Robert S. Krouse
Cancer Chemother Rev. 2008;3(4):152-160. ©2008 P. Permanyer
Palliative care is increasingly recognized as an important component of quality care for cancer patients. Given an estimated 1,437,180 new patients diagnosed with cancer in the USA in 2008 , and approximately 565,650 cancer-related deaths, care for those patients who are near the end of life is an essential aspect of cancer care. Palliative care is an interdisciplinary team approach to care, with a focus on comfort and quality of life rather than prolongation of life or “cure” for a patient and their loved ones. Depending on the palliative care issue, many various treatments approaches may be available to manage symptoms and complications of advanced cancer. Common palliative care problems include pain, cachexia, asthenia, and wound issues. Examples of frequent concerns that necessitate an interdisciplinary team approach include pain, dyspnea, and malignant bowel obstruction. It is imperative to consider invasive or minimally invasive approaches in addition to noninvasive approaches for each of these problems. Each of these issues may mandate the expertise of specialists beyond the palliative care practitioner or medical oncologist, including surgeons, interventional radiologists, gastroenterologists, radiation oncologists, or anesthesiologists. Often there is a lack of high-quality research related to the optimal approach. The absence of an established evidence base in many areas of palliative care, at least in part due to the major challenges investigators face in designing palliative-care trials, emphasizes the need to involve other specialists in the care of these patients. In this way, the optimal approaches can be offered at this time of distress for patients and families.
Approximately 565,650 people die in the USA each year related to cancer. Care for those patients who are near the end of life is an essential aspect of cancer care. The World Health Organization (WHO) defines palliative care as “the active total care of patients whose disease is not responsive to curative treatment. Control of pain, of other symptoms, and of psychological, social, and spiritual problems is paramount. The goal of palliative care is achievement of the best QOL for patients and their families.” Quite simply, palliative care is treatment with the intent to improve the quality of life (QOL) for patients. Palliative care is an interdisciplinary team approach to care, with a focus on comfort and QOL rather than prolongation or “cure” for a patient. The goal of palliative care is to relieve suffering and to improve QOL. In addition to curative treatment for cancer patients, recent years have seen a dramatic increase in a focus on palliative care. Although the past 10 years have seen impressive growth in palliative care research, this rate of growth appears to be particularly rapid for interventional research, including controlled trials of pain medications,[5,6] interventional procedures for pain, and other nonpharmacologic interventions to improve a variety of aspects of end-of-life care.
Interdisciplinary Nature of Care for Patients Facing the End of Life
There are multiple potential treatments for palliative care problems. These can include medical symptom management, surgical interventions, radiation therapy options, endoscopic opportunities, chemotherapy, as well as many innovative and complementary alternatives. In addition, palliative care teams must include nursing, social work, chaplain services, along with other potential specialties that could impact on a patient’s QOL. There are often widely variant therapies for a specific QOL problem, enforcing the need for interdisciplinary teams to design optimal treatment approaches.
Goals of Treatment
The benefits and risks of treatments are always of paramount importance, and are crystallized in the patient with advanced cancer. Therapies should always focus on quality of life, symptom control, and symptom prevention. One must also consider that there will frequently be a secondary benefit: survival. This is clearly an important goal of patients and families and must not be forgotten, even in the setting of incurable disease. Unfortunately, the literature frequently focuses exclusively on survival as an endpoint, leaving surgeons with little information on an intervention’s impact on QOL.
A major dilemma for the practitioner caring for a patient with a terminal cancer is that measures of success are unclear. Often the literature is a poor guide for decision-making for this population of patients. Outcome measures related to QOL are not clearly defined and documented. For example, what little focus there is on palliation in the surgical literature has been remiss in examining appropriate QOL outcomes. In fact, from 1990 to 1996, quality of life measurements have been included in only 17% of reports of palliative procedures in the surgical literature and only 12% examined pain. This is in contrast to the more common outcome measures of physiologic response (69%), survival (64%), and morbidity and mortality (61%). While it is imperative to understand these outcomes, they should not be the primary focus of palliative procedures as they may not equate with an improvement in QOL. In addition, goals for palliative procedures may be broad and multifaceted. When queried about the major goals of palliative procedures, in addition to the obvious aims of symptom relief and pain relief, surgeons also felt that common objectives of such procedures include maintaining independence and function, symptom avoidance, and fewer and shorter hospitalizations. One specific example of the lack of a defined literature related to determining success is malignant bowel obstruction, where multiple outcomes are measured leading to no consensus for practicing surgeons.
