Pediatr Blood Cancer

Chemotherapy Compliance in Patients With Osteosarcoma

Jyoti Bajpai, MD, DM,1* Ajay Puri, MS,2 Kajal Shah, MD,1 Deepa Susan, MD,1 Nirmala Jambhekar, MD,3

Bharat Rekhi, MD,3 Saral Desai, MD,3 Ashish Gulia, MS,2 and Sudeep Gupta, DM1

INTRODUCTION

Osteosarcoma is the most common primary malignant bone

tumor in children and adolescents [1]. In the current era, long-

term survival is achieved in two-thirds of osteosarcoma patients

with a localized, extremity-based primary tumor and in a quarter

to one-third of patients with an axial primary or those presenting

with pulmonary metastases [1–4]. Neoadjuvant chemotherapy

(NACT) permits histological examination of tumor resection

specimens for evidence of treatment response. This is accom-

plished by grading the degree of chemotherapy-induced histolog-

ical necrosis (HN) in a schema established by Huvos et al. [5,6].

This system classifies tumor response (TR) as grade I (little or no

effect), grade II (partial response, �50% necrosis), grade III

(>90% necrosis), and grade IV (no viable tumor). TR is also

categorized as poor responders (PR; grade I/II, <90% necrosis)

or good responders (GR; III/IV, �90% necrosis). This classifica-

tion has now been universally adopted. Previous studies from

Memorial Sloan-Kettering Cancer Center (MSKCC) suggested

that patients achieving a PR to NACT had an inferior survival,

compared to those achieving a GR [3,7]. Subsequent studies have

consistently demonstrated a 5-year event-free survival (EFS) of

35–45% in PR and 70–80% in GR. These data have served as

outcomes for comparison by other groups [7].

Compliance with drug treatment is quite prevalent in many

branches of medicine but is not widely recognized in clinical

oncology. Lewis et al. [8] attempted to broaden the concept of

compliance that in earlier decades was understood only as

patients’ adherence to a prescribed treatment regimen. They

identified certain psychological and behavioral aspects like the

treating physician’s attitude, doctor–patient relationship, and the

degree of psychosocial support available to the patient, as impor-

tant determinants for compliance. Chemotherapy compliance can

affect dose intensity and density, as well as final disease outcome.

Therefore, undue concern for safety which might affect compli-

ance should not be allowed to obscure the principal goal of

efficacy. There is sparse literature available as regards treatment

compliance in oncology. The present study aimed to evaluate the

effect of chemotherapy compliance on HR and survival and to

identify possible reasons for non-compliance.

METHODS

A retrospective review of surgically operated osteosarcoma

patients receiving NACT in the year 2010 at our center was

conducted. Clinical details were retrieved from patient charts

and Electronic Medical Records. Previously untreated, histologi-

cally confirmed high-grade osteosarcomas of the extremities,

shoulder and pelvic girdle received three cycles of NACT. The

chemotherapy protocol included a combination of drugs (ifosfa-

mide, adriamycin, and cisplatin) in alternating cycles. The first

cycle consists of ifosfamide (9 g) and adriamycin (75 mg) and the

second cycle consists of cisplatin (120 mg) and adriamycin

(75 mg). The third cycle is similar to the first cycle. Compliance

was defined as receipt of planned number of cycles in the planned

doses within the planned duration or up to 25% additional time.

Treatment response was assessed by evaluation of HN. GR were

defined as those with �90% HN, while PRs were those with

<90% HN.

Data were analyzed using SPSS (version 18). The descriptive

statistics was represented as median or percentage. The normality

of the data was established using Kolmogorov–Smirnov test.

