-asparaginase (L-ASP) administered in a randomized trial during intensification therapy resulted in fewer treatment failures in patients with non–T-cell ALL, induced into complete remission using vincristine, prednisone, and doxorubicin.9 Moreover, at the same institution, the study 81-01 demonstrated that, for patients with SR ALL, a program using four-drug induction and extended use of weekly HD-L-ASP during intensification therapy resulted in an event-free survival (EFS) probability of 86% at 4 years.10 These data, although generated in a nonrandomized setting, were widely accepted as a further strong suggestion of therapeutic efficacy of HD-L-ASP.
In the past, the two forms of native L-ASP mainly used in clinical practice were derived from two different bacterial species (ie, E coli and Erwinia chrysanthemi). These products have, however, different pharmacokinetic and immunogenic properties; the Erwinia chrysanthemi L-ASP displays a mean half-life shorter than that of the E coli product.11 Moreover, time to recovery of serum asparagine levels after administration of Erwinia-asparaginase was demonstrated to be shorter than that observed after E coli-asparaginase.12 For many years, the E coli product (Crasnitin Bayer, Leverkusen, Germany) was the only E coli–derived L-ASP preparation available in Europe. The Erwinia product (Erwinase, Speywood, Maidenhead, United Kingdom) was used mainly as second-line treatment for patients experiencing severe allergic reactions to the E coli preparation.13,14 In the 1990s, Crasnitin became no longer available in Europe and, thus, in many European countries, Erwinase was adopted in front-line treatment, with the same dosage and schedule.
In 1991, within the International Berlin-Frankfurt-Muenster Study Group (I-BFM-SG), a European randomized study denominated IDH-ALL-91 was started; the Italian (I), Dutch (D), and Hungarian (H) pediatric oncology cooperative groups participated in this study. The main objective of the study was to evaluate whether prolonged administration of HD-L-ASP at the beginning of continuation therapy could offer an advantage in terms of final outcome in children with SR ALL who received BFM-type chemotherapy, with a reduced-intensity induction phase, and in which two doses of anthracyclines were omitted during reinduction. We report here the long-term results of this trial.
PATIENTS AND METHODS
Study Design
The study was designed as a prospective, intergroup, multicenter randomized trial aimed at evaluating the efficacy of the addition to a BFM backbone, during early continuation therapy, of extended HD-L-ASP (25,000 IU/m2/week x 20 weeks) in patients with standard risk ALL. The main end point of the study was the comparison of disease-free survival (DFS) between the standard control regimen and the experimental regimen.
The study was planned to have an 80% power to detect a 10% improvement in the experimental arm (ie, that including HD-L-ASP), estimating an 80% DFS probability at 5 years for the control arm, and = .05 (one sided). The calculated target number of patients per arm was 164, with an accrual time of 48 months and an overall study duration of 9 years and at least 49 events for the final analysis. Random assignment was planned according to randomized permuted blocks, stratified by country; it was centrally performed in each group data center after check of eligibility criteria.
Treatment Protocol
Treatment consisted of a BFM-type modified chemotherapy15: after 7 days of steroid prephase and one injection of intrathecal methotrexate (IT-MTX),16 all patients received a four-drug induction (protocol IA) with the omission of the B part, which consists of two administrations of cyclophosphamide (1 g/m2 on days 43 and 71), cytarabine (four consecutive weekly courses of four daily subcutaneous injection at a dosage of 75 mg/m2/day) and 6-mercaptopurine (60 mg/m2/day from day 43 to day 70). Consolidation therapy consisted of four courses of HD MTX 2 g/m2; reinduction therapy (also called protocol II) included only the first two doses of doxorubicin instead of the four usually employed in the original BFM treatment protocol; continuation therapy consisted of oral 6-mercaptopurine (50 mg/m2 daily), weekly MTX (20 mg/m2 intramuscularly) and extended triple IT chemotherapy (TIT), for a total treatment duration of 24 months (Table 1).
At the beginning of continuation therapy, the patients were randomly assigned to receive (YES-ASP) or not (NO-ASP) 20 weekly high-doses of L-ASP (25,000 IU/m2). Due to unavailability of E coli asparaginase (Crasnitin) soon after the trial start, more than 90% of enrolled patients received the Erwinia chrysanthemi asparaginase (Erwinase). The minority of patients receiving Crasnitin were distributed evenly in the two randomized arms. Supportive care was given according to each individual center standards and uniformly applied to the patients in both groups.
Definitions
Complete remission (CR) was defined as no physical sign of leukemia, no detectable leukemia cells on blood smear, a bone marrow with active hemopoiesis, and less than 5% morphologically identifiable leukemia blast cells, and normal cerebro-spinal fluid (CSF). Marrow aspiration was examined on day 42 for evaluation of CR.
Study Population
Criteria for eligibility in the study of children with SR ALL included age between 1 and 15 years; non–T-ALL; low tumor burden, defined as BFM risk factor [calculated as RF = 0.2 x log10 (blast cell count + 1) + 0.06 x cm of palpable liver + 0.04 x cm of palpable spleen]15 < 0.8; prednisone good response (PGR; < 1 x 109/L blasts in peripheral blood after 7 days of steroids and one injection of IT-MTX).16 Patients with CNS disease at diagnosis, t(9;22) or t(4;11) translocations or failure to achieve CR by day 42 were excluded from the study, and the latter two groups assigned to the high-risk group.
The study was approved by the internal review board of each participating institution, and written informed consent was obtained in all randomly assigned cases from patients' parents or legal guardian.
A total of 494 children with SR ALL were enrolled in the trial. The Italian group enrolled 290 patients, diagnosed between March 1991 and April 1995; the Dutch group 170, diagnosed between September 1991 and December 1996; and the Hungarian group 34, diagnosed between March 1991 and December 1995.
