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 5 years.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

The prognosis of patients with MBD of unknown origin highly relies on the timing of diagnosis and treatment. The primary challenge in managing patients with MBD of unknown origin lies in the absence of consensus on prioritizing supporting examinations. Unfortunately, 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 through a rigorous scientific process. We conducted a systematic review, registered in the research registry with the unique number reviewregistry1457. The results of our review are currently under review in a Scopus-indexed journal. This algorithm provides tailored recommendations for prioritizing supporting examinations based on the patient's clinical condition. Diverging from conventional methods, the examinations in the INA-MBD algorithm are not executed sequentially and exhaustively. The diagnostic and management patterns of this algorithm were preliminarily tested in our hospital with a limited sample. Both in theory and practice, the INA-MBD algorithm has proven effective in reducing the time required to diagnose primary malignancy in MBD cases and in lowering costs due to fewer supporting examinations. 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 Another challenge arises when no fractures are found, or patients have no prior history of cancer, making it difficult to diagnose bone metastasis conditions.⁸ This delay can negatively impact prognosis and increase the risk of Skeletal Related Events (SREs), including pathological fractures or spinal cord compression.¹ Therefore, it is crucial to promptly identify the origin of bone metastasis using optimal diagnostic strategies.

Various types and modalities of radiological examinations are recommended for diagnosing MBD of unknown origin. Complaints of pain in patients over 50 years old with multiple osteolytic bone lesions with ill-defined borders, with or without pathological fractures, can suggest MBD condition. Hence, routine chest X-rays or imaging of affected lesions should be performed in patients suspected of having MBD of unknown origin.^8–11 Other radiological examinations that may be conducted include ultrasound, bone scans, Computed Tomography (CT) scans, Magnetic Resonance Imaging (MRI), and PET scans. However, each type of radiological examination has its conditions and limitations.

Katagiri et al. reported that supportive examinations of the gastrointestinal and female reproductive organs often waste time and money, so they are not routinely recommended unless specific symptoms are present.¹⁰ Takagi et al. used whole-body CT scans to obtain general body imaging of patients to replace bone scans.¹ This study reported a high success rate in diagnosis using a combination of medical history, physical examination, chest X-rays, blood tests, and tumor markers. Lawrenz et al.¹¹ reported that PET/CT scans have poor diagnostic capabilities for MBD of unknown origin, a finding supported by Budak et al., who recommended the use of PET/CT scans only to search for other metastatic lesions, not for diagnosis confirmation.¹² Although bone scans are considered the best technique for early diagnosis of bone metastasis, their high cost means they are not routinely performed.

Bone survey can be used as an option to diagnose MBD of unknown origin. The sensitivity of bone surveys in detecting bone lesions ranges only from 44-50%, and it is lower compared to bone scans which have a sensitivity of 78%. However, the detection rate of bone surveys is better than bone scans when accompanied by clinical symptoms suggestive of MBD. The cost of the bone survey is also cheaper, making it still used to evaluate MBD lesions. The use of a bone survey is also recommended to confirm abnormal findings from bone scans.¹³

In conclusion, when determining the type of supportive examination to use in diagnosing MBD of unknown origin, besides considering the sensitivity and specificity values, the consequences of the examination should also be taken into account. The results of supportive examinations can directly or indirectly affect a person's health condition and outcomes. Health conditions can be influenced by factors such as the accuracy of diagnosis, the success of therapy, or psychological conditions, which are influenced by the cost of diagnostic tests or the amount of management costs given to patients.

Tsukamoto et al. (2021) advocate the diagnostic algorithm for diagnosing MBD of unknown origin.¹⁴ 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^4,14 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%.¹⁵

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. 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. This research aims to establish the INA-MBD algorithm as an evidence-based alternative for managing MBD of unknown origin. The utilization of the INA-MBD algorithm is expected to improve outcomes for patients with MBD of unknown origin and alleviate the financial burden associated with management.

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.).