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Postradiotherapy Pelvic Fractures.  Cause for Concern or Opportunity for Future Research?   (for other reviews go here and here)

William Small, Jr, MD; Lisa Kachnic, MD

JAMA. 2005;294:2635-2637.

Radiation toxicity can roughly be divided into early and late effects. Early or acute effects, such as nausea, skin reactions, diarrhea, and neutropenia, tend to be temporary and, for the most part, resolve shortly after the completion of therapy. Late effects, such as connective tissue fibrosis and secondary malignancies, can occur long after the completion of radiation therapy. The causes for late radiation injuries are not completely understood. The 2 main theories consist of damage to the cellular matrix and vascular injury. However, the etiology for long-term sequelae is probably much more complex and likely involves a cascade of cellular, vascular, and cytokine changes induced by radiation.

In this issue of JAMA, Baxter and colleagues provide compelling evidence for what many radiation oncologists have long believed, despite a paucity of literature about modern radiation delivery: that pelvic radiotherapy increases the risk of bone fractures. Of the 6428 women in the study, 556 were diagnosed with anal cancer, 1605 with cervical cancer, and 4267 with rectal cancer. Overall, 44.4% received radiation therapy and 55.6% did not. The cumulative incidence of pelvic fractures within the first 5 years of the study was increased for women in the irradiated group compared with women in the nonirradiated group: 14% vs 7.5% for women with anal cancer, 8.2% vs 5.9% for cervical cancer, and 11.2% vs 8.7% for rectal cancer. As Baxter et al show, an increase in the relative risk of pelvic fractures associated with the administration of pelvic radiotherapy is a significant public health issue that deserves attention.

Pelvic insufficiency fractures may be a common postradiotherapy toxicity. These hairline fractures result from radiation-induced weakening of pelvic bone and may occur by virtue of the pelvis being unable to support body weight. In one study of postmenopausal women who received radiation therapy for advanced cervical cancer, the pelvic insufficiency fracture rate was 17%. Insufficiency fractures can be asymptomatic or associated with pain. Painful lesions tend to be associated with multiple fractures on magnetic resonance imaging. The majority of symptoms will improve with conservative measures. Primary care physicians and oncologists should be aware that pelvic insufficiency can occur after pelvic radiotherapy. Some patients who initially are diagnosed with metastatic disease related to pelvic pain and a positive bone scan ultimately may be diagnosed with an insufficiency fracture. This can lead to considerable patient anxiety and, in the extreme case, to unnecessary and potentially harmful application of anticancer therapy. Moreno and colleagues reviewed 8 symptomatic cases of pelvic insufficiency fractures and noted 5 of these patients to be originally diagnosed with metastasis.Isolated pelvic bone metastasis in the absence of other metastatic disease is an uncommon event in cervical, rectal, and anal cancer. If patients develop pain and isolated pelvic bone scan findings after pelvic radiotherapy, conservative measures should be the first line of therapy.

In addition, there should be attempts to minimize the known risks for pelvic fractures. These include aggressive treatment of underlying osteopenia in concordance with current guidelines. Efforts for reducing osseous effects should be pursued with secondary end points, such as bone density used to guide such study.

An important area of research involves the prevention of cancer treatment morbidity with improvements in patient quality of life. One solution is to minimize radiotherapy to only the at-risk regions—commonly referred to as the clinical target volume. In general, the clinical target volume is surrounded by a margin of normal tissue to account for patient set up variations and internal organ motion. This volume is commonly referred to as the planning target volume. The bony structures of the pelvis are rarely part of the clinical target volume for cancers of the rectum, cervix, and anus. Emerging evidence suggests that newer radiation treatment techniques have the ability to reduce the volume of normal tissue irradiated outside the clinical target volume.

In addition to improved targeting of radiotherapy, consideration of agents that may reduce toxicity or improve the osseous environment after radiotherapy may be warranted. Amifostine (WR 2721) is a free radical scavenger that appears to be taken up in normal tissue preferentially over tumor cells, providing normal tissue radioprotection without protection of the cancer. This agent has been found to reduce xerostomia in patients who received head and neck radiotherapy and decreases toxicity in patients with ovarian cancer receiving chemotherapy.Preclinical data in a rat model suggest that amifostine reduces bone loss by decreasing osteoclastic bone resorption and improves bone mineral density after radiotherapyas compared with animal controls.Amifostine appears to improve other effects of pelvic radiotherapy such as mucosal toxicity and is under investigation in patients receiving radiotherapy for cervical cancer in a prospective multicenter Radiation Therapy Oncology Group trial.Other attempts to improve the osseous environment after radiotherapy could include the prophylactic use of biphosphonates in nonosteopenic patients. The Radiation Therapy Oncology Group is currently developing a phase 3 trial (W.S. and L.K., unpublished data, 2005) to evaluate the potential benefit of bisphosphonate therapy in the prevention of osteoporosis-associated bone fractures in patients receiving hormonal therapy and pelvic radiation for locally advanced adenocarcinoma of the prostate.

