MANAGEMENT OF RADIATION PROCTITIS

Radiotherapy is frequently used in the treatment of cancer inc ombination with other treatments.

In men the two most prevalent cancers requiring radiotherapy are cancer of the bladder and cancer of the prostate.

“As after radical surgery where complications may occur, radiotherapy is not without problems,” reports Dr Chapuis.

Rectal bleeding is a known treatment complication of prostate cancer. Three different terms are used to describe this condition. They are:

•Actinic proctitis

•Radiation proctitis

•Chronic radiation-induced rectal bleeding (CRRB).


Rectal bleeding may complicate treatment in 5 to 10 percent of patients. Rectal bleeding is caused by radiation thickening of the walls of small arteries supplying the rectum, and so by narrowing them to restrict the blood flow to the rectal wall.

To compensate for this, new thread-like capillaries grow in profusion very close to the internal surface of the rectum. It is the fragility of these capillaries that causes the bleeding. As this does not involve true inflammation, “proctitis” is an inappropriate term.

Professor Chapuis prefers the third description: chronic radiation-induced rectal bleeding(CRRB). The rectal bleeding may not start until some 12 months to three years after treatment. Because bleeding is a known side effectof radiation therapy for prostate cancer, and rarely may be life-threatening, patients should be informed of this risk and consent to such treatment.

Rectal symptoms can fall into two broad categories which are partly dose-related: acute and chronic.


Acute:

Symptoms include tenesmus (pain on passing stools), diarrhoea, urgency of defaecation and bleeding.

Chronic:

Symptoms include stricture (narrowing or restriction), fistula (abnormal passage), CRRB, varying degrees of incontinence, loss of compliance and storage capacity of the rectum.


Clinical features of CRRB include:

• It is classed as Grade III on a scale of seriousness from I to IV, ie quite serious. Around 50 percent of cases are late onset (ie, starting later than one year after treatment).

• From a situation with the patient not experiencing any problems, it may become chronic with progressively increasing bleeding resulting in iron deficiency anaemia which may require daily dosage of iron tablets.

• Fifteen to 20 years ago it quite often led to transfusion-dependent anaemia, necessitating frequent blood transfusions, but this is now very unusual as a result of much improved radiotherapy techniques. It is important for prostate cancer patients to recognise that some degree of “collateral” damage will inevitably occur to the rectum due to the radiation treatment.

Late development of bleeding will be experienced by a small proportion of these patients, but this is nowhere near as common or severe a problem as in the past. A critical decision is whether the benefit of the radiation treatment of the cancer outweighs the risks of rectal bleeding or other complications as a result of that treatment.


The factors which affect the risk include:

• The total dose of the radiation

• The fractionation of the dose ie, how it is delivered

• The build of patient, as obese people are more susceptible

• Diabetes

• Hypertension

• Previous abdominal or pelvic surgery (adhesions)

• Chronic diverticular disease of the proximal bowel

• Bleeding may be exacerbated if taking drugs such as Asprin,Warfarin or Plavix Possibly because of their genetic make-up, some men are inherently more sensitive to radiation.


Quality of life issues that may influence the decision whether to opt for/out of radiotherapy include:

• The alarm caused by unexpected bleeds

• The late onset (leading to several years of anxiety about whether bleeding will occur)

• The absence of identifiable risk factors in many cases pre-venting prediction of whether any particular patient will be affected

• Whether the patient has other conditions, such as diabetesor hypertension.


Additional issues include:

• The unpredictable nature of the bleeding which is socially inconvenient and can be acutely embarrassing

• The resulting anaemia is debilitating

• Poor response to treatment

• Simple treatments often pre-scribed (like steroid supposito-ries or enemas) are usually of little benefit

• The condition can last a longtime

• There is a (small) possibility of it progressing to Transfusion Dependent Anaemia.


Patients with CRRB should be thoroughly assessed, including their history and a physical examination, a blood test including a full blood count, iron studies and coagulation profile. Then a safe and thorough examination by colonoscopy of the large bowel enables the severity of the condition to be determined and identification of other sources of bleeding.

A cystoscopy and/or special small bowel X-ray are sometimes appropriate. Sometimes anorectal manometry is needed to test the strength of the sphincter muscle prior to treatment.

The patient may be asked to keep a record of bleeds by marking a calendar as treatment progresses. There are several options for treatment, which will be influenced by the location of the source of bleeding and the extent of the condition.


Minimally invasive therapy includes:

• Electrocautery

• Argon Plasma Coagulation Therapy (APC)

• Endoscopic laser

• Formalin (formaldehyde) dressings applied under a general anaesthetic

• Hyperbaric oxygenation with multiple treatment episodes required.


In the case of APC or endoscopic laser, each potential bleeding pointneeds to be separately treated. The procedure may require several visits, spaced a few weeks apart, to allow the lining of the rectum to recover. The procedure may be undertaken under conscious sedation or general anaesthesia.

The use of formalin began in the1960s. It was found that the formalin destroyed the superficial lining (which then separated off) thus causing the bleeding to stop and allowing the new lining to regrow without blood vessels.

However, the appropriate concentration for the formalin was uncertain, and the approach was abandoned until more recently, when a particular low concentration has been found to be both effective and safe.

A blood count is taken before and after treatment. The patient undergoes a general anaesthetic and is prepared by applying plastic skin dressings applied to the skin surrounding the anal passage. A speculum is inserted and dressings containing formalin are packed into the rectum through it and left for five to ten minutes before being removed. This is repeated until bleeding ceases.


Up to 20% of patients treated with the formalin method experience complications, like:

• Mucus incontinence either from treatment or from the initial radiotherapy

• Some patients may need to wear a pad

• Acute prostatitis (very rare)

• Narrowing of the rectum (veryrare)

• Ischaemic ulcer.

This is pre-vented by taking care to cover exterior of anus with a plastic skin during treatment. Use of either the laser or the formalin method, or both together, results in 75 – 80% success.

However, treatment and follow up may be necessary for up to 12 months. For otherwise intractable cases, several surgical options exist.

Our sincere thanks to Dr Chapuis for his carefully structured presentation and clear explanations, and for fielding wide ranging questions. Summarised by Mark Tweed-dale and Pam Sandoe. Edited and approved by Dr Chapuis; 'The Management of Radiation Proctitis'.

Hormone Therapy applicable for Prostate Cancer

Researchers made a new study which suggests hormone suppression therapy could increase substantially an advanced prostate cancer patient's chances of living free of the disease.

