- Email: [email protected]
Developing leukemia protocols in cooperation between the Netherlands and Indonesia
Pediatric Hematology Oncology Journal 5 (2020) 7e10
Contents lists available at ScienceDirect
Pediatric Hematology Oncology Journal journal homepage: https://www.elsevier.com/journals/pediatrichematology-oncology-journal/
Developing leukemia protocols in cooperation between the Netherlands and Indonesia Anjo J.P. Veerman a, *, Eddy Supriyadi b, Sutaryo Sutaryo b a
VU University, Amsterdam, the Netherlands Division of Pediatric Hematology and Oncology, Dr. Sardjito Hospital - Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 January 2020 Received in revised form 6 March 2020 Accepted 10 March 2020 Available online 30 March 2020
Since 1990 two departments of Pediatric Oncology in Indonesia and the Netherlands have worked together to improve staff capacities in the Estella Clinic in Yogyakarta and Indonesian clinics general, through workshops for pediatricians, nurses, technicians, psycho-social workers. Teleconferences were conducted weekly. Protocols for leukemia were developed. Joint research projects led to research experience for about 50 Dutch medical students, about 60 international publications and 8 PhD theses. The patients with acute Lymphoblastic Leukemia benefitted and showed increasing survival rates. Possible improvements in the future are also discussed. © 2020 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Publishing Services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Keywords: Pediatric oncology International cooperation Leukemia
1. Introduction Leukemia used to be an invariably fatal disease until the late 1960s. In the years before, studies in mice had shown that some wartime toxic substances and some anti-metabolites could suppress leukemia. In the USA, the CALGB group started using these drugs, as well as corticosteroids in children with leukemia. The first real successes were obtained when dr Pinkel in the St Jude Children’s Research Hospital supposed that only combinations of drugs would be effective, similar to the experience in tuberculosis. In a series of studies, labeled Total Therapy, successes were obtained, but most often the children relapsed after some time. However, Total Therapy V (1967e1968) showed long term remissions in 22 out of 41 patients [1]. In the 1970’s dr Riehm devised a protocol using more drugs, and a reinduction schedule. This led to a general principle of treatment of Acute Lymphoblastic Leukemia (ALL) with induction, consolidation, reinduction, and maintenance. The BerlinFrankfurt-Munster (BFM) cooperative group of initially 9 German hospitals treated between 1976 and 1979 158 children and adolescents with ALL and achieved 70% disease-free survival [2]. This result was unheard of, and was initially unbelieved by many
* Corresponding author. E-mail address: [email protected] (A.J.P. Veerman). Peer review under responsibility of Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics.
colleagues. Nowadays survival of children with ALL has increased to over 90% in high-income countries, where pharmacokinetic surveyance and Minimal Residual Disease (MRD) determinations are possible, and where most children come early and in good nutritional status [3]. Of course, in low and middle-income countries, the situation is quite different. 2. Cooperation between a Dutch and an Indonesian pediatric oncology clinic In 1972 the Dutch Childhood Leukemia Study Group, later Dutch Childhood Oncology Group (DCOG), was founded and started a protocol based upon the Pinkel schedule. The protocol was amended every few years, using randomized controlled trials to try to improve results. In 1984 the 6th version of the Dutch protocol introduced dexamethasone as corticosteroid, based upon a little known (at the time) randomized trial of the CALGB group that found dexamethasone more effective than prednisone. At the same time, High Dose Methotrexate was introduced as consolidation and central nervous system relapse prevention, cranial irradiation was totally abolished. This protocol was rather more simple than the BFM protocols but proved surprisingly effective [4]. In the late 80’s, contacts between pediatric oncologists from Indonesia and the Netherlands were stimulated by a father of a Dutch patient. He was urging us to do something for children with ALL in Indonesia. At that time, most children in Indonesia were still treated with the
https://doi.org/10.1016/j.phoj.2020.03.007 2468-1245/© 2020 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Publishing Services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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1972 Dutch protocol, and only a few of them survived. So cooperation between VU University Amsterdam and Gadjah Mada University Yogyakarta started. In cooperation with dr Sutaryo, with whom we were already cooperating with on the subject of Dengue fever, a project was developed, involving a new ALL protocol, based upon DCOG ALL-VI study, and educating staff, not only doctors, but also nurses and technicians [5]. Since there was no health insurance for all at that time, the Dutch charity Estella Fonds provided part of the essential medicines, as well as some financial support for other needs. Later on, research projects and randomized protocols were introduced. In 1998 the Dutch Cancer Association (Koningin Wilhelmina Fonds, KWF) supported us with a number of grants for education and research. So the workshops we already conducted were intensified and were open to all health care personnel interested in pediatric oncology. They came mainly from 14 State University Hospitals all over Indonesia. 