truetrsa, ue tu
s/.&ill cord compression, and raised intracranial More pragmatic fractionation schedules are being
cmbral metastases.
that are eom~t~bie with good resume in terms of ~~ii~iv~ end &d-s, giving shorter courses with feuer hos@al attendances for patient and family comfort and coolvenience. More ctinicd research and evaluation of palliative radiotherapy are redry. J Pain ~ymFtorn Manage ~9~~;~:3~~3~~.
Radiotherapy as a clinical art and science has existed now for almost a ~ntury. It began with the formidable discweries of Wilhelm Roentgen (t rays, 1895) and Marie Curie (radium, 1898). The histo~ and influence of radiation oncology and biology on our modern understanding of cancer is a fascinating and remarkahle story.’ For much of the twentieth century it has been the most effective available nonsurgical tool for cancer treatment. Against a background of a strong curative focus. radiation on-
cologists have a key role as palliators of incurable malignant disease. The relative indications for radiotherapy have changed over the years, with a move toward the multidisciplina~ and multimodal management of cancer. Improvements in technical equipment and biological unders~nd~ng have heen implant influences. A radiation oncology department is a highly technical and scientific environment that has often developed historically in relative isolation from the rest of the hospital world. As such, it may seem to be intimidating to both patients and other health care professionals. Medical students, junior medical staff, and nurses may be taught very little about it, and much more education and outreach by the radiation oncology community is required to correct this. Patients may have negative experiences from 0885-3924191/$8.50
their c~t~lrn~tlities where a friend or relative mlderwent ~~~~tberapy, appeared to be very ill, and died. The radiotherapy may as the cause, ~ltho~gb in rarity th cess may have been ig~ore~, a0d t radiotherapy and its side effects are misunderstood. Some practices in the past were suboptimal (often due to technological limitations), and left long-lasting negative impressions that require correctiou in light of modern techniques and attitudes. Most departments now make considerable efforts to make sure that patients (and their families) referred to them are well informed, counselled. and supported througbout the treatment process. The majority of patients acclimatize well after the initial encoiinters. This review is written for those who have no prior knowledge of the subject, and hence an attempt is made to intr~~duc~ and define some of the technical ter~nitlology. Tbis will enable tbe reader to follow this evaluation of modern palliative radiotherapy, as well as the author’s views on future directions and philosophies.
Radiotherapy is the delivery of ionizing radiation into a delined volume of the body in order to eradicate (sterilize) or substantially depopulate the tumor cells within that volume, without exceeding the tolerance of normal tissues. The external beam of ionizing radiation used nowadays usually consists of megavoltage photons 01 electrons delivered by linear accelerators, or megavoltage gamma rays from cobalt units. Orthovoltage X rays are still useful for more superficial tumors, and modern isotope implants or intracavitary treatment may be indicated occasionally for palliation. There is renewed interest in unsealed isotopes for the palliation of bone pain, but this is still largely experimental.” Intrinsic to the understanding of radiotherapy is the principle of the therapeutic ratio, which, just as in pharmacology, is the risk/benefit analysis that allows us to weigh benefit and side effects of at.~ :her;lpeutic intervention. An ethically based argument for the decisionmaking process for palliative care based on the therapeutic ratio has been proposed.” A sideeffect profile should be the minimum compatible with achieving the palliative aims of the treatment, and responses should be defined in
Delivery of a course of radiation with the intent of complete eradication of the tumor. A high dose to the t(~lera~lce of the normal tissues in the irri~~liati~~1~ volume is re(lLaired iti>r most IUIIIO~S.AS the ail,1 is cure and prolonged survival, a high level 01’ morbidity (side effec IS or toxicity) may be ilCCt!l)ltXl. zk?
Delivery of a course of radiation with the intent of imposing growtl: restraint on a tumor, or reduction or abolition of symptoms caused by the tumor (or both). Where the former is the intent, a high dose may be required, however, in many pailiative situations. a short course, or high-dose single-fraction treatment may be sufficient to achieve the favorable end point desired. A lower level of morbidity should be set for such situations. The higIl-dense irradiation of tumors that are deemed incurable at presentation for the purpose of local control is often justified, and may be compatible with preservation of function and body image.’ Important examples occur in head and neck, gynecological, breast, urological, lung, skin, and colorectal cancers.
