Prediction of Adverse Radiotherapeutic Effects in Prostate Cancer Patients Prior to Radiation

It is estimated that there will be 241,740 new Prostate Cancer (PCa) cases diagnosed in the U.S. in 2012 [1]. Radiotherapy is a widely used treatment modality for PCa. A recent review revealed that approximately 48% of patients diagnosed with prostate cancer received some form of radiotherapy for their initial treatment [2]. This amounts to around 100,000 patients per year receiving radiotherapy for PCa in the United States alone with a risk of grade 2 or higher bladder or gastrointestinal toxicity of 7-38% [3-5]. This adds up to 7,000 to 38,000 moderate or worse toxicities and up to 2000 severe toxicities each year. Indeed, most PCa patients have mild to moderate side-effects from radiotherapy, but some patients do have severe Adverse Radiotherapeutic Effects (AREs), such as severe lower urinary tract irritation, erectile dysfunction, and rectal bleeding, ulceration or dysfunction, despite the fact that radiotherapy doses and techniques are generally uniform. These severe side effects cause significant morbidity and require costly intervention.

Increasing evidence indicates that there is significant variability in the response to radiation in the general population. It is estimated that approximately 80% to 90% of the variability is attributed to deterministic differences, possibly arising from potential individual genetic makeup, whereas only 10% to 20% of the variations result from stochastic events associated with the random nature of radiationinduced cell killing, in addition to random variations in dosimetry and dose delivery [6]. Common manifestations of late injury include fibrosis, telangiectasia, and atrophy [7]. Many patients may have bladder irritation, impotence, or rectal bleeding for the rest of their lives or even require surgical intervention [3-5]. If we can identify these patients at high risk for developing significant AREs prior to radiotherapy, then we can offer them alternative therapies that may lower their risk of developing severe side effects. For patients at low risk for AREs, radiation dose escalation may be implemented to increase cure rates without increasing toxicity. However, the best strategy to determine the risk of AREs is currently unknown.

Single Nucleotide Polymorphisms (SNPs) of a limited number of genes have been shown to be associated with variable AREs in general populations. For example, ATM 5557G>A is associated with radiotherapy-induced fibrosis in PCa patients [8,9]. Kerns et al. [10] performed a genome-wide association study on 27 cases and 52 controls and found that SNP rs2268363, located in the follicle-stimulating hormone receptor gene was associated with erectile dysfunction following external beam radiotherapy in African American PCa patients.

Besides the patient’s genetic predisposition, other factors including age, smoking history, androgen deprivation therapy, use of alphablockers, use of anticoagulants, prostate volume, comorbidities such as diabetes and hypertension, baseline toxicity/function scores, and different types of radiotherapy may contribute to radiation toxicity as well [11-20]. However, these clinical variables cannot fully explain the variability in AREs [21-24] .

To accurately predict the risk of AREs in PCa patient, more studies are needed to identify variables that significantly influence radiationinduced normal tissue injuries in PCa patients, determine the individual contribution of each genetic and non-genetic factor to AREs, and develop models to predict the risk of AREs. Using these models, we will be able to identify patients who are at a high risk of AREs. For those patients, other effective therapeutic modalities such as radical prostatectomy, hormonal therapy, cryotherapy, or active surveillance [25] may be offered instead of radiotherapy. Therefore, a great number of severe AREs may be avoided if we use alternative therapies with fewer side effects for these patients at high risk. Similarly, if patients are found to be at low risk for AREs, radiation dose escalation may be implemented to increase cure rates without increasing toxicity. In prostate cancer, dose escalation has been show to improve disease control in multiple studies [26-28]. If we can successfully predict the risk of AREs in prostate cancer patients, we will be able to develop similar models to predict AREs in patients with other cancers or other diseases treated with radiotherapy. These models may become important tools for individualizing cancer therapy.