ATC codes:
L01XA03
EMLc
Indication
Malignant neoplasm metastasis in large intestine
ICD11 code:
2E25
INN
Oxaliplatin
Medicine type
Chemical agent
List type
Complementary
(EML)
(EMLc)
(EMLc)
Formulations
Parenteral > General injections > IV:
50 mg in vial powder for injection ;
100 mg in vial powder for injection ;
50 mg per 10 mL in 10 mL vial ;
100 mg per 20 mL in 20 mL vial ;
200 mg per 40 mL in 40 mL vial
Sex
All
Age
Also recommended for children
Therapeutic alternatives
The recommendation is for this specific medicine
Patent information
Patents have expired in most jurisdictions
Read more
about patents.
Expert Committee recommendation
The Expert Committee recommended the addition to the complementary list
of the EMLc of ATRA, dasatinib, fluorouracil, imatinib, irinotecan, nilotinib,
oxaliplatin, procarbazine and rituximab for the paediatric cancer indications
outlined in the table below.
The Committee also recommended the extension of the current listings
on the EMLc of bleomycin, doxorubicin, vincristine, cisplatin, cyclophosphamide,
prednisolone, cytarabine, daunorubicin, mercaptopurine, methotrexate, cytarabine
and hydroxycarbamide to include the indications outlined in the table below.
The Committee also recommended the addition to the core list of the
EMLc of enoxaparin with a square box for use as an anticoagulant in children.
The Expert Committee did not recommend the addition of zoledronic acid
to the complementary list of the EMLc for the treatment of malignancy-related
bone disease. The Committee noted that data for its use in children are scant and
fragmented. The Committee was also concerned that the effects of zoledronic acid
in some paediatric cancers (e.g. osteosarcoma) were largely negative, and that
there are insufficient long-term safety data of bisphosphonate use in paediatric
cancer patients to be reassured of an acceptable benefit–to–harm ratio.
Furthermore, the Committee noted that although use of bisphosphonates
in paediatric patients has been reported to be well tolerated, the impact of use in
the context of patients with actively growing skeleton is not yet fully known.
New medicines for EMLc
All-trans retinoic acid: Acute promyelocytic leukaemia
Dasatinib: Imatinib-resistant chronic myeloid leukaemia
Fluorouracil: Nasopharyngeal carcinoma, early-stage colon cancer, early-stage rectal cancer, metastatic colorectal cancer
Imatinib: Chronic myeloid leukaemia, gastrointestinal stromal tumour
Irinotecan: Metastatic colorectal cancer
Nilotinib: Imatinib-resistant chronic myeloid leukaemia
Oxaliplatin: Early stage colon cancer, metastatic colorectal cancer
Procarbazine: Hodgkin lymphoma
Rituximab: Diffuse large B-cell lymphoma
Enoxaparin: Anticoagulant (core list)
Extension of indications for currently listed medicines
BleomycinL: Kaposi sarcoma
Doxorubicin: Kaposi sarcoma
Vincristine: Kaposi sarcoma
Cisplatin: Nasopharyngeal carcinoma
Cyclophosphamide: Diffuse large B-cell lymphoma
Prednisolone: Diffuse large B-cell lymphoma
Cytarabine: Acute promyelocytic leukaemia, acute myelogenous leukaemia
Daunorubicin: Acute promyelocytic leukaemia
Mercaptopurine: Acute promyelocytic leukaemia
Methotrexate: Acute promyelocytic leukaemia
Hydroxycarbamide: Chronic myeloid leukaemia
Background
The application proposed an extension of adult cancer indications to paediatrics
and corresponding inclusion on the EMLc. The proposal involves both the
inclusion of new indications for some cancer medicines currently on the EMLc
and the addition of selected new cancer and supportive care medicines to the
EMLc. (Refer to TRS 1021 for the proposed listing extensions).
The proposed medicines and corresponding indications had not previously been
considered for inclusion on the EMLc.
The application applied the following rationale in proposing the medicines
and indications for inclusion on the EMLc:
■ The medicine must already be listed on the EML or EMLc.
■ The indications listed for adults are also diagnosed in children aged
12 years and under.
■ The medicines have been reported for treatment in children aged
12 years and under for the same indication as listed on the EML for
treatment in adults.
■ Published literature supports the extension of the indication to
children, including clinical studies, peer-reviewed consensus
documents and/or clinical guidelines support the medicine’s role as
standard of care.
Public health relevance
Cancer is a leading cause of death for children globally with the most common
cancer types occurring in children being leukaemias, lymphomas and central
nervous system tumours (1). Childhood cancers generally cannot be prevented
nor screened for, so improving outcomes for children with cancer relies on early
and accurate diagnosis and access to effective treatments.
In 2018, WHO launched the Global Initiative for Childhood Cancer,
to provide leadership and technical assistance to Member States to build and
sustain high quality childhood cancer programmes. The goal of this initiative is
to achieve at least 60% survival for all children with cancer globally by 2030 (2).