Prophlylactic Delivery is of a course of radiation (in the radical context) with the intent of preventing regrowth of a tumor after complete tumor eradication by other means (e.g., surgery or chemotherapy) where established prognostic factors predict a high probability of tumor recurrence or spread, p&cularly where there Is evidence of microscopic or macrosc~~pic residual tumor. prophylactic treatment may also be applicable to the palliative situation. where treatment may be given to prevent a predicted event related to tumor progression at a given sile, as fi>r example, erosion into or compression of ad-
jacent vessels, structures, or organs, or to prevent fracture of a bone. This role remains to be validated.
T&k 1 Examplesof Some Palliative Fractionations (Prescription) Total dose (Gy)
e SI unit of absorbed radiation dose is the Gray (Gy), which has replaced the often more familiar units, the Rad (100 rads = 100 CGY = 1 Gy), and the Roentgen. A radiotherapist prescribes a certain number of Grays at a given defined reference point in the body {often the center of the volume, or a specified point on or low the skin surface).
Simply comparing the total dose in terms of the number of Grays prescribed is a common error for those unfamiliar wit,h radiation oncology. The biological effect of radiation on tissues is a complex and partially understood interaction. It is broadly divided into early radiation damage, which is manifested by acute side effects during and immediately after treatment, and late damage, which may not become apparent until months or years later. It is dependent on the volume (how much of the body is treated), the dose delivered per fraction (treatment session), the overall treatment time, and the type of radiation. In simple terms, the larger the volume, the lower the dose tolerated. The dose per fraction has an important inftuence on late normal tissue damage. For radical curative treatments, a large number of small fractions will be delivered to a small- or medium-sized volume, and a standard treatment regime might be 6Q Gy in 36 fractions over 6 weeks of daily treatment (2 Gy per fraction). For palliative end points, a small number of larger doses per fraction are often adequate, e.g., 20 Gy in 5 fractions over I week of daily treatment; sometimes a large single fraction of 6-8 Gy may be used. Some common palliative fractionation prescriptions are summarized in Table 1. For more information on radiobiology. the reader is referred to two readable and accessible reviews.“.”
If only the tumor and a margin around it are treated, then this is termed invo&f f;eti t. If a larger area is treated or a whole region is irradiated, then this may be referred to It is possias loca-regional or u&tej&Mtrmtment.
Dose per fraction (GyI Number of”reactions Overall time Number of fractions” Per day Per week
35 2.33
30 3
20 4
6-8 tL-8
::
10 12
5 5
I 1
1 5
1 5
1 1
1 5
S’reatment session or visit to the RT department.
ble to treat the whole body or half body. The volume is defined by a process of treatment plameing, that may require simulation (the use of a dwagnostic X ray unit specially constructed for radiotherapy planning) and computerized tomography assistance. For radical treatment, this may be a complicated, highly technical, and precise pmcess. However, for palliative work, planning citn often be kept to a minimum to ensure as little inconvenience and discomfort to the patient as possible. side E&?&s There is no doubt that radiotherapy gives rise to significant side effects, although every effort is made to minimize these in the palliative scenario. These may be divided into two groups: those that are confined to the irradiated volume, and systemic effects. Early normal tissue damage toxicity is summarized in Table 2. Most are transient and mild. and are alleviated by simple remedies. It is significant that acute skin reactions are often referred to perjoratively as burns, when, in fact, they represent a transient depopulation of the basal cells of the skin. Although this may be a description close to the truth, it implies a lack of care or misadventure, which is unfortunate. Severe skin reactions may occur in radical treatment, but they are rarely a significant cause of morbidity in palliative treatment. It is sometimes also feared that hair loss will occur even when the volume does no: include the scalp. Counselling and education are required to dispel these myths. Late normal tissue damage is a phenomenon of slowly or nondividing cell lines. Structures, such as the central nervous system (particularly the spinal cord), lung, kidney, the lens of the eye, and microvasculature everywhere, are especially sensitive. Late normal tissue damage is
Systemic-not confined to irradiation volume Malaise Nausea or vomiting
Pain relief
Anorexia Fatigue Specific-confined to irradiation volume Skin Redness Itching Breakdown Abdomen and pelvis Nausea Vomiting Diarrhea Frequency, dysuria, hematuria (cystitis) Head and Neck Dysphagia (murositis) Dry mouth
Control of bleeding (Hemoplysis. vaginal bleeding, hematuria, and rectal bleeding) Control of fungation and ulceration Dyspnea Oncological emergencies (Superior vena cava obstruction. spinal cord compression, cerebral mm*-qlases causing raised intracranial pressuS:) Relief of blockage of hollow viscera Shrinkage of tumor masses causing symptoms by
Taste aheralion Chest Painful dysphagia Head Alopecia Bone Marrow Myelosuppression
virtue of site or spare occupancy
ihe (esophagitis)
not often a significant problem for palliative patients, as the majority do not live long enough to be at risk of developing such damage. However, sound practice usually dictates that all treatments are within safe, late, normal damage limits, although on occasion these constraints may be waived for short-term comfort when it is clear that survival will be very short.