3. Protocol development In 1990 we used the dexamethasone based successful Dutch ALL-VI protocol together with elements from the BFM protocols for high risk (HR) ALL patients as basis for the first Indonesian protocol: COM-ALL 92. The problems were many: abscondence was high, 4025%, and toxic deaths almost as frequent. Apparently, a less intensive protocol was needed. The economic crisis in 1997 made imported drugs in Indonesia 5 times as expensive almost overnight; that was also an important reason that a more economical protocol was necessary. A basic protocol was devised at a workshop in 1998, with KWF funding, where all 14 involved pediatric oncology units in Indonesia were present. The protocol was named Wiyaja Kusuma protocol, after the flower that is reputed to cure all ailments. The result, after five years, was less than optimal; still, abscondence and toxic death were big problems, as was interruption of treatment. A significant problem was the fact that children on chemotherapy were treated on general pediatric wards, amidst others with infectious diseases. In the meantime, health insurance had improved, from almost none to covering most drugs needed for treatment. Since support for medication was no longer needed, the Estella Fonds shifted focus and started to raise funds for dedicated wards for children with cancer and hematological diseases. The first Estella Clinic was opened in Manado in 2001 with 18 beds in a separate building next to the pediatric clinic. Also, a guesthouse close by was funded, for the many patients who came from far away. A little bit later, the second Estella Clinic with 41 beds in Yogyakarta was opened, of which the dr Sardjito Hospital funded half, and the Estella Fonds the other half. In 2006 and 2013, revised versions of the ALL protocol were designed without much input from the Dutch experts. In the ALL 2013 protocol, for Standard Risk (SR) ALL prednisone was used instead of dexamethasone, and anthracyclines were reduced to just 2 doses. The HR patients, who were more than half as opposed to about a quarter in the Netherlands, were treated on dexamethasone induction, with a 4 drug induction schedule, including 4 doses of doxorubicin in weeks 2,3,4 and 5. Both got a consolidation schedule, consisting of 6Mercaptopurine, with three courses of Methotrexate (MTX) 1,000mg/m2, with leucovorin rescue. Unfortunately, Methotrexate serum levels could not be measured, so higher dose MTX did not seem feasible. The abscondence rate was reduced in this period, but fatal toxicities still occurred too often. Therefore, in 2016 a few simple alterations to the ALL 2013 protocol were introduced to reduce toxicities, especially in the induction phase. This is the ALL 2016 Pilot protocol. Prednisone induction was now prescribed for all patients, both SR and HR. For HR patients, a reinduction schedule with dexamethasone was included. Anthracyclines were omitted in SR, and only two doses of doxorubicin were used in HR patients and
scheduled in the first two weeks (Fig. 1). The rationale being that there is international consensus that 3 drug induction is adequate for SR patients, and the anthracyclines are best used early in induction, because then the leukemic cell burden has to be reduced quickly, so that later in the (6 weeks) induction, bone marrow can recover. Using anthracyclines later in induction results in many patients with aplastic bone marrow post induction. Apart from that, rebound cells (‘hematogones’) often occur, which lead to quite a few erroneous diagnoses of No Remission after induction. The ALL 2016 Pilot protocol is still too early for final evaluation, but the 2year results are much improved over the 2013 protocol. We anticipate that probably about 60e70% of children with ALL may be cured. Already it is clear that the number of toxic deaths early in the treatment is reduced, and concomitantly, also less patients drop out. From our earlier research, it appeared that drop out is related to toxic deaths: parents who see other children succumb to toxicity sometimes conclude that the treatment is too dangerous, and thus they abscond. Over time, the number of referrals of children with ALL, and the number included in the protocols has increased (Table 1), with many patients now coming from regions adjacent to the province of Yogyakarta. 4. Education From early on, education and training of the pediatric oncology teams in Indonesia was closely linked to research projects. The education came in two forms: annual seminars and workshops of one week duration and teleconferences every week. The workshops were held in rotating cities, Yogyakarta, Manado, Semarang, Surabaya, Jakarta, Medan. The docents, pediatric oncologists, nurses, pathologists and technicians who were twinned, matching those from Holland with those from Indonesia. After a symposium day, for health care personnel generally and some interested lay people, the workshop courses were divided into separate flows, for training of pediatricians, for nurses together with psychologists, and pathologists plus technicians. They were coming together in general sessions on the last day of the workshop. For the nurses is was essential to have lectures and discussion translated from English to Indonesian. The division in three flows ensured that the number of participants per group was about 12e24 people, making it as interactive as possible. It was instructive and fun to have a multiplechoice test pre-course, and the same test post-course. For instance, the question: ‘‘Your patient with ALL in induction develops a fever at midnight, can that wait until 7 a.m. before calling the doctor?’’ yielded 95% of ’yes’ answers at pretest and fortunately a much lower percentage at posttest. A number of issues became evident through these and other answers and observations. First, a sense of urgency is not innate, and not especially pronounced in the Indonesian-Javanese culture. Second: hierarchy is different and stronger in Indonesia, as compared to the Netherlands. At night a nurse would be very reluctant (to say the least) to wake up a doctorresident on call. Moreover, a resident will have to surmount a high barrier before asking his superior to advise him if a problem occurs at an inconvenient time. This cultural setting may be a background for several treatment delays that might have been prevented by adequate early reaction. The exchange of staff, doctors and nurses, was also elucidating. Some habits were only seen when staff members from the Netherlands were on site in Indonesia for a longer period. Pediatric oncologists from VU visited the Estella clinic for 1e2 weeks. Nurses staid for up to 3 months. All of them in their own time. One observation was for instance, that economic use of medication sometimes was pushed too far. It is not a good idea to keep an open vial of 50 mg Methotrexate for a week at room temperature, so that 4 doses of 12 mg can be extracted. Even if you top the vial with a sterile cap.
A.J.P. Veerman et al. / Pediatric Hematology Oncology Journal 5 (2020) 7e10
9
Fig. 1. Example of flow chart for ALL High Risk patients.