Of 490 patients eligible for random assignment, 355 (72.4%) were randomly assigned (I, 242, 85%; D, 85, 50%, H, 28, 82%), between September 1991 and May 1997, to YES-ASP (n = 178) or NO-ASP (n = 177) HD-L-ASP. The remaining 135 were not assigned mainly for the following reasons: parents' refusal (I, n = 9; D, n = 47), physician decision not to participate into the study or clinical reasons (I, n = 13; D, n = 38), others nonspecified (I, n = 22, H, n = 6).
Statistical Analysis
Patient data were collected on protocol-specific forms and reviewed before input every year by the trial data center, which also performed the statistical analysis. EFS, DFS, and survival curves were calculated according to the Kaplan-Meier method.17 The starting point for the observation time was the date of random assignment, when the analysis was limited to randomly assigned patients, whereas it was the date of diagnosis otherwise. For calculation of EFS for the overall population, induction failure, relapse, death in continuous CR, or secondary malignancy were counted as events. For estimation of DFS for randomly assigned patients, relapse, death in continuous CR or secondary malignancy were counted as events. Calculation of DFS was performed according to the intention-to-treat principle. In calculating the survival probabilities, death from any cause was considered an event. The observation time was censored at the time of the last contact, both when no event was recorded and when the patient was lost to follow-up. Analysis used June 1, 2003, as the reference date, (ie, the day at which all centers locked data on patient outcomes); five randomly assigned patients (1.5%) were lost to follow-up while in continuous CR. The log-rank test was applied for comparing the outcome of the randomly assigned groups, and the test was one-sided as by study design. All other tests were two-sided. The Cox regression model was applied to estimate treatment effect adjusting for known prognostic variables (WBC, age, sex).18 All of these analyses were stratified by participating group. The estimated hazard ratio is reported as relative risk in the results. The Wald test was used to assess the role of covariates. Before applying the Cox model, the presence of major departures from the proportional hazard assumptions was excluded by graphical checks. The analyses were carried out with the SAS package (SAS Institute, Cary, NC).
RESULTS
Overall Outcome and Random Assignment
After a median duration of follow-up of 9 years, the 494 study patients enrolled in the IDH-ALL-91 study had an EFS probability of 84.6% (SE, 1.6) at 5 years and 82.5% (SE, 1.8) at 10 years, with a survival probability of 91.3% (SE, 1.3) and 90.3% (SE, 1.3), respectively. Two patients died during induction therapy as a result of fungal pneumonia and septicemia with pneumonia, respectively; one patient was lost to follow-up within the first few months, and one relapsed before the time set for random assignment (start of continuation therapy), leaving 490 patients eligible for random assignment. Of these 490 eligible patients, 355 patients were allocated to either the YES-ASP (n = 178) or the NO-ASP (n = 177) arm. Their presenting clinical and laboratory features are shown in Table 2.
The long-term outcome of the 135 non–randomly assigned patients was comparable to that of the randomly assigned patients, with a 5- and 10-year EFS of 84.4% (SE, 3.1) and 83.0% (SE, 12.1) versus 85.3% (SE, 1.9) and 83.0% (SE, 2.1), respectively (P = .83).
Outcome of Randomly Assigned Patients
Approximately 10% of patients presented allergic reactions to prolonged administration of HD-L-ASP, which, in most cases, was easily managed by antihistaminic and/or steroid drug administration; only one third of children who experienced adverse events required treatment discontinuation. These children were included in the analysis. Fifty-eight events were observed after random assignment: one second malignancy and 57 relapses. Twenty-two relapses occurred in the YES-ASP arm and 35 in the NO-ASP arm (Table 3). Most of the relapses occurred in the bone marrow (17 v 25); the remaining disease recurrences occurred in the CNS (one in each arm), testis (two v four), testis and marrow (one v four), and other sites (one in each arm). No death in CR was recorded.
The DFS probability at 5 and 10 years of patients randomly assigned to receive HD-L-ASP was 88.1% (SE, 2.4) and 87.5% (SE, 2.5) versus 82.5% (SE, 2.9) and 78.7% (SE, 3.3) for patients allocated in the NO-ASP arm, respectively (one-sided P = .03; Fig 1). The survival estimate at 5 and 10 years was 94.4% (SE, 1.7) and 93.7% (SE, 1.9) in the YES-ASP arm versus 89.8% (SE, 2.3) and 88.6% (SE, 2.4) in the NO-ASP arm, respectively (one-sided P = .05).
Overall, the hazard ratio estimated by the Cox model of YES-ASP versus NO-ASP arm was 0.60 (90% CI, 0.38 to 0.93), thus indicating a 40% relative reduction of the risk of failure in the YES-ASP versus the control arm. In order to evaluate the presence of a possible country effect, we calculated the hazard ratios of YES-ASP and NO-ASP arms for the two groups randomly assigning the largest number of patients (ie, Italy and the Netherlands), obtaining comparable values: 0.63 (95% CI, 0.34 to 1.15) and 0.58 (95% CI, 0.19 to 1.72), respectively.
When treatment comparison was adjusted by prognostic factors in a Cox regression model, NO-ASP arm (P = .028, one sided), male sex (P = .004) and age older than 10 years (P = .0003) had a significantly adverse impact, whereas leukocyte count (P = .46) did not. The beneficial effect of HD-L-ASP seems to be more pronounced in patients older than 10 years and in males, although the difference is not statistically significant in the Cox regression model (P = .69 and P = .66 for sex and age, respectively).
DISCUSSION
In this randomized intergroup study on children with SR ALL, treated with a reduced BFM-type chemotherapy, the 20 weekly administrations of HD-L-ASP—mostly Erwinase—during continuation therapy was associated with a better outcome, which became evident only after an adequately prolonged follow-up, due to the relatively low number of events, which, moreover are spread over several years.
