Collagen vascular disease (CVD) represents a spectrum of disorders characterized by abnormalities in immunoregulatory processes resulting in the production of autoantibodies and anomalies in cell-medicated immunity (Hamilton 2005). The autoantibodies are typically formed against components of the extracellular matrix, including collagen and elastin. Patients with CVDs may exhibit skin rash, fibrosis, arthritis, and in more severe cases, organ damage. A series of case reports, often of pronounced and even dramatic radiation reactions and toxicity, initially suggested that patients diagnosed with CVDs were at an increased risk for radiation injuries resulting from radiotherapy (Nilsen et al. 1967; Glasenapp 1968; Urtasun 1971; Ransom and Cameron 1987; Olivotto et al. 1989; Robertson et al. 1991; Varga et al. 1991; Rathmell and Taylor 1992; Abu-Shakra and Lee 1993; Hareyama et al. 1995; Bliss et al. 1996; Mayr and Riggs 1997; Rakfal and Deutsch 1998; Khoo et al. 2004; Wo and Taghian 2007). In response to these case reports, radiation oncologists have been cautious in treating patients with CVDs. In addition, based upon these findings, the American College of Radiology stated in their guidelines concerning breast cancer (Winchester and Cox 1998) that “a history of collagen vascular disease is a relative contraindication to breast conservation treatment because published reports indicate that such patients tolerate irradiation poorly”.

To examine the question as to whether patients with CVD are at increased risk for radiation injuries following radiotherapy, several retrospective studies were performed (Ross et al. 1993; Morris and Powell 1997; Chen and Obedian 2001; Phan et al. 2003; Gold et al. 2007, 2008; Pinn et al. 2008). The patients studied primarily included those affected with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), dermatomyositis, polymyositis, and systemic sclerosis (scleroderma). In addition, some of these patients exhibited overlapping syndromes, referred to as mixed connective tissue disorders. In a study of 20 patients specifically diagnosed with scleroderma, Gold et al. (2007) reported that only 15 % of the subjects developed late radiation toxicities, which is similar to the rates of historical controls. In addition, only a small percentage of patients displayed grade 3 or worse acute toxicities, comparable to the rates in historic control populations. However, in a subsequent publication, Gold et al. (2008) reported in a study of 41 patients with either scleroderma or SLE, that patients who were diagnosed with high severity CVD were at greater risk to develop radiation-induced toxicities resulting from radiotherapy compared with patients with low-severity CVD. In addition, the manifestations of radiation injury appeared earlier in the high-severity CVD group. In a study of 21 patients with SLE, Pinn et al. (2008) reported that patients with SLE renal involvement were at a greater risk for the development of chronic radiation toxicity resulting from radiotherapy. These authors concluded that both acute and chronic toxicities resulting from radiotherapy were moderate among patients with SLE and therefore the use of RT should not be avoided in these patients, although patients with more advanced SLE may be at an increased risk for the development of adverse effects resulting from RT.

In order to reach a more definitive conclusion as to whether CVDs predispose patients to complications from RT, the results of three matched case–control studies (Ross et al. 1993; Chen and Obedian 2001; Phan et al. 2003) and one large retrospective study (Morris and Powell 1997) have been published. Ross et al. (1993) reported the results for 61 patients with CVDs (39 RA, 13 SLE, 4 scleroderma, 4 dermatomyositis, and 1 polymyositis) treated with radiotherapy. No significant difference was found between the group of patients with CVDs and matched controls in terms of either acute or late effects of radiation. Phan (2003) performed a case–control study of 38 patients with CVDs (21 SLE, two scleroderma, four Raynaud’s phenomena, three fibromyalgia, three polymyalgia, three Sjogren’s syndrome, two polymyositis-dermatomyositis) and reported no significant differences in the incidence of either early or late complications between the case and control groups, although the patients with scleroderma exhibited an increase in both acute and late effects. Chen et al. (2001) performed a case control study of patients diagnosed with CVDs who received breast conserving therapy. Similar to previous studies, no significant differences were found in the incidence of acute effects between the cases and controls. However, this study found an increased risk of late radiation toxicity in the CVD patients compared with controls. This was primarily due to the development of late morbidity in 75 % of the scleroderma patients, although this group consisted of only four subjects. A retrospective report from Morris and Powell (1997) of 209 patients diagnosed with CVDs (136 RA, 28 SLE, 17 polymyositis-dermatomyositis, 16 scleroderma, 8 ankylosing spondylitis, 4 mixed tissue disorders) reported a similar rate of acute reactions to the Ross et al. study (1993). However, this study found that severe late radiation toxicity was significantly associated with non-RA CVDs. Thus, these authors concluded that aside from RA, CVD may be associated with an enhanced risk of late effects following standard radiotherapy. Holscher et al. (2006) performed a review of the literature and calculated a pooled relative risk of 2.0 (95 % confidence interval, 0.99–4.1) for the development of late effects in patients diagnosed with CVDs following radiotherapy compared with RT patients without a history of CVD.

