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Appendix 2:
Osteonecrosis in Cancer Patients
Zometa® (zoledronic
acid) Injection
and
Aredia® (pamidronate disodium) Injection
Submitted:
Oncologic Drugs Advisory Committee Meeting
Property of Novartis Pharmaceuticals
Corporation
All rights reserved
Available for public disclosure without
redaction
Table of contents
Table of
contents................................................................................................................... 1
List of tables.......................................................................................................................... 2
1.... Executive summary................................................................................................................ 3
2.... Background........................................................................................................................... 4
3.... Objectives............................................................................................................................. 4
4.... Methods................................................................................................................................ 4
4.1 Literature search........................................................................................................ 4
4.2 Population-based database study............................................................................... 4
4.2.1 Source population and study cohorts......................................................... 4
4.2.2 Case ascertainment................................................................................... 5
4.2.3 Person-time calculation.............................................................................. 5
4.2.4 Analysis.................................................................................................... 5
5.... Results.................................................................................................................................. 5
5.1 Literature-based evidence.......................................................................................... 5
5.1.1 Incidence of ON in cancer patients............................................................ 6
5.1.2 Risk factors for ON.................................................................................. 6
5.2 Population-based evidence........................................................................................ 7
5.2.1 Incidence of ON in cancer patients............................................................ 7
5.2.2 Risk of ON in systemic corticosteroids users.............................................. 8
6.... Discussion............................................................................................................................. 8
7.... Conclusions........................................................................................................................... 9
8.... Tables................................................................................................................................... 9
9.... References.......................................................................................................................... 11
Table 8-1.................... READ, OXMIS and ICD 8 codes used for case
identification.................... 9
Table 8-2.................... READ,
OXMIS and ICD 8 codes for mandibulectomy and maxillectomy. 10
Table 8-3.................... Incidence
of ON in GPRD in the United Kingdom................................... 10
Table 8-4.................... Incidence
of ON by age-group among a cohort of cancer patients in GPRD 11
Table 8-5.................... Incidence
of ON by age-group among general population of patients in GPRD 11
Table 8-6.................... Incidence
rate and relative risk of ON in systemic corticosteroids users compared to the
general population............................................................................................... 11
Incidence of osteonecrosis (ON) in cancer patients and main risk factors
for the disorder were evaluated based on literature review and an
epidemiological study performed in the
· Literature-based evidence:
· ON has been frequently described in cancer patients in association with cancer treatment: radiotherapy or chemotherapy with and without corticosteroids.
· Systemic corticosteroid therapy is the most common risk factor for non-traumatic ON. Other include alcohol abuse, sickle cell disease, Gaucher disease, dysbaric conditions, coagulopathies, hyperlipidemias, radiotherapy, anti-cancer chemotherapy, chronic liver disease, pancreatitis, HIV infection and pregnancy.
· Fungal, bacterial and viral infections, trauma and local anesthesia are common risk factors for ON of the jaws.
· Population-based evidence:
· Methods: A source population of 5,597,148 persons (8,998,314 person-years) 20 to 84 years of age with information recorded in GPRD during the period of 01-01-1994 to 31-12-2001 was identified as the general population cohort and used to derive three additional cohorts: cancer patients, systemic corticosteroids users and systemic corticosteroids non users. Incidence rates of ON were calculated for all these cohorts.
· Results: The estimated incidence of ON of all sites among the cancer cohort was 1.31 per 10,000 person-yrs (95% CI: 0.72-2.21). For comparison, in general population the incidence rate was estimated to be 0.31 per 10,000 person-yrs (95%CI: 0.27-0.35). The estimated incidence rate of ON among corticosteroids users was 0.99 per 10,000 person-yrs (95%CI: 0.74-1.31). When compared to the risk among non users, the relative risk for corticosteroid use was 3.96 (95%CI: 2.60-5.39).
· Conclusions:
· Systemic corticosteroid therapy is a strong risk factor for ON.
·
ON is a well documented complication of
anti-cancer therapy. In GPRD in the
·
The jaw bones, unique among skeletal structure
because of the presence of the teeth, are frequently subject of local
infections, which is considered to be an additional main risk factor for ON in
this location.
This epidemiological review has been prepared to support actions
in response to the MHRA request regarding osteonecrosis
(ON) in association with pamidronate.