The advantage in terms of DFS experienced by patients who received HD-L-ASP may be due to the treatment reduction applied in the second part of induction therapy in this protocol (ie, the so-called BFM phase IB) on the basis of the use of cyclophosphamide, cytarabine and 6-mercaptopurine, which was omitted, together with the elimination of two doses of anthracyclines during reinduction, in both arms. The extended use of HD-L-ASP during early maintenance seems to be able to compensate the inferior leukemia control associated with such a reduced treatment, preventing leukemia recurrence. Patients randomly assigned in the control (ie, NO-ASP) arm had a 5-year DFS of 82%, a result in line with that estimated at time of sample size calculation and with that obtained in the AIEOP ALL 88 study,19 but which is inferior to the results obtained by other groups that, in contemporaneous studies, did not omit phase IB and doses of anthracyclines in reinduction.20 This finding supports the hypothesis that HD-L-ASP may have a beneficial role when dose reduction or nonadministration of drugs currently employed in the treatment of children with good prognosis ALL is chosen. This study also underlines that treatment reduction in patients with SR ALL should be approached with caution—especially in patients older than 10 years and in males—unless different criteria for monitoring treatment efficacy be employed. Indeed, in the current study AIEOP (Associazione Italiana di Ematologia ed Oncologia Pediatrica) -BFM-ALL-2000, in addition to the usual clinical criteria, we are using the polymerase chain reaction–based determination of minimal residual disease to stratify patients with childhood ALL in the classic three groups, namely standard, intermediate and high risk, and only patients with early clearance of leukemia blasts are allowed in the SR arm.
It is also noteworthy that, in the intermediate risk group of the same study AIEOP-ALL-91 (9102 protocol), no advantage was observed for patients randomly assigned to receive extended HD-L-ASP, administered for the same number of doses during reinduction and early continuation therapy.21 Because these patients received an unmodified BFM-chemotherapy regimen, the most likely interpretation of this finding is that the therapeutic effect deriving from the application of the BFM intensive regimen is already maximal and thus cannot be further improved by the addition of protracted HD-L-ASP administration. This last consideration reinforces the concept that the efficacy of additional or alternative treatment components for childhood ALL should always be considered in the frame of overall treatment intensity and that the use of extended HD-L-ASP might be beneficial mainly to children with ALL at a lower risk of recurrence and when relevant treatment reduction is adopted.
The European Organisation for Research and Treatment of Cancer recently performed a comparative study (58,881 trial, based on a BFM backbone) of the two types of asparaginase during the remission-induction phase in a large number of children with either ALL or, in a minority of cases, with lymphoma.19 Patients enrolled onto this trial and randomly assigned to receive the E coli L-ASP product (either Medac or Kidrolase, both produced by Kyowa Hakko, Tokyo, Japan) enjoyed a significantly better outcome compared with those randomly assigned to receive the Erwinia chrysanthemi product, despite a higher incidence of coagulation abnormalities.22 In view of these findings, it is possible to speculate that a more extensive use of these types of E coli L-ASP could theoretically lead to a further benefit from the application of HD-L-ASP also in less favorable childhood ALL subpopulations. However, this is only a hypothesis that remains to be tested; more potent products might also lead to increased toxicity.
A unique peculiarity of this study is that it represents the first international randomized trial conducted in Europe within the I-BFM-SG. The study organization was centralized in a trial data center, but each country data center maintained its role in random assignment, data collection, and querying. This type of intergroup cooperation has become a model for subsequent studies conducted within the I-BFM-SG.23
Twenty-eight percent of the eligible patients were not randomly assigned. This phenomenon represents one of the difficulties in planning and performing large-scale, international, prospective randomized studies. This said, the non-negligible failure to accrue all the potentially randomly assignable cases should not have influenced the main message deriving from the trial because the hazard ratios of YES-ASP and NO-ASP arms in the two countries enrolling the largest number of cases did not differ.
In conclusion, the final results of this study show that application of extended HD-L-ASP may compensate reduced leukemia control resulting from adoption of a reduced intensity BFM-backbone for treatment of children with SR ALL, selected with criteria not including monitoring of minimal residual disease. It remains to be definitively proven whether the extended use of E Coli HD-L-ASP, combined with the omission of doses of drugs associated with more relevant long-term adverse effects (ie, anthracyclines and cyclophosphamide), could offer the same outcome achieved with a full-intensity BFM protocol in SR patients.
Appendix