Palliation is most commonly considered in the setting of an active symptom that needs to be addressed. Less attention has been given to the prevention of symptoms in the palliative setting, but this too is a goal of treatment, especially palliative surgery. Many symptoms related to tumors are known to occur, but it is less understood if or when the symptom will actually occur. Therefore, it is not always clear when or if a procedure would be helpful. Appropriate preemptive palliative surgery must consider prognostication related to a particular symptom, as well as the lifespan of a patient. For example, in the setting of biliary obstruction where a surgical bypass is attempted, one must also consider a gastric bypass to alleviate the risk of a patient having a gastric outlet obstruction prior to death. Another example may be with nodal dissections in the setting of positive sentinel node mappings, especially if distant disease is noted. A nodal dissection will have little effect on long-term survival, but this procedure may alleviate the risk of nodal recurrence and the suffering this may cause. Therefore, while there is frequently no clear direction for surgeons in these settings, preemptive palliative procedures should be considered in settings where tumor-related morbidity can be anticipated. As always, the inherent risks of an operation must be considered, but these are more difficult to assess when the benefits are ultimately unknown.
Risk of Treatment
With every goal of success there must be an understanding of risk. While all treatments contain risk, this is magnified with patients who are facing the end of life. Complications will still occur even with the most fastidious care, especially if the patient is debilitated related to the cancer or underlying conditions. Related to operations, morbidity may include complications not directly related to the procedure, such as pneumonia, deep venous thrombosis, ileus, and heart failure. With meticulous care, these can often be avoided. Related to any procedure, pain is a major issue that must be recognized and it may persist throughout the patient’s course. Epidural, patient-controlled analgesia and local anesthetic pumps may improve pain control and ultimate outcomes. In addition, wound complications may always occur. For example, it has been noted that lymph node dissections may have quite high rates of wound problems (47% for axillary node and 71% after inguinal node dissections). Issues such as seromas and infections may be long-term problems that take weeks to months to heal. Patients with advanced cancers may not have time to heal these wounds. Lymphatic leaks may necessitate procedures to isolate the offending lymphatic vessel. As new innovations are utilized, outcomes will continue to improve for patients. Next, acceptance of major disfigurement and lifestyle changes are most pronounced in the immediate postoperative setting. For example, the shock of a permanent stoma may be overwhelming for many patients. While QOL problems related to ostomies may diminish with time, this may not be possible for the patient facing the end of life. It must be considered that symptoms may actually worsen after a procedure. Hospital stays may be longer if complications occur. Finally, any aggressive treatment may hasten someone’s death, which is the ultimate poor outcome.
There are multiple issues to consider when deciding who is a candidate for palliative interventions. These considerations may lead to a successful palliation with limited morbidity and mortality. For example, patient nutritional status, and specifically albumin level, is frequently an excellent tool to decide when not to operate. Related to esophageal resections, which for many patients is a procedure whose goal is primarily the ability to swallow, albumin along with pulmonary function may be the best determiner of likely success. In addition, it is important to assess the overall condition of patients, including other medical problems and how they may affect overall risk. In all, there are no defined criteria of what is the optimal palliative intervention, but there are multiple clues as to which treatment is likely to result in the best (or worst) outcome.
Overview of Palliative Care Problems
There are multiple examples of problems that can affect the QOL for a patient facing the end of life. These can be categorized based on symptoms or systems in the body that are affected. Major symptoms include pain, dyspnea, anorexia, and depression. Related to body systems, one can imagine a potential symptom related to each body system. Neurologic problems include fatigue, headache and other pain syndromes, and delirium. Pulmonary complications include dyspnea, fatigue, and immobility. Cardiac symptoms include shortness of breath, fatigue, and pain. Gastrointestinal problems include obstructions, diarrhea, nausea, vomiting, and anorexia. Musculoskeletal complications include fractures, functional loss, and pain. Epidermal problems mainly focus on wound problems, but also can include poor cosmesis and pain. Complications related to the hematologic system include infection and fatigue. Urologic problems include ureteral obstructions, bleeding, and pain. It is this compendium of problems that palliative care research focuses on, rather than increase in survival time or cure.