Osteonecrosis (avascular
necrosis of bone, ischemic necrosis or osteochondritis
dissecans) is the death of bone that results in the
collapse of the architectural bony structure, leading to bone pain, destruction
and loss of function. It is considered to be not a specific disease entity but
the final common pathway of a number of conditions leading to an impairment of
the blood supply to the bone. The most commonly affected sites are the femoral
head, the humeral head and the knees (femoral condyles
and proximal tibia) (Assouline-Dayan 2002, Pavelka 2000).
The main objective of this report is to review and summarize data on the incidence of ON in cancer patients. In addition, the risk factors of ON, especially those most relevant to cancer patients, are analyzed.
An electronic literature search of English-language studies was
conducted through the MEDLINE database from 1970 to the present time to obtain
all published studies relating to the incidence of ON and specifically ON of
the jaws among cancer patients and the risk factors for this condition. Special
attention and focus was placed to the occurrence of this disorder among patients
with the breast and multiple myeloma malignancies.
Key words included “osteonecrosis” combined with: “cancer patients”, “jaws”, “maxilla“, “mandible”, “breast cancer”, “multiple myeloma” and “risk factors”.
Bibliographic references of retrieved articles were reviewed to
identify additional studies not captured by the initial search. Case series and
case reports publications were included when they were considered to provide
relevant information.
The General Practice Research Database (GPRD) in the
The study population was derived from all persons from 20 to 84
years of age registered in GPRD and identified during the period between
· cancer cohort; patients with a diagnosis of a cancer,
· patients on systemic corticosteroid therapy,
· general population with systemic corticosteroids users excluded
All members in the general population cohort and the three cohorts above were followed-up until the earliest of the following endpoints: 1) diagnosis of ON; 2) death; or 3) end of the study period.
The following codes were used for the diagnosis of cancer: ICD-8 codes 1400 through 1738 plus 1740 through 2090 plus 971 for isotope therapy and 972 for cancer chemotherapy.
Among the four cohorts members potential cases were identified through an automated search for READ, OXMIS and ICD-8 codes listed in Table 8-1. In addition to assure identification of all cases, codes for mandibulectomy and maxillectomy (Table 8-2) were used for the cancer cohort.
Computerized patient profiles of potential cases identified in the cancer cohort were manually reviewed. All patients identified using codes listed in Table 8-1 fulfilled the case criterion (diagnosis of ON). The search performed with codes for mandibulectomy and maxillectomy revealed 13 additional potential cases. However, none of them fulfilled the case criterion. Therefore, only codes listed in Table 8-1 were used for the automated search.
Person-years of follow-up were calculated as follows:
· for general population cohorts: from time of the beginning of the study period to the earliest endpoint;
· for cancer cohorts: from time of the diagnosis of cancer to the earliest endpoint; and
· for corticosteroids users cohort: from time of the first systemic corticosteroid prescription to the earliest endpoint.
Incidence rates of ON were calculated using person-time at risk as
denominator. Ninety-five percent confidence intervals were computed on the
basis of a Poisson distribution of case counts (Breslow and Day 1987).
The Stata program was used to obtain estimates of
rate ratios (STATA 1998).
From the initial search of “osteonecrosis in cancer patients”, two hundred and thirteen (213) published articles were identified by the described method. Neither the malignancy specific searches on osteonecrosis in breast cancer and multiple myeloma nor the search with the key words “osteonecrosis” combined with “jaws”, “maxilla” or “mandible” retrieved additional articles. When the key words “osteonecrosis” and “risk factors” were combined, three hundred and two (302) publications were identified, some of them overlapping with the results of the initial search.
Twenty individual publications providing data in relation to the incidence of ON in cancer patients and/or risk factors for the condition were selected for review. Most of the publications appeared in the form of case-report or case-series reports. Although they could not be used for incidence estimation, they were included as they provided key information on the occurrence of the condition and its association with potential predisposing factors.
There are few data in literature on the incidence of ON. A large
epidemiological study in 1989 reported 2,500-3,300 new cases of non-traumatic
ON per annum in
Data on incidence of ON in cancer patients are scarce. ON is estimated to occur in 1 -10% of patients with lymphomas and acute leukemias treated with corticosteroids (Kozuch et al 2000). Cook et al (2001) reported the prevalence of ON of 3.8 % with a 3 year actuarial risk of 6.3% in patients treated with chemotherapy for testicular tumors. However, a careful search of the literature did not reveal any data on incidence of ON in general cancer population. To provide this information population-based study in GPRD was performed (see below).
Non-traumatic ON occurs most commonly as a complication of corticosteroid
therapy. In
ON has been described as a complication of chemotherapy, especially where it includes intermittent high dose corticosteroids. Several reports have been published recently describing ON in patients treated with combination chemotherapy for testicular tumors who received corticosteroids as part of the anti-emetic regimen (Kozuch 2000, Virik 2001). A case of ON following chemotherapy with short term corticosteroids (total dose of dexamethasone 200mg) for small cell bronchogenic carcinoma has also been reported.