Group comparison was made using chi-squared test and Mann–

Whitney U-test (as appropriate). A univariate analysis was

carried out to assess the significant factors associated with

Purpose. Histological response (HR) to neoadjuvant-chemother-apy (NACT) is considered as a robust prognostic marker in treatedosteosarcomas. Chemotherapy compliance can affect both, doseintensity and density and may affect the final outcome in thesecases. This vital aspect has been inadequately addressed andtherefore merits further investigation. Method. A retrospective studyof NACT-treated osteosarcoma patients, during the year 2010 wasconducted. Compliance was defined as receipt of planned cycles ofchemotherapy in the planned doses, within the planned duration orup to 25% additional time. HR was assessed by grading forhistological necrosis (HN). Good responders (GR) included thosewith tumors showing �90% HN. Results.Of 124 patients, 115 wereanalyzed for post-NACT HR. Of the 73 (64%) compliant patients,47 were GR and of the 42 (36%) non-compliant patients, 18 wereGR. There was significant association between GR and compliance

(P ¼ 0.031). However, at a median follow-up of 7.9 months, therewas no significant difference in survival between the noncompliantversus compliant group. Non-compliance was justifiable in 26patients and not justifiable in 16 patients. Using univariate analysis,T-size, pain, performance status, albumin, LDH, and educationwere identified as significant factors, while in multivariate analysis,only poor performance status was identified as an independentvariable for non-compliance. Conclusions. Two-thirds patientswere found to be compliant with NACT. There was a significantassociation between GR and compliant patients. Significant corre-lation between compliance and survival may be established with alonger follow-up particularly since ‘‘good necrosis’’ is generallypredictive of good survival. Pediatr Blood Cancer� 2012 Wiley Periodicals, Inc.

Key words: chemotherapy; compliance; osteosarcoma

1Department of Medical Oncology, Tata Memorial Center, Mumbai,

India; 2Department of Surgical Oncology (Bone and Soft Tissue),

Tata Memorial Center, Mumbai, India; 3Department of Pathology,

Tata Memorial Center, Mumbai, India

Conflict of interest: Nothing to declare.

*Correspondence to: Dr. Jyoti Bajpai, MD, DM, Assistant Professor,

Department of Medical Oncology, Tata Memorial Cancer Center,

Mumbai 400012, India. E-mail: dr_jyotibajpai@yahoo.co.in

Received 25 January 2012; Accepted 6 March 2012

� 2012 Wiley Periodicals, Inc.DOI 10.1002/pbc.24155Published online in Wiley Online Library(wileyonlinelibrary.com).

non-compliance and later these variables were tested in multivari-

ate analysis to identify the independent variable for non-

compliance. The variables tested by univariate analysis were

age, gender, pain, duration of illness, tumor site, tumor size,

ECOG-performance status (ECOG-PS), presence of metastasis,

type of surgery, serum alkaline phosphatase (SAP), and serum

LDH. The variables tested in univariate and multivariate analysis

were displayed in Tables I and II, respectively. Survival analysis

was performed using Kaplan–Meier method and the comparison

was made using Log-rank test. P-value <0.05 was considered to

be statistically significant. As none of the variable was found

significant for survival analysis univariately, multivariate analysis

using Cox proportional hazards model could not be done, and

hence, no hazard ratio was obtained.

RESULTS

A total of 124 patients underwent surgery during the study

period. Six patients underwent surgery prior to chemotherapy, two

underwent extra corporeal radiotherapy and reimplantation, and a

single patient underwent scar excision (operated elsewhere). As

these specimens could not be assessed for post-NACT histopath-

ological response only 115 of 124 patients were analyzed. The

median age was 17 years (range: 8–61). There were 85 males and

30 females (Table I).

Of the 115 patients, 73 (63.5%) were compliant to NACT,

while 42 (36.5%) were found to be non-compliant. Within the

compliant group, 47 (64.38%) were GR and 26 (35.62%) were

PRs. In the non-compliant group, 18 (42.86%) were GR and 24

(57.14%) were PRs. There was a statistically significant associa-

tion between good histological TR and compliance (P ¼ 0.031;

Fig. 1).

There were justifiable reasons for non-compliance (chemother-

apy-related myelosuppression and febrile neutropenia) in 26

patients. In 16 patients there were no justifiable reasons for

non-compliance. The latter included 8 patients with financial

constraints, 7 with communication failure and 1 patient who faced

an undue delay for surgery. On univariate analysis, larger tumor

size, severe pain, poor performance status, low albumin level,

higher LDH level, and lower level of education at presentation

were significantly associated with non-compliance. There were 19

cases with metastatic disease (Table II). The non-compliant group

included twice as many cases with metastatic disease in contrast

to the compliant group. Other variables that were studied but did

not show a significant association with non-compliant behavior

were age, gender, geographic region, site, and the type of surgery

(Table I). However, on multivariate analysis only poor perfor-

mance status was independently associated with non-compliance

(Table III).