Benefits
Acute promyelocytic leukaemia (APML)
New medicine: all-trans retinoic acid (ATRA)
New indication: cytarabine, daunorubicin, mercaptopurine, methotrexate
The median age of children with APML has been reported as 10 years (3).
Standard regimens used for children with APML include ATRA (3, 4), with
prior randomized trial data demonstrating significant disease-free survival
improvement for children randomized to receive ATRA vs not (48% at 5 years,
vs 0%, p<0.0001), with overall survival rates sustained at 10 years (5). The use
of ATRA is acknowledged in standard guidelines for the treatment of APML,
and is considered to be a paradigm for a targeted approach to the treatment of
leukaemia (6–10). The treatment of APML is typically provided in the context
of poly-chemotherapy, involving cytarabine, daunorubicin, mercaptopurine and
methotrexate (3–5).
Acute myeloid leukaemia (AML)
New indication: cytarabine
The safety and effectiveness of cytarabine for the treatment of childhood AML
have been evaluated in controlled clinical trials (11–13). It is considered the
standard of care, used internationally for children with AML, as in adults (14, 15).
Chronic myeloid leukaemia (CML)
New medicines: imatinib, dasatinib, nilotinib, hydroxycarbamide
CML is a very rare disease in children, estimated to be responsible for 2% of all
leukaemias in children less than 15 years of age with an annual incidence of one
case per million children in that age range (16). The tyrosine kinase inhibitors
introduced a chance of cure for CML, with long lasting disease control and
significantly improved outcomes (17).
Imatinib has shown clinical benefit in children with CML, with results
comparable to those seen in adults (18). In particular, a clinical study of the
use of imatinib in patients aged less than 18 years with CML in the chronic
phase demonstrated the efficacy, safety and long-term benefit of imatinib in
children (19).
Dasatinib and nilotinib have been used in children with CML including
(but not limited to) imatinib-resistant cases. A Phase II trial of dasatinib in 113
paediatric patients with CML demonstrated a complete cytogenetic response was
achieved in 76% of imatinib-resistant patients, with an acceptable safety profile
that did not include pleural or pericardial effusion, commonly seen in dasatinibtreated adults (20). The effectiveness and safety of nilotinib in children with CML
has also been reported (21). Nilotinib has been approved by the United States
FDA for treatment of paediatric patients with newly diagnosed or resistant CML
on the basis of the results from two open-label, single-arm trials involving 69
patients (22, 23). For imatinib-resistant patients, the major molecular response
rate was 40.9%. No new safety concerns were reported, noting transient and
manageable laboratory abnormalities: hyperbilirubinaemia and moderate to
severe transaminitis.
Hydroxycarbamide has a recognized debulking/cytoreductive role for
myeloid malignancies and for palliative purpose in all settings. In addition,
hydroxycarbamide can have an important role in settings where resource
limitations affect access to imatinib or other tyrosine kinase inhibitors, to allow
commencement of antineoplastic therapy (24). A general expert consensus
recommendation for childhood CML includes hydroxycarbamide as standard
initial therapy in all settings, while awaiting confirmatory diagnostic testing
results as well as initial clinical response (25).
Gastrointestinal stromal tumour (GIST)
New medicine: imatinib
Imatinib is the preferred treatment for molecularly-selected GIST in adults and
children, where c-KIT sensitive mutations are demonstrated. Paediatric GISTs
represent a distinct entity, and may be associated with genetic syndromes (such
as Carney Triad, Carney-Stratakis syndrome or neurofibromatosis 1 (NF1)/
Von Recklinghausen disease). It is also less common for paediatric patients
with GIST to have the activating mutations in KIT and platelet-derived growth
factor receptor alpha (PDGFRA) seen in adults. Data on the effectiveness and
activity of imatinib in paediatric GIST is scarce, as it is a very rare entity (1–2%
of all the cases). Children less than 18 years of age typically have more indolent
disease with more favourable prognosis than in adults (approximating 100%
five-year overall survival), as reported in a long-term retrospective analysis of
a large observational study, that included a sub-group of 28 patients in this age
group (26).
Diffuse large B-cell lymphoma (DLBCL)
New medicine: rituximab
New indication: cyclophosphamide, doxorubicin, prednisolone, vincristine
Different studies of DLBCL have established a role for rituximab in paediatric
populations, with studies often spanning all age groups including adults and
children starting at age 9 years (27), and confirming efficacy and safety in children
(28). Rituximab is administrated in the context of a combination regimen with
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) (27, 28).
CHOP alone may be administered in settings where rituximab is not available.
Kaposi sarcoma
New indication: bleomycin, doxorubicin, vincristine
Kaposi sarcoma in children primarily occurs as either endemic (HIV-unrelated)
or epidemic (HIV-related) disease. According to the data known from registries
and literature, Kaposi’s sarcoma primarily occurs in the elderly population of the
Mediterranean region, while the occurrence in children is restricted to smaller
series (29). Data from paediatric cohorts and clinical trials showed a median age
of diagnosis at 8 years old. Chemotherapy indicated for Kaposi sarcoma includes
bleomycin, vincristine and doxorubicin (30–34). One of the regimens combining
doxorubicin, bleomycin and vincristine (ABV) has reported 80% remission for
stage I HIV-positive patients treated in South Africa (32). Bleomycin, vincristine
and doxorubicin have also been included as standard treatment agents in
international expert consensus recommendations (35).