Institutions that randomly assigned patients in IDH-ALL-91 study. Italy—AIEOP: Ancona, Clinica Pediatrica (Prof. G.V. Coppa, Dott. P. Pirani); Bari, Clinica Pediatrica I (Prof. F. Schettini, Dott. N. Santoro); Bari, Clinica Pediatrica II (Prof. N. Rigillo, Dott.ssa S. Bagnulo); Bergamo, Div. Pediatria (Dott. P.E. Cornelli), Ematologia (Prof. T. Barbui); Bologna, Clinica Pediatrica (Prof. G. Paolucci, Prof. A. Pession); Brescia, Clinica Pediatrica (Prof. A.G. Ugazio, Dott. A. Arrighini); Cagliari, Servizio Oncoematologia Pediatrica (Prof. P.F. Biddau, Dott.ssa R. Mura); Catania, Div. Oncoematologia Pediatrica (Prof. G. Schilirò, Dott. L. Lo Nigro); Catanzaro, Div. Ematologia (Prof. S. Magro, Dott.ssa C. Consarino); Firenze, Ospedale Meyer, Dip. Pediatria, U.O. Oncoematologia Pediatrica (Prof.ssa G. Bernini, Dott.ssa A. Lippi); Genova, Ist. "G.Gaslini" (Prof. P.G. Mori, Dott.ssa C. Micalizzi); Modena, Clinica Pediatrica (Prof. S. Bernasconi, Dott.ssa M. Cellini); Monza, Clinica Pediatrica (Prof. Giuseppe Masera, Dott. Valentino Conter); Napoli, Ospedale Pausilipon (Prof. V. Poggi, Dott.ssa M.F. Pintà Boccalatte); Napoli, II Università, Dip. Pediatria, Servizio Autonomo Oncologia Pediatrica (Prof.ssa M.T. Di Tullio, Prof.ssa F. Casale); Napoli, Ospedale SS Annunziata (Prof. F. Tancredi, Dott. A. Correra); Padova, Clinica Pediatrica II (Prof. L. Zanesco, Dott.ssa C. Messina); Palermo, Clinica Pediatrica I (Prof.ssa M. Lo Curto, Dott.ssa G. Fugardi); Parma, Clinica Pediatrica (Dott. G. Izzi, Dott.ssa P. Bertolini); Pavia, Clinica Pediatrica (Prof. F. Locatelli, Dott. M. Aricò,); Perugia, Div. Oncoematologia Pediatrica, Osp. Silvestrini (Dott. A. Amici, Dott. P. Zucchetti); Pescara, Div. Ematologia (Dott. Fioritoni, Dott. A. Di Marzio); Pisa, Clinica Pediatrica III (Prof. P. Macchia, Dott. C. Favre); Reggio Calabria, Div. Ematologia, Ospedali Riuniti (Prof. F. Nobile, Dott.ssa M. Comis); Roma, Div. Ematologia Pediatrica, Osp. "Bambin Gesu; (Prof. G. De Rossi, Dott. C. Miano); Roma, Cattedra Ematologia (Prof. F. Mandelli, Dott.ssa A.M. Testi); San Giovanni Rotondo, Ospedale "Casa Sollievo della Sofferenza," Div. Pediatria, Sezione Ematologia ed Oncologia Pediatrica (Prof. P. Paolucci, Dott. S. Ladogana); Sassari, Clinica Pediatrica (Prof. D. Gallisai, Dott. C. Cosmi); Torino, Clinica Pediatrica (Prof. E. Madon, Dott.ssa E. Barisone); Trieste, Clinica Pediatrica (Prof. P. Tamaro, Dott. G.A. Zanazzo); Verona, Clinica Pediatrica (Prof. L. Tatò, Dott. P.L. Marradi). AIEOP data center: COFONOP, Clinica Pediatrica Università di Bologna (Prof. A. Pession, Dr. R. Rondelli) & CORS, Clinica Pediatrica, Università di Milano Bicocca (Prof. M.G. Valsecchi, Dr. D. Silvestri).
Dutch Childhood Oncology Group (DCOG): Amsterdam, Academic Medical Centre Amsterdam/Emma Childrens' Hospital (Dr. R.S. Weening, Dr. H. van den Berg); Amsterdam, VU University Medical Centre Amsterdam (Prof. Dr. A.J.P. Veerman); Groningen, University Medical Centre Groningen (Prof. Dr. W.A. Kamps); Leiden, Leiden University Medical Centre (Drs. E.Th. van 't Veer-Korthof); Nijmegen, University Medical Centre St. Radboud (Dr. J.P.M. B?kkerink); Rotterdam, Erasmus MC University Medical Centre Rotterdam (Dr. K. H?hlen, Drs. F.G.A.J. Hakvoort-Cammel); Utrecht, University Medical Centre Utrecht (Dr. T. Révész).
Hungary—Hungarian Pediatric Hematology Oncology Group (HPOG): Budapest, University Medical Clinic I. (Dr. I. Rényi); Budapest, University Medical Clinic II. (Dr. G. Kovács); Budapest, Madarász Children Hospital (Dr. J. Galántai); Budapest, Bethesda Children Hospital (Dr. A. Békési); Budapest, Madarász Children Hospital (Dr. E. Magyarosy); Pécs, University Medical Center (Prof. Dr. P. Kajtár); Szeged, University Medical Center (Dr. K. Bartyik); Debrecen, University Medical Center I. (Prof. Dr. Cs. Kiss); Szombathely, Markusovszky Children Hospital (Dr. P. Masát); Miskolc, Borsod-Abaúj-Zemplén Megyei Kórház (Prof. Dr. K. Nagy); HPOG data center: Dr. Zsuzsanna Jakab.
Trial data center. Medical Statistics Unit, Università di Milano Bicocca (Prof. M.G. Valsecchi).
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank Daniela Silvestri for her valuable work in central collection, pooling and reviewing of data for the trial, and Piero De Stefano for his contribution in the writing of the paper.
NOTES
Supported by grants from the Associazione Italiana Ricerca sul Cancro.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Department of Pediatrics, University of Bologna, Bologna
Medical Statistics Unit, University of Milano-Bicocca, Italy
Department of Pediatrics, University of Milano, Milano
Ospedale San Gerardo, Monza
Center of Pediatric Hematology-Oncology, Università di Catania, Catania
Pediatric Hematology-Oncology, Policlinico San Matteo, Pavia
Department of Pediatrics, University of Padova, Padova
Pediatric Hematology-Oncology, Ospedale dei Bambini G. Di Cristina, Palermo, Italy
the Hungarian Pediatric Hematology Oncology Group (HPOG)
Heim Pal Children Hospital, Budapest, Hungary
the Dutch Childhood Oncology Group, the Hague
Beatrix Children's Hospital, Department of Pediatric Oncology, Groningen, the Netherlands
ABSTRACT
PURPOSE: Between September 1991 and May 1997, within the International Berlin-Frankfurt-Muenster Study Group (I-BFM-SG), a randomized study was performed aimed at assessing the efficacy of prolonged use of high-dose L-asparaginase (HD-L-ASP) during continuation therapy in children with standard risk (SR) acute lymphoblastic leukemia (ALL), treated with a reduced BFM-type chemotherapy.
PATIENTS AND METHODS: The Italian, Dutch, and Hungarian groups participated in this study denominated IDH-ALL-91, and 494 children were enrolled. Treatment consisted of a BFM-type modified backbone with omission of the IB part in induction and elimination of two doses of anthracyclines during reinduction in both arms at the beginning of continuation therapy. Patients were randomly assigned to receive (YES-ASP) or not (NO-ASP) 20 weekly HD-L-ASP (25,000 IU/m2).