Michel Bolla, a professor at Grenoble University Hospital, examined the potential benefits of suppressing the male hormone androgen, similar to the more commonly known male hormone testosterone, among 400 patients in advanced stages// of their prostate cancer, meaning their chances of survival were deteriorating. The international study involved patients throughout Europe as well as in Canada and Israel.

In the study, the men were randomly assigned to receive either radiation therapy alone or androgen suppression given during and after radiotherapy for three years. The average follow-up period was five and a half years.

Study results revealed almost three-quarters of the men who received the combination therapy, or 70 percent, had an increased five-year, disease-free survival rate compared to only 30 percent of patients who received only radiotherapy. Overall, survival rates were 80 percent within the hormone-suppression group and 62 percent for the radiotherapy group.

Bolla felt that at the present time a long-term hormone therapy 2 or 3 years compared to short-term resulted in statistically significant improvements in overall survival, as shown by this trial. The long-term survival rate for men with aggressive prostate cancer is poor, so additional therapies are needed to improve their chances. He added the findings also indicate hormone suppression with radiotherapy or external irradiation could trigger apoptosis -- the cancer cells destroying themselves.

However, there were side effects, Bolla said, including hot flashes, loss of libido and impotency. Kenneth Koeneman, urology professor at University of Texas Southwestern Medical Center at Dallas, said the side effects go beyond sexual dysfunction. "It's systemic castration," Koeneman told UPI.

Hormone suppression also can cause breast enlargement, a drop in muscle mass and an increase in body fat, he said. Prostate cancer patients on this particular therapy also are vulnerable to osteoporosis.

Hormone suppression is used in the United States, "but not necessarily for three years," he said. The reason it is used cautiously is "taking away the male hormone actually affects the marker we use" to detect cancer levels, Koeneman explained. That marker is called prostate-specific antigen or PSA, which is hormone-dependent. Hormone suppression may lower PSA levels suggesting the prostate cancer has been cut back, which might be an incorrect assumption.

"We may just be fooling ourselves that the cancer is not there," Koeneman said. He also questioned Bolla's assertion androgen suppression could contribute to cancer cell death. "Androgen suppression in the history of man has never cured anybody that we know of." Dr. Rowan Chlebowski, chief of medical oncology at the Harbor-UCLA Research Education Institute in Los Angeles, said doctors sometimes walk a tightrope between the potential benefits and downsides of hormone therapy.

Conservative therapies for hemorrhagic radiation proctitis: a review

ABSTRACT

Chronic radiation proctitis represents a challenging condition seen with increased frequency due to the common use of radiation for treatment of pelvic cancer. Hemorrhagic radiation proctitis represents the most feared complication of chronic radiation proctitis. There is no consensus for the management of this condition despite the great number of clinical approaches and techniques that have been employed. Rectal resection represents an available option although associated with high morbidity and risk of permanent colostomy. The effectiveness of nonoperative approaches remains far from desirable, and hemorrhagic recurrence represents a major drawback that leads to a need for consecutive therapeutic sessions and combination of techniques. We conducted a critical review of published reports regarding conservative management of hemorrhagic chronic radiation proctitis. Although prospective randomized trials about hemorrhagic radiation proctitis are still lacking, there is enough evidence to conclude that topical formalin therapy and an endoscopic approach delivering an argon plasma coagulation represent available options associated with elevated effectiveness for interruption of rectal bleeding in patients with chronic radiation proctitis.

GENERAL CONSIDERATIONS

Radiation proctitis can be classified as acute or chronic. Acute radiation proctitis (ARP) can begin during or shortly after irradiation but usually resolves in up to 6 months. It is characterized by diarrhea, intermittent bleeding, nausea, abdominal pain, mucous discharge, and constipation or even urinary symptoms. Histological alterations are usually confined to the mucosa5, and in general, has a short duration and improves with conservative measures. However, about 20% of the patients with RP require interruption of the treatment for 1 to 2 weeks in order to improve clinical status. Following this acute episode most of the patients remain asymptomatic, but up to 20% of this contingent will develop chronic radiation proctitis (CRP)6. The development of CRP may take up to 2 years and has no relationship with the occurrence of ARP7.

During the course of radiotherapy, virtually all patients present symptoms related to ARP. However, such symptoms usually subside from 2 to 3 months after the end of RDT8. Nevertheless, 2% to 10% of the patients develop CRP, usually 6 to 24 months after RDT, but clinical symptoms may appear up to 30 years after treatment9,10.

Chronic radiation proctitis has several forms of clinical presentation, including mucous rectal discharge, diarrhea, urgency, pain, and bleeding. Recto-vaginal fistula, enteric fistula, cutaneous fistula, perforation, and rectal stenosis can rarely occur. Histological alterations are mainly of a vascular nature, such as subintimal fibrosis and platelet thrombi in the arterioles of the submucosa with fibrosis of connective tissue5.

The development of RP is directly related to the dose of radiation, the irradiated volume, type of radiation exposure, dose fraction regimens, and the interval between sessions. Smith et al. reported a 20% incidence of RP with a radiation dose up to 7.500 Cgy and a 60% incidence of RP with doses greater than 7.500 Cgy11.

Other factors predispose to RP, including previous abdomino-pelvic surgery, obesity, diabetes mellitus, hypertension, atherosclerosis, and simultaneous chemotherapy. In 1997, Bertuccelli et al. studied the effect of the combination of chemotherapy with RDT in the treatment of rectal cancer and observed an increase in incidence of severe diarrhea in the group that received RDT plus chemotherapy when compared to the group that underwent RDT alone (20% versus 10%)12.

Endoscopic findings of RP are also variable. Since 1923, when the first endoscopic findings were reported, there have been many attempts to establish a standardized endoscopic approach to its diagnosis13. Paleness, erythema, vascular abnormalities, and ulcerations are easily recognized alterations. However, in order to correlate the clinical picture to endoscopic findings, Wachter et al. proposed a score for RP based on terminology of the World Organization of Digestive Endoscopy (OMED) and its 5 main alterations, namely telangiectasias, congestion, ulcerations, stenosis, and necrosis14.

The prognosis of RP remains obscure. Gilinsky et al., in 1983, reported on 88 patients with RP followed for more than 8 years. Fifty percent presented slight to moderate symptoms with distinct endoscopic findings that resolved spontaneously in 2 years10. Nevertheless, 17 patients presented refractory symptoms. Cho et al. observed that 19 out of 101 patients developed RP after radiation therapy for prostate cancer15.