The list of palliative care problems is exhaustive; several have limited approaches to care. For example, the most common problem for patients with advanced cancer is asthenia. Asthenia is often seen in a symptom cluster along with pain and depression. It is also highly associated with anorexia and cachexia. In almost all settings, fatigue is treated utilizing medications to augment appetite, antidepressants, or possibly blood transfusions or medications to increase hemoglobin production. Another consideration is the elimination of sedating medications, although in the setting of pain this may not be reasonable. An example of a problem that is managed without medical interventions is exemplified by wound care, for which local care or surgical debridement is typically the best option. Three examples of common palliative care conundrums that are more interdisciplinary in nature and have multiple options, including medical, surgical, gastrointestinal, or radiation therapies, are pain, dyspnea, and malignant bowel obstruction.
The issue of pain related to cancer and its treatment is quite common and plays an overwhelming role in a patient’s life. Nearly 75% of patients with advanced cancer have pain, with most having moderate or greater levels of pain. Chronic pain may be related to nerve disruption at the time of surgery, tumor-related persistent pain, or other treatment- related issues. Frequently, these may not be well described by the patient or well understood by the medical team. The psychological health of the patient may have a significant role in the perception of pain, and chronic pain may also severely negatively impact a patient’s psychological health. If a patient has a poor prognosis, pain may be accentuated in comparison to a patient who is in remission.
A focus on pain has brought anesthesia pain specialists, palliative care specialists, and others together to study optimal approaches to the myriad of pain syndromes that long-term cancer survivors face. Clearly, there are many approaches to the treatment of pain. The etiology, type, intensity, location, and time course of pain, as well as a patient’s tolerance to pain, may all impact the choices of care. Tumor-specific pain is most commonly treated with an opioid, and nonsteroidal medications may also have a role. The predominant rule of treating cancer pain is to play close attention to the patients’ report of pain and to treat with doses necessary to relieve pain, even though the amounts may seem prohibitively high. In addition, it must be remembered that as tumors grow, pain may increase, leading to greater requirements of medications. While oral medications are most common, intravenous or transdermal options must be considered. Subcutaneous dosing has the major detriment of being quite painful, and typically should not be considered.
Alternative treatment approaches to pain should often be considered, especially in those with pain that is difficult to control with medications, or where the medications do not allow the patient to achieve other activities of import, such as spending time with loved ones. Practitioners including interventional radiologists, anesthesiology pain specialists, radiation oncologists, surgical oncologists, and pharmacists should be part of the team with complex pain issues. Additionally, the use of complementary non-drug techniques may play an increasing role as they are studied. For example, it has recently been reported that massage therapy is an effective and safe adjuvant therapy for the relief of acute postoperative pain after a major operation. Acupuncture may have a role, although the benefits may not be clear at this time.[20,21] Other techniques, such as hypnosis and Reiki therapy, may also have benefits. Importantly, any specialist that could offer a beneficial treatment should be involved early to impact patient care as best as possible. Based on a thorough understanding of the pain experienced by the patient, the optimal approach or approaches can be initiated.
The use of chemotherapy as a treatment option in end-of-life care remains controversial. Related to pain, tumor shrinkage and relief of pain is a reasonable goal in limited instances. One clear example where chemotherapy may be of benefit for pain relief is in the setting of unresectable pancreatic cancer. Gemcitabine, alone or with other chemotherapies, has been shown to improve pain via decreases analgesic consumption and pain severity in up to 57% of patients.[23-25] The use of chemotherapy with the goal of improving pain or other symptoms must be carefully weighed against the burden of this treatment. In addition, the intent of treatment must be clear to the patient and family so that miscommunications do not arise.
While many examples can be considered, bone metastases and pain provides an excellent model of the interdisciplinary care that should be considered. Opioids are a standard approach to initially treat this problem. If pain is more severe, palliative radiation, most commonly via the external-beam approach, is highly effective. Different external-beam techniques are available, and it is unclear which has the greatest benefit. Other options may include nerve blockade, commonly by an anesthesia pain specialist, or the use of radiofrequency ablation to treat soft tissue pain, which is a novel attempt to treat pain based on a new technology.
