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One of the most important concerns of patients with cancer, particularly those with metastatic disease, is "Will I be in constant pain?" This is a similar concern voiced by patients with late-stage human immunodeficiency virus infection. The management of chronic pain has enormous implications on a patient's ability to function and on his or her quality of life. In June 1996, Medical Interface convened a panel of experts in Chicago to discuss pain management therapies, guidelines, and how these issues will affect, and be affected by, the managed care environment.
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PMID:Pain management guidelines: implications for managed care--a roundtable discussion. 1016 85

To the Editors: We have read with interest and some concern the recently published editorial, "We've Got a Treatment, but What's the Disease," by Rosenthal and Glatstein. This editorial enunciates these common anxieties (? "mid-life") about radiosurgery: A) that thedure as currently practiced worldwide, even in the United States, does not in all cases rely on the talents of radiation oncologists; B) that the technique disregards fundamental (? proven) principles about radiobiology, and C) that the authors of the editorial have chosen to ignore a tremendous body of historical and clinical literature relative to outcomes. In fact, long-term clinical data have been published in a wide variety of reports during the last ten years. Their reference list does not include a single article published beyond 1992. Now let's address the first issue. While it is true that the advantages obtained by closed skull focused stereotactic single session irradiation of a small but well-defined intracranial target volume (radiosurgery) were first espoused and practiced by neuosurgeons, the goal was not to impact upon the turf of the radiation oncologist. The goal was to provide a minimally invasive treatment for many problems deep within the brain for which traditional neurosurgical procedures were neither satisfactory nor effective. The tools that allowed neurosurgeons to accomplish this goal included focused particle beams or photon beams generated by the gamma knife or by linear accelerators. The technique also required highly precise (<1 mm) intracranial guiding systems (stereotactic technology). The initial evolution of this technology was cautious. It was based on more than 30 years of experimental and clinical work that preceded its introduction into the worldwide medical community beginning in the mid-1980s. In the United States, the vast majority of centers provide this technology based on the multidisciplinary input of neurosurgeons, radiation oncologists and medical physicists. The team provides both the necessary experience as well as the different perspectives that facilitate safe intervention and effective outcomes. The issue of responsibility in this multidisciplinary medical team should not be obfuscated by individual socio-economic concerns (who's in charge, who gets paid?). The recent purchase of an expensive deice for fractionated frameless radiotherapy by Southwest Medical Center may impact on Rosenthal and Glatstein's recent publication. In fact, stereotactic fractionated radiotherapy is the expensive treatment in search of a disease to pay for it Of greater concern is the authors' misconceptions (misunderstanding?) about the goals of radiosurgery (the second issue). Initially, radiosurgery was created to provide small volume destruction (in this case, true necrosis) of small target volumes withinthe basal ganglia, thalamus, or internal capsule for the treatment of intractable movement disorders, chronic pain, or medically refractory neuroses. With the redesign of the technology, deep-seated neoplasms and vascular malformations became more appealing targets with an entirely different radiobiologic goal. Instead, the goal became radiobiological inactivation of the ability of a tumor cell to divide and multiply (for tumors) or progressive luminal closure induced by endothelial hyperplasia (in the case of vascular malformations). Preservation of the surrounding normal brain (a feature brought about by the very sharp fall-off of the radiation dose delivered to small volumes with precise technology) reduced the risk of complications to normal brain, especially in contrast to surgical extirpation. Fractionated radiation therapy has rarely been an alternative to the usage of radiosurgery for these conditions. For malignant tumors, radiosurgery is most often used in conjunction with fractionated radiation therapy to take advantage of the single fraction destructive effects of radiosurgery followed or preceded by conventional fractionated radiation therapy. Such an approach enhances the likelihood of a satisfactory response based on the standard 4 Rs of curret radiobiological thinking. Stereotactic radiosurgery is a single "fraction" treatment; fractionated stereotactic radiosurgery is an absolute oxymoron. Certainly, renewed interest in the risk-benefit of fractionated radiation therapy is a logical outgrowth of the current tremendousave of enthusiasm for radiosurgery. In fact, the growth of radiosurgery has made radiation oncologists re-think their own practice of conventional radiation therapy. Similarly, it has had a profound impact on procedure selection by neurological surgeons. The third issue is addressed by the enormous volume of literature relative to outcomes in vascular malformations, malignant tumors, and benign tumors. The usage of radiosurgical