Despite the fact that the incidence of RP tends to increase with time, RP still lacks research and attention. It should be noted that no consensus exists about its clinical and endoscopic evaluation and its natural history. Its behavior and prognosis are not completely known.

Rectal bleeding due to RP usually represents a chronic condition, and anemia is a common finding; sometimes bleeding may be severe. Several treatments for this presentation have been used, and as a result of its high recurrence rate, they were rarely utilized in a cyclic manner, which makes their evaluation difficult. We opted to review and analyze the results of conservative treatments of hemorrhagic CRP.

Steroids

In 1976, Goldstein et al. observed clinical improvement of a patient with radiation-induced proctitis who received salicylazosulfapyridine in combination with prednisone16. Subsequently, other studies were developed in an attempt to evaluate the use of steroids as a therapeutic alternative for RP, alone and also in combination with other modalities.

In 1984, Ben Bouali et al. demonstrated clinical and endoscopic improvement in 4 out of 33 patients treated with daily rectal administration of 5 mg of betamethasone in combination with diphenoxylate17. In 1977, Pajares et al. also observed a decrease of rectal bleeding after administration of prednisone18. More recently, Triantafillidis et al. reported 5 patients treated for RP with enemas containing 5 mg of betamethasone without any clinical improvement19.

In a prospective randomized study, Kochhar et al. compared the use of enemas containing prednisolone and 3 g of oral sulfasalazine in 18 patients to the use of enemas containing sucralfate in combination with an oral placebo in 19 patients for 4 weeks20. Clinical improvement was appraised by a score based on the number of bowel movements, bleeding, and tenesmus. Therapy with sucralfate was more efficient, better tolerated, and cheaper.

Another prospective randomized study in mice analyzed administration of 90 mg of hydrocortisone and showed endoscopic improvement and better tolerance when compared with betamethasone enemas21.

Steroids have been used for many years in the treatment of RP despite the absence of larger and well-designed studies22. Moreover, steroids were not able to achieve sustained resolution of symptoms for patients with CRP.

Aminosalicylates

Derivatives of 5-aminosalicylic acids (5ASA), also known as aminosalicylates, have been the object of research in treatment of RP since the studies of Menie et al. in 1975 showed efficiency of the 5-aminosalicylic acid drugs versus placebo in the prevention of diarrhea in patients undergoing pelvic RDT, as well as studies for their previous use in the management of inflammatory proctitis. Aminosalicylates act in reducing the production of prostaglandins in the intestinal mucosa20.

Goldstein et al. demonstrated the effectiveness of oral sulfasalazine in combination with steroid enemas in 1 patient16. Bem Bouali et al. demonstrated that administration of sulfasalazine, in oral or enema form, provided clinical and endoscopic improvement in 60% of patients17. In 1989, Ladas et al. demonstrated that administration of sulfasalazine in combination with sucralfate enemas was effective in controlling rectal bleeding and promoted endoscopic improvement in 1 patient with CRP.23

On the other hand, in 1989, Baum et al. showed that daily administration of enemas containing 5ASA for a period of 2 to 6 months was not able to induce clinical, endoscopic, or histological improvement in 4 patients with CRP24. Another study of 5 patients performed by Triantafillidis et al. demonstrated no improvement over 5ASA enemas.19

We believe that multicenter prospective randomized studies of aminosalicylates are needed to confirm their role in the management of RP, but available evidence suggests that they are not effective.

Sucralfate

Sucralfate is an aluminum salt that adheres to the mucous membrane, promoting the formation of a protective barrier that has been used for many years in the treatment of peptic ulcers. Its possible effectiveness for inflammatory proctitis and for colonic bleeding after endoscopic polypectomy is also under investigation.

The cytoprotective action of sucralfate seems to be derived from the production of prostaglandins and promotion of epithelial cell proliferation. In animal models of colitis in mice, rectal administration of sucralfate induced high E2-prostaglandin levels and increased cellularity of the colonic mucosa25.

The best route for sucralfate administration remains controversial. In 1988, Kochhar et al. used enemas containing 2 g of sucralfate in 4 patients with hemorrhagic RP and demonstrated reduced bleeding26. A previous study by Henriksson et al. in 1987 showed the usefulness of oral sucralfate administered for 2 to 6 weeks after RDT in the reduction of bowel movements, mucous discharge, and rectal bleeding after 1 year27. Another study by Kochhar in 1991 demonstrated the superiority of topical sucralfate over steroid enemas administered in combination with sulfasalazine20.

In 1996, Stockdale and Biswas reported that administration of enemas containing 2 g of sucralfate in a patient with hemorrhagic RP resulted in long-term control of CRP as revealed from 4 years of follow-up28. Again in 1996, Tada et al. demonstrated endoscopic improvement of CRP in 6 out of 7 patients treated with 2 g sucralfate enemas.29

In 1997, O'Brien et al. published the negative effect of a sucralfate suspension for prevention of ARP30. In this multicenter Australian study, 86 patients were randomized into 2 groups: 1 group received 3 g sucralfate enemas and the other group received a placebo. Enemas were administered once daily for a period of 2 weeks after RDT. Sucralfate enemas did not reduce symptoms associated with ARP and therefore should not be recommended in clinical practice.

In 1998, Sasai et al. published 3 cases of patients with hemorrhagic RP who had undergone previous sulfasalazine and steroid treatment without success. They experienced significant improvement of rectal bleeding after daily administration of 4 g of sucralfate during 1 to 2 months31. The authors emphasized the advantages of oral sucralfate, which include good tolerance and few side effects associated with control of the symptoms for a long period.

More recently in 1999, Kochhar et al. demonstrated that topical sucralfate produced sustained resolution of symptoms, in agreement with previous authors32. Stockdale and Biswas 28studied 26 patients with hemorrhagic RP that were treated with 2 g sucralfate enemas twice daily. The patients were examined every 4 weeks in the first 16 weeks of treatment and after that at an interval of 8 to 12 weeks. Twenty patients had a significant reduction of bleeding in the first 4 weeks of treatment, as did another 4 patients after 16 weeks. At a mean of 45 weeks, 7 patients had some kind of symptomatic recurrence. However, bleeding ceased soon after the sucralfate treatment was reintroduced.

