|LETTER TO EDITOR
|Ahead of print publication
Is it necessary to do surgical fixation in metastatic bone disease impending pathologic fracture before 177Lu-prostate-specific membrane antigen radionuclide therapy?
Department of Molecular Imaging and Radionuclide Therapy, The Persian Gulf Nuclear Medicine Research Center, Bushehr Medical University Hospital, Bushehr University of Medical Sciences, Bushehr, Iran
|Date of Submission||08-Nov-2020|
|Date of Decision||14-Dec-2020|
|Date of Acceptance||26-Dec-2020|
|Date of Web Publication||22-Sep-2021|
Department of Molecular Imaging and Radionuclide Therapy, The Persian Gulf Nuclear Medicine Research Center, Bushehr Medical University Hospital, Bushehr University of Medical Sciences, Bushehr
Source of Support: None, Conflict of Interest: None
|How to cite this URL:|
Assadi M. Is it necessary to do surgical fixation in metastatic bone disease impending pathologic fracture before 177Lu-prostate-specific membrane antigen radionuclide therapy?. World J Nucl Med [Epub ahead of print] [cited 2021 Oct 21]. Available from: http://www.wjnm.org/preprintarticle.asp?id=326402
Current advance in treatment options of patients with prostate cancer has improved the mean survival of patients with disseminated disease. Recently, Lu-prostate-specific membrane antigen (PSMA) radionuclide therapy as a ubiquitous molecular radiotherapy approach is considered an effective treatment in patients with metastatic castration-resistant prostate cancer.
However, most candidate patients have metastatic bone lesions predisposing the bone to an impending fracture. The pathologic fractures are sometimes seen following Lu-PSMA radionuclide therapy, even after one cycle, in the spine, pelvis, and extremities. As a fact, hormonal ablation as the principal treatment partly predisposes the patients to bone loss in prostate cancer.
A pathologic fracture during molecular radiotherapy using Lu-PSMA would expose the patients to devastating pain, immediate hospitalization, and surgical intervention in the situation that are not ideal. Hence, forecasting an impending fracture and preventive fixation before Lu-PSMA radionuclide therapy are vital to minimize debilitating complications.
Actually, there are no comprehensive reports on this issue but few studies presented as a side effects through clinical outcome assessment following 177Lu-PSMA therapy. In a prospective pilot study in 21 Asian populations with advanced prostate cancer taking 177Lu-PSMA, two patients had pathological hip and humeral fractures.
The key question is whether it is necessary to fix the bony lesions before Lu-PSMA radionuclide therapy.
In this regard, a number of studies were conducted to determine the features of an impending pathologic fracture. Mirels suggested a practical, reproducible, and accurate rating system protocol to categorize the risk of pathologic fracture that could serve a basis for decision-making regarding prophylactic fixation in metastatic diseases in long bones before using drugs or radiotherapy.
Mirels' classification predicts the highest risk of pathological fracture among metastatic diseases in long bones based on the site, nature, size, and pain. All of the parameters are scored from 1 to 3.
The lesion site is divided into three parts including upper extremity, lower extremity, and peritrochanteric area of the femur, and scored from 1 to 3, respectively. In general, it is seen that those lesions in the peritrochanteric area are at high risk for fracture; moreover, the chance of pathologic fractures is higher for weight-bearing skeleton compared to nonweight-bearing bones. The nature or matrix of the lesion is also subclassified into three parts (scored from 1 to 3) including blastic, mixed, and lytic, and the chance of fracture in three categories is 0%, 32%, and 48%, respectively.
The lesion size is presented as a proportion of the cortical thickness. A score of 1, 2, and 3 is given to lesions/cortex ratios of <1.3, 1.3–2.3, and >2.3, respectively. The frequency of pathologic fracture is 0% for lesions <1.3 of the cortex, 5% for lesions between 1.3 and 2.3 of the cortex, and 81% for lesions involving >2.3 of the cortex.
The only subjective parameter in Mirels' criteria is pain in which mild, moderate, or functional pain received a score of 1, 2, and 3, respectively. The frequency of fracture is only 10% in patients with mild-to-moderate pain in contrast to progression of fracture in patients with functional pain. Moreover, there is a relationship between pain and the lesion size.
According to the overall score, a recommendation is proposed regarding prophylactic fixation of the lesion. Based on the Mirels' classification, preventive fixation is strongly recommended for a lesion with a total score of 9 or higher. A lesion with a total score of 7 or less can be treated with radiotherapy and drugs without concerns. A total score of 8 presents a clinical dilemma; however, Mirels proposed that clinicians use clinical appraisal in such situations and conduct prophylactic fixation.