RESULTS: The event-free-survival and overall survival probabilities at 10 years for the entire group were 82.5% (1.8) and 90.3% (1.3), respectively. Of the 490 patients eligible for random assignment, 355 (72.4%) were randomly assigned (178 YES-ASP and 177 NO-ASP). After a median follow-up of 9 years, the probability of disease-free survival at 10 years was 87.5% (SE, 2.5) for YES-ASP arm versus 78.7% (SE, 3.3) for NO-ASP arm (P = .03). In multivariate analysis, NO-ASP arm (P = .03), male sex (P = .004), and age older than 10 years (P = .0003) had a significantly adverse impact on outcome.
CONCLUSION: In this subset of patients, selected with criteria not including monitoring of minimal residual disease, application of extended HD-L-ASP may improve prognosis, compensating reduced leukemia control that results from adoption of a reduced-intensity BFM-backbone for treatment of children with SR ALL.
INTRODUCTION
Several cooperative groups or large single institutions worldwide have demonstrated that acute lymphoblastic leukemia (ALL), the most common type of cancer in children, is highly responsive to chemotherapy, with more than 75% of patients cured with current chemotherapy regimens.1-7
The outcome of children with standard risk (SR) childhood ALL is even better. Further improvement of treatment results for this subset of patients may be difficult to obtain because the degree of improvement to be expected with any modification of treatment is small and the number of patients needed to test relevant questions in a reasonable length of time is proportionally high.
The enzyme L-asparaginase has been used in the treatment of lymphoblastic malignancies in children since 1970 and its antileukemia effect is believed to result from the depletion of circulating asparagine, which is essential for most malignant lymphoblasts.8-10 At the Dana-Farber Cancer Institute (Boston, MA), weekly administration of high-dose (HD) Escherichia coli L-asparaginase (L-ASP) administered in a randomized trial during intensification therapy resulted in fewer treatment failures in patients with non–T-cell ALL, induced into complete remission using vincristine, prednisone, and doxorubicin.9 Moreover, at the same institution, the study 81-01 demonstrated that, for patients with SR ALL, a program using four-drug induction and extended use of weekly HD-L-ASP during intensification therapy resulted in an event-free survival (EFS) probability of 86% at 4 years.10 These data, although generated in a nonrandomized setting, were widely accepted as a further strong suggestion of therapeutic efficacy of HD-L-ASP.
In the past, the two forms of native L-ASP mainly used in clinical practice were derived from two different bacterial species (ie, E coli and Erwinia chrysanthemi). These products have, however, different pharmacokinetic and immunogenic properties; the Erwinia chrysanthemi L-ASP displays a mean half-life shorter than that of the E coli product.11 Moreover, time to recovery of serum asparagine levels after administration of Erwinia-asparaginase was demonstrated to be shorter than that observed after E coli-asparaginase.12 For many years, the E coli product (Crasnitin Bayer, Leverkusen, Germany) was the only E coli–derived L-ASP preparation available in Europe. The Erwinia product (Erwinase, Speywood, Maidenhead, United Kingdom) was used mainly as second-line treatment for patients experiencing severe allergic reactions to the E coli preparation.13,14 In the 1990s, Crasnitin became no longer available in Europe and, thus, in many European countries, Erwinase was adopted in front-line treatment, with the same dosage and schedule.
In 1991, within the International Berlin-Frankfurt-Muenster Study Group (I-BFM-SG), a European randomized study denominated IDH-ALL-91 was started; the Italian (I), Dutch (D), and Hungarian (H) pediatric oncology cooperative groups participated in this study. The main objective of the study was to evaluate whether prolonged administration of HD-L-ASP at the beginning of continuation therapy could offer an advantage in terms of final outcome in children with SR ALL who received BFM-type chemotherapy, with a reduced-intensity induction phase, and in which two doses of anthracyclines were omitted during reinduction. We report here the long-term results of this trial.
PATIENTS AND METHODS
Study Design
The study was designed as a prospective, intergroup, multicenter randomized trial aimed at evaluating the efficacy of the addition to a BFM backbone, during early continuation therapy, of extended HD-L-ASP (25,000 IU/m2/week x 20 weeks) in patients with standard risk ALL. The main end point of the study was the comparison of disease-free survival (DFS) between the standard control regimen and the experimental regimen.
The study was planned to have an 80% power to detect a 10% improvement in the experimental arm (ie, that including HD-L-ASP), estimating an 80% DFS probability at 5 years for the control arm, and = .05 (one sided). The calculated target number of patients per arm was 164, with an accrual time of 48 months and an overall study duration of 9 years and at least 49 events for the final analysis. Random assignment was planned according to randomized permuted blocks, stratified by country; it was centrally performed in each group data center after check of eligibility criteria.
Treatment Protocol
Treatment consisted of a BFM-type modified chemotherapy15: after 7 days of steroid prephase and one injection of intrathecal methotrexate (IT-MTX),16 all patients received a four-drug induction (protocol IA) with the omission of the B part, which consists of two administrations of cyclophosphamide (1 g/m2 on days 43 and 71), cytarabine (four consecutive weekly courses of four daily subcutaneous injection at a dosage of 75 mg/m2/day) and 6-mercaptopurine (60 mg/m2/day from day 43 to day 70). Consolidation therapy consisted of four courses of HD MTX 2 g/m2; reinduction therapy (also called protocol II) included only the first two doses of doxorubicin instead of the four usually employed in the original BFM treatment protocol; continuation therapy consisted of oral 6-mercaptopurine (50 mg/m2 daily), weekly MTX (20 mg/m2 intramuscularly) and extended triple IT chemotherapy (TIT), for a total treatment duration of 24 months (Table 1).
At the beginning of continuation therapy, the patients were randomly assigned to receive (YES-ASP) or not (NO-ASP) 20 weekly high-doses of L-ASP (25,000 IU/m2). Due to unavailability of E coli asparaginase (Crasnitin) soon after the trial start, more than 90% of enrolled patients received the Erwinia chrysanthemi asparaginase (Erwinase). The minority of patients receiving Crasnitin were distributed evenly in the two randomized arms. Supportive care was given according to each individual center standards and uniformly applied to the patients in both groups.