Short-Chain Fatty Acids (SCFA)

During the past few years, many studies have been performed on short-chain fatty acids (SCFA) so that knowledge regarding these substances has increased. Short-chain fatty acids are organic acids containing from 1 to 6 carbons that are a product of bacterial metabolism of some carbohydrates in the colon; they are the main source of energy for colonocytes. Butyrate is the most important SCFA and is preferentially metabolized by colonic mucosa when compared to propionate and acetate. The dependence of the colon related to the oxidation of SCFA increases towards the rectum, and 70% of the oxygen consumed by the colonic epithelial cells is used in the oxidation of SCFA33.

The effect of SCFA on rectal and colonic mucosa has been tested in patients with RP in an attempt to obtain healing of mucous lesions33,34. In 1999, Pinto et al. in a double-blind randomized placebo-controlled trial studied 19 patients with CRP35. They demonstrated a beneficial effect from administration of 2 daily enemas with 60 mmol SCFA for 5 weeks in comparison with the administration of an isotonic solution. There was a significant decrease of rectal bleeding with SCFA as well as an endoscopic improvement. In 1995, Mamel et al. also demonstrated the efficacy of enemas containing 60 mL of SCFA twice daily for 4 weeks in the improvement of 6 patients with CRP36. In 1996, Al Sababagh et al. using the same solution described in the previous studies achieved clinical, endoscopic, and histological improvement in 7 patients with hemorrhagic RP37.

These results were not reproduced by Chen et al. in a prospective study, where they evaluated the evolution of 12 patients with hemorrhagic CRP for 2 weeks and did not find any significant difference in clinical, endoscopic, and histological aspects of patients treated with SCFA38.

More recently, Talley et al. compared daily administration of 2 enemas with 60 mL of butyrate in a concentration of 40 mmol to placebo for 2 weeks in a randomized double-blind study of 15 patients with CRP. They found no benefit from SCFA39.

In 1998, Cook and Sellin performed a literature review about SCFA in the management of colitis33. Regarding RP, the authors observed that studies showed early reduction of bleeding episodes, but SCFA had no influence in other symptoms such as chronic pain and tenesmus.

In spite of the great progress in the knowledge of the structure, metabolism, and action of SCFA, there is still need for additional data to confirm its effectiveness. Because of these conflicting data, there are no commercial preparations available for clinical use.

Formalin

The use of formalin in the management of RP emerged from its use in the treatment of bleeding tumors of the bladder and radiation cystitis40,41, 2.

In 1986, Rubinstein et al. successfully used a rectal wash with formalin for the first time in the treatment of RP42. The authors reported a 71-year-old patient irradiated for bladder cancer who developed diffuse hemorrhagic RP. The patient underwent general anesthesia and the rectum was irrigated with two liters of 3.6% formalin for 15 minutes, followed by irrigation with saline. An insufflated vesical probe was used in order to protect the sigmoid colon. The procedure was repeated after 2 weeks and after 3 months. Bleeding episodes immediately ceased and the patient was asymptomatic after 14 months.

After these results, many authors initiated treatments of hemorrhagic CRP with formalin. In 1993, Seow-Choen et al. used formalin in 8 patients with hemorrhagic CRP refractory to steroids and with a constant need for blood transfusions43. In this study, a 4% solution-soaked gauze was applied to the rectum through a rectoscope. Patients underwent regional anesthesia and had their perianal skin protected to avoid direct contact with the formalin. Contact between the gauze and rectal mucosa was maintained until the bleeding stopped (from 2 to 3 minutes). Bleeding ceased in 7 patients after a single session, while another patient needed an additional application.

In 1995, the same authors confirmed the effectiveness of direct application of formalin solution soaked gauze in 29 patients followed for 12 months44. In this study, rectal bleeding ceased right after application in 17 patients. Four patients needed a second application (72% success rate). The 5 remaining patients obtained only partial improvement.

The instillation technique proposed by Rubinstein et al. was modified by 2 groups. One of them used rectal instillation with 4% formalin after placement of a Foley catheter in order to delineate the superior limit of the instillation and protect the normal intestine in 14 patients resistant to steroid and/or sulfasalazine treatment45. Treatment was well tolerated, and 11 patients needed 2 applications while other 3 patients needed 3 sessions. After 6 months, 9 patients were asymptomatic (64%), 3 patients had incomplete resolution of symptoms, and 2 had no improvement. Saclarides et al. reported a study in which aliquots of 50 mL of 4% formalin were instilled into the rectum for 30 seconds each, with a total of 400 to 500 mL per session in 16 patients. They achieved complete symptom control in 81% of after 1 or 2 applications46. Four patients developed fissures in the anal verge and 1 developed tenesmus.

The technique of soaked gauze proposed by Seow-Choen was revised by 5 groups, with a total of 41 patients. Complete success rate ranged from 80% to 100% after 1 to 4 sessions (Table 1)43,47-51.

Recently, in an Australian study, a combination of formalin and Nd:YAG (neodymium yttrium-aluminum-garnet) laser was used in 14 patients52. First, the patients underwent an endoscopic Nd:YAG laser procedure and then were treated with a formalin application as described by Seow-Choen. A single session was enough for 9 patients, 2 sessions were necessary for3 patients, and 3 sessions forthe other 2 patients. After a 3-year follow-up, 10 (71%) patients had no rectal bleeding, and another one had a significant decrease in bleeding episodes. Two patients required an operation to manage their symptoms.

After these first published series with formalin as a therapeutic alternative for hemorrhagic RP, investigators have been trying to determine the best concentration and form of its application as well as its side effects. In low concentrations, formalin is not toxic. However, high concentrations can result in severe toxic effects. Additionally, the nutritional state and smoking can alter blood levels of formalin. The only reported case of intoxication after rectal irrigation occurred due to accidental infusion of 100 mL of 10% formalin. The patient developed chronic colitis that resolved after 2 months53.

Evidence suggests that formalin is very effective in the treatment of hemorrhagic CRP, mainly in cases in which the 2 distal thirds of the rectum are affected. Other advantages of formalin application are low cost, low incidence of side effects, availability, and its easy manipulation.

Endoscopic

Endoscopic management of CRP is based on endoscopic coagulation induced by Nd:YAG laser, electrocoagulation, or argon plasma coagulation (APC).

The first description of Nd:YAG laser use in CRP was published by Leuchter in 1982. The author reported the success of this technique for the control of rectal hemorrhage after 4 applications in 1 patient in which he used 30 shots driven to the endoscopically identified vascular alterations54.