Table 1 List of protocols cooperation Indonesia-UGM with the Netherlands-VU. Era and Name of protocol
Number patients in trial
1992e2000 2000e2006 2006e2013 2013e2016 2016e2019
±70 171 412 160 234
COM-ALL Wijaya Kusuma 2000 Indonesian ALL 2006 Indonesian ALL 2013 Yogya pilot ALL 2016
5. Research The beginning of all research efforts to evaluate ALL therapy is: registration and follow up of patients, and a sound database. Fortunately, in Yogyakarta in 1992, a dedicated and very efficient data manager was in place, and three technicians were hired for a pediatric hematology lab which evaluated all blood smears and bone marrow samples. Unfortunately, all four of them were later made redundant and replaced by a central laboratory, and by the hospital administration. All far from the pediatric oncology ward, less experienced, less interested it seems. Based on the excellent data recording, it was possible to conduct research projects. Young pediatric oncologists in Yogyakarta were embarking on PhD studies. They were supported by Dutch medical students, who dedicated their three months research electives (plus three months of their own time) to gather data on certain aspects of the patients with ALL. For instance conducting questionnaires among parents, and health care workers. Some of them later did a PhD themselves. All of the Indonesian PhD students did the final writing of their theses in the Netherlands. That provided protected time, and close by contact with the Dutch supervisor. The subjects of study were, among others, epidemiology [6], adherence to therapy [7], and randomized trials: dexamethasone versus prednisone [8], quinolone prophylaxis during induction [9], and psycho-social
evaluations and interventions [10]. Among the last was a small randomized trial of providing a diary to the parents to keep track of laboratory tests and medication. Interestingly, the children with ALL of well-educated parents benefitted from having a diary: their survival rose from 40% to 62% (p < 0.05). Their adherence to protocol apparently improved. However, children from lower educated, poorer backgrounds did not benefit. Their survival remained at 29% [11]. These data point to the importance of socioeconomic factors in the results of treatment: the protocol is only part of the equation. From the joined research, 8 PhD theses resulted, 6 at VU and 2 at UGM, and about 60 international publications.
6. Conclusions Through the initiative of one parent in the Netherlands, father of Estella, who unfortunately succumbed to ALL after 2 relapses, a cooperation project developed, from one doctor on both sides to a Memorandum of Understanding (MOU) between two departments. Later more cooperative projects developed also between other departments, and an MOU between the Medical faculties and Academic Hospitals of the VU University and UGM was signed. In 2014 both Universities signed an MOU which covered all faculties. How did the children with ALL fare? From a survival of probably less than 5% before 1992, it rose but slowly, to an estimated survival of 60e70% in the most recent ALL 2016 Pilot protocol. What did we do good? Education, research, and stepwise development of the ALL protocol. The annual workshops were essential for staff building, but also improved cooperation between the 14 pediatric clinics in Indonesia, leading to joint ALL protocols. Since 2008 similar workshops were held in Singapore for Southeast Asia through the efforts of the VIVA Foundation: also an enterprise which was instituted through a parent of a child with ALL! What could we have done better? Not introducing dexamethasone as induction
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A.J.P. Veerman et al. / Pediatric Hematology Oncology Journal 5 (2020) 7e10
steroid, which had proved an excellent choice for the Netherlands and the UK, but less so in Indonesia. Although much more effective against ALL, and penetrating the blood-brain barrier better than prednisone, in the UK dexamethasone also resulted in about twice as many fatalities (4.5% vs 2.8%) in a randomized study of UKALL [12]. Although the difference was not statistically significant, even with two arms of 800þ patients, we concluded that if the same were true for Indonesia, the number of fatalities might almost have been doubled from 10 to 20%. However, the randomized trial conducted in Yogyakarta did not find much difference between dexamethasone or prednisone in induction [8]. Nevertheless, we went back to prednisone for induction, using dexamethasone in reinduction (HR patients only) and in maintenance for both SR and HR patients. What more could we have done better? We failed to hold on to adequate data management and laboratory tests in the Estella Clinic. We could (and should) have insisted more on retaining essential facilities on site. Another problem: the number of doctors and nurses relative to the number of new patients has not kept pace with the increased number of admissions. The Estella Clinic in Yogyakarta has almost the same number of new ALL patients in a year as we see in the whole of Holland, but far less than 20% of staff members. The actual daily patient care rests mainly upon residents, who rotate every month. So the continuity of care and the expertise lies in the hands of the nursing staff, of whom about half are permanent pediatric oncology nurses, the other half is rotating too. The last few years, fellows in training for pediatric hematologyoncology are also important for the continuity of care. They stay in place for 2 years. The 4 pediatric oncologists are top-docents and as such are requested for a host of other education and management chores, from student classes to being head of department, secretary of the faculty, member of the University Board, etcetera. Apart from that, most of them have private practices, because the academic salaries are very low indeed. Probably the main factor limiting the survival of children with ALL in Indonesia is poverty and lack of education. As stated above, from the less poor and better-educated families, 62% of patients could survive on a very basic protocol, while