Chemotherapeutic drugs themselves have also been causally implicated in ON. Harper, Trask and Souhami (1984) described multisite ON in a patient who received vinblastine and bleomycin for a testicular embryonal carcinoma. Obrist, Hartmann and Obrecht (1978) reported ON of the humeral head after cyclophosphamide, methotrexate and 5-fluorouracil for breast carcinoma. Marymont and Kaufman (1986) described ON of the femoral condyles of both knees in a woman receiving adriamycin, methotrexate, and 5-fluorouracil for breast carcinoma.
The jaw bones, mandible and maxilla, are unique among skeletal
structures because of the presence of the teeth - frequent route of local
infections. Another specificity of this location is repeated use of local
anesthesia for routine dental restorative procedures. Vasoconstrictors
typically contained in anesthetics can severely decrease regional blood flow
increasing risk for ON (Bouquot and McMahon 2000). Therefore, main risk factors for
ON of the jaws differ slightly comparing to the rest of the skeleton and
include fungal, bacterial and viral infections (Pogrel and Miller 2003), trauma and local anesthesia. Sung et al (2002)
presented a case of ON of the maxilla in a 48-year old woman with acute myelogenous leukemia after chemotherapy (idarubicin, cytarabine) without
corticosteroid administration. In this immunocompromised
patient ulcerations associated with oral herpes simplex virus provided enough
breach of the mucosal integrity to allow for the normal microflora
of the oral cavity to invade the maxilla and cause infection leading to ON.
A total of
5,597,148 persons (8,998,314 person-years) 20 to 84 years of age
with information recorded in GPRD during the period of
Fourteen (14) patients with ON were identified among the cancer cohort . The incidence was estimated to be 1.31 per 10,000 person-yrs. For comparison, two hundred seventy eight (278) cases of ON were found in the general study population. The estimated incidence of ON was 0.31 per 10,000 person-yrs. (Table 8-3). The estimated incidence rates of ON among the cancer cohort and among the general population cohort by age group are displayed in Table 8-4 and Table 8-5, respectively.
The initial study population described above was used to form two
additional cohorts: a cohort of systemic steroids users (502,817 persons-yrs)
and a cohort of steroids non users, i.e. general population with systemic
corticosteroids users excluded (7,866,530 person-yrs). Fifty (50) and one
hundred ninety eight (198) cases of ON, respectively, were identified among
these cohorts. The estimated relative risk of ON in systemic corticosteroids
users compared to non users was 3.96 (Table 8-6).
ON has been frequently described in cancer patients. Although ON in cancer patients has been usually considered to be caused by cancer treatment, malignancy itself has been also associated with ON in general reviews (Assouline-Dayan 2002, Bouquot 2000). Bouquot and McMahon (2000) listed cancer-induced hypercoagulation as a factor capable of compromising marrow blood flow thus increasing risk of ON.
In the GPRD study presented here, the estimated incidence rates of ON were 1.13 per 10,000 person-years (95% CI: 0.72-2.21) and 0.31 per 10,000 person-years (95%CI: 0.27-0.35), for the cancer cohort and general population, respectively. However, because underdiagnosis and misdiagnosis of ON in the past (Bouquot and McMahon 2000) the actual rate may be much higher than reported in the database. The list of codes used to identify patients with ON (Table 8-1) consisted of some rather aspecific terms (e.g., debridement). The review of computerized patients profiles of potential cases in the cancer cohort revealed that all identified patients fulfilled the case criterion. However, profiles of patients identified among the general population were not manually reviewed. Therefore, it cannot be excluded that the number of cases in the general population was overestimated and so was the incidence rate of ON. In such instance, the difference between ON incidence rates in the cancer cohort and general population would be even more striking.
Cancer treatment: chemotherapy with and without corticosteroids, and radiotherapy is well described risk factor for ON. Several chemotherapeutic agents, e.g., adriamycin, bleomycin, methotrexate, cyclophosphamide, 5-fluorouracil and cytarabine have been reported to cause this severe side effect (Harper 1984, Obrist 1978, Marymont 1986, Sung 2002, Schwartz 1982). In the GPRD study presented here, the risk of ON induced by chemotherapy was not evaluated. Details on chemotherapy are not registered in this outpatients database, thus not allowing such analysis in short time without contacting general practitioners.