The effectiveness of the Nd:YAG laser was confirmed by other authors in series with a total of 98 patients. One of the most important was published by Viggiono et al. in 1993 reporting on 47 patients. After an average of 2 sessions (7950 joules each), a 79% control rate of rectal bleeding was achieved55.

In 1998, Swaroop et al. described the technique for therapy with a Nd:YAG laser56. Initially, the patient should undergo a complete colonoscopy to determine the extent of the lesion. With an initial energy of 40 W and a maximum pulse duration of half a second, the laser is applied without direct contact to the mucosa, but with its tip less than 1 cm away from it. All visible lesions should be coagulated in the distal direction. A white clot should be obtained as a final effect, avoiding cavities in the intestinal mucosa. Complications of Nd:YAG laser therapy include tenesmus, abdominal pain, rectal stenosis, prostatitis, and recto-vaginal fistula55,57.

Laser therapy for hemorrhagic CRP was supplanted by argon plasma coagulation (APC) because it is more readily available, cheaper, and requires fewer safety precautions, while still yielding excellent results. Argon plasma coagulation is a diathermy method in which there is no direct contact between the electrode and the patient, and high frequency energy is applied to the tissue through the ionized argon. This technique is very suitable for coagulation of large bleeding surfaces and features the advantage of limited penetration (2 to 3 millimeters), minimizing the risks of perforation, stenosis, and fistulization. The char generated with APC promotes an interruption of the current passing through the tissue while Nd:laser continues to penetrate the tissue until it is switched off.

Since the first use of APC with a flexible endoscope described by Grund et al.58 in 1994, it has gained a wide popularity. Silva et al. in a study of 28 patients obtained good results59 and emphasized the possibility of application of the argon plasma in any direction, resulting in excellent access to vascular lesions. Gas flow eliminates oxygen from the coagulation area, avoiding carbonization of the tissue and smoke production. Moreover, light produced by gas ionization promotes good visual control of the procedure. Those authors also propose the use of 50 W of energy and a 1.5 L/min flow for the procedure. Fantin et al. demonstrated the effectiveness of APC in 7 patients after 2 to 4 applications, using as parameters an energy of 60 W and a flow of 3 L/min60.

Other authors have also obtained good results with APC. Taylor et al. used APC in 14 patients with hemorrhagic CRP61. Bleeding episodes ceased in 10 patients (71%), although they needed complementary applications. The summarized series are reported in table 261-63.

Argon plasma coagulation has proven beneficial in almost all available studies. Use of argon plasma technology for other applications especially in surgery increases the usefulness of the equipment.

Endoscopic treatment through electrocoagulation is simple, widely available, and cheap. Bipolar electrocoagulation may be safer than monopolar. Electrocoagulation and heater probes are readily available at most hospitals without significant additional cost. Because of its ready availability, it is one of our first options for hemorrhagic CRP. Distal telangiectasias can be treated conveniently by this method. All visible lesions should be treated in a single session. The most important technical aspect of telangiectasiasablation is to use the smallest possible amount of energy for coagulation, avoiding formation of deep ulcers. After the initial session of coagulation, an interval should be intervene before reexamination, since coagulated areas need time for healing.

Hyperbaric Oxygen Therapy

Hyperbaric oxygen (HBO) has been used in the treatment of the RP after previous experiences with other radiation-induced lesions (cystitis and dermatitis) with satisfactory results.

Its mechanism of action is based on the decrease of tissue hypoxia with consequent acceleration of healing process, restoration of local anti-infectious defenses, and directly toxic effects to bacteria.

Four publications reported excellent results with the use of HBO in 8 patients with hemorrhagic RP64-67. However, 2 recent studies demonstrated more modest results. The first of these obtained a 56% rate of good results for 18 patients68. The other was able to achieve 64% good results in 14 patients69. These studies were retrospective with controversial results. There may be recurrences, and it may take a long period of treatment for symptoms to resolve. In addition to the lack of scientific support, HBO is an expensive technique that is still restricted to specialized centers.

CONCLUSIONS

Many alternative techniques and research with other possible therapeutic agents for the treatment of hemorrhagic CRP, the most frequent chronic complication of radiation injury to the rectum, are currently under investigation71-73.The effectiveness of many therapeutic options has still not been shown with solid scientific evidence from controlled trials, and basic research may open a new perspective. Nowadays, the best alternatives for management of hemorrhagic CRP seem to be topical formalin and APC.

Despite all therapeutic strategies available for the management of CRP, the best one remains its prevention. Use of more advanced radiation techniques in the past few decades and introduction of less toxic regimens are good examples that may contribute to a decrease in incidence of CRP. However, the prevalence of CRP may increase as result of widespread use of radiotherapy for cancer treatment.

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May 26, 2003.

Preventing and Treating the Side Effects of Testosterone Deprivation Therapy in Men with Prostate Cancer A Guide for Patients and Physicians

Edited from PCRI Insights November, 2007 vol. 10, no.4

Brad Guess PA-C Former PCRI Executive Director

In the early 1940s, Drs. Huggins and Hodges discovered that when testosterone was removed by castration, men with advanced metastatic prostate cancer went into remission for 2-3 years. (1) They found that prostate cancer was “sensitive” to testosterone; prostate cancer grew when testosterone was present, and it died or went into remission when it was not. This ultimately led to the development of drugs that could eliminate testosterone and thereby accomplish the same thing without surgically removing the testicles.

Today, Testosterone deprivation therapy (also widely known as Androgen Deprivation Therapy) has largely replaced surgical castration through the use of Testosterone Inactivating Pharmaceuticals (TIP) that eliminate testosterone production or to block it at a cellular level at all stages of prostate cancer. LHRH agonists (Lupron®, Zoladex®, etc.) are drugs that eliminate testosterone. Antiandrogens (Eulexin®, Casodex®, or Nilandron®) block testosterone at a cellular level. This type of treatment is very effective at controlling prostate cancer, often for many years. However, you only have to speak briefly with a man who is taking these drugs to find out that there are a lot of side effects from having no testosterone!

This guide is intended for those men who find themselves on a TIP* for prostate cancer, and may or may not already be experiencing side effects of having no testosterone. Table 1 lists the most common acute side effects and Table 2 lists the most common chronic side effects of TIPs. The guide should not be used as a substitute for medical advice from a qualified medical provider. Rather, prostate cancer patients and their physicians should use the guide to discuss strategies for preventing and treating these side effects.