from poor and lower educated families, only 29% survived [11]. Education and close surveillance may help to combat abscondence, non-compliance, and may reduce toxic deaths that remained a problem over the whole period from 1992 until recently, especially in poorer families. Infections are more of a problem in poor families with crowding and inadequate housing and low hygienic circumstances. Interruptions of treatment for non-medical reasons are still frequent. Sometimes because parents not believing full treatment is necessary. But quite often some drugs were temporarily unavailable, LAsparaginase, MTX, 6 MP, causing insufficient induction therapies in some, and frequent interruptions of maintenance therapy in many patients. Interruption of treatment has been shown to be an important factor for relapses [13]. Especially CNS relapses are too frequent still in Yogyakarta. Lower results may also be related to the mix of patients: about half of the patients are HR, as opposed to only about a quarter in the Netherlands. There are also indications that the genetic make-up of ALL in Asia is different from that in the Netherlands, with more higher risk genotypes [14]. So patients come with higher risk factors, often late, after they have tried alternative treatments without success. These circumstances influence cure rates negatively. Notwithstanding all these drawbacks, a lot has been achieved. About 50 Dutch medical students had an excellent research experience, 8 PhD theses by Indonesian pediatricians have successfully been defended, and most importantly, the survival of ALL patients has increased dramatically. The advocacy of support groups and parents associations were of immense importance. Their help should be asked to influence the authorities to provide for health
insurance and to help with continuous availability of essential drugs. Of course, improvement in many aspects is still needed. Laboratory techniques such as MTX serum levels and MRD evaluation have to be introduced. Immunophenotyping has to be refined. More genetic tests are needed to weed out the patients with special needs, to come to personalized treatment protocols. Furthermore, we need to keep up the efforts to train new health care personnel. We are glad that the Prinses Maxima Clinic, the new centralized hospital for children with cancer in the Netherlands, now has taken over the cooperation between pediatric oncologists in the Netherlands and in Indonesia, to continue and enlarge the cooperation to the benefit of children with all types of childhood cancer. Acknowledgments Our gratitude is for all patients and parents who participated in the studies described in this article. The Estella Foundation, the Koningin Wilhelmina Fonds, Yayasan Kanker Anak, and other local charities in Indonesia were invaluable in their support. All staff members from both the VU and the UGM that participated were essential for the education, research, and patient care over the years, we thank them all. Finally, the support from the departments of Pediatrics, the Medical faculties, and the VU and UGM was much appreciated. References [1] Pinkel D, Simone JH, Hustu O, Aur RJA. Nine years’ experience with “total therapy” of childhood acute lymphocytic leukemia. Pediatrics 1972;50:246. €mswig H, Breu H, Gadner G, Schellong K, et al. [2] Henze G, Langermann J, Bra Ergebnisse der Studie BFM 76/79 zur Behandlung der akuten lymphoblastischen Leuk€ amie bei Kindern und Jugendlichen. The BFM 76/79 Acute Lymphoblastic Leukemia Therapy Study. Klin P€ adiatr 1981;193(3):145e54. [3] Pui C-H, Evans WE. A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol 2013 July;50(3):185e96. [4] Veerman AJP, H€ ahlen K, Kamps WA, Van Leeuwen EF, De Vaan GAM, Van Wering ER, et al. Dutch childhood leukemia study group: early results of study ALL VI (1984-1988). Haematol Blood Transfus 1990;33:473e7. [5] Veerman AJ, Sutaryo, Sumadiono. Twinning: a rewarding scenario for development of oncology services in transitional countries. Pediatr Blood Canc 2005;45:103e6. [6] Supriyadi E, Widjajanto PH, Purwanto I, Cloos J, Veerman AJ, Sutaryo S. Incidence of childhood leukemia in Yogyakarta, Indonesia, 1998-2009. Pediatr Blood Canc 2011;57:588e93. [7] Mostert S, Sitaresmi MN, Gundy CM, Sutaryo, Veerman AJP. Influence of socioeconomic status on childhood acute lymphoblastic leukemia treatment in Indonesia. Pediatrics 2006;118:1600e6. [8] Widjajanto Pudjo H, Supriyadi Eddy, Purwanto Ignatius, Cloos Jacqueline, vdVen Peter M, Veerman Sutaryo Anjo JP, et al. Dexamethasone versus prednisone in childhood acute lymphoblastic leukemia treatment: results of the Indonesian randomized trial. J Canc Ther 2017;8:735e50. [9] Widjajanto PH, Sumadiono S, Cloos J, Purwanto I, Sutaryo S, Veerman AJ. Randomized double blind trial of ciprofloxacin prophylaxis during induction treatment in childhood acute lymphoblastic leukemia in the WK-ALL protocol in Indonesia. J Blood Med 2013;4:1e9. [10] Mostert S, Sitaresmi MN, Gundy CM, Janes V, Sutaryo, Veerman AJP. Comparing childhood leukaemia treatment before and after the introduction of a parental education programme in Indonesia. Arch Dis Child 2010;95: 20e5. [11] Sitaresmi MN, Mostert S, Gundy CM, Ismail D, Veerman AJ. A medication diary-book for pediatric patients with acute lymphoblastic leukemia in Indonesia. Pediatr Blood Canc 2013;60:1593e7. [12] Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A. Eden TO; medical research council childhood leukaemia working party. Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK medical research council ALL97 randomized trial. Br J Haematol 2005;129:734e45. [13] Bhatia S, Landier W, Shangguan M, Hageman L, Schaible AN, et al. Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and nonHispanic white children with acute lymphoblastic leukemia: a report from the children’s oncology group. J Clin Oncol 2012;30:2094e101. [14] Giovannetti E, Ugrasena DG, Supriyadi E, Vroling L, Azzarello A, de Lange D, et al. Methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase promoter (TSER) polymorphisms in Indonesian children with and without leukemia. Leuk Res 2008;32:19e24.