The main indications are summarized in Table 3. It is important that a radiation oncologist be consulted, to prevent inappropriate a priori decisions. It is particularly unfortunate that patients are not referred when it is considered that a tumor is not “radiosensitive.” Radiownsitivily is a radiobiological term referring to the intrinsic response of a given cell line to radiation. Radioresponsiveness is the clinical counterpart. In fact, most tumors “respond” to radiotherapy, although there is a quite marked variation in this response. For palliative end points, even the so-called “radioresistant” tumors will respond favorably, often without measurable tumor regression.
Pain. The role oI’ radiotherapy in t management of pain due to rPlalignant bone metastases is unquestioned, and this indicatic~n (mainly for patients with lung, breast, and prostate primaries) constitutes approximat 20% iation of the total numbers referred to most oncology departments. ‘-’ The pathogenesis of metastatic hone pain and the mechanism of action of radiotherapy are not understood. The similar results achieved with a very wide range of doses and fractionation schedules, with overall responses usually in the region of 70%-SO%, indicate a dissociation between tumor regression and pain relief. The rapidity of action, usually within 24 hr, which is achieved after singlefraction local or hemibody irradiation, is similar to that observed after pituitary ablation.“’ It has often been proprosed that an effect on chemical mediators of the inflammatory response may be operative. A randomized study from Tokyo emphasized patient factors rather than fractionation in achieving pain control,” and a retrospective study from Rome showed lower response rates for adenocarcinoma of the kidney and non-small-cell lung cancer primary histologies, and limb sites of metastases. A dose response was described for total absorbed radiation dose, but not for fraction size,‘2 Retrospective dose response data must, however, be viewed with caution. Higher doses for the palliation of renal cell carcinoma have been adThe key issues revolve vocated elsewhere.” around questions of what dose, fractionation, and field size are required to produce an acceptable irjcidence of sustained pain relief with tnin-
imal toxicity and inconvenience to patients and their families. There has been considerable interest in the administration of large single fractions for bone metastases. In a randomized study” at the Royal Marsden Hospital, a single fraction of 8 Cy was compared with a fractionated course of 30 Gy in 10 daily fractions. No difference was found in the speed of onset or duration of pain relief, which was independent of the histology of the primary tumor. A subsequent study from the same group looked at 4&y single fractions. ts the further expiuration of lowand fractions.“S This is supported by a dose small study from Bxfotd, which also observed that there was a 25% retreatment need in the
8..Gy group and a higher incidence, albeit short duration, of gastrointestinal side effects,” Thus, there is a growing body of ~dence to show that pragmatic treatment of bone me(repeatable) ftactions is safe, ceptable to patients. Crellin and colleagues have discussed the possible reasons many radiation oncologists in the United Kingdom have been reluctant to change their prescribing habits. They emphasize the fact that an apprenticeship training system has more influence than the published literature on practice, and discuss the difficulties of study methodology and the lack of information on late normal tissue damage for large fractions.” The justification of higher total fractionated courses for the prevention of pathological fracture or vertebral fracture due to lyric metastases in the presence of neurological involvement, has wide acceptance, but there is no evidence in favor of these arguments,n*t” The use of hemibody irradiation for bone pain is the subject of increasing interest.“-“’ This may be either the superior or lower half, or both in sequence (usually separated by an interval of 4-6 wk). The tnain indications have been for widespread disease such as a very advanced stage of multiple myeloma or prostatic carcinoma. No difference in terms of response is noted between the two histologies in one comparative evaluation, ‘a but significant toxicity is described using the doses that are widely used at pnxent: 8 Cy to the lower, and 6 Gy to the upper half. An exploration of lower doses is recommended to reduce toxicity while retaining igh wed response rates, in the region of There is also considerable interest in the
use of sequential hemibody irradiation as a systetnic therapy for widespread God-Hodgki~s Iymphoma, breast cancer, or small-cell lung cancer which has failed chemotherapy.“-‘” With refinements in terms of selection, indications, technique, and fractionation, this approach shows considerable promise, and may have a small but definite place in the palliation of these, and possibly othe,? tumors. There has been some recent increase in the idea of the systemic use of radioisotopes for bone pain.’ It is present y regarded as suitable for comparison with hemibody irradiation, but appears to have major disadvantages in terms of late onset of pain relief at Z-4 wk compared with 24-48 hr for hemibody irradiation, and unpredictable differential isotope distribution between normal and tumor-bearing bone. Furthrr evaluation ij clearly required, and its use in combination with external beam radiotherapy may be interesting.