* Editor’s Note: The acronym TIP describes all testosterone inactivating pharmaceuticals. Hence, in this article use of the acronym TIP may refer to a single pharmaceutical or several pharmaceuticals.


Table 1. Common Acute Side Effects from Testosterone Deprivation Therapy


ACUTE SIDE EFFECTS

(Symptoms usually start to occur within the first 2-3 months after starting testosterone deprivation therapy)

• Loss of Libido (“sexual drive”)
• Loss of nocturnal erections (associated with ED)
• Hot flushes (can affect quality of life in some men)
• Breast tenderness (usually is felt before growth is observed)
• Anemia (a drop in hemoglobin can occur in as quickly as one month)
• Cognition and memory decline (should be assessed on a regular basis)
• Diarrhea (occurs more often with flutamide than with Casodex®)
• Abnormal liver function test results (seen with the testosterone blocking medications, they must be stopped)

Table 2. Common Chronic Side Effects from Testosterone Deprivation Therapy

CHRONIC SIDE EFFECTS

(Symptoms usually start to occur 3-4 months after starting testosterone deprivation therapy and can persist)

• Erectile dysfunction/Disuse atrophy of the penis (probably a result of loss of nocturnal erections)
• Dry ejaculations (from atrophy of prostate)
• Bothersome urinary symptoms (sometimes gets better, sometimes gets worse)
• Bone mineral density loss (4-10% in the first year of a TIP use)
• Loss of muscle strength (will continue without resistance training)
• Joint aches and pains (usually in the hands)
• Breast growth (much worse for men on testosterone blocking monotherapy)
• Fatigue/excessive daytime sleepiness (probably from loss of muscle strength, can get worse with time)
• Changes in metabolism, weight gain, body composition, and lipid profiles
• Depression and emotional distress (patients and their family need to discuss this with their medical providers)
• Changes in blood pressure (up or down)
• Dry skin and loss of body hair
  

Most of the suggestions in the guide are based on clinical research studies; however, since research in the prevention and treatment of certain side effects is often lacking, some of the suggestions are based on my own clinical experience. The references cited in the guide come from a paper I co-wrote entitled “Preventing and Treating the Side Effects of Testosterone Inactivating Pharmaceuticals in Men with Prostate Cancer”, published in Seminars in Preventive and Alternative Medicine, June, 2006.


Erectile Dysfunction, Loss of Libido, and Loss of Nocturnal Erections

About one-third of men over the age of 40 have some degree of trouble getting and maintaining erections. (2) Since men with prostate cancer tend to be older, many may have erectile dysfunction (ED) prior to starting testosterone deprivation therapy. The loss of testosterone usually makes this situation worse or creates ED for the first time in a man’s life. There are two components to ED in men on a TIP:

The loss of libido (sexual interest) occurs in as many as 8-9 out of 10 men on testosterone deprivation therapy. (3) Many men will lose their libido completely, while others lose it only partially.

The loss of nocturnal erections (the spontaneous erections all men get at night when they sleep), can lead to atrophy (shrinkage) of the penis and progressive difficulty getting erections.

Prevention / Treatment Strategies

Unfortunately, there is no treatment for the loss of libido. However, it usually returns once testosterone deprivation therapy is stopped and testosterone levels return to normal. A four-step prevention and treatment strategy for men with prostate cancer on a TIP is outlined in Table 3. It should be noted that this strategy should be discussed thoroughly with your medical provider, since it potentially involves several different medications. Some men may find this strategy cumbersome, especially if their libido is gone. However, remember that it is a strategy for “maintenance” of erectile function. The idea is to maintain function, so that if the time comes when testosterone deprivation therapy is stopped, things can return to normal.


Table 3.

Four step prevention and treatment strategy for maintenance of erectile function in men receiving TIP.

Step 1: Nightly (every other night when Cialis® is used) low doses of an oral PDE-5 inhibitor. This is used to maintain nocturnal erections.

Step 2: Daily (if possible) use of a vacuum erection device for “exercising” the penis to prevent atrophy.

Step 3: Use an oral PDE-5 inhibitor (men should be encouraged to try each of the available choices to determine which works the best for them) as needed for sexual intercourse. Men can combine the PDE-5 inhibitor and vacuum erection device if needed.

Step 4: Consider the use of Muse® (as an urethral suppository or intercavernosal injection) in cases where an adequate erection for intercourse is not achieved with Step 3. Men can combine Muse® and a PDE-5 inhibitor if needed (only after discussing with their medical provider).


Dry Ejaculation

In men who have an intact prostate and have not had it removed, radiated or frozen, the normal fluid production of the prostate stops while they are on testosterone deprivation therapy. Therefore, when a man ejaculates it will be dry. Some men report that the pleasure of an orgasm with dry ejaculation is reduced.

Prevention / Treatment Strategies

Unfortunately there is no way to prevent or treat this problem. However, once testosterone deprivation therapy is completed and testosterone levels return to normal, the prostate typically begins to produce fluid again and ejaculate returns.


Bothersome Urinary Symptoms

Some men notice that bothersome urinary symptoms (such as a slow urine flow, getting up frequently at night to urinate, and dribbling urine) improve after they are on a TIP. This is probably due to the shrinkage that takes place in the prostate after testosterone is removed. On the other hand, some men have an increase in such bothersome urinary symptoms.

Prevention / Treatment Strategies

Discuss with your doctor a simple test to check your “postvoid urine residual” (how much urine is left in your bladder after you urinate). If the amount is greater than 100 ml (a little less than half a cup), you may benefit from a class of drugs call “alpha blockers”. Examples are Flomax or Uroxatrol. If your postvoid residual urine is less than 100 ml and you are having trouble holding your urine or dribbling, “Kegal” exercises can be helpful (your medical provider can explain these and information about how to do them can be found on the Internet). If Kegel exercises do not help, a number of anticholinergic drugs such as Detrol® or Ditropan® may improve the symptoms.


Bone Mineral Loss

The loss of bone mineral density is usually a silent side effect of testosterone deprivation therapy. It can occur at a rate of 4-10% after the first 12 months of a TIP application. (4) , (5) Given that most men with prostate cancer are older and as many as half of men starting testosterone deprivation therapy may already have some bone mineral loss or even osteoporosis, the risk of a bone fracture warrants serious attention. It is essential that men be screened for osteoporosis with a bone mineral density test prior to starting the application of a TIP or soon after.