In conclusion, Baxter et al have provided compelling evidence for a significant increase in pelvic fracture risk with the use of pelvic radiotherapy as a component of definitive cancer management. The morbidity associated with pelvic fractures and the widespread use of pelvic radiotherapy make research into reducing such osseous effects a high priority.

Risk of Pelvic Fractures in Older Women Following Pelvic Irradiation

Nancy N. Baxter,   JAMA. 2005;294:2587-2593.

Pelvic fractures, including hip fractures, are a major source of morbidity and mortality in older women. Although therapeutic pelvic irradiation could increase the risk of such fractures, this effect has not been studied. We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results (SEER) cancer registry data linked to Medicare claims data. A total of 6428 women aged 65 years and older diagnosed with pelvic malignancies from 1986 through 1999 were included. We compared results for women who did (n = 2855) vs did not (n = 3573) undergo radiation therapy. To assess the influence of selection bias, we also evaluated the effect of irradiation on osteoporotic fractures in nonirradiated sites (arm and spine).

We evaluated the effect of irradiation on the incidence of pelvic fractures over time, and adjusted for potential confounders using a proportional hazards model. Women who underwent radiation therapy were more likely to have a pelvic fracture than women who did not undergo radiation therapy (cumulative 5-year fracture rate, 14.0% vs 7.5% in women with anal cancer, 8.2% vs 5.9% in women with cervical cancer, and 11.2% vs 8.7% in women with rectal cancer); the difference was statistically significant and most fractures (90%) were hip fractures. We controlled for potential confounders including age, race, cancer stage, and geographic location. The impact of irradiation varied by cancer site: treatment for anal cancer was associated with a higher risk of pelvic fractures (hazard ratio, 3.16; 95% confidence interval, 1.48-6.73); than for cervical cancer (hazard ratio, 1.66; 95% confidence interval, 1.06-2.59); or rectal cancer (hazard ratio, 1.65; 95% confidence interval, 1.33-2.05). No statistically significant difference was found in the rate of arm or spine fractures between the irradiated and nonirradiated groups (hazard ratio, 1.15; 95% confidence interval, 0.89-1.48).

Conclusions  Pelvic irradiation substantially increases the risk of pelvic fractures in older women. Given the high baseline risk of pelvic fracture, this finding is of particular concern.

It is well recognized that therapeutic radiation can result in bone damage and may increase fracture risks. However, the risks have not been well studied, particularly the risks with standard-course fractionation. The main evidence for the effect of irradiation on fracture risk comes from a long-term follow-up study of 2 European randomized trials (Stockholm I and II)evaluating the effect of short-course irradiation in patients with operable rectal cancer. In that follow-up study, patients who underwent short-course irradiation were twice as likely to be admitted to the hospital for hip fractures than patients who did not undergo short-course irradiation. But short-course irradiation (with a high dose per fraction) is generally not used in the United States and many other centers. So, it is unclear whether fracture risk is increased by the standard (in the United States and many other locations) irradiation schedules with a lower dose per fraction, given over 5 to 6 weeks. However, because of the high baseline incidence of fractures in older people and the significant morbidity and mortality associated with fractures, even a small increase in the fracture rate would be an important finding.

Our population-based, retrospective cohort study demonstrates that pelvic irradiation is associated with an increased risk of pelvic fractures in older women. The increased risk associated with anal cancer was substantial: women with anal cancer who underwent radiation therapy were more than 3 times more likely to develop a pelvic fracture at any point in follow-up, compared with women with anal cancer who did not undergo radiation therapy. The high risk of pelvic fracture after radiation therapy for anal cancer may reflect the radiation therapy technique used to treat this disease. In the treatment of anal cancer, it is usually appropriate to treat the inguinal nodes because of the risk of disease at this site. Because of the location of these nodes with respect to the femoral head and neck, it has been difficult to treat these nodes well without concomitant irradiation of the femur, and thus the femoral heads are exposed to a relatively high irradiation dose in the treatment of anal cancer patients.

For patients with rectal or cervical cancer, the inguinal nodes are not routinely treated as they are usually at very low risk of involvement with the tumor(s). Thus, sparing of the bony structures in the treatment of these cancers can be accomplished much more easily. In addition, the standard irradiation-sensitizing chemotherapy given to patients with anal cancer differs from standard treatment in rectal and cervical cancers, and this potentially could increase the risk of pelvic fractures. Nevertheless, radiation therapy given for rectal and cervical cancer was also associated with a substantial increase in pelvic fractures.

Given the high baseline rate of fractures in women aged 65 years or older, the hazard ratio of 1.65 that we found in our study may represent an increased lifetime incidence of fractures from the baseline rate of 17% to 27%—a substantial and clinically significant absolute increase. We did not find an increase in osteoporotic fractures in nonirradiated sites, which indicates that the effect of radiation therapy on pelvic fractures is specific to the area treated and is not due to confounding from patient selection.