Shortness of breath is quite common in cancer patients near the end of life, and has been noted to be as high as 70% in the last six weeks of life. Importantly, it may or may not be related to intrathoracic cancers and complications.[28,29] Dyspnea portends a short survival, and this must be understood by caretakers and family. Finally, breathlessness can lead to great distress for patients and families[31-34] and therefore an algorithm of care is imperative.
Dyspnea may be due to many etiologies, including treatment-related lung injury, illnesses such as pneumonia, or pulmonary effusions. It may be enhanced if the patient has preexisting pulmonary problems or medical illnesses such as heart failure. For example, the incidence of lung injury after breast irradiation is minimal, but not irrelevant.[35-37] In the context of the large numbers of women undergoing lumpectomy and radiation therapy as a primary treatment for breast cancer, this problem may be significant, and even more so among women who have underlying lung disease. There are many chemotherapeutic agents that can cause pulmonary injury. Bleomycin may be the most notorious, although others include cyclophosphamide, mitomycin, carmustine, and methotrexate. Whenever using these medications, this complication should be anticipated. Therefore, it is recommended to assess pulmonary function tests at baseline and every three months while on therapy, and carefully follow patients for signs of impending problems such as dyspnea and hypoxia. Finally, major resections, such as pneumonectomy, may leave patients debilitated and unable to carryout normal functions.
While treatment of dyspnea is often related to the etiology, many causes are irreversible and without simple treatment options. Therefore, other considerations are available. This may be as simple as a fan and facial cooling to reduce the sensation of breathlessness. Oxygen and air can be efficacious and may be more related to the flow of gas than the actual oxygen.[41,42] While it does not benefit all patients, it clearly is of benefit to some.[42-44] Opioids are commonly utilized for dyspnea, especially morphine. While studies are inconclusive, there are sufficient reports to warrant its use when trying to eliminate or lessen dyspnea. Another commonly used group of medications to treat breathlessness is benzodiazepines as they can help with the anxiety that either leads to or is a cause of dyspnea. Midazolam and lorazepam and diazepam have been utilized. While there is no standard regimen, low-doses of these medications, possibly along with morphine, may have a role in treating breathlessness.
If shortness of breath is related to pulmonary effusion, there are several interventions that may have great impact. The major options are repeated fluid aspiration, permanent drainage catheter insertion, and chemical or surgical pleurodesis. For most patients, repetitive aspirations can be difficult, with multiple visits to the hospital and painful needle sticks. In addition, the anxiety of a re-accumulation of fluid and recurrent dyspnea always looms. In the hospice setting, with debilitated patients or those unwilling to consider a larger procedure, this can be accomplished safely with adequate relief of symptoms.
Chemical pleurodesis, frequently with talc or a chemotherapeutic agent, can be highly successful for the life of the patient, in some series approaching 100%.[46-49] This approach may be painful and requires at least a temporary chest tube. While there has been debate as to the safety of talc, it is likely not associated with acute respiratory distress syndrome and is safe for use in this setting. Pleurodesis utilizing video-assisted thoracoscopic surgery (VATS) is another approach that also commonly uses talc. This approach is quite efficacious and will usually alleviate the problem for the life of the patient. While there is some evidence that VATS is superior to talc pleurodesis via a chest tube, there are contrary reports to this, and VATS carries higher morbidity including pain.[49,52]
A “permanent” catheter may be a reasonable option for many patients, and can keep them home with loved ones, provided they are able to care for the catheter and apply suction canisters as necessary.[53,54] This can be placed by an interventional radiologist or a surgeon. It may lead to a shorter hospitalization than chemical pleurodesis, and may lead to a spontaneous pleurodesis in over 50% of patients.[55-57] Infection is also a consideration for this approach, but is likely quite low.
Other more invasive surgical approaches can be attempted, likely in those who have failed other therapies. One is a pleuroperitoneal shunt. While successful palliation is seen in 95% of cases, complications occur in 15%. Finally, a thoracotomy with pleurectomy is another approach, but the morbidity and associated pain makes this an unlikely choice for most patients with a malignant pleural effusion. In the patient facing the end of life, a major surgical procedure is less attractive and a less invasive approach is typically utilized before these procedures are considered.
