Sacral Insufficiency Fractures After Preoperative Chemoradiation for Rectal Cancer: Incidence, Risk Factors, and Clinical Course

We have here reported the first study to systematically characterize the incidence, risk factors, and clinical course of sacral insufficiency fractures in patients treated with chemoradiation for rectal cancer. The risk of developing sacral insufficiency fractures was relatively low, although the risk was higher in women compared with men and in whites compared with non-whites. Although pain symptoms could last for several months, patients could be managed conservatively with pain medications.

The widespread use of radiotherapy for rectal cancer makes it very important for clinicians to understand the presenting features and clinical course of sacral insufficiency fractures. Although sacral insufficiency fractures are relatively uncommon, these can cause considerable morbidity and need to be treated appropriately. The most common presenting symptom is pain that is typically severe and acute in onset, although more indolent onsets have also been described. The pain can be localized to the low back, pelvis, or abdomen, and accompanied by hip, buttock, or thigh pain. Radicular symptoms can be present in a minority of patients. Blood tests are notable only for a mild elevation in serum alkaline phosphatase levels. Unfortunately, patients with sacral insufficiency fractures often face missed or delayed diagnosis. In patients with rectal cancer, sacral insufficiency fractures can mimic pelvic recurrences in their presentation, often prompting further evaluation which can be very stressful to patients.

Imaging studies can help differentiate insufficiency fractures from recurrences, thus obviating the need for biopsies and other interventions. Plain radiographs of the pelvis can show sclerotic bands, cortical disruption, and fracture lines in the sacral ala. However, subtle findings are not usually identifiable or diagnostic on plain films. Bone scintigraphy can reveal the classic butterfly shaped or “H” pattern, which is produced when there are fractures of both sacral alae and a horizontal component involving the sacral body, although other patterns can also be seen Characteristic findings on CT scans include fracture lines or sclerotic lines within the sacral ala or areas of sclerosis within the sacral ala parallel to the sacroiliac joints. Frequently, there is disruption of the anterior cortex of the sacral ala with associated displacement of the fracture fragment. In the setting of an insufficiency fracture, the remainder of the bony trabeculae is intact, rather than destroyed by a space-occupying lesion, as in the case of a malignancy. On magnetic resonance imaging, presence of a fracture line on T1-weighted images and high signal intensity parallel to the sacroiliac joints on T2-weighted images are virtually diagnostic of insufficiency fractures. On diffusion-weighted magnetic resonance, an insufficiency fracture appears low in signal because of the bony sclerosis around fracture lines, whereas a pathologic fracture can show high signal intensity. In contrast, positron emission tomography with fluorodeoxyglucose is nonspecific and can show increased activity in tumors as well as insufficiency fractures.

The incidence of sacral insufficiency fractures among the general population remains unknown. Weber et al. reported that the incidence of sacral insufficiency fractures was 1.8% among women older than 55 admitted to the rheumatology department at a hospital in Switzerland. The baseline incidence of sacral insufficiency fractures among the general population is likely to be much lower than that in the selected population studied by Weber et al. Although the patients in our study had a certain baseline risk of sacral insufficiency fractures even without radiotherapy, we believe that the insufficiency fractures could be predominantly attributed to radiotherapy, especially because this study included both genders and had relatively young patients.

Many previous studies have investigated pelvic fractures after radiotherapy. Using the Surveillance, Epidemiology, and End Results/Medicare database, Baxter et al. reported that elderly women (age ≥65 years) who underwent radiotherapy had a higher risk of pelvic fracture than women who did not undergo radiotherapy. The cumulative 5-year fracture rates were 14%, 8.2%, and 11.2%, respectively, in women with anal, cervical, and rectal cancer who underwent radiotherapy, whereas the rates were 7.5%, 5.9%, and 8.7%, respectively, in women with anal, cervical, and rectal cancer who did not undergo radiotherapy. In the study by Baxter et al., hip fractures constituted 90% of the pelvic fractures. In contrast, none of the patients in our study was found to have a femoral neck fracture. The risk of developing a femoral neck fracture is likely associated with the use of groin irradiation, which was not administered to any of the patients in this study. Moreover, the median age was nearly 58 years, and women represented only 37% of patients in this study; these demographic characteristics may also explain the lack of femoral fractures in our study. The study by Baxter et al. did not specifically discuss insufficiency fractures; the Surveillance, Epidemiology, and End Results/Medicare database may not have had sufficiently detailed information to identify insufficiency fractures.

A number of previous studies have investigated pelvic insufficiency fractures after radiotherapy for cervical and other gynecologic malignancies, whereas some case reports have described insufficiency fractures after radiotherapy for rectal cancer. Oh et al. and Ogino et al. have reported that older age, lower body weight, and higher radiotherapy dose are associated with a higher risk of pelvic insufficiency fractures. In our study, older patients and patients treated with higher radiotherapy dose had numerically higher rates of insufficiency fractures, but the differences were not statistically significant. Three studies from Japan and Korea have reported that the cumulative incidence of insufficiency fractures in patients treated with radiotherapy for gynecologic cancers was 11.4%, 17%, and 19.7%. In contrast, the 3-year actuarial incidence of sacral insufficiency fractures was only 3.1% among all patients and 5.8% among women in the present study. Differences in patient characteristics, such as age, body weight, and ethnicity, and differences in treatment parameters, such as radiotherapy dose and technique, could have contributed to the difference in incidence of insufficiency fractures. However, the clinical course of sacral insufficiency fractures in our study is similar to that reported in patients with gynecologic cancers.

As with all retrospective studies, there are some limitations in our findings. Complete follow-up information was not available for all patients. Imaging studies were reviewed only in patients with known pelvic fractures and not on all 562 patients in the study, although radiology reports and medical records were reviewed in detail for all patients. The study was restricted to medical records at M. D. Anderson Cancer Center, and could have potentially left out sacral insufficiency fractures identified at other institutions. However, the majority of patients had prolonged follow-up at M.D. Anderson; hence, it is unlikely that this study significantly underestimated the risk of sacral insufficiency fractures. We did not have adequate information to evaluate the impact of certain potential predictors, such as body weight. Finally, because this is a retrospective study, it is difficult to draw firm conclusions regarding the clinical course of these patients.

Many opportunities exist for further studies on sacral insufficiency fractures. For example, investigations could be conducted on whether bone mineral density tests can predict which patients are most likely to develop insufficiency fractures. Studies could be conducted on whether medications such as bisphosphonates could reduce the risk of sacral insufficiency fractures among high-risk groups, such as white women. However, the low rate of insufficiency fractures makes it difficult to design and conduct such studies. A case report has suggested that pentoxifylline can cause clinical improvement of sacral insufficiency fracture. A new therapeutic intervention, sacroplasty, has been developed recently to treat sacral insufficiency fracture. Such interventions need to be studied further to determine their indications and efficacy.

In conclusion, sacral insufficiency fractures are an uncommon but important late side effect in patients treated with pelvic radiotherapy for rectal cancer. Women and whites have a higher risk of developing sacral insufficiency fractures. Distinguishing sacral insufficiency fractures from pelvic recurrences may help reduce unnecessary biopsies and other interventions. Most patients with sacral insufficiency fractures can be managed conservatively with pain medications; however, new therapeutic interventions are now under investigation.