Contents lists available at ScienceDirect
Pediatric Hematology Oncology Journal journal homepage: https://www.elsevier.com/journals/pediatrichematology-oncology-journal/
Developing leukemia protocols in cooperation between the Netherlands and Indonesia Anjo J.P. Veerman a, *, Eddy Supriyadi b, Sutaryo Sutaryo b a
VU University, Amsterdam, the Netherlands Division of Pediatric Hematology and Oncology, Dr. Sardjito Hospital - Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 January 2020 Received in revised form 6 March 2020 Accepted 10 March 2020 Available online 30 March 2020
Since 1990 two departments of Pediatric Oncology in Indonesia and the Netherlands have worked together to improve staff capacities in the Estella Clinic in Yogyakarta and Indonesian clinics general, through workshops for pediatricians, nurses, technicians, psycho-social workers. Teleconferences were conducted weekly. Protocols for leukemia were developed. Joint research projects led to research experience for about 50 Dutch medical students, about 60 international publications and 8 PhD theses. The patients with acute Lymphoblastic Leukemia benefitted and showed increasing survival rates. Possible improvements in the future are also discussed. © 2020 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Publishing Services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Keywords: Pediatric oncology International cooperation Leukemia
1. Introduction Leukemia used to be an invariably fatal disease until the late 1960s. In the years before, studies in mice had shown that some wartime toxic substances and some anti-metabolites could suppress leukemia. In the USA, the CALGB group started using these drugs, as well as corticosteroids in children with leukemia. The first real successes were obtained when dr Pinkel in the St Jude Children’s Research Hospital supposed that only combinations of drugs would be effective, similar to the experience in tuberculosis. In a series of studies, labeled Total Therapy, successes were obtained, but most often the children relapsed after some time. However, Total Therapy V (1967e1968) showed long term remissions in 22 out of 41 patients [1]. In the 1970’s dr Riehm devised a protocol using more drugs, and a reinduction schedule. This led to a general principle of treatment of Acute Lymphoblastic Leukemia (ALL) with induction, consolidation, reinduction, and maintenance. The BerlinFrankfurt-Munster (BFM) cooperative group of initially 9 German hospitals treated between 1976 and 1979 158 children and adolescents with ALL and achieved 70% disease-free survival [2]. This result was unheard of, and was initially unbelieved by many
* Corresponding author. E-mail address: [email protected] (A.J.P. Veerman). Peer review under responsibility of Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics.
colleagues. Nowadays survival of children with ALL has increased to over 90% in high-income countries, where pharmacokinetic surveyance and Minimal Residual Disease (MRD) determinations are possible, and where most children come early and in good nutritional status [3]. Of course, in low and middle-income countries, the situation is quite different. 2. Cooperation between a Dutch and an Indonesian pediatric oncology clinic In 1972 the Dutch Childhood Leukemia Study Group, later Dutch Childhood Oncology Group (DCOG), was founded and started a protocol based upon the Pinkel schedule. The protocol was amended every few years, using randomized controlled trials to try to improve results. In 1984 the 6th version of the Dutch protocol introduced dexamethasone as corticosteroid, based upon a little known (at the time) randomized trial of the CALGB group that found dexamethasone more effective than prednisone. At the same time, High Dose Methotrexate was introduced as consolidation and central nervous system relapse prevention, cranial irradiation was totally abolished. This protocol was rather more simple than the BFM protocols but proved surprisingly effective [4]. In the late 80’s, contacts between pediatric oncologists from Indonesia and the Netherlands were stimulated by a father of a Dutch patient. He was urging us to do something for children with ALL in Indonesia. At that time, most children in Indonesia were still treated with the
https://doi.org/10.1016/j.phoj.2020.03.007 2468-1245/© 2020 Pediatric Hematology Oncology Chapter of Indian Academy of Pediatrics. Publishing Services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
8
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1972 Dutch protocol, and only a few of them survived. So cooperation between VU University Amsterdam and Gadjah Mada University Yogyakarta started. In cooperation with dr Sutaryo, with whom we were already cooperating with on the subject of Dengue fever, a project was developed, involving a new ALL protocol, based upon DCOG ALL-VI study, and educating staff, not only doctors, but also nurses and technicians [5]. Since there was no health insurance for all at that time, the Dutch charity Estella Fonds provided part of the essential medicines, as well as some financial support for other needs. Later on, research projects and randomized protocols were introduced. In 1998 the Dutch Cancer Association (Koningin Wilhelmina Fonds, KWF) supported us with a number of grants for education and research. So the workshops we already conducted were intensified and were open to all health care personnel interested in pediatric oncology. They came mainly from 14 State University Hospitals all over Indonesia. 