Definitions
Complete remission (CR) was defined as no physical sign of leukemia, no detectable leukemia cells on blood smear, a bone marrow with active hemopoiesis, and less than 5% morphologically identifiable leukemia blast cells, and normal cerebro-spinal fluid (CSF). Marrow aspiration was examined on day 42 for evaluation of CR.
Study Population
Criteria for eligibility in the study of children with SR ALL included age between 1 and 15 years; non–T-ALL; low tumor burden, defined as BFM risk factor [calculated as RF = 0.2 x log10 (blast cell count + 1) + 0.06 x cm of palpable liver + 0.04 x cm of palpable spleen]15 < 0.8; prednisone good response (PGR; < 1 x 109/L blasts in peripheral blood after 7 days of steroids and one injection of IT-MTX).16 Patients with CNS disease at diagnosis, t(9;22) or t(4;11) translocations or failure to achieve CR by day 42 were excluded from the study, and the latter two groups assigned to the high-risk group.
The study was approved by the internal review board of each participating institution, and written informed consent was obtained in all randomly assigned cases from patients' parents or legal guardian.
A total of 494 children with SR ALL were enrolled in the trial. The Italian group enrolled 290 patients, diagnosed between March 1991 and April 1995; the Dutch group 170, diagnosed between September 1991 and December 1996; and the Hungarian group 34, diagnosed between March 1991 and December 1995.
Of 490 patients eligible for random assignment, 355 (72.4%) were randomly assigned (I, 242, 85%; D, 85, 50%, H, 28, 82%), between September 1991 and May 1997, to YES-ASP (n = 178) or NO-ASP (n = 177) HD-L-ASP. The remaining 135 were not assigned mainly for the following reasons: parents' refusal (I, n = 9; D, n = 47), physician decision not to participate into the study or clinical reasons (I, n = 13; D, n = 38), others nonspecified (I, n = 22, H, n = 6).
Statistical Analysis
Patient data were collected on protocol-specific forms and reviewed before input every year by the trial data center, which also performed the statistical analysis. EFS, DFS, and survival curves were calculated according to the Kaplan-Meier method.17 The starting point for the observation time was the date of random assignment, when the analysis was limited to randomly assigned patients, whereas it was the date of diagnosis otherwise. For calculation of EFS for the overall population, induction failure, relapse, death in continuous CR, or secondary malignancy were counted as events. For estimation of DFS for randomly assigned patients, relapse, death in continuous CR or secondary malignancy were counted as events. Calculation of DFS was performed according to the intention-to-treat principle. In calculating the survival probabilities, death from any cause was considered an event. The observation time was censored at the time of the last contact, both when no event was recorded and when the patient was lost to follow-up. Analysis used June 1, 2003, as the reference date, (ie, the day at which all centers locked data on patient outcomes); five randomly assigned patients (1.5%) were lost to follow-up while in continuous CR. The log-rank test was applied for comparing the outcome of the randomly assigned groups, and the test was one-sided as by study design. All other tests were two-sided. The Cox regression model was applied to estimate treatment effect adjusting for known prognostic variables (WBC, age, sex).18 All of these analyses were stratified by participating group. The estimated hazard ratio is reported as relative risk in the results. The Wald test was used to assess the role of covariates. Before applying the Cox model, the presence of major departures from the proportional hazard assumptions was excluded by graphical checks. The analyses were carried out with the SAS package (SAS Institute, Cary, NC).
RESULTS
Overall Outcome and Random Assignment
After a median duration of follow-up of 9 years, the 494 study patients enrolled in the IDH-ALL-91 study had an EFS probability of 84.6% (SE, 1.6) at 5 years and 82.5% (SE, 1.8) at 10 years, with a survival probability of 91.3% (SE, 1.3) and 90.3% (SE, 1.3), respectively. Two patients died during induction therapy as a result of fungal pneumonia and septicemia with pneumonia, respectively; one patient was lost to follow-up within the first few months, and one relapsed before the time set for random assignment (start of continuation therapy), leaving 490 patients eligible for random assignment. Of these 490 eligible patients, 355 patients were allocated to either the YES-ASP (n = 178) or the NO-ASP (n = 177) arm. Their presenting clinical and laboratory features are shown in Table 2.
The long-term outcome of the 135 non–randomly assigned patients was comparable to that of the randomly assigned patients, with a 5- and 10-year EFS of 84.4% (SE, 3.1) and 83.0% (SE, 12.1) versus 85.3% (SE, 1.9) and 83.0% (SE, 2.1), respectively (P = .83).
Outcome of Randomly Assigned Patients
Approximately 10% of patients presented allergic reactions to prolonged administration of HD-L-ASP, which, in most cases, was easily managed by antihistaminic and/or steroid drug administration; only one third of children who experienced adverse events required treatment discontinuation. These children were included in the analysis. Fifty-eight events were observed after random assignment: one second malignancy and 57 relapses. Twenty-two relapses occurred in the YES-ASP arm and 35 in the NO-ASP arm (Table 3). Most of the relapses occurred in the bone marrow (17 v 25); the remaining disease recurrences occurred in the CNS (one in each arm), testis (two v four), testis and marrow (one v four), and other sites (one in each arm). No death in CR was recorded.
The DFS probability at 5 and 10 years of patients randomly assigned to receive HD-L-ASP was 88.1% (SE, 2.4) and 87.5% (SE, 2.5) versus 82.5% (SE, 2.9) and 78.7% (SE, 3.3) for patients allocated in the NO-ASP arm, respectively (one-sided P = .03; Fig 1). The survival estimate at 5 and 10 years was 94.4% (SE, 1.7) and 93.7% (SE, 1.9) in the YES-ASP arm versus 89.8% (SE, 2.3) and 88.6% (SE, 2.4) in the NO-ASP arm, respectively (one-sided P = .05).