technology should continue to stimulate thoughtful investigators to advance outcomes in these difficult conditions and reduce the risks of standard surgical techniques. It must be based on a collegial and multidisciplinary approach. The timing of Rosenthal and Glatstein's editorial was a mystery, appearing almost atavistic, especially considering the enormous growth of understanding and experience accumulated in the ten-year interval since both linac and gamma knife radiosurgical tecnologies became available in North America. AUTHORS' RESPONSE: In response to the Letter to the Editor by Lunsford, Flickinger and Larson, our main objectives in writing that article were twofold. The first was to review those principles of fractionation derived from a near century's experience in clinical radiobioloy. We have learned over and over again that, in general, hypofractionation leads to poorer tumor control, and more frequent and severe normal tissue complications. We believe that this point was, perhaps, not as fully appreciated during the development of radiosurgery because of a more surgical rather than radiotherapeutic influence. The second objective regards the safety issues of the even more widespread use of radiosurgery for brain tumors during the period when long-term follow-up data (ten years or more) are still emerging. Radiosurgery is in common use at our institution, the University of Pennsylvania Medical Center. We in no way wish to diminish the established safety and effectiveness of radiosurgery for arteriovenous malformations (AVMs). Additionally, we wholeheartedly encourage continued investigation for benign and malignant intracranial tumors. Our chief concern is the objective scientific validation of radiosurgery for these latter applications in prospective trials which have adequate long-term follow-up to establish safety. The central nervous system is the most unforgiving organ in terms of late radiation effects. Are all patients undergoing radiosurgery for benign tumors being accurately informed of the good results of modern fractionated radiotherapy, and those who undergo it for malignant tumors, that objective phase III validation and long-term safety data are NOT yet available? It frightens us even more that Lunsford et al. state, "In fact, the growth of radiosurgery has made radiation oncologists re-think their own practice of conventional raiation therapy." Just when do we evaluate the new clothes for the emperor Lunsford et al. tell us that radiosurgery technology has been "re-designed" with ".an entirely different radiobiologic goal. (the) inability of a tumor cell to divide and multiply." Radiation oncologists have long been taught as residents that raiologists accept the definition of "radiobiologic cell death" as the loss of continual clonogenicity. We all strive to this end in the treatment of tumors, but we are concerned about the extrapolation of the accepted application of radiosurgery for AVM tumors. More than 10,000 patients have had radiosurgery for brain tumors. Many of these have been benign, and more than 1,000 patients were treated with protons at the Harvard Cyclotron Unit, mostly for pituitary adenoma. Their experience has established safety, but the data for photon radiosurgery is not as large or mature, and one wonders how much photon radiosurgery adds to the excellent results achievable by conventional fractionated radiotherapy, especially for patients with pituitary tumors. With respect to malignant primary tumors or metastases, there have been fewer patients so treated. We recognize that longer term follow-up is not as important an issue for this unfortunate patient population whose survival period is generally short. Nonetheless, we reiterate that: A) hypofractionation has historically been shown to lead both to decreased control and increased complications, and B) that the higher the grade of a brain tumor, the more difficulty we have in localizing its extensions, especially when a treatment volume is <3 cc. There is absolutely no evidence that fractionated stereotactic treatment is an "oxymoron." Those data are only now beginning to emerge. It makes sense to encourage the investigation of radiosurgery as a boost followingonventional fractionated radiotherapy, or, for those who had the wherewithal to develop practical and cost-effective methods to treat with "fractionated radiosurgery" (read "stereotactic radiotherapy") to use those principles of clinical radiobiology twe have learned painstakingly over the last century to drive clinical investigation, and not rely solely on the impetus of new technology. Such investigation is ongoing at our institution, as we strive for the scientific evaluation of the comparative efficacy and long-term safety of radiosurgery for brain tumors. Had Coutard and Baclesse not pioneered fractionation, radiotherapy probably would have fallen into oblivion due to the morbidities of single shot treatment. Indeed, much of the first half of this century was spent learning that doses large enough to sterilize a mass of tumor cells (10 logs) cannot be predictably given safely. Instead, fractionation evolved which permitted us to exploit repopulation, redistribution, reoxygenation and repair. The use of these large single doses remains, at least in our minds, investigational in the treatment of especially malignant tumors. This is the way this subject is presented to patients here.
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PMID:Regarding: Rosenthal DI, Glatstein E. "We've Got a Treatment, but What's the Disease?" The Oncologist 1996;1. 1038 30