Radiotherapy is often helpful in situations where tumor directly infiltrates into nervous or soft tissues. It is usually administered in combination with steroids or nonsteroidal antinflammatory drugs. Higher doses of radiation may be required for these indications than for bone pain. Careful planning of treatment to include known neurological pathways is important. This is particularly the case for head and neck tumors where there is a propensity for perineurat spread, and in situations where spread into the spinal canal might have occurred. Caution with fractionation is required where large volumes of nervous system tissue are irradiated, such as in brachial and lumbosacral plexus invasion, where late normal tissue damage may be a particular danger. Apical lung cancers may give rise to brachial plexus invasion, or produce the classical Pancoast’s syndrome, and radical irradiation may give worthwhile and sustained loco-regional control and symptom relief.
Hem~ptysis,vaginal bkeding, hmnaturia,and rectul Radiotherapy has a long track record bkding of controlling hemorrhage from exophytic bleeding tumors. It has been known for sometime that vaginal bleeding from cervical carcinoma may be arrested by intracavitary isotope
Equally, external bea irradiation is e ctive eitber as a s ve course, or where indicated, in a high-dose radicai treatment context. In advanced disease, there is now good experience of using a few large fracinsertion.
tjons.2’.25
Control ~fi%ngatim and ?Jlceratim Most disfiguring and distressing cases of superficial tumor fungation and ulceration can be helped by radiotherapy. The most common of these tumors encountered in oncological practice are breast cancer on the chest wall, fungating bead and neck cancer, and both melanoma and nonmclanoma skin cancer. High doses may be required where the clinical situation warrants this, but a few large fractions may also be helpful fat elderly patients, or those wit91 a very poor prop;.. nosis.“” L$@rtea The most common tumor causing shortness of breath is lung cancer, although metastases from other primary sites may, and frequently do produce respiratory symptoms. The mechanisms of dyspnea are not completely understood, may be multifactorial, and often coexist with significant levels of established chronic lung damage-most commonly, chronic obstructive airways disease. Radiotherapy can give excellent palliation for dyspnea due to endobronchial obstruction or extrinsic nodal compression of the bronchi, and for hemoptysis, cough, chest pain, superior venal caval obstt-uction, and dysphagia due to extrinsic esophageal compression. A British consensus document sets out a pragmatic treatment guide for lung cancer, and emphasizes that there is no evidence of a benefit for early treatment ofasymptomatic incurabie patients and that short courses of radiotherapy are usually as effective as more protracted fractionation schedules for palliative end
oncologkd
Emgencies
Su@rior vma cava obstruction The treat men t of superior vena cava obstruction with radiotherapy and steroids is well established, particularly when associated with other features of mediastinal obstruction. The urgency of commencing treatment may have been slightly overemphasized in the past. The use of high-dose steroids, opioid analgesics, anxiolytics, and oxygen (if indicated) in the acute situation can often produce
S@al cord compression Metastatir spinal cord com93res.G~ is a devastating complica(jon 09 malignant disease. Considerable clinical vigilance is required to ensure early diagnosis and the prompt institution of emergency lreatment. Clinical signs ant9 syrnpfoms may 91esubtle and atypical,and levels of‘ compression may i)e mu!tiplt!. assyn~etric-a9, dllcl of Inixetl upper and lower motor neutrons. Vague complaims of back pain. leg weakness. shooting pains, d~~3sthesias, anc9 sphillcrer clisturbance should always be taken seriously. Early delecliotl rather t91an tumor cell type a9,pears to be important in determining the functional outcome.‘!’ A full clinical arid radiologic
assessmem
is essential,
anti
either computerized tomography, myelography, or magnetic resonance imaging if available, is indicated,“” together with the early commencement of high-dose corticosteroids. Consultation with a neurosurgicai service is always advisable. Result:; obtained with radiotherapy or with surgery appear to be similar,“’ and Findlay has suggested a useful a9gorithmic approach to the problem.‘” Further work is required to identify subgroups who may benefit from one modality rather than the other. The poor prognosis of patients with cord compression should not obscure the itnportance of obtaining the best palliative functional result, and patients who are thought to be unsuitable for surgical intervention should usually immediately commence a course of radiotherapy to the compression site. The results for patients with evidence of established complete cord “section” who fail to respond to steroids are so poor that it is questionable if they should be subjected to treatment, although radiotherapy is always indicated for pain control if pain is present.