Of the 115 patients, 11 were lost to follow-up during adjuvant

treatment. Therefore, 104 patients were included in the survival

analysis. Median follow-up period was 7.9 months. There was

no statistically significant difference in non-compliant versus

compliant group in terms of disease-free (DFS) or overall survival

(OS; Figs. 2A and 2B).

DISCUSSION

Compliance to a prescribed treatment is a complex and multi-

faceted issue. Traditionally, compliance has been understood as

the degree to which a patient’s behavior coincides with the

prescribed medical regimen. However, apart from patient behav-

ior, there are other factors affecting compliance; the treating

physician’s behavior, patient–physician relationship, and the sup-

port system. Various factors concerning the patient, disease,

TABLE I. Patient Characteristics (N ¼ 115)

Characteristic

Compliant

(n ¼ 73)

Non-compliant

(n ¼ 42)

Age (years)

Median 17 17

Range 9–53 8–61

Gender, no. (%)

Male 56 (76.7) 29 (69)

Female 17 (23.3) 13 (31)

Pain, no. (%)

Mild 48 (65.8) 0

Moderate 25 (34.2) 18 (42.9)

Severe 0 24 (57.1)

Duration of illness

(months), no. (%)

�4 68 (93.2) 21 (50.0)

>4 5 (6.8) 21(50.0)

Longest tumor

dimension (cm), no. (%)

�9 24 (32.9) 6 (14.3)

>9 49 (67.1) 36 (85.7)

ECOG-performance

status, no. (%)

1 53 (72.6) 13 (31)

2 19 (26.0) 29 (69)

3 1 (1.40) 0

Metastasis, no. (%)

Yes 9 (12.3) 10 (23.8)

No 64 (87.7) 32 (76.2)

Hemoglobin (g/dl),

no. (%)

Low 3 (4.1) 4 (9.5)

Normal (11–15 g%) 58 (79.5) 34 (81.0)

High 12 (16.4) 4 (9.5)

Albumin (g/dl), no. (%)

Low 1 (1.4) 2 (4.8)

Normal (3.5–5.2 g/dl) 65 (89) 40 (95.2)

High 7 (9.6) 0

LDH (U/L), no. (%)

Low 1 (1.4) 0

Normal (100–190 U/L) 38 (52.1) 13 (31)

High 34 (46.6) 29 (69)

Serum alkaline

phosphate (U/L), no. (%)

Low 0 0

Normal (74–390 U/L) 10 (13.7) 12 (28.6)

High 63 (86.3) 30 (71.4)

Surgery, no. (%)

Amputation 17 (23.3) 11 (26.2)

Limb-sparing surgery 56 (76.7) 31 (73.8)

Site, no. (%)

Femur 35 (47.9) 18 (42.9)

Fibula 4 (5.5) 2 (4.8)

Humerus 5 (6.8) 3 (7.1)

Radius and/or ulna 1 (1.4) 3 (7.1)

Tibia 28 (38.4) 14 (33.3)

Scapula 0 1 (2.4)

Pelvis 0 1 (2.4)

2 Bajpai et al.

Pediatr Blood Cancer DOI 10.1002/pbc

health providers, and treatment characteristics determine the treat-

ment compliance [8]. Considering the many determinants and

confounding factors involved, it is often difficult to identify

non-compliers or to predict the level of a patients’ adherence to

the prescribed treatment.

Current cancer care treatment is delivered more often with

curative intent. Non-compliance may affect the outcome especial-

ly in a curative setting. The availability of questionnaires, tests

and devices can help to measure a patient’s level of compliance to

a certain extent [9]. Family and social support, individualized

programs, reminders to reduce forgetfulness, personalized needs

assessment, and education are measures that can help improve

compliance [10].

Several studies analyzing chemotherapy compliance in other

malignancies are available in literature [9,11–14]. No such study

in osteosarcoma has been accomplished. Reported compliance

rates to breast cancer management guidelines vary from as low

as 54% to as high as 97% [9,11,12]. Excellent compliance rates to

adjuvant treatment guidelines in node-negative breast cancer

patients have been seen in the British Columbia province of

Canada (97% and 96% for radiotherapy and chemotherapy,

respectively). This has been partly attributed to factors such as

centralization of care and emphasis on the opinion of experts [13].