Overall, the hazard ratio estimated by the Cox model of YES-ASP versus NO-ASP arm was 0.60 (90% CI, 0.38 to 0.93), thus indicating a 40% relative reduction of the risk of failure in the YES-ASP versus the control arm. In order to evaluate the presence of a possible country effect, we calculated the hazard ratios of YES-ASP and NO-ASP arms for the two groups randomly assigning the largest number of patients (ie, Italy and the Netherlands), obtaining comparable values: 0.63 (95% CI, 0.34 to 1.15) and 0.58 (95% CI, 0.19 to 1.72), respectively.
When treatment comparison was adjusted by prognostic factors in a Cox regression model, NO-ASP arm (P = .028, one sided), male sex (P = .004) and age older than 10 years (P = .0003) had a significantly adverse impact, whereas leukocyte count (P = .46) did not. The beneficial effect of HD-L-ASP seems to be more pronounced in patients older than 10 years and in males, although the difference is not statistically significant in the Cox regression model (P = .69 and P = .66 for sex and age, respectively).
DISCUSSION
In this randomized intergroup study on children with SR ALL, treated with a reduced BFM-type chemotherapy, the 20 weekly administrations of HD-L-ASP—mostly Erwinase—during continuation therapy was associated with a better outcome, which became evident only after an adequately prolonged follow-up, due to the relatively low number of events, which, moreover are spread over several years.
The advantage in terms of DFS experienced by patients who received HD-L-ASP may be due to the treatment reduction applied in the second part of induction therapy in this protocol (ie, the so-called BFM phase IB) on the basis of the use of cyclophosphamide, cytarabine and 6-mercaptopurine, which was omitted, together with the elimination of two doses of anthracyclines during reinduction, in both arms. The extended use of HD-L-ASP during early maintenance seems to be able to compensate the inferior leukemia control associated with such a reduced treatment, preventing leukemia recurrence. Patients randomly assigned in the control (ie, NO-ASP) arm had a 5-year DFS of 82%, a result in line with that estimated at time of sample size calculation and with that obtained in the AIEOP ALL 88 study,19 but which is inferior to the results obtained by other groups that, in contemporaneous studies, did not omit phase IB and doses of anthracyclines in reinduction.20 This finding supports the hypothesis that HD-L-ASP may have a beneficial role when dose reduction or nonadministration of drugs currently employed in the treatment of children with good prognosis ALL is chosen. This study also underlines that treatment reduction in patients with SR ALL should be approached with caution—especially in patients older than 10 years and in males—unless different criteria for monitoring treatment efficacy be employed. Indeed, in the current study AIEOP (Associazione Italiana di Ematologia ed Oncologia Pediatrica) -BFM-ALL-2000, in addition to the usual clinical criteria, we are using the polymerase chain reaction–based determination of minimal residual disease to stratify patients with childhood ALL in the classic three groups, namely standard, intermediate and high risk, and only patients with early clearance of leukemia blasts are allowed in the SR arm.
It is also noteworthy that, in the intermediate risk group of the same study AIEOP-ALL-91 (9102 protocol), no advantage was observed for patients randomly assigned to receive extended HD-L-ASP, administered for the same number of doses during reinduction and early continuation therapy.21 Because these patients received an unmodified BFM-chemotherapy regimen, the most likely interpretation of this finding is that the therapeutic effect deriving from the application of the BFM intensive regimen is already maximal and thus cannot be further improved by the addition of protracted HD-L-ASP administration. This last consideration reinforces the concept that the efficacy of additional or alternative treatment components for childhood ALL should always be considered in the frame of overall treatment intensity and that the use of extended HD-L-ASP might be beneficial mainly to children with ALL at a lower risk of recurrence and when relevant treatment reduction is adopted.
The European Organisation for Research and Treatment of Cancer recently performed a comparative study (58,881 trial, based on a BFM backbone) of the two types of asparaginase during the remission-induction phase in a large number of children with either ALL or, in a minority of cases, with lymphoma.19 Patients enrolled onto this trial and randomly assigned to receive the E coli L-ASP product (either Medac or Kidrolase, both produced by Kyowa Hakko, Tokyo, Japan) enjoyed a significantly better outcome compared with those randomly assigned to receive the Erwinia chrysanthemi product, despite a higher incidence of coagulation abnormalities.22 In view of these findings, it is possible to speculate that a more extensive use of these types of E coli L-ASP could theoretically lead to a further benefit from the application of HD-L-ASP also in less favorable childhood ALL subpopulations. However, this is only a hypothesis that remains to be tested; more potent products might also lead to increased toxicity.
A unique peculiarity of this study is that it represents the first international randomized trial conducted in Europe within the I-BFM-SG. The study organization was centralized in a trial data center, but each country data center maintained its role in random assignment, data collection, and querying. This type of intergroup cooperation has become a model for subsequent studies conducted within the I-BFM-SG.23
Twenty-eight percent of the eligible patients were not randomly assigned. This phenomenon represents one of the difficulties in planning and performing large-scale, international, prospective randomized studies. This said, the non-negligible failure to accrue all the potentially randomly assignable cases should not have influenced the main message deriving from the trial because the hazard ratios of YES-ASP and NO-ASP arms in the two countries enrolling the largest number of cases did not differ.
In conclusion, the final results of this study show that application of extended HD-L-ASP may compensate reduced leukemia control resulting from adoption of a reduced intensity BFM-backbone for treatment of children with SR ALL, selected with criteria not including monitoring of minimal residual disease. It remains to be definitively proven whether the extended use of E Coli HD-L-ASP, combined with the omission of doses of drugs associated with more relevant long-term adverse effects (ie, anthracyclines and cyclophosphamide), could offer the same outcome achieved with a full-intensity BFM protocol in SR patients.