melashes causing raised id pressure Irradiation of the whole brain for cerebral metastases has an important role in tbe pa99iation of this common and inevitably fatal cosn919L cation of malignancy, but documentation of indications and results could be better. The role
of steroids in the emergency control of raised intracranial pressure is undisputed, but much remains to be understood about the mechanism of action, optimal preparation, dose. and scheduling. sp This review stresses the importance of trying to reduce and tail off the steroids as soon as neurological function is stable. There is considerable scope for more clinical research, particularly with regard to selection criteria for radiotherapy, Failure to respond to steroids, impaired conscious level, and neuropsychiatric presentations seem unfavorable prognostic factors for response to radiotherapy, whereas motor neu~lo~~cal deficits that respond to steroids tter, The use of radiotherapy in the acute situation for critically raised intracranial pressure together with steroids may sometimes produce impressive results in the short term. For solitary metastases, there is evidence that surgical excision is of value both tn itirrns of quality and quandty of lifee.sWs Some controversy surrounds the issue of whether higher doses of radiotherapy produce better results, either to multiple or solitary metastases, with the balance of opinion pointing towards a negative conclusion,Y~’ Several studies have addressed malignant melanoma as an entity of special interest. There are conflicting reports about the role of chemotherapy, with one study showing a few longterm survivors,s” and another a negative conclusion. Despite suggestions that large-dose-perfraction treatment is beneficial for radiobioul reztsons, Chai and colleagues conclude a short overall treatment time is more important?” The overall picture is gloomy for most patients with cerebral metastases. However, short palliative courses of cerebral radiotherapy should always be considered, although more information concerning prognostic selection factors would be helpful. Most studies seem to focus too much on survival, and more focus on palliative issues is required. Patients with solitary metastases should have the benefit of a neutosurgical opinion, and stereotactic radiosury may he a promising avenue for selected
lumen, wall, or extrinsic compression to the helpstructure. Palliative radiotherapy may ful in many of these situations, although more information on outcomes would be helpful. Examples include the bronchi, esophagus, upper airway or digestive tract, bile ducts, ureters, lymphatic channels, and blood vessels.
oftumor tm.sS@S calcsing syvnptom ty
drMost tumors can be e of radiotherapy, reor histology. The important question to be posed in each case is whether a volume reduction will have a favorable effect on symptom control and quality of life. Where gains in terms of palliative end points are either likely to be small or nonexistent, it may be best not to embark on treatment. Such individual decisions may be difficult, and there is often no literature to act as a guide. Very large masses adjacent to critical normal tissues, particularly those that respond less favqrably, such as sarcoma and melanoma. may be best not treated.
Owing to disappointing results in the aggressive management of most of the common solid tumors.41 the focus of oncology has shifted in recent years. Communities. patients, and their fam!lies have requested that more interest be shown in palliative care issues. Research into palliative radiotherapy methods and outcomes has been largely neglected until recently, but changes in practice are already apparent. Radiation oncologists have a duty to communicate what they have to offer patients with advanced incurable cancer. and at a time when more and more such patients are being managed in nononcological settings, such as hospices or at home, it is important for their caregivers to know when to call the radiation oncologist.