Prevention / Treatment Strategies

If osteoporosis is detected with screening prior to the start of testosterone deprivation therapy, it is important that you discuss with your medical provider the potential for other causes of bone mineral loss, besides that which occurs as a part of normal aging. Restricting the excess use of alcohol, tobacco, caffeine, and vitamin A is the first step in preventing and treating bone mineral loss. You should do resistance exercises and supplement your diet with 1200-1500 mg of calcium (preferable calcium citrate) and 2000 IU of Vitamin D should be implemented. If osteoporosis is detected with screening and no other underlying cause has been identified, discuss the use of oral or intravenous bisphosphonates with your medical provider. Bisphosphonates are a class of drugs that inhibit osteoclast-mediated bone resorption (the breaking down process of bone that can occur while on a TIP). Urine tests such as N-telopeptide and Pyrilinks-D can be performed periodically to monitor excessive bone breakdown while on a TIP. Yearly bone mineral density testing is recommended for men on (TIP).


Sarcopenia (Loss of Muscle Strength)

The elimination of testosterone in men leads to a deterioration of lean muscle mass, an increase in fat mass, and a subjective decrease in physical function. In other words, men get weak, gain weight and don’t feel as well when they are on testosterone deprivation therapy. These side effects become evident within the first three or four months after starting on a TIP and progress the longer a man continues treatment.

Prevention / Treatment Strategies

Research shows that strength training can often prevent or reverse the loss of muscle mass and physical well-being associated with the reduction of testosterone. (6) The importance of regular strength training cannot be stressed enough. It should be a priority in any strategy to prevent and treat the side effects of any TIP. The essence of a successful strength-training program is lifting weights to the point of muscle failure. Programs to build muscle need to start slowly for the first few months so that no injuries develop. A professional trainer is highly desirable.


Joint Aches and Pains

Men who are on testosterone deprivation therapy for six months or more will commonly complain of the onset of new joint aches and pains, particularly in the hands but sometimes in other joints.

Prevention / Treatment Strategies

Speak with your medical provider about the use of over the counter preparations such as glucosamine, MSM (methylsulfonylmethane) or nonsteroidal anti-inflammatory drugs (NSAID’s) such as ibuprofen and naproxen (there is weak evidence that chondroiten may not be advisable for men with prostate cancer). Maintaining good muscle strength and tone will provide better joint support and can minimize these aches and pains.


Hot Flushes

Hot flushes are described as sudden, intense warmth in the face, neck and chest, often followed by sweating. Hot flushes are one of the most common side effects in men on testosterone deprivation therapy, occurring in up to 70% of men. (7) Generally, men regard hot flushes as an irritating, but tolerable nuisance. However, some men find that hot flushes have a significant impact on their quality of life, sleep and work.

Prevention / Treatment Strategies

There is no known way to prevent hot flushes in men on a TIP, and treatment for them should generally be reserved for those men with severe hot flushes that affect their daily living. There are several treatments that have been shown to be effective at reducing the number and severity of hot flushes.

1. Acupuncture (twice a week) has been shown to decrease the number of hot flushes by as much as 70%. (8)

2. The use of isolated soy protein powder (40g/day) added to the diet can reduce hot flushes by up to 45% (vs. a 30% reduction with placebo). (9)

3. The most effective treatment for men with severe hot flushes when on a TIP is the hormone progesterone, which is administered as medroxyprogesterone. (10) This medication is given as a shot (400mg) and often is sufficient to control hot flushes for 6-12 months.

4. Another form of the hormone progesterone is progestin megestrol acetate (Megace®); in doses of 20 mg twice per day, it can be very helpful. The most common side effect of progesterone is an increased appetite. A brief word of caution; there has been a single report in the literature of a case of prostate cancer progression associated with the use of progesterone. (11)

5. Low-dose estrogen (1 mg in the form diethylstilbestrol) can improve hot flush symptoms by up to 70%. (12) However, estrogen, even at low doses, can cause breast tenderness and growth, swelling of the lower legs and on rare occasion blood clots. Diethylstilbestrol (DES) is not commercially available at retail pharmacies, but can be obtained relatively inexpensively at most compounding pharmacies.

6. The antidepressant venlafaxine (Effexor-XR®) at a dose of 12.5 to 37.5 mg can be very effective at reducing hot flushes. (13) If men also have symptoms of depression while on a TIP, venlafaxine should be considered as the first choice of medication for severe hot flushes.

7. Gabapentin (Neurotin®), an anti-seizure medication, can be tried by men who have failed to respond to other treatments. The commonly used dosage of gabapentin is 300-900 mg divided in two to three does daily.


Breast Tenderness and Growth (Gynecomastia)

Between 13-22% of men treated with a testosterone-lowering drug such as Trelstar® or Zoladex® report having breast growth and or tenderness. (14) This problem can occur in as high as 50-73% of men who are on a testosterone blocking medication alone, such as Casodex® or Eulexin®. (15) , (16 )

Prevention / Treatment Strategies

Breast tenderness and growth can be reduced or prevented if treated before symptoms develop. However, once growth becomes established, the condition is irreversible and can only be corrected with surgery (mastecotomy or liposuction). The following list of treatments can be helpful and should be discussed at length with your medical provider:

1. Radiation to the breast (usually just around the nipples) before the start of testosterone deprivation therapy can reduce the risk of breast growth and tenderness by as much as 65%. (17) This is especially important for a man to discuss with his medical provider prior to starting monotherapy with Casodex® or Eulexin®, because of the high incidence of breast growth and tenderness with this type of testosterone blocking treatment.

2. The medication tamoxifen (Nolvadex®) (used to treat breast cancer) can prevent breast growth and tenderness in over 60% of men on a TIP.18 However, there is some concern that it may increase the risk of a blood clot or hot flashes.

3. The medication letrozole (Femara®) (also used to treat breast cancer), can be very effective and has few side effects. However, there are no clinical studies that have confirmed its effectiveness when used by prostate cancer patients on a TIP. This suggestion is based on the author’s experience.


Fatigue/Excessive Daytime Sleepiness

The main cause of fatigue for men on testosterone deprivation therapy probably comes from the loss of muscle mass and strength. As men loss muscle mass and strength, many also complain of excessive daytime sleepiness.

Prevention / Treatment Strategies

1. The most important strategy for men to prevent or reduce fatigue while on a TIP is a regular strength training program. As mentioned before, this strategy is best accomplished with the help of a qualified personal trainer.