Appendix
Institutions that randomly assigned patients in IDH-ALL-91 study. Italy—AIEOP: Ancona, Clinica Pediatrica (Prof. G.V. Coppa, Dott. P. Pirani); Bari, Clinica Pediatrica I (Prof. F. Schettini, Dott. N. Santoro); Bari, Clinica Pediatrica II (Prof. N. Rigillo, Dott.ssa S. Bagnulo); Bergamo, Div. Pediatria (Dott. P.E. Cornelli), Ematologia (Prof. T. Barbui); Bologna, Clinica Pediatrica (Prof. G. Paolucci, Prof. A. Pession); Brescia, Clinica Pediatrica (Prof. A.G. Ugazio, Dott. A. Arrighini); Cagliari, Servizio Oncoematologia Pediatrica (Prof. P.F. Biddau, Dott.ssa R. Mura); Catania, Div. Oncoematologia Pediatrica (Prof. G. Schilirò, Dott. L. Lo Nigro); Catanzaro, Div. Ematologia (Prof. S. Magro, Dott.ssa C. Consarino); Firenze, Ospedale Meyer, Dip. Pediatria, U.O. Oncoematologia Pediatrica (Prof.ssa G. Bernini, Dott.ssa A. Lippi); Genova, Ist. "G.Gaslini" (Prof. P.G. Mori, Dott.ssa C. Micalizzi); Modena, Clinica Pediatrica (Prof. S. Bernasconi, Dott.ssa M. Cellini); Monza, Clinica Pediatrica (Prof. Giuseppe Masera, Dott. Valentino Conter); Napoli, Ospedale Pausilipon (Prof. V. Poggi, Dott.ssa M.F. Pintà Boccalatte); Napoli, II Università, Dip. Pediatria, Servizio Autonomo Oncologia Pediatrica (Prof.ssa M.T. Di Tullio, Prof.ssa F. Casale); Napoli, Ospedale SS Annunziata (Prof. F. Tancredi, Dott. A. Correra); Padova, Clinica Pediatrica II (Prof. L. Zanesco, Dott.ssa C. Messina); Palermo, Clinica Pediatrica I (Prof.ssa M. Lo Curto, Dott.ssa G. Fugardi); Parma, Clinica Pediatrica (Dott. G. Izzi, Dott.ssa P. Bertolini); Pavia, Clinica Pediatrica (Prof. F. Locatelli, Dott. M. Aricò,); Perugia, Div. Oncoematologia Pediatrica, Osp. Silvestrini (Dott. A. Amici, Dott. P. Zucchetti); Pescara, Div. Ematologia (Dott. Fioritoni, Dott. A. Di Marzio); Pisa, Clinica Pediatrica III (Prof. P. Macchia, Dott. C. Favre); Reggio Calabria, Div. Ematologia, Ospedali Riuniti (Prof. F. Nobile, Dott.ssa M. Comis); Roma, Div. Ematologia Pediatrica, Osp. "Bambin Gesu; (Prof. G. De Rossi, Dott. C. Miano); Roma, Cattedra Ematologia (Prof. F. Mandelli, Dott.ssa A.M. Testi); San Giovanni Rotondo, Ospedale "Casa Sollievo della Sofferenza," Div. Pediatria, Sezione Ematologia ed Oncologia Pediatrica (Prof. P. Paolucci, Dott. S. Ladogana); Sassari, Clinica Pediatrica (Prof. D. Gallisai, Dott. C. Cosmi); Torino, Clinica Pediatrica (Prof. E. Madon, Dott.ssa E. Barisone); Trieste, Clinica Pediatrica (Prof. P. Tamaro, Dott. G.A. Zanazzo); Verona, Clinica Pediatrica (Prof. L. Tatò, Dott. P.L. Marradi). AIEOP data center: COFONOP, Clinica Pediatrica Università di Bologna (Prof. A. Pession, Dr. R. Rondelli) & CORS, Clinica Pediatrica, Università di Milano Bicocca (Prof. M.G. Valsecchi, Dr. D. Silvestri).
Dutch Childhood Oncology Group (DCOG): Amsterdam, Academic Medical Centre Amsterdam/Emma Childrens' Hospital (Dr. R.S. Weening, Dr. H. van den Berg); Amsterdam, VU University Medical Centre Amsterdam (Prof. Dr. A.J.P. Veerman); Groningen, University Medical Centre Groningen (Prof. Dr. W.A. Kamps); Leiden, Leiden University Medical Centre (Drs. E.Th. van 't Veer-Korthof); Nijmegen, University Medical Centre St. Radboud (Dr. J.P.M. B?kkerink); Rotterdam, Erasmus MC University Medical Centre Rotterdam (Dr. K. H?hlen, Drs. F.G.A.J. Hakvoort-Cammel); Utrecht, University Medical Centre Utrecht (Dr. T. Révész).
Hungary—Hungarian Pediatric Hematology Oncology Group (HPOG): Budapest, University Medical Clinic I. (Dr. I. Rényi); Budapest, University Medical Clinic II. (Dr. G. Kovács); Budapest, Madarász Children Hospital (Dr. J. Galántai); Budapest, Bethesda Children Hospital (Dr. A. Békési); Budapest, Madarász Children Hospital (Dr. E. Magyarosy); Pécs, University Medical Center (Prof. Dr. P. Kajtár); Szeged, University Medical Center (Dr. K. Bartyik); Debrecen, University Medical Center I. (Prof. Dr. Cs. Kiss); Szombathely, Markusovszky Children Hospital (Dr. P. Masát); Miskolc, Borsod-Abaúj-Zemplén Megyei Kórház (Prof. Dr. K. Nagy); HPOG data center: Dr. Zsuzsanna Jakab.
Trial data center. Medical Statistics Unit, Università di Milano Bicocca (Prof. M.G. Valsecchi).
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We thank Daniela Silvestri for her valuable work in central collection, pooling and reviewing of data for the trial, and Piero De Stefano for his contribution in the writing of the paper.
NOTES
Supported by grants from the Associazione Italiana Ricerca sul Cancro.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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