Malignant Bowel Obstruction
Malignant bowel obstruction is a common problem in patients with ovarian and colorectal cancer. It also occurs with other abdominal (e.g. pseudomyxoma peritonei, peritoneal mesothelioma, primary peritoneal carcinomas, and gastric or pancreatic carcinomas) and occasionally with non-abdominal malignancies (e.g. melanoma, lung or breast cancers). Malignant bowel obstruction may be related to cancer (intraluminal or extraluminal tumor growth), its treatment (e.g. radiation enteritis), or benign etiologies (e.g. adhesions or internal hernia). The goals of treatment include relieving nausea and vomiting, allowing oral intake, alleviating pain, and permitting the patient to return to their chosen care setting. Persistent obstructions in the face of conservative therapy (usually nasogastric decompression, hydration, and bowel rest) or evidence of complete obstructions are indications that a surgical procedure should be considered. Invasive treatment options should be contemplated for all patients with malignant bowel obstruction, except those who are actively dying.
In cases where surgical management is not feasible, carries prohibitive risk, or there is unclear benefit, medical management can be very effective at relieving symptoms. Pain control is imperative. In cases where nausea persists with nasogastric tubes, antiemetics should also be employed. Corticosteroids are frequently utilized. While their utility is mixed, they may have a role in treatment.[60,61] Anti-secretory agents also likely have a role. Anticholinergics, such as scopolamine, have been used with some success. The somatostatin analog octreotide is the most commonly employed agent in this setting, dramatically decreasing gastrointestinal secretions and prolonging small bowel transit time. It can also delay the onset of edema and ischemia of the intestine. Response is frequent (75-100%), with it most often being a complete resolution of symptoms.[64-66] In addition, control of vomiting might be rapid, often within 2-4 hours of achieving the correct daily dose of octreotide; it is usually several days before a complete response can be obtained. Toxicity is rare or nonexistent, and is mainly related to pain at the subcutaneous injection site. Duration of treatment may be short-lived (median 9.4 to 17.5 days),[64,66] although symptoms are frequently relieved for the life of the patients.
For those in whom a surgical procedure is considered, potential contraindications include ascites or carcinomatosis, and in a patient who has multiple obstructions, palpable intraabdominal mass, overwhelming disease, or poor clinical status, are relatively strong contraindications for operative intervention. If the patient is a surgical candidate, the optimal procedure is that which offers the quickest, safest, and most efficacious ability to alleviate the obstruction and improve symptoms. Options include bowel resection, which may lead to the best overall outcome,[68,69] bypass, or a gastrostomy. An intestinal stoma may be necessary after resection or to adequately bypass the blockage. Laparoscopic procedures may be attempted, although this approach may be difficult due to adhesions, carcinomatosis, or bowel dilatation. Cytoreductive procedures (resection of intraperitoneal tumor) frequently carry a high morbidity and usually are only considered with very low-grade tumors such as pseudomyxoma peritonei. Surgical risks must be carefully considered prior to an operation, as morbidity (42%) and mortality (5-32%)[11,69,70] are common, and the re-obstruction rate is high (10-50%).[11,71] Although it is recognized that improvement in QOL after surgery is variable (42-85%),[11,72] there is no consistent parameter used to determine this clinical outcome.
Endoscopic procedures may be indicated in multiple settings, including in patients who are poor operative candidates or who decline an operation. They also may obviate the need for an intestinal stoma. The major approaches include stenting and percutaneous endoscopic gastrostomy (PEG) tube placement. Stenting may include procedures to initially canalize the lumen (e.g. laser or balloon dilatation). These procedures often necessitate a skilled gastroenterologist and are not available at all institutions. Most stenting procedures are not amenable to the majority of the bowel, and are limited to the large bowel, and often the distal colon or rectum. Endoluminal wall stents have a high success rate for relief of symptoms (64-100%) in complete and incomplete colorectal obstructions, and in over 70% of upper intestinal malignant obstructions including gastric outlet, duodenal and jejunal obstructions. While risks include perforation (0-15%), stent migration (0-40%), or re-occlusion (0-33%), stents can frequently lead to adequate palliation for long periods of time. Stent occlusion by tumor in-growth is usually amenable to another endoscopic intervention. The PEG tubes are generally well-tolerated “venting” procedures that can alleviate symptoms of intractable vomiting and nausea for upper gastrointestinal obstructions. In combination with other medical techniques, both open and percutaneous gastrostomy offers the possibility of intermittent oral intake. Complications related to PEG use are rare, even when puncturing other organs. The presence of significant ascites is a relative contraindication.