High rates of compliance are also associated with practices linked

to better outcomes (use of chemotherapy in premenopausal lymph

node-positive women) as well as for practices related to prognos-

tic importance (axillary lymph node dissection) [12]. In their audit

of compliance to adjuvant treatment guidelines in breast cancer

cases Subramanian et al. showed that non-compliance could be

attributed to justifiable reasons like, patient declining treatment,

non-eligibility by age-criteria and prior radiotherapy. Borras et al.

[14] in a randomized trial of 87 cases of colorectal cancer,

observed 33% non-compliance rate to chemotherapy. The reasons

described were voluntary withdrawal, unacceptable toxicity,

disease progression, and doctor’s discretion. Voluntary with-

drawals were 12% higher in the outpatient group than in the

home-treated group. However, there were no differences between

the two groups for withdrawals due to medical reasons [14].

Alam et al. [15] investigated 215 non-small-cell lung cancer

cases in the chemotherapy arm of JBR.10 trial. They observed

that apart from the death and disease progression, inter-current

illness, chemotoxicity, and patient’s unwillingness for treatment

contributed for non-compliance [15].

In the present study 63.5% patients were compliant, while

36.5% were found to be non-compliant. There were justifiable

reasons for non-compliance in 26 patients, while in 16 patients

non-compliance was not justified. Unjustifiable reasons included

financial constraints, communication failure, and delay in surgery.

TABLE II. Univariate Analysis: Significant Variables for

Non-Compliance

Variable P-value�

Age 0.584

Gender 0.37

Pain <0.001Duration of illness <0.001Longest tumor dimension 0.03ECOG-performance status <0.001Metastasis 0.112

Hemoglobin 0.154

Albumin 0.022LDH 0.018

Serum alkaline phosphate 0.052

Surgery 0.728

Site 0.715

P-values, which are statistically significant, are highlighted in bold.�P-value generated using Mann–Whitney U-test and chi-squared test

(as appropriate).

Fig. 1. Compliance versus histological necrosis (N ¼ 115). There

was statistically significant association between good histological

response and compliance (P ¼ 0.031). [Color figure can be seen in

the online version of this article, available at http://wileyonlinelibrary.

com/journal/pbc]

TABLE III. Multivariate Analysis: Significant Variables for

Non-Compliance

Variables P-value Odds ratio

95% CI for odds ratio

Lower Upper

Duration of illness 0.599 0.644 0.125 3.318

ECOG-performance

status

0.045 0.219 0.050 0.967

Longest tumor

dimension

0.655 1.683 0.172 16.497

Albumin

Low 0.998 1.352E16 0.000

Normal 0.999 3.169E8 0.000

LDH

Low 0.983 0.000 0.000

Normal 0.854 0.867 0.188 3.996

Pain

Mild 0.996 0.000 0.000

Moderate 0.998 0.000 0.000

P-values, which are statistically significant, are highlighted in bold.

Chemotherapy Compliance in Osteosarcoma 3

Pediatr Blood Cancer DOI 10.1002/pbc

Communication failure was defined as failure in conveying opti-

mum information to the patient by the medical staff. This can be

either due to an inability to correctly interpret information given

to the patient, inadequate time spent on counseling, or language

barriers. Compliance to chemotherapy may be improved by

strengthening patient–physician relationship and developing bet-

ter communication between physician and patients.

Multiple factors were found to be significantly associated with

non-compliant behavior on univariate analysis. Financial con-

straints are invariably a limiting factor especially in resource

challenged populations. Strengthening the family and social sup-

port system, providing individualized and personalized care and

better education may help improve compliance to treatment

[8,10].

On multivariate analysis, only poor performance status was

identified as an independent variable for non-compliance. One

can hypothesize that poor performance status at presentation

reflects aggressive disease biology in a rapidly growing tumor

and/or prolonged neglect in seeking health care for a slow grow-

ing disease. Both these factors can lead to poor tolerance to

chemotherapy resulting in non-compliance. Other factors like

level of education although significant on univariate analysis,

lost significance on multivariate analysis. This may be explained

by small sample size bias; further validation in large studies might

help establish these as well.