2. The medication modafinil (Provigil®), which is FDA approved for the treatment of narcolepsy, sleep apnea and shift work sleep disorder, can be helpful for men with excessive fatigue and daytime sleepiness. Modafinil has few drug-to-drug interactions and is usually well tolerated, with the most frequent side effect being transient headaches. However, the use of modafinil has not been studied in men with prostate cancer on testosterone deprivation therapy.

3. Low doses (5-10 mg) of the stimulant methylphenidate (Ritalin®) taken in the morning can also be helpful for men with excessive fatigue and daytime sleepiness while on a TIP. Methylphenidate must be used with caution in patients with hypertension or a history of arrhythmias (abnormal heartbeat).


Changes in Metabolism, Body Composition, and Lipid Profiles

Some of the most troubling and often overlooked side effects in men with prostate cancer treated with a TIP are those that can negatively impact cardiovascular health. Studies of men on testosterone deprivation therapy show an increase in weight, body fat, serum levels of glucose and insulin, uric acid, total cholesterol, triglycerides, and the stiffness of arteries.

Prevention / Treatment Strategies

Prostate cancer patients who are on a TIP should regularly have their weight, blood pressure, lipid profile, homocysteine and C-reactive protein monitored. Patients in collaboration with their medical providers should thoroughly review the role and appropriateness of antioxidants, low dose aspirin, vitamin B-12, folic acid, fish oil, low glycemic index diets, and statin drugs. Screening for cardiovascular disease with an exercise stress test or a coronary artery calcification scan should be considered. (18)


Anaemia

The development of anemia (low red blood cell counts) is common in prostate cancer patients treated with a TIP. Fortunately, most men have no symptoms and do not require treatment for anemia related to testosterone elimination. However, about 15% of men will have symptoms such as fatigue, shortness of breath, and a decrease in quality of life. (19) So anemia should be discussed at length with your medical provider.

Prevention / Treatment Strategies

For those men who are symptomatic from anemia while on a TIP, an evaluation of other potential causes of anemia such as bleeding, iron, B-12 or folate deficiencies should be considered. Anemia related to testosterone elimination is not related to deficiencies of iron, B-12 or folate and can be treated and reversed quickly with low doses of synthetic erythropoietin (Procrit®, Aranesp®).


Cognition and Memory Decline

Research on the effects of testosterone deprivation therapy in men with prostate cancer on cognition and memory is limited and inconclusive. However, many men do complain, “my memory is just not what it used to be” or “I’m just not able to concentrate as I used to”.

Prevention / Treatment Strategies

The importance of keeping intellectually stimulated and mentally active during treatment with a TIP cannot be underestimated. Because most men treated with a TIP are elderly, it is important for medical providers to assess whether negative changes in cognition and memory represent early signs of Alzheimer’s, vascular dementia, or other cognitive disorders.


Depression and Emotional Distress

Prostate cancer patients on testosterone deprivation therapy report feeling depressed and having wide emotional swings (crying one minute and being angry the next. The cause of this is unknown, and no research exists to answer the question

Prevention / Treatment Strategies

If men develop depression and or emotional swings after starting, it is important for them or their family to discuss the problem with their medical providers, because depression and emotional swings can have a significant negative impact on quality of life. The group of antidepressants called selective serotonin reuptake inhibitors (SSRIs ex: Prozac®) and selective serotonin and norepinephrine reuptake inhibitors (SSNRIs ex: Effexor®) are often effective in this situation. As previously mentioned, if a man has significant hot flashes in addition to feelings of depression or emotional swings while on a TIP, the medication venlafaxine (Effexor®) may the best first choice for treatment. Individual psychotherapy with a licensed clinical psychologist can also be very helpful for some patients. The combination of an SSRI and individual psychotherapy is the most effective treatment for men with moderate to severe depression.


Changes in Blood Pressure

Changes in blood pressure, both upward and downward, have been observed in men on testosterone deprivation therapy. However, there is no research available to validate these observations.

Prevention / Treatment Strategies

Regular blood pressure measurements should be performed on men receiving a TIP. Standard management similar to that used for patients who are not on testosterone deprivation therapy (the addition or removal of blood pressure medications) is effective.


Diarrhea

Flutamide causes diarrhea in approximately 6.1% of men and Casodex® causes diarrhea in 0.5% of men. (20)

Prevention / Treatment Strategies

Diet modification and symptomatic treatment with anti-diarrhea medication may be helpful. However, the medication almost always has to be stopped. In my experience, if patients develop diarrhea with one of the testosterone blocking medications, they can usually switch to other medications with little difficulty.


Abnormal Liver Function Test Results (Liver Toxicity)

Liver toxicity can occur in approximately 2.5 and 1.4% of men taking the testosterone blocking medications flutamide and Casodex®, respectively. (20)

Prevention / Treatment Strategies

Routine monitoring of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) will detect liver toxicity early. Usually it is necessary to stop the medication. However, in mild cases, the problem may be transient and may cease when the medication is stopped or the dose is reduced. Men who have liver toxicity from one testosterone blocking medication can usually be safely treated when taking another. Some evidence exists that milk thistle (Silybum marianum) may have a protective effect on the liver and may possibly be beneficial for reducing ALT, although this has not been clearly established. Fortunately, available evidence does suggest that milk thistle is associated with few, generally minor adverse effects. The usual dose of milk thistle is 200 mg taken three times a day.


Dry Skin and Loss of Body Hair

Men on testosterone deprivation therapy often complain of dry skin and generalized loss of body hair.

Prevention / Treatment Strategies

The regular use of moisturizing lotion will reduce the bother of dry skin. These side effects cease with the end of treatment, when testosterone levels return to normal.


Conclusion

The medical evidence that testosterone deprivation therapy has substantial anti-prostate cancer effects continues to mount. Consequently, its use has become increasingly more common for all stages of prostate cancer. However, the potential for significant side effects that can dramatically reduce a man’s quality of life are a real concern with this type of therapy. Unfortunately, little attention has been given to the prevention and treatment of these side effects. It is my hope that this guide will open the lines of communication between men and their medical providers, and provide a tool to help them prevent and treat these side effects effectively, so that men can gain the full benefit of this treatment and still maintain a good quality of life.

Editor’s Note: This guide was the last document written by Brad before his untimely death from a heart attack in June 2006.

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