The overall sensitivity and specificity of the Mirels' protocol for predicting fracture are 91% and 35%, respectively, which may cause a substantial degree of overtreatment; nevertheless, once a pathologic fracture occurs, the consequences are even more serious.
As mentioned earlier, the Mirels' system is only appropriate for metastatic lesions in long bones and cannot be used in the spine and presumably oncological management is discussed in the spine separately from nonspine metastases. The spine is frequently affected by prostate cancer and could be assessed by an alternative noninvasive approach proposed by Snyder et al. What's more, Fisher et al. presented a unique classification model for spinal instability in metastatic disease.
The Spine Instability Neoplastic Score is a holistic approach that can help clinicians in ascertaining when cases with malignant disease of the spine may advantage from surgical consultation. It includes pain, spinal alignment, global spinal location of tumor, bone lesion quality, posterior involvement, and vertebral body collapse. It also could be helpful for surgical decision-making when take account with other key parameters such as neurologic symptoms, disease extension, prognosis, patient health elements, types of tumors, and tumor radiosensitivity.
It needs to be emphasized that a few important issues should be considered to make an informed decision.
The Mirels' score was validated in patients with bone metastases to the appendicular skeleton who were evaluated with radiographs and subsequently treated with external beam radiotherapy. This patient population presents starkly different characteristics from prostate cancer patients treated with Lu-177 PSMA radioligand therapy in the following ways:
- Initial assessment is done more commonly with Ga-68 PSMA positron emission tomography/computed tomography (CT). The CT component of this hybrid imaging has a significantly different performance than radiographs
- Prostate cancer metastases occur first to the more richly vascularized axial skeleton compared with the appendicular skeletal metastases on which the Mirels' score was validated.
- Mirels' cohort was treated with external beam radiotherapy. The dense energy impacted within a short period of time in radiotherapy contrast with the longer duration of irradiation of cancer cells and surrounding bone tissue in radionuclide therapy.
There are some unanswered points in this challenging issue. First, the method of calculating the total score is not clear in patients with multiple metastases of varying sizes in different locations with different levels of pain intensity, which are commonly seen in the patients referred for Lu-PSMA radionuclide therapy, the method overall score calculation is unknown. Second, there is a relationship between the histology of the primary lesion and fracture, which is not considered in the Mirels' classification. Third, in addition to four included parameters in this system, several other factors should be assessed as predictors of fracture, including previous treatments, comorbidities, estimated period of survival, other disease sites, level of activity, and bone mineral density, which are not addressed in this classification system.
The Mirels' classification system for impending pathologic fracture could be a reasonable approach for prostate cancer patients with metastases in long bones referred for Lu-PSMA radionuclide therapy until further specific valid methods are developed in this regard. However, there is still room for developing a more specific system for radionuclide therapy in bone metastases. In addition, given widespread use of Lu-PSMA radionuclide therapy in prostate cancer patients, it seems necessary to take appropriate measures to maintain and promote bone health in the patients referred for this therapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ahmadzadehfar H, Rahbar K, Baum RP, Seifert R, Kessel K, Bögemann M, et al
. Prior therapies as prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients treated with [(177)Lu]Lu-PSMA-617. A WARMTH multicenter study (the 617 trial). Eur J Nucl Med Mol Imaging 2020.[in print]
Ameb S, Salawu A, Brown JE. Bone health in men with prostate cancer: Review article. Curr Osteoporos Rep 2019;17:527-37.
Thang SP, Lam WW, Tong AK, Allen JC Jr., Ler AS, Tay YS, et al
. Clinical outcomes of 177lutetium-prostate-specific membrane antigen therapy in advanced prostate cancer-a prospective pilot study in an Asian population. Nucl Med Commun 2020;41:618-28.
Mirels HI. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res 1989;249:256-64.
Damron TA, Morgan H, Prakash D, Grant W, Aronowitz J, Heiner J. Critical evaluation of Mirels' rating system for impending pathologic fractures. Clin Orthop Relat Res 2003;415:S201-7.
Challapalli A, Aziz S, Khoo V, Kumar A, Olson R, Ashford RU, et al
. Spine and non-spine bone metastases-current controversies and future direction. Clin Oncol (R Coll Radiol) 2020;32:728-44.
Snyder BD, Cordio MA, Nazarian A, Kwak SD, Chang DJ, Entezari V, et al.
Noninvasive prediction of fracture risk in patients with metastatic cancer to the spine. Clin Cancer Res 2009;15:7676-83.
Fisher CG, DiPaola CP, Ryken TC, Bilsky MH, Shaffrey CI, Berven SH, et al
. A novel classification system for spinal instability in neoplastic disease: An evidence-based approach and expert consensus from the spine oncology study group. Spine (Phila Pa 1976) 2010;35:E1221-9.