Even with resource constraints, two-third of our patients were

compliant to NACT. These data though immature does bring to

the fore the correlation of survival and compliance by using

‘‘good necrosis’’ as a surrogate indicator of ‘‘good survival.’’ A

subsequent communication with a longer follow up is vital to shed

further light on the fact that advanced healthcare delivery systems

and optimum compliance are mutually reinforcing. Both are

indispensable.

In conclusion, the early results from our study suggest that

better compliance to chemotherapy protocols in osteosarcoma

patients might translate into improved survival. Further studies

along similar avenues with larger numbers and a wide follow-up

could possibly help in establishing a stronger association between

the two and in prospectively identifying correct potential causes

for non-compliance.

REFERENCES

1. Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004:

Data from the Surveillance, Epidemiology, and End Results Program. Cancer 2009;115:1531–1543.

2. Meyers PA, Heller G, Healey J, et al. Chemotherapy for nonmetastatic osteogenic sarcoma: The

Memorial Sloan–Kettering experience. J Clin Oncol 1992;10:5–15.

3. Bielack S, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the

extremities or trunk: An analysis of 1702 patients treated on neoadjuvant cooperative osteosarcoma

study group protocols. J Clin Oncol 2002;20:776–790.

4. Bacci G, Longhi A, Versari M, et al. Prognostic factors for osteosarcoma of the extremity treated with

neoadjuvant chemotherapy: 15-Year experience in 789 patients treated at a single institution. Cancer

2006;106:1154–1161.

5. Rosen G, Marcove RC, Caparros B, et al. Primary osteogenic sarcoma: The rationale for preoperative

chemotherapy and delayed surgery. Cancer 1979;43:2163–2177.

6. Huvos AG, Rosen G, Marcove RC. Primary osteogenic sarcoma: Pathologic aspects in 20 patients after

treatment with chemotherapy, en bloc resection, and prosthetic bone replacement. Arch Pathol Lab

Med 1977;101:14–18.

7. Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma: Selection

of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative

chemotherapy. Cancer 1982;49:1221–1230.

8. Lewis C, Linet MS, Abeloff MD. Compliance with cancer therapy by patients and physicians. Am J

Med 1983;74:673–678.

9. Olivotto A, Coldman AJ, Hislop TG, et al. Compliance with practice guidelines for node-negative

breast cancer. J Clin Oncol 1997;15:216–222.

10. Balasubramanian SP, Murrow S, Holt S, et al. Audit of compliance to adjuvant chemotherapy and

radiotherapy guidelines in breast cancer in a cancer network. Breast 2003;12:136–141.

11. Ray-Coquard I, Philip T, Lehmann M, et al. Impact of a clinical guidelines program for breastand

colon cancer in a French cancer center. JAMA 1997;278:1591–1595.

12. Guadagnoli E, Shapiro CL, Weeks JC, et al. The quality of care for treatment of early stage breast

carcinoma. Is it consistent with national guidelines? Cancer 1998;83:302–309.

13. Smith TJ, Hillner BE. Ensuring quality cancer care by the use of clinical practice guidelines and

critical pathways. J Clin Oncol 2001;19:2886–2897.

14. Borras JM, SanchezHernandez A, Navarro M, et al. Compliance, satisfaction, and quality of life of

patients with colorectal cancer receiving home chemotherapy or outpatient treatment: A randomized

controlled trial. BMJ 2001;322:1–5.

15. Alam N, Shepherd FA, Winton T. Compliance with post-operative adjuvant chemotherapy in non-small

cell lung cancer. An analysis of National Cancer Institute of Canada and Intergroup Trial JBR.10 and a

review of the literature. Lung Cancer 2005;47:385–394.

Fig. 2. Survival statistics in compliant versus non-compliant group (N ¼ 104, compliant ¼ 67, non-compliant ¼ 37). At a median follow-up

of 7.9 months, there was no statistically significant difference observed in non-compliant versus compliant group in terms of disease-free

survival (A) or overall-survival (B). [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/

journal/pbc]

4 Bajpai et al.

Pediatr Blood Cancer DOI 10.1002/pbc