Acute pains requiring emergency management in oncology can be considered as physiopathological, somatic or visceral nociceptive pains. They are linked: to the tumour, indicating a modification of the tumoural evolution (necrosis, haemorrhage, fracture, acute obstruction of hollow organs or canals, occlusion, hydronephrosis); to the treatment: (inflammation of mucosal membranes, anusitis, post PL syndromes); and to invasive investigations. They are equally neuropathic, revealing an underlying threatened or confirmed medullary compression, or induced by neurotoxic chemotherapy. They are also analysed according to their mode of apparition: mechanical, arising as acute on chronic pain (the pre-fracture pain of metastases); insufficiency of the duration of therapeutic efficacity; an acute episode of neuropathic pain that is often lancing, unpredictable and inevitable. In all cases, it needs to be quantitatively and qualitatively analysed: evaluation, flavour of the symptoms; in order to choose one or a combination of adapted molecules, true antalgics or co-antalgics, antidepressants and anticonvulsants. To counteract this pain, medications with a short onset of action and a short half-life should be used to avoid side effects. These are administered in an intercurrent manner, initially starting at a low dose, modified daily according to the utilisation of supplementary doses. It is necessary to anticipate pain provoked by physical examinations or nursing care as much in the timing as the pharmacology, in using antalgics and/or anxiolytics with a short duration of action. Acutely emerging pains, whatever be their type, arising in the context of cancer and long-term pain are sensitising elements to all further pains, as they imprint in the memory, and are very negatively conditioned by the anguishing context of the illness.
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PMID:[Emergency management of acute pain in oncology]. 1500 70

Capsaicin specifically activates or destroys small diameter nociceptive sensory neurons that contain the capsaicin receptor, also called vanilloid receptor 1. Neurons sensitive to capsaicin mediate inflammatory pain and are important targets for management of chronic pain. These neurons also regulate local tissue homeostasis, inflammation, healing and development, especially under conditions of psychological stress. Stress contributes to increased cancer recurrence and metastasis through as yet undefined mechanisms. Likewise, activity of capsaicin-sensitive neurons is altered by pathological conditions that may lead to metastatic growth (e.g. stress). Therefore, we examined effects of a treatment that induces sensory nerve denervation on breast cancer metastases. Systemic denervation of sensory neurons caused by treatment with 125 mg/kg capsaicin resulted in significantly more lung and cardiac metastases in adult mice injected orthotopically with syngeneic 4T1 mammary carcinoma cells than was observed in vehicle-treated controls. Heart metastases, normally very rare, occurred as pericardial nodules, intra-myocardial nodules, or combined pericardial-myocardial lesions. Since the rate of primary tumor growth was unaffected, effects on metastases appear to be host tissue-specific. Although preliminary, these observations provide one possible explanation for resistance of cardiac tissue to tumor involvement and highlight contributions of host tissue, including sensory neurons, in the efficiency of cancer metastasis.
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PMID:Capsaicin-mediated denervation of sensory neurons promotes mammary tumor metastasis to lung and heart. 1516 Oct 56

Although bone cancer pain can be severe and is relatively common, as it frequently arises from metastases from breast, prostate, and lung tumours, very little is known about the basic mechanisms that generate and maintain this chronic pain. To begin to define the mechanisms that give rise to bone cancer pain, we have developed mouse and rat models using the intramedullary injection and containment of tumour cells into the femur. These tumour cells induced bone remodelling as well as ongoing and movement evoked pain behaviours similar to that found in patients with bone cancer pain. In addition there is a significant reorganization of the spinal cord that received sensory input from the cancerous bone and this reorganization generated a neurochemical signature of bone cancer pain that is both dramatic and significantly different from that observed in mouse and rat models of chronic neuropathic or inflammatory pain. These models have provided insight into the mechanisms that drive cancer pain and have begun to allow the development of mechanism-based therapies. Together these advances should reduce tumour-induced pain and suffering and significantly improve the quality of life of cancer patients.
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PMID:Mechanisms that generate and maintain bone cancer pain. 1528 53

While chronic pain is experienced by approximately 50-90% of patients with metastatic cancer, little is known about sex differences in chronic cancer pain. Therefore, the purposes of this study, in a sample of oncology outpatients (n=187) who were experiencing pain from bone metastasis, were: 1) to determine if there were sex differences in various pain characteristics, including pain intensity, and 2) to determine if there were sex differences in the prescription and consumption of analgesic medications. No significant sex differences were found in any of the baseline pain characteristics. In addition, no significant sex differences were found in analgesic prescriptions or intake of analgesic medications. Of note, men reported significantly higher pain interference scores for sexual activity than women. The study findings are important because they suggest that, unlike in acute pain, sex may not influence patients' perceptions of and responses to chronic cancer pain.
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PMID:No evidence for sex differences in the severity and treatment of cancer pain. 1533 34