3. Protocol development In 1990 we used the dexamethasone based successful Dutch ALL-VI protocol together with elements from the BFM protocols for high risk (HR) ALL patients as basis for the first Indonesian protocol: COM-ALL 92. The problems were many: abscondence was high, 4025%, and toxic deaths almost as frequent. Apparently, a less intensive protocol was needed. The economic crisis in 1997 made imported drugs in Indonesia 5 times as expensive almost overnight; that was also an important reason that a more economical protocol was necessary. A basic protocol was devised at a workshop in 1998, with KWF funding, where all 14 involved pediatric oncology units in Indonesia were present. The protocol was named Wiyaja Kusuma protocol, after the flower that is reputed to cure all ailments. The result, after five years, was less than optimal; still, abscondence and toxic death were big problems, as was interruption of treatment. A significant problem was the fact that children on chemotherapy were treated on general pediatric wards, amidst others with infectious diseases. In the meantime, health insurance had improved, from almost none to covering most drugs needed for treatment. Since support for medication was no longer needed, the Estella Fonds shifted focus and started to raise funds for dedicated wards for children with cancer and hematological diseases. The first Estella Clinic was opened in Manado in 2001 with 18 beds in a separate building next to the pediatric clinic. Also, a guesthouse close by was funded, for the many patients who came from far away. A little bit later, the second Estella Clinic with 41 beds in Yogyakarta was opened, of which the dr Sardjito Hospital funded half, and the Estella Fonds the other half. In 2006 and 2013, revised versions of the ALL protocol were designed without much input from the Dutch experts. In the ALL 2013 protocol, for Standard Risk (SR) ALL prednisone was used instead of dexamethasone, and anthracyclines were reduced to just 2 doses. The HR patients, who were more than half as opposed to about a quarter in the Netherlands, were treated on dexamethasone induction, with a 4 drug induction schedule, including 4 doses of doxorubicin in weeks 2,3,4 and 5. Both got a consolidation schedule, consisting of 6Mercaptopurine, with three courses of Methotrexate (MTX) 1,000mg/m2, with leucovorin rescue. Unfortunately, Methotrexate serum levels could not be measured, so higher dose MTX did not seem feasible. The abscondence rate was reduced in this period, but fatal toxicities still occurred too often. Therefore, in 2016 a few simple alterations to the ALL 2013 protocol were introduced to reduce toxicities, especially in the induction phase. This is the ALL 2016 Pilot protocol. Prednisone induction was now prescribed for all patients, both SR and HR. For HR patients, a reinduction schedule with dexamethasone was included. Anthracyclines were omitted in SR, and only two doses of doxorubicin were used in HR patients and
scheduled in the first two weeks (Fig. 1). The rationale being that there is international consensus that 3 drug induction is adequate for SR patients, and the anthracyclines are best used early in induction, because then the leukemic cell burden has to be reduced quickly, so that later in the (6 weeks) induction, bone marrow can recover. Using anthracyclines later in induction results in many patients with aplastic bone marrow post induction. Apart from that, rebound cells (‘hematogones’) often occur, which lead to quite a few erroneous diagnoses of No Remission after induction. The ALL 2016 Pilot protocol is still too early for final evaluation, but the 2year results are much improved over the 2013 protocol. We anticipate that probably about 60e70% of children with ALL may be cured. Already it is clear that the number of toxic deaths early in the treatment is reduced, and concomitantly, also less patients drop out. From our earlier research, it appeared that drop out is related to toxic deaths: parents who see other children succumb to toxicity sometimes conclude that the treatment is too dangerous, and thus they abscond. Over time, the number of referrals of children with ALL, and the number included in the protocols has increased (Table 1), with many patients now coming from regions adjacent to the province of Yogyakarta. 4. Education From early on, education and training of the pediatric oncology teams in Indonesia was closely linked to research projects. The education came in two forms: annual seminars and workshops of one week duration and teleconferences every week. The workshops were held in rotating cities, Yogyakarta, Manado, Semarang, Surabaya, Jakarta, Medan. The docents, pediatric oncologists, nurses, pathologists and technicians who were twinned, matching those from Holland with those from Indonesia. After a symposium day, for health care personnel generally and some interested lay people, the workshop courses were divided into separate flows, for training of pediatricians, for nurses together with psychologists, and pathologists plus technicians. They were coming together in general sessions on the last day of the workshop. For the nurses is was essential to have lectures and discussion translated from English to Indonesian. The division in three flows ensured that the number of participants per group was about 12e24 people, making it as interactive as possible. It was instructive and fun to have a multiplechoice test pre-course, and the same test post-course. For instance, the question: ‘‘Your patient with ALL in induction develops a fever at midnight, can that wait until 7 a.m. before calling the doctor?’’ yielded 95% of ’yes’ answers at pretest and fortunately a much lower percentage at posttest. A number of issues became evident through these and other answers and observations. First, a sense of urgency is not innate, and not especially pronounced in the Indonesian-Javanese culture. Second: hierarchy is different and stronger in Indonesia, as compared to the Netherlands. At night a nurse would be very reluctant (to say the least) to wake up a doctorresident on call. Moreover, a resident will have to surmount a high barrier before asking his superior to advise him if a problem occurs at an inconvenient time. This cultural setting may be a background for several treatment delays that might have been prevented by adequate early reaction. The exchange of staff, doctors and nurses, was also elucidating. Some habits were only seen when staff members from the Netherlands were on site in Indonesia for a longer period. Pediatric oncologists from VU visited the Estella clinic for 1e2 weeks. Nurses staid for up to 3 months. All of them in their own time. One observation was for instance, that economic use of medication sometimes was pushed too far. It is not a good idea to keep an open vial of 50 mg Methotrexate for a week at room temperature, so that 4 doses of 12 mg can be extracted. Even if you top the vial with a sterile cap.
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Fig. 1. Example of flow chart for ALL High Risk patients.