Thus, although some studies have suggested an increased risk of late effects in certain patients, particularly those people diagnosed with scleroderma, none of the retrospective series has confirmed the substantial increase in the susceptibility of patients with CVDs to radiation-induced normal tissue toxicities that were reported in earlier case reports.

Diabetes and hypertension often have similar vascular pathologies to patients with CVDs, although without an autoimmune etiology. Herold et al. (1999); Chon and Loeffler (2002) reported upon radiation toxicities in a population of 944 patients treated with EBRT for prostate cancer, 121 of whom had diabetes. They found that the rates of gastrointestinal and genitourinary morbidity were somewhat higher in the diabetic patients compared with men not exhibiting evidence of diabetes. Maruyama et al. (1974) reviewed the records of 271 patients treated with RT for cervical cancer and concluded that patients with diabetes were more likely to develop small bowel obstructions following RT. VanNagell et al. (1974) also reported on cervical cancer RT patients with the finding of a correlation between diabetes with the development of radiation-induced bladder and rectal injuries.

Inflammatory bowel diseases (IBD) comprise patients with ulcerative colitis and Crohn’s disease. IBD has been considered a relative contraindication for pelvic or abdominal RT since this disease is characterized by an inflammatory reaction in the mucosa and it has been thought that radiation would exacerbate this condition. Willet et al. (2000) reported on 28 patients with IBD (10 Crohn’s disease and 18 ulcerative colitis). A higher rate of radiation toxicities was observed in IBD patients who underwent abdominal or pelvic RT compared with morbidity rates of non-IBD patients who received similar treatments. Thus, these authors suggested that RT should be used judiciously in these patients. Green et al. (1999) reported on the outcomes for 47 IBD patients (35 ulcerative colitis and 12 Crohn’s disease) treated with RT for rectal cancer. The rates of acute and late complications were similar in this group to those reported in randomized trials of RT for rectal cancer. In addition, two studies (Grann and Wallner 1998; Peters et al. 2006) of patients with IBD who received brachytherapy for prostate cancer reported that these patients tolerated this treatment and exhibited similar rates of rectal complications to non-IBD patients.

In summary, a series of case reports have described radiotherapy-related injuries in patients with CVDs, diabetes, hypertension, and IBD, thereby raising concerns about patients diagnosed with these types of diseases as to their suitability for radiotherapy. However, retrospective series, with several exceptions, have generally reported a tolerable incidence of complications among these patients. In addition, publication bias may have prevented some negative studies from being reported. Thus, the avoidance of radiotherapy for patients diagnosed with these diseases based upon case reports may have resulted in overly cautious treatment recommendations. However, it must be recognized that some people, in particular patients with active CVD, IBD, or a combination of uncontrolled hypertension with diabetes, may be at a greater risk for the development of normal tissue injuries resulting from a standard course of radiotherapy and should be treated with particular care.