Although bone cancer pain can be severe and is relatively common, as it frequently arises from metastases from breast, prostate and lung tumours, relatively little is known about the basic mechanisms that generate and maintain this chronic pain. To begin to define the mechanisms that give rise to bone cancer pain, we developed a mouse model using the intramedullary injection and containment of osteolytic sarcoma cells into the mouse femur. These tumour cells induced bone destruction as well as ongoing and movement evoked pain behaviours similar to that found in patients with bone cancer pain. In addition, there was a significant neurochemical reorganization of sensory neurons that innervate the tumour bearing bone as well as in the spinal cord segments that received sensory input from the cancerous bone. This reorganization generated a neurochemical signature of bone cancer pain that was different from that observed in mouse models of chronic neuropathic or inflammatory pain. These data suggest that there is an inflammatory, neuropathic and tumorigenic component to bone cancer pain. Therefore defining when and how these different components drive bone cancer pain may allow the development of more selective analgesic agents to treat this chronic pain state.
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PMID:A mechanism-based understanding of bone cancer pain. 1546 52

Bone is the most common site of chronic pain in patients with metastatic cancer. What remains unclear are the mechanisms that generate this pain and why bone cancer pain can be so severe and refractory to treatment with opioids. Here we show that following injection and confinement of NCTC 2472 osteolytic tumor cells within the mouse femur, tumor cells sensitize and injure the unmyelinated and myelinated sensory fibers that innervate the marrow and mineralized bone. This tumor-induced injury of sensory nerve fibers is accompanied by an increase in ongoing and movement-evoked pain behaviors, an upregulation of activating transcription factor 3 (ATF3) and galanin by sensory neurons that innervate the tumor-bearing femur, upregulation of glial fibrillary acidic protein (GFAP) and hypertrophy of satellite cells surrounding sensory neuron cell bodies within the ipsilateral dorsal root ganglia (DRG), and macrophage infiltration of the DRG ipsilateral to the tumor-bearing femur. Similar neurochemical changes have been described following peripheral nerve injury and in other non-cancerous neuropathic pain states. Chronic treatment with gabapentin did not influence tumor growth, tumor-induced bone destruction or the tumor-induced neurochemical reorganization that occurs in sensory neurons or the spinal cord, but it did attenuate both ongoing and movement-evoked bone cancer-related pain behaviors. These results suggest that even when the tumor is confined within the bone, a component of bone cancer pain is due to tumor-induced injury to primary afferent nerve fibers that innervate the tumor-bearing bone. Tumor-derived, inflammatory, and neuropathic mechanisms may therefore be simultaneously driving this chronic pain state.
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PMID:Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. 1581 67

Inspite the new informations about the physiology and biochemistry of pain, it remains true that pain is only partially understood. Cancer pain is often experienced as several different types of pain, with combined somatic and neuropathic types the most frequently. If the acute cancer pain does not subside with initial therapy, patients experience pain of more constant nature, the characteristics of wich vary with the cause and the involved sites. Chronic pain related to cancer can be considered as tumor-induced pain, chemotherapy-induced pain, and radiation therapy-induced pain. Certain pain mechanisms are present in cancer patients. These include inflammation due to infection, such as local sepsis or the pain of herpes zoster, and pain due to the obstruction or occlusion of a hollow organ, such as that caused by large bowel in cancer of colon. Pain also is commonly due to destruction of tissue, such as is often seen with bony metastases. Bony metastases also produce pain because of periostal irritation, medullary pressure, and fractures. Pain may be produced by the growth of tumor in a closed area richly supplied with pain receptors (nociceptors). Examples are tumors growing within the capsule of an organ such as the pancreas. Chest pain occurring after tumor of the lung or the mediastinum due to invasion of the pleura. Certain tumors produce characteristic types of pain. For example, back pain is seen with multiple myeloma, and severe shoulder pain and arm pain is seen with Pancoast tumors.
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PMID:Cancer pain (classification and pain syndromes). 1601 3

Cancer pain most commonly occurs in patients with locally advanced or metastatic disease. Certain characteristics of cancer-related pain, including its multifocal nature, severity, heterogeneity, progressive nature, and other special challenges, distinguish it from most other types of chronic pain. Bone metastases are the most common cause of pain in patients with malignant disease, in part due to the high frequency of axial (vertebrae, rib, and pelvis) and appendicular (femoral and humeral) fractures. Relief begins with a thorough understanding of the extent of the disease and the risks of associated complications, such as spinal cord compression. Pharmacologic approaches to pain treatment include acetaminophen, anti-inflammatory agents, opiates, and bisphosphonates. As new investigational treatments continue to develop, clinicians must continue to rely on skilled assessment techniques and an understanding of the many causes of cancer-related pain to effectively diagnose and treat pain caused by bone metastasis.
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PMID:Cancer-related pain and its pharmacologic management in the patient with bone metastasis. 1649 40


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