There are several reports on the use of palliative chemotherapy for patients with intestinal obstruction in ovarian cancer.[76,77] Chemotherapy can provide some symptom relief for patients who are newly diagnosed; for patients who have been treated previously, chemotherapy probably has no role for malignant bowel obstruction. Doyle, et al. showed that significant improvement in nausea, vomiting, and pain can be seen in some patients with advanced ovarian cancer, as well as substantive improvement in their emotional function and global quality of life. Unfortunately, women were frequently unrealistic concerning the perceived ability of chemotherapy to improve their survival or cure them.
Radiation therapy may be an option and could produce local palliation for isolated and targetable disease. This can include pelvic, duodenal, and intestinal stoma blockages, though small bowel obstruction or diffuse disease is usually unsuitable for radiation treatments. In a palliative setting, a subjective response rate for rectal tumors of 63% (objective response of 82%) has been reported, although results were combined with several different tumor-related symptoms. A wide range of response from obstruction has been reported for advanced gynecologic malignancies (20-88%), but most reports have small numbers of patients. Along with continuous infusion 5-fluorouracil, radiation therapy has been shown to prevent the need for a diverting colostomy from colorectal tumor-related bowel obstruction in 89% of patients with unresectable pelvic or metastatic disease. Responses are slow and complications increase with dose, so radiation therapy can be used with endoscopic techniques, such as lasers, to treat malignant rectal obstructions. Because many of the complications occur long after the radiation therapy, they might never manifest for the end-of-life patient. Because of the overall poor condition of many terminal patients, radiotherapy might be a suboptimal option because it would necessitate multiple trips to the hospital for treatment.
Importance of Research and Technological Advancements for Patients Facing the End of Life
As clinicians strive to improve their care of patients with palliative care issues, research will also need to follow suit. Palliative care is fraught with anecdote and opinion. There is a clear lack of evidence related to the best treatments for palliative care problems. Therefore, we may not be delivering the best care for a large number of patients in the USA each year. Clearly, the future for palliative care trials mandates the full compendium of research to ensure the best treatments are available. There is great hope that research for palliative problems will expand in the future as there is more national and international focus on patients facing the end of life.
There are many potential reasons for the lack of palliative care research. Many of them are related to ethical aspects of this research. There are also innate barriers, such as a lack of trained researchers and the challenges of subject recruitment. For instance, many hospice facilities are more willing to increase their involvement in palliative care research, although many institutions may not be willing to enroll patients at this time. Finally, there has been a historical lack of funding for such research, although this may be improving with time.
It is important to do research for patients facing the end of life and it would be unethical not to do so. There is frequently the belief that no such research is morally justifiable in this patient population. Although others find the arguments to this conclusion unacceptable, this still might be a prevailing belief among many practitioners. It is imperative that the research and clinical community do not bias themselves to palliative care research protocols. In fact, it can be argued, based on the Declaration of Helsinki and the generally accepted ethical code of practice in clinical research, that not offering patients at the end stage of life the opportunity to take part in clinical research is unethical. Ultimately, additional importance placed on palliative care through research could lead to a greater importance of QOL issues for clinicians.
As technology improves for the treatment of tumors for cure, this will also have impact on palliative care. For example, the use of radiofrequency ablation techniques for primary hepatomas and metastatic colorectal cancers also has a role for the less common endocrine metastases. Many other technologies, including minimally invasive techniques, may effectively treat complications related to tumors or their care with less morbidity. As chemotherapeutics evolve, there is likely to be an increasing role for palliative care. In addition, as medications to avoid treatment-related symptoms improve, chemotherapy may become a more realistic option in the palliative setting.
Palliative care is an important component of the practice for all practitioners who care for cancer patients. It is imperative to understand all treatment options afforded each patient. The patient, family, and treating teams must have a solid understanding of the realistic goals of success which focus on QOL. In addition, the chances of attaining those goals must be understood. Finally, the risks of the treatment, including worsening of symptoms and death, must be clearly described. Finally, follow-up is imperative to ensure treatment approaches attain success, or another approach should be implemented. There may also be evolution of disease so that alternate therapies are subsequently indicated.
Sidebar: Key Issues
Robert S. Krouse, Southern Arizona VA Health Sciences Center Surgical Care Line, 2-112 Tucson, AZ 85723, USA; E-mail: Robert.Krouse@va.gov