As a manifestation of an inherent genetic susceptibility to radiation toxicity, studies were performed in which the in vitro radiosensitivity of skin fibroblasts was measured. It should be noted that although it could be expected that cell killing by radiation may play a central role in the etiology of early effects, late radiation effects in the skin are more likely a manifestation of a cytokine cascade induced by radiation resulting in an inflammatory response leading to a fibrotic reaction (Bentzen 2006). Thus, a correlation between killing of skin fibroblasts with late effects would be unlikely. Nevertheless, several initial studies reported an association between dermal fibroblast radiation sensitivity with the severity for both early and late effects (Loeffler et al. 1990; Oppitz et al. 2001). However, replication studies generally were not able to validate these initial findings as there was a lack of correlation between fibroblast radiosensitivity with late effects and only a weak association with early skin responses (Begg et al. 1993).

The initial results examining lymphocyte radiosensitivity did not suggest a correlation with adverse radiotherapy effects. In addition, because lymphocytes display differential radiation sensitivity, the changes in the levels of different lymphocyte cell-types resulted in large experimental variation (Stewart et al. 1988; Crompton and Ozsahin 1997). However, in more recent work that takes into account the cell-type specific radiosensitivities, it has been reported that the response of CD4 and CD8 T-lymphocytes to irradiation correlates with radiation-induced morbidity in a breast cancer patient population treated with radiotherapy (Crompton et al. 1999, 2001; Ozsahin et al. 1997; Azria et al. 2004; Ozsahin et al. 2005). In particular, an inverse correlation has been reported between radiation-induced T-lymphocyte apoptosis, especially in CD8 cells, with the development of late effects in patients from whom the lymphocytes were derived.

With the development of gene expression microarrays that provide the ability to measure the expression of a large number of genes following irradiation, it is now possible to examine whether differential expression of certain genes following irradiation correlates with the development of radiation-induced injuries resulting from radiotherapy. Expression was studied in fibroblast cell lines derived from breast cancer patients exhibiting a range of subcutaneous fibrotic reactions following post-mastectomy radiotherapy (Alsner et al. 2007; Rodningen et al. 2008). RNA was isolated 2 h following irradiation of fibroblasts and analyzed using a 15 K cDNA microarray. The results were compared with gene expression in unirradiated fibroblasts. A minimum set of 18 genes was identified that could differentiate patients who were at low risk for fibrosis compared with patients at high risk based upon the differential expression of these genes in the two populations. Using quantitative real time PCR, it was found that the relative magnitude of the increase in irradiated compared with unirradiated fibroblasts provided even greater discrimination between patients who were either sensitive or resistant to the development of subcutaneous fibrosis following radiotherapy. The results of this study indicated that differential gene expression of specific genes could distinguish between patients at low risk from those at high risk for a fibrotic response.

The most direct way to identify the genetic factors associated with susceptibility for the development of radiation-induced adverse effects is to identify the genetic variants that correlate with the manifestation of different forms of radiation-induced injuries resulting from radiotherapy. Putting aside copy number variants, humans are 99.9 % identical in their genetic makeup. Thus, about once every 1,000 nucleotides at least 1 % of the population exhibits a change in the DNA sequence that is the result of an ancestral mutation which has spread throughout the population resulting in substitution of a variant base pair at a specific nucleotide in the human genome for the one observed in the majority of the population (Frazer et al. 2007). These are referred to as single nucleotide polymorphisms or SNPs. Therefore, each individual is either homozygous for the major allele (the more common base pair), homozygous for the minor allele (less common pair base) or heterozygous for the allele (possessing the more common base pair in one copy of the chromosome and the less common base pair in the other chromosome of the pair). Although many of the SNPs in the human genome have little or no functional consequence, it is thought that some number of these genetic variants are associated with a susceptibility to the development of a diversity of biological end-points including physical attributes such height, weight and intelligence, an increased risk for a particular disease, and variation in the response to drugs and radiotherapy. This forms the basis of personalized medicine, which is the use of a person’s genotype to select a medical treatment for a certain disease or a preventative measure against the development of a specific disorder that is most appropriate for that particular person.