Table 1 List of protocols cooperation Indonesia-UGM with the Netherlands-VU. Era and Name of protocol
Number patients in trial
1992e2000 2000e2006 2006e2013 2013e2016 2016e2019
±70 171 412 160 234
COM-ALL Wijaya Kusuma 2000 Indonesian ALL 2006 Indonesian ALL 2013 Yogya pilot ALL 2016
5. Research The beginning of all research efforts to evaluate ALL therapy is: registration and follow up of patients, and a sound database. Fortunately, in Yogyakarta in 1992, a dedicated and very efficient data manager was in place, and three technicians were hired for a pediatric hematology lab which evaluated all blood smears and bone marrow samples. Unfortunately, all four of them were later made redundant and replaced by a central laboratory, and by the hospital administration. All far from the pediatric oncology ward, less experienced, less interested it seems. Based on the excellent data recording, it was possible to conduct research projects. Young pediatric oncologists in Yogyakarta were embarking on PhD studies. They were supported by Dutch medical students, who dedicated their three months research electives (plus three months of their own time) to gather data on certain aspects of the patients with ALL. For instance conducting questionnaires among parents, and health care workers. Some of them later did a PhD themselves. All of the Indonesian PhD students did the final writing of their theses in the Netherlands. That provided protected time, and close by contact with the Dutch supervisor. The subjects of study were, among others, epidemiology [6], adherence to therapy [7], and randomized trials: dexamethasone versus prednisone [8], quinolone prophylaxis during induction [9], and psycho-social
evaluations and interventions [10]. Among the last was a small randomized trial of providing a diary to the parents to keep track of laboratory tests and medication. Interestingly, the children with ALL of well-educated parents benefitted from having a diary: their survival rose from 40% to 62% (p < 0.05). Their adherence to protocol apparently improved. However, children from lower educated, poorer backgrounds did not benefit. Their survival remained at 29% [11]. These data point to the importance of socioeconomic factors in the results of treatment: the protocol is only part of the equation. From the joined research, 8 PhD theses resulted, 6 at VU and 2 at UGM, and about 60 international publications.
6. Conclusions Through the initiative of one parent in the Netherlands, father of Estella, who unfortunately succumbed to ALL after 2 relapses, a cooperation project developed, from one doctor on both sides to a Memorandum of Understanding (MOU) between two departments. Later more cooperative projects developed also between other departments, and an MOU between the Medical faculties and Academic Hospitals of the VU University and UGM was signed. In 2014 both Universities signed an MOU which covered all faculties. How did the children with ALL fare? From a survival of probably less than 5% before 1992, it rose but slowly, to an estimated survival of 60e70% in the most recent ALL 2016 Pilot protocol. What did we do good? Education, research, and stepwise development of the ALL protocol. The annual workshops were essential for staff building, but also improved cooperation between the 14 pediatric clinics in Indonesia, leading to joint ALL protocols. Since 2008 similar workshops were held in Singapore for Southeast Asia through the efforts of the VIVA Foundation: also an enterprise which was instituted through a parent of a child with ALL! What could we have done better? Not introducing dexamethasone as induction
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steroid, which had proved an excellent choice for the Netherlands and the UK, but less so in Indonesia. Although much more effective against ALL, and penetrating the blood-brain barrier better than prednisone, in the UK dexamethasone also resulted in about twice as many fatalities (4.5% vs 2.8%) in a randomized study of UKALL [12]. Although the difference was not statistically significant, even with two arms of 800þ patients, we concluded that if the same were true for Indonesia, the number of fatalities might almost have been doubled from 10 to 20%. However, the randomized trial conducted in Yogyakarta did not find much difference between dexamethasone or prednisone in induction [8]. Nevertheless, we went back to prednisone for induction, using dexamethasone in reinduction (HR patients only) and in maintenance for both SR and HR patients. What more could we have done better? We failed to hold on to adequate data management and laboratory tests in the Estella Clinic. We could (and should) have insisted more on retaining essential facilities on site. Another problem: the number of doctors and nurses relative to the number of new patients has not kept pace with the increased number of admissions. The Estella Clinic in Yogyakarta has almost the same number of new ALL patients in a year as we see in the whole of Holland, but far less than 20% of staff members. The actual daily patient care rests mainly upon residents, who rotate every month. So the continuity of care and the expertise lies in the hands of the nursing staff, of whom about half are permanent pediatric oncology nurses, the other half is rotating too. The last few years, fellows in training for pediatric hematologyoncology are also important for the continuity of care. They stay in place for 2 years. The 4 pediatric oncologists are top-docents and as such are requested for a host of other education and management chores, from student classes to being head of department, secretary of the faculty, member of the University Board, etcetera. Apart from that, most of them have private practices, because the academic salaries are very low indeed. Probably the main factor limiting the survival of children with ALL in Indonesia is poverty and lack of education. As stated above, from the less poor and better-educated families, 62% of patients could survive on a very basic protocol, while from poor and lower educated families, only 