The bony structures of the pelvis and groin lie in close proximity to genitourinary pelvic organs, gastrointestinal pelvic organs, and the lymphatic drainage of these organs. Therefore, when traditional irradiation is used to treat anal, cervical, or rectal cancer, bony structures are also irradiated. It is well-recognized that therapeutic irradiation can result in bone damage. Bone changes after irradiation were first described by Ewing in 1926. A variety of complications from irradiation delivered to the bones in the pelvis have been described, including fractures of the femur, pubic rami, and pubic symphysis; acetabular failure; and avascular necrosis.The effects of irradiation on bone are not completely understood; however, damage appears to occur at the bone matrix and cellular level as well as at the vascular level. Irradiation can kill osteoblasts, osteocytes, and osteoclasts, resulting in a reduction in bone matrix production. Reduction of the functional components of bone leads to atrophy and renders the bone more susceptible to fracture at weight-bearing areas. In addition, irradiation damage to the vascular supply to the bone may lead to further bone loss. Small-vessel damage induced by irradiation leads to microcirculation occlusion and further compromises osteoblastic function. Fractures after radiation therapy are more difficult to treat; hip replacements after radiation therapy have been associated with an increased risk of complications including infection and mechanical insufficiency.

Despite the potential of bone injury from pelvic irradiation, the risks to bone have not been well studied. Case series have included relatively small numbers of patients. Even with small sample sizes, pelvic and/or hip fractures have been described after irradiation for cervical cancer, uterine cancer, anal cancer, and rectal cancer. Fractures have occurred as soon as 3 weeks after completion of irradiation. Still, the relatively small numbers of patients in those studies make it difficult to estimate the true fracture rate. Also, few such studies have included a control group, so it is difficult to determine whether pelvic irradiation actually increases the fracture rate above baseline.

Until now, the long-term follow-up study of the Stockholm I and Stockholm II trials provided the most compelling evidence of an association between pelvic irradiation and fracture risk. The Stockholm trials were randomized studies evaluating the effect of short-course radiation therapy on operable rectal cancer. In both trials, patients in the irradiation group received a total dose of 2500 cGy over 5 or 7 days. The Stockholm I trial used a 2-field (AP-PA) technique; the Stockholm II trial, a 4-field box technique (AP-PA, R/L laterals). The long-term follow-up study focused on the 1027 curatively treated patients in the 2 trials. A total of 27 patients (5.3%) in their irradiated group and 13 patients (2.4%) in their nonirradiated group were hospitalized with a femoral neck or pelvic fracture during follow-up, a statistically significant doubling of the fracture risk. Short-course radiation therapy (with a high dose per fraction that may be associated with an increased fracture risk) is not standard in many centers (including the United States) and is known to increase late toxicity in many tissues. In addition, short-course radiation therapy is generally used only for rectal cancer; thus the findings of this study were not widely generalized.

Any increase in late effects, such as the hip fracture risk in our study, must be put into the context of the benefit from irradiation. For example, the alternative to irradiation in women with anal cancer is an abdominoperineal resection with a permanent colostomy and probably a lower chance of cure. In women with locally advanced cervical cancer, there are no good treatment alternatives to primary irradiation (now routinely combined with chemotherapy). In women with rectal cancer, omission of irradiation would lead to an increased risk of local failure, an increased colostomy rate, and potentially decreased survival. However, the use of irradiation is increasing28 and therefore it is essential that long-term risks are understood. Increasing our knowledge regarding the long-term consequences of irradiation will improve our ability to inform patients of the risks and benefits of treatment, may lead to changes in therapy that decrease the risk, and will prompt research evaluating potential preventive strategies and the benefits of early detection.

Our study has several limitations. First, information about the type and method of radiation therapy delivery was limited, with no available data on dosage or fields. Changes in radiation therapy delivery techniques over time may have affected risk. Today’s more sophisticated approaches of conformal irradiation and intensity-modulated irradiation use smaller irradiation fields, and have the potential to reduce the irradiation dose to bone, particularly to the femoral neck and head. Further studies evaluating the effect of irradiation dosage, fields, and techniques on fracture risk are needed. Because our study relied on observational data, rather than on the results of a randomized trial, the potential for patient selection bias, although small, remains. Likewise, we had no information about risk factors for fracture other than age and race, although it is unlikely that such risk factors would have resulted in differential treatment selection. Therefore, it is unlikely that these limitations would have altered our final conclusion, namely that pelvic irradiation for anal, cervical, and rectal cancer in older women results in an increased risk of pelvic fractures over time. However, these findings should be confirmed using other data sources. In addition, as the pelvic fracture events were determined using data from hospitalizations, untreated pelvic insufficiency fractures, or those treated in the outpatient setting were not included in our evaluation. Such fractures may be a source of great morbidity to patients, and should be studied further.

It is important to note that our study population (older, predominantly white women) was already at high risk for pelvic fractures. Therefore, our results cannot be generalized to other populations (eg, men, younger age groups). The risk of pelvic fractures after irradiation in other populations should be the focus of future studies.

In conclusion, older women undergoing irradiation therapy for anal, cervical, or rectal cancer should be counseled with respect to fracture risks from irradiation. Potentially, these women could be targeted for preventive strategies, such as bone mineral densitometry screening, medical regimens aimed at preventing osteoporosis, and fall prevention. Such strategies should be evaluated in prospective studies. In addition, changes in irradiation techniques for high-risk individuals to minimize the irradiation dose received by bone should be investigated.