Nasopharyngeal cancer
New indication: cisplatin, fluorouracil
Nasopharyngeal carcinoma (NPC) is the most commonly diagnosed head
and neck malignant neoplasm in China and South-East Asian countries, but
is considered relatively rare among children. Treatment schemes are typically
adapted for children from adult-based regimens. Cisplatin-based regimens are
the standard of care for children with NPC. Together with cisplatin, fluorouracil
(5-FU) is included in standard regimens for children with NPC, with standard
administration of two courses 21 days apart (36–39). The use of cisplatin
including as a radiosensitizer (with concomitant cisplatin and radiation therapy)
following cisplatin/5-FU in the systemic treatment of NPC in children is
recognized as standard across different institutions and countries, extrapolating
from the adult treatment experience (40–43).
Colon and rectal cancers
New medicine: irinotecan, oxaliplatin
New indication: cisplatin, fluorouracil
While very rare, colorectal cancers can occur in children (reported in as young
as nine months old) and typically utilize the same chemotherapy agents as in
adults, including 5-FU for the neoadjuvant treatment of rectal cancer, 5-FU and
oxaliplatin for the adjuvant treatment of colon and rectal tumours, and 5-FU,
oxaliplatin and irinotecan for advanced or metastatic colorectal cancer (44–47).
Hodgkin lymphoma
New medicine: procarbazine
Procarbazine is commonly included as a drug of choice in children for the
treatment of Hodgkin lymphoma. According to clinical guidelines and literature,
procarbazine is a standard inclusion in multi-agent chemotherapy regimens
for Hodgkin lymphoma in children (48, 49). For the paediatric population,
multiple regimens containing procarbazine are used, in particular BEACOPP
that contains bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine,
procarbazine, and prednisone. It is often used in more resource-limited settings.
Local selection and use should consider known gonadotoxicity and effects on
male fertility (50).
Malignancy-related bone disease
New medicine: zoledronic acid
Although certain malignancy-related bone diseases, such as osteonecrosis, occur
more often in older children, patients as young as age 4 to 6 years have been
affected and required treatment (51–53). The administration of zoledronic acid
in paediatric oncology appears safe, and may result in improved bone strength
and pain control. In a retrospective chart review of inpatients and outpatients
less than 21 years old who received zoledronic acid at the Children's Hospital of
Philadelphia, safety of the bisphosphonate was assessed. The safety profile was
consistent with the known experience in adults, including preventable alterations
in calcium levels, with no major side-effects reported (51).
Anti-coagulation
New medicines: enoxaparin
The use of low molecular weight heparin (LMWH) as an anticoagulant is
considered standard of care for prophylaxis and treatment in children, including
but not limited to children with cancer. Malignancy as well as treatment-related
factors such as immobilization and central venous access can increase risk for
thrombosis (54). Enoxaparin as standard antithrombotic therapy is used as a first
option in routine practice in many settings (55–57).
Harms
Not reported separately in the application.
Additional evidence
A randomized, multicentre, open-label Phase III trial (OS2006) compared
standard chemotherapy with or without zoledronic acid in 318 patients aged
between 5 years and 50 years (median 15.5 years) with newly diagnosed highgrade osteosarcoma (58). The trial results indicated that zoledronic acid did not
improve event-free survival, percentage of good histological response or overall
survival. No significant differences in toxicity or orthopaedic complications
were observed between treatment groups. The trial was stopped after the second
interim analysis for futility and the authors concluded that the use of zoledronic
acid in osteosarcoma patients was not recommended.
A retrospective analysis of the use of zoledronic acid for treatment
of chemotherapy related osteonecrosis in 20 children and adolescents with
osteonecrosis found that zoledronic acid was well tolerated and improved joint
pain in the majority of patients (53). However, among patients with osteonecrosis
of the hip, the majority had progressive joint destruction requiring arthroplasty,
despite treatment with zoledronic acid.
Cost / cost effectiveness
Not reported in the application.
Availability
The proposed medicines are already included on the EML and/or EMLc.
Other considerations
The Expert Committee recognized the public health need for access to cancer
therapies for children. The Committee acknowledged that there is limited clinical
trial evidence available for the use of many cancer medicines in children, and
that it is often necessary to rely on extrapolated data from trials in adults, clinical
consensus and/or clinical practice guidelines, that lend support to a medicine’s
role as the standard of care in paediatric patients.
Comments on the application were received from the WHO Department of
Management of NCDs, Disability, Violence & Injury Prevention. The technical
unit advised that it supports the proposal to extend the listing of specified cancer
medicines and indications on the EML to the EMLc.
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