Analysis of the effectiveness and efficiency of the Indonesian metastatic bone disease of unknown origin algorithm (INA-MBD): time to diagnosis and cost to diagnosis: Quasi-experimental study

Introduction

Patients diagnosed with Metastatic Bone Disease (MBD) of unknown origin are at greater risk of higher mortality and morbidity rates, mainly due to skeletal-related events, with a solely 5% survival rate over a 5-year period.¹ In three-quarters of MBD cases, the diagnosis of primary malignancy is made after the patient’s condition deteriorates, typically around four months into the progression of the disease.² Alarmingly, it has been brought to attention that late establishment of the primary cancer diagnosis significantly contributes to treatment delay up to 86%.³ The prolonged process of diagnosing the unknown origin of MBD is further exacerbated by a series of routine laboratory examinations, including tumor markers.⁴

Prognosis of patients with MBD of unknown origin highly relies on the timing of diagnosis and treatment. There is no current guideline on the selection of preliminary examinations to identify primary lesions in MBD.¹ This lack of consensus adds to the financial burden, with Indonesian national health insurance allocating 18% of the total budget for catastrophic diseases to the care of cancer patients.⁵ In the United States, the direct cost of MBD is approximately $75,329, double the cost of treating cancer patients without MBD, at $31,382 per year.^6,7 Common diagnostic procedures involve a series of laboratory tests such as tumor markers and ALP, X-rays of the chest and affected limbs, CT scans, MRIs, bone scans, and PET scans, followed by bone or organ biopsies. These procedures contribute to prolonged diagnosis times and increased financial burdens, intensifying the complexities associated with addressing MBD-related challenges.

Certainly, we have developed the INA-MBD algorithm based on our literature review and clinical experience in managing patients with MBD of unknown origin. This algorithm provides tailored recommendations for prioritizing supporting examinations based on the patient’s clinical condition. Diverging from conventional methods, the screening checks in the INA-MBD algorithm are not executed sequentially and exhaustively. The main objective is for an early and secure biopsy to speed up the diagnostic process, leading to reduced further examination costs without compromising the success of diagnosing MBD of unknown origin.

Objective: The objective of this study was to assess the impact of implementing the INA-MBD algorithm on the direct treatment costs and the time to diagnose primary malignancy in patients with MBD of unknown origin.

Protocol

Variable

Independent variable

The INA-MBD algorithm (Figures 1 and 2) will be used as the independent variable. The interventional group will use the INA-MBD algorithm as a management guideline, while the non-interventional group relied on retrospective data from medical records.

Figure 1. INA-MBD algorithm without pathological fracture.

This figure is our original creation synthesized from both literature and our clinical experience.

Show steps and list of management in patients with MBD of unknown origin without pathological fracture. CXR (Chest X-Ray), IHC (Immunohistochemistry), CPC (Clinicopathological conference)/ multidisciplinary team discussion

Figure 2. INA-MBD algorithm with pathological fracture.

This figure is our original creation synthesized from both literature and our clinical experience.

Show steps and list of management in patients with MBD of unknown origin with pathological fracture. CXR (Chest X-Ray), IHC (Immunohistochemistry), CPC (Clinicopathological conference)/multidisciplinary team discussion.

Discussion

The diagnostic challenge in identifying primary malignancies often leads to patients with MBD of unknown origin being misdiagnosed with primary bone tumors or hematological malignancies. An additional complication is that not all MBD patients have a cancer history, with 71% being diagnosed with their primary malignancy only after a clinical deterioration.² In addition, therapeutic approaches for MBD necessitate concurrent treatment for the primary malignancy.

The diagnostic process for primary malignancy in MBD typically involves a series of relatively non-invasive imaging examinations. Tsukamoto et al. (2021) advocate for plain X-rays, CT scans, and MRI for all patients with bone lesions. If bone destruction is observed without periosteal reaction, then metastasis is suspected, prompting further examinations like abdominal, thoracic, or pelvic CT scans, tumor markers, serum electrophoresis, Bence Jones protein, and bone scans or PET/CT scans. Biopsy is reserved for the conclusion after completing all imaging and laboratory examinations.⁸ Tumor marker examinations, including CEA, CA-125, CA19-1, and AFP, exhibit low sensitivity and specificity in determining the primary malignancy in MBD of unknown origin. Tumor markers are not exclusively produced by malignant cells, making serum tumor markers more relevant for therapy monitoring or determining cancer prognosis.⁴

The extensive use of radiological examinations extends the time required to establish a primary malignancy diagnosis, contributing to an increased financial burden. Therefore, there is a crucial need for selective use of supportive imaging examinations. Imaging examinations of the gastrointestinal and female reproductive organs often result in waste of time and resources. Thus, not recommended as routine examinations in diagnosing primary lesions in MBD of unknown origin.¹ Bone scans alone cannot confirm malignancy origin in MBD and still require a bone survey for lesion confirmation. The cost-effectiveness of a bone survey influences our preference for it over a bone scan.⁹

More invasive examinations, such as biopsy, can confirm the origin of the primary malignancy in MBD patients. Biopsy can be performed on metastatic bone lesions, with or without pathological fractures, and on lesions suspected to be primary malignancies. Bone biopsies can confirm the origin of malignancy up to 70%.¹⁰

We have devised an algorithm named INA-MBD through clinical and evidence-based methods. The INA-MBD algorithm offers guidelines for managing patients with MBD of unknown origin, in concordance with the patient’s clinical condition, whether or not pathological fractures are present. This aims to provide more selective guidance in choosing imaging modalities. The INA-MBD algorithm excludes serum tumor marker examinations as a diagnostic tool for the reasons explained above. It also serves as a guide for performing biopsies not only on suspected primary lesions but also on bone lesions. This research seeks to evaluate the effectiveness and efficiency of using the INA-MBD algorithm in diagnosing primary malignancies in patients with MBD of unknown origin. The measurable variables representing the effectiveness of the INA-MBD algorithm include time-to-diagnosis and the cost-effectiveness of managing patients with MBD of unknown origin.

Author contributions

Conceptualization: (Y.A.P., A.W., T.A., I., R.M., D.P.) Data Curation: (Y.A.P., D.P., A.W., P.A.S., A.F.) Formal Analysis: (Y.A.P.)., A.W., T.A., I., R.M., D.P) Investigation: (Y.A.P., A.W., P.A.S., A.F) Methodology: (Y.A.P., D.P., A.W., M.P.J., M.A.A.) Software: (Y.A.P., P.A.S., A.F.) Supervision: (T.A., I., RM., D.P., M.P.J., M.A.A.) Validation: (Y.A.P., T.A. I., R.M., D.P., M.P.J., M.A.A.) Writing original draft: (Y.A.P., A.W., P.A.S., A.F.) Writing review & editing: Y.A.P., T.A., I., R.M., D.P., M.P.J., M.A.A., A.W., P.A.S., A.F.).