Fourteen cases of ON were found among cancer patients in GPRD. None of them was recorded to be treated with bisphosphonates. However, it is likely that information regarding IV bisphosphonates use was not collected in this outpatients database. Therefore, no conclusions may be drawn from this data.
According to published evidence, systemic corticosteroid therapy is the main risk factor for non-traumatic ON. In our study, the risk of ON in systemic corticosteroids users was almost 4 times higher than in general population. However, data on other risk factors for ON which could be present in the corticosteroids cohort, e.g., anti-cancer treatment or diagnosis of SLE, were not collected. Therefore, the results can be confounded.
·
Systemic corticosteroid therapy is a strong risk
factor for ON.
·
ON is a well documented complication of anti-cancer
therapy. In GPRD in the
·
The jaw bones, unique among skeletal structure
because of the presence of the teeth, are frequently subject of local
infections, which is considered to be an additional main risk factor for ON in
this location. Other specific risk factors for the jaw ON are trauma and local
anesthesia.
|
READ code |
Diagnosis |
|
J06y600 N334900 N334C00 NyuC400 NyuC500 NyuCC00 N301.13 7K1C200 N334000 N334.00 N334100 N334200 N334300 N334311 N334400 N334500 N334600 N334700 N334800 N334z00 7K12B00 7K12D00 7K35400 |
Osteoradionecrosis of jaw Osteonecrosis due to drugs Osteonecrosis due to haemoglobinopathy Other secondary osteonecrosis Other osteonecrosis Osteonecrosis in other diseases classified elsewhere Sequestrum of bone Sequestrectomy of bone Avascular necrosis of bone, site unspecified Avascular necrosis of bone Avascular necrosis of the head of humerus Avascular necrosis of the head of femur Avascular necrosis of the medial femoral condyle Femoral condylar avascular necrosis Avascular necrosis of the talus Avascular necrosis of capitellum Avascular necrosis of lateral femoral condyle Avascular necrosis of other bone Idiopathic aseptic necrosis of bone Avascular bone necrosis NOS Debridement of bone Arthroscopic debridement of patella Arthroscopic debridement of knee joint |
|
OXMIS code |
Diagnosis |
|
7201NB 7239AF 7329AH 9906ON K004E K7941A K7941AA |
Bone necrosis Femur head avascular necrosis Avascular necrosis hip Osteoradionecrosis Sequestrectomy skull Ankle sequestrectomy Sequestrectomy bone |
|
ICD 8 code |
Diagnosis |
|
7211 |
Aseptic necrosis of bone |
|
READ code |
Diagnosis |
|
7J11.12 7J11400 7J11500 7J16A00 7J16B00 7J10100 7J10.12 7J10200 7J10300 |
Mandibulectomy Total mandibulectomy Segmental mandibulectomy Sagittal split mandibular osteotomy Vertical sub-sigmoid mandibular osteotomy Total maxillectomy Maxillectomy Partial maxillectomy Extended maxillectomy |
|
OXMIS code |
Diagnosis |
|
K2582 K2582AB |
Mandibulectomy Mandibulectomy |
|
|
ON cases (No) |
Person-yrs |
Incidence Rate (x 10,000 person-yrs) (95% CI) |
|
Cancer cohort |
14 |
106,477 |
1.31 (0.72-2.21) |
|
General population |
278 |
8,998,314 |
0.31 (0.27-0.35) |
|
Age-group
(yrs) |
Person-yrs |
ON cases (No) |
Incidence
Rate (x10,000
person-yrs) |
|
20 -39 |
6,539 |
0 |
0 |
|
40 -59 |
29,135 |
4 |
1.37 |
|
60 -84 |
70,801 |
10 |
1.41 |
|
Total |
106,475 |
14 |
1.13 |
|
Age-group
(yrs) |
Person-yrs |
ON cases (No) |
Incidence
Rate (x10,000
person-yrs) |
|
20 -39 |
3,268,001 |
62 |
0.19 |
|
40 -59 |
3,286,455 |
93 |
0.28 |
|
60 -84 |
2,443,855 |
123 |
0.50 |
|
Total |
8,998,314 |
278 |
0.31 |
|
|
Incidence Rate (x 10,000 person-yrs) (95% CI) |
Relative Risk (95% CI) |
|
Corticosteroids non users cohort* |
0.25 (0.22-0.29) |
1 |
|
Corticosteroids user cohort |
0.99 (0.74- 1.31) |
3.96 (2.60-5.39) |
|
*General population cohort with systemic corticosteroids users
excluded. |
||
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