1. Fletcher GH. Regaud lecture and perspectives on the history of radiotherapy. Kadiother Oncol 1988;12:253-271. 2. Editorial. Strontium 1990;335:38+-385.
c$ lrollow visceru Any hollow ay be partially or completely obstructed by the presence of a tumor in the
and bone
pain.
Lancet
3. Ashby M, Stoffell B. Therapeutic ratio and defined phases: proposal of ethical framework for palliative care. Br Med J 1991;302:1322-1324.
4. P~l~~l~on~.The rcspvns~bjl~ty of ~adiologis~5 in tbc
~~se~vatio~l of breast and rectum in cancer treatment. Clin Radio1 1986:37:303-309. 5. Suit HD. Radiation biology: The conceptual and practical impact on radiation therapy. Radiat 1983:94: 10-40. 6. Hall EJ. Basic radiobiology. 1988;11(3):220-258.
Am J Clin Oncol
7. Coia LR. Hanks GE, Martz K. Steinfeld A. Diamond jJ, Kramer 5. Practice patterns of palliative care for the United States 19X4-1985. lnt J Radiat Oncol Biol Phys 1988;14: 1261-1269. 8. Crellin AM, Marks A. Maher EJ. Why don’t British radiotherapists give single fractions of radiotherapy for bone metastases? Clin Oncol 1989; 1:63-66. 9. Pouhen HS. Nielsen OS. Klee M, Korth M. Palliative irradiation of bone metastases. Cancer Treat Rev 1989:16:41-48. IO. Bates ‘I‘. Kadiotherapy Oncol 1989; I :57-58.
for bone metastases. Clin
Il. Okawa ‘1‘.Kita M. Goto M. Nishijima H, Miy;rji N. Randomized prospective clinical study of small, large and twice-a-day fraction radiotherapy for painful bone metastases. Radiother Oncol 1988:13:99-104.
isonl of single dose and fractionared re~~~~eI~s. Int ,j Rihlt Olld Biol Phys 19H9: 17: 128 1-i 28.5. 21. LJrtasun R(Z. B&b A, Rodoar 1). Hemi diation: An XtiW herapeutic modaliy for the ~~~tYll~ll1 Of ptk~ltS With small cell lurlg cancer. Kadiat Oncol Biol Phys I9H3;9: I.i75-157#.
m
Ir
2% Jullien D. Vilcoq JR, Campana F. irradiations hCmlcorporelles: Kesultats chez 92 patientes porteuses de cancer du scin polymetastatique trairees i l’lnstitut Curie. Agence lnternationale de 1’Eneqrie Atomique. Colloque International sur la Kadiotberapie dans les I’ays en D&eloppement ---Situations et Tendances. Vienne 1986347: 1-7. 23. Duchesne GM. Harmcr (IL. emibody irradiatiou in lymphomas and related malignancies. lilt .j Kadiat Onto1 Biol Phys 19X5: I 1:2003-2006. ?4. Ha11cJS. K~senman .j(;, Varia MA, For&r W(:, Walton LA, (:urrie JL. 1000 c
s/.&ill cord compression, and raised intracranial More pragmatic fractionation schedules are being
cmbral metastases.
that are eom~t~bie with good resume in terms of ~~ii~iv~ end &d-s, giving shorter courses with feuer hos@al attendances for patient and family comfort and coolvenience. More ctinicd research and evaluation of palliative radiotherapy are redry. J Pain ~ymFtorn Manage ~9~~;~:3~~3~~.