29% survived [11]. Education and close surveillance may help to combat abscondence, non-compliance, and may reduce toxic deaths that remained a problem over the whole period from 1992 until recently, especially in poorer families. Infections are more of a problem in poor families with crowding and inadequate housing and low hygienic circumstances. Interruptions of treatment for non-medical reasons are still frequent. Sometimes because parents not believing full treatment is necessary. But quite often some drugs were temporarily unavailable, LAsparaginase, MTX, 6 MP, causing insufficient induction therapies in some, and frequent interruptions of maintenance therapy in many patients. Interruption of treatment has been shown to be an important factor for relapses [13]. Especially CNS relapses are too frequent still in Yogyakarta. Lower results may also be related to the mix of patients: about half of the patients are HR, as opposed to only about a quarter in the Netherlands. There are also indications that the genetic make-up of ALL in Asia is different from that in the Netherlands, with more higher risk genotypes [14]. So patients come with higher risk factors, often late, after they have tried alternative treatments without success. These circumstances influence cure rates negatively. Notwithstanding all these drawbacks, a lot has been achieved. About 50 Dutch medical students had an excellent research experience, 8 PhD theses by Indonesian pediatricians have successfully been defended, and most importantly, the survival of ALL patients has increased dramatically. The advocacy of support groups and parents associations were of immense importance. Their help should be asked to influence the authorities to provide for health
insurance and to help with continuous availability of essential drugs. Of course, improvement in many aspects is still needed. Laboratory techniques such as MTX serum levels and MRD evaluation have to be introduced. Immunophenotyping has to be refined. More genetic tests are needed to weed out the patients with special needs, to come to personalized treatment protocols. Furthermore, we need to keep up the efforts to train new health care personnel. We are glad that the Prinses Maxima Clinic, the new centralized hospital for children with cancer in the Netherlands, now has taken over the cooperation between pediatric oncologists in the Netherlands and in Indonesia, to continue and enlarge the cooperation to the benefit of children with all types of childhood cancer. Acknowledgments Our gratitude is for all patients and parents who participated in the studies described in this article. The Estella Foundation, the Koningin Wilhelmina Fonds, Yayasan Kanker Anak, and other local charities in Indonesia were invaluable in their support. All staff members from both the VU and the UGM that participated were essential for the education, research, and patient care over the years, we thank them all. Finally, the support from the departments of Pediatrics, the Medical faculties, and the VU and UGM was much appreciated. References [1] Pinkel D, Simone JH, Hustu O, Aur RJA. Nine years’ experience with “total therapy” of childhood acute lymphocytic leukemia. Pediatrics 1972;50:246. €mswig H, Breu H, Gadner G, Schellong K, et al. [2] Henze G, Langermann J, Bra Ergebnisse der Studie BFM 76/79 zur Behandlung der akuten lymphoblastischen Leuk€ amie bei Kindern und Jugendlichen. The BFM 76/79 Acute Lymphoblastic Leukemia Therapy Study. Klin P€ adiatr 1981;193(3):145e54. [3] Pui C-H, Evans WE. A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol 2013 July;50(3):185e96. [4] Veerman AJP, H€ ahlen K, Kamps WA, Van Leeuwen EF, De Vaan GAM, Van Wering ER, et al. Dutch childhood leukemia study group: early results of study ALL VI (1984-1988). Haematol Blood Transfus 1990;33:473e7. [5] Veerman AJ, Sutaryo, Sumadiono. Twinning: a rewarding scenario for development of oncology services in transitional countries. Pediatr Blood Canc 2005;45:103e6. [6] Supriyadi E, Widjajanto PH, Purwanto I, Cloos J, Veerman AJ, Sutaryo S. Incidence of childhood leukemia in Yogyakarta, Indonesia, 1998-2009. Pediatr Blood Canc 2011;57:588e93. [7] Mostert S, Sitaresmi MN, Gundy CM, Sutaryo, Veerman AJP. Influence of socioeconomic status on childhood acute lymphoblastic leukemia treatment in Indonesia. Pediatrics 2006;118:1600e6. [8] Widjajanto Pudjo H, Supriyadi Eddy, Purwanto Ignatius, Cloos Jacqueline, vdVen Peter M, Veerman Sutaryo Anjo JP, et al. Dexamethasone versus prednisone in childhood acute lymphoblastic leukemia treatment: results of the Indonesian randomized trial. J Canc Ther 2017;8:735e50. [9] Widjajanto PH, Sumadiono S, Cloos J, Purwanto I, Sutaryo S, Veerman AJ. Randomized double blind trial of ciprofloxacin prophylaxis during induction treatment in childhood acute lymphoblastic leukemia in the WK-ALL protocol in Indonesia. J Blood Med 2013;4:1e9. [10] Mostert S, Sitaresmi MN, Gundy CM, Janes V, Sutaryo, Veerman AJP. Comparing childhood leukaemia treatment before and after the introduction of a parental education programme in Indonesia. Arch Dis Child 2010;95: 20e5. [11] Sitaresmi MN, Mostert S, Gundy CM, Ismail D, Veerman AJ. A medication diary-book for pediatric patients with acute lymphoblastic leukemia in Indonesia. Pediatr Blood Canc 2013;60:1593e7. [12] Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A. Eden TO; medical research council childhood leukaemia working party. Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK medical research council ALL97 randomized trial. Br J Haematol 2005;129:734e45. [13] Bhatia S, Landier W, Shangguan M, Hageman L, Schaible AN, et al. Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and nonHispanic white children with acute lymphoblastic leukemia: a report from the children’s oncology group. J Clin Oncol 2012;30:2094e101. [14] Giovannetti E, Ugrasena DG, Supriyadi E, Vroling L, Azzarello A, de Lange D, et al. Methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase promoter (TSER) polymorphisms in Indonesian children with and without leukemia. Leuk Res 2008;32:19e24.