Radiotherapy as a clinical art and science has existed now for almost a ~ntury. It began with the formidable discweries of Wilhelm Roentgen (t rays, 1895) and Marie Curie (radium, 1898). The histo~ and influence of radiation oncology and biology on our modern understanding of cancer is a fascinating and remarkahle story.’ For much of the twentieth century it has been the most effective available nonsurgical tool for cancer treatment. Against a background of a strong curative focus. radiation on-
cologists have a key role as palliators of incurable malignant disease. The relative indications for radiotherapy have changed over the years, with a move toward the multidisciplina~ and multimodal management of cancer. Improvements in technical equipment and biological unders~nd~ng have heen implant influences. A radiation oncology department is a highly technical and scientific environment that has often developed historically in relative isolation from the rest of the hospital world. As such, it may seem to be intimidating to both patients and other health care professionals. Medical students, junior medical staff, and nurses may be taught very little about it, and much more education and outreach by the radiation oncology community is required to correct this. Patients may have negative experiences from 0885-3924191/$8.50
their c~t~lrn~tlities where a friend or relative mlderwent ~~~~tberapy, appeared to be very ill, and died. The radiotherapy may as the cause, ~ltho~gb in rarity th cess may have been ig~ore~, a0d t radiotherapy and its side effects are misunderstood. Some practices in the past were suboptimal (often due to technological limitations), and left long-lasting negative impressions that require correctiou in light of modern techniques and attitudes. Most departments now make considerable efforts to make sure that patients (and their families) referred to them are well informed, counselled. and supported througbout the treatment process. The majority of patients acclimatize well after the initial encoiinters. This review is written for those who have no prior knowledge of the subject, and hence an attempt is made to intr~~duc~ and define some of the technical ter~nitlology. Tbis will enable tbe reader to follow this evaluation of modern palliative radiotherapy, as well as the author’s views on future directions and philosophies.
Radiotherapy is the delivery of ionizing radiation into a delined volume of the body in order to eradicate (sterilize) or substantially depopulate the tumor cells within that volume, without exceeding the tolerance of normal tissues. The external beam of ionizing radiation used nowadays usually consists of megavoltage photons 01 electrons delivered by linear accelerators, or megavoltage gamma rays from cobalt units. Orthovoltage X rays are still useful for more superficial tumors, and modern isotope implants or intracavitary treatment may be indicated occasionally for palliation. There is renewed interest in unsealed isotopes for the palliation of bone pain, but this is still largely experimental.” Intrinsic to the understanding of radiotherapy is the principle of the therapeutic ratio, which, just as in pharmacology, is the risk/benefit analysis that allows us to weigh benefit and side effects of at.~ :her;lpeutic intervention. An ethically based argument for the decisionmaking process for palliative care based on the therapeutic ratio has been proposed.” A sideeffect profile should be the minimum compatible with achieving the palliative aims of the treatment, and responses should be defined in
Delivery of a course of radiation with the intent of complete eradication of the tumor. A high dose to the t(~lera~lce of the normal tissues in the irri~~liati~~1~ volume is re(lLaired iti>r most IUIIIO~S.AS the ail,1 is cure and prolonged survival, a high level 01’ morbidity (side effec IS or toxicity) may be ilCCt!l)ltXl. zk?
Delivery of a course of radiation with the intent of imposing growtl: restraint on a tumor, or reduction or abolition of symptoms caused by the tumor (or both). Where the former is the intent, a high dose may be required, however, in many pailiative situations. a short course, or high-dose single-fraction treatment may be sufficient to achieve the favorable end point desired. A lower level of morbidity should be set for such situations. The higIl-dense irradiation of tumors that are deemed incurable at presentation for the purpose of local control is often justified, and may be compatible with preservation of function and body image.’ Important examples occur in head and neck, gynecological, breast, urological, lung, skin, and colorectal cancers.
Prophlylactic Delivery is of a course of radiation (in the radical context) with the intent of preventing regrowth of a tumor after complete tumor eradication by other means (e.g., surgery or chemotherapy) where established prognostic factors predict a high probability of tumor recurrence or spread, p&cularly where there Is evidence of microscopic or macrosc~~pic residual tumor. prophylactic treatment may also be applicable to the palliative situation. where treatment may be given to prevent a predicted event related to tumor progression at a given sile, as fi>r example, erosion into or compression of ad-
jacent vessels, structures, or organs, or to prevent fracture of a bone. This role remains to be validated.
T&k 1 Examplesof Some Palliative Fractionations (Prescription) Total dose (Gy)
e SI unit of absorbed radiation dose is the Gray (Gy), which has replaced the often more familiar units, the Rad (100 rads = 100 CGY = 1 Gy), and the Roentgen. A radiotherapist prescribes a certain number of Grays at a given defined reference point in the body {often the center of the volume, or a specified point on or low the skin surface).
Simply comparing the total dose in terms of the number of Grays prescribed is a common error for those unfamiliar wit,h radiation oncology. The biological effect of radiation on tissues is a complex and partially understood interaction. It is broadly divided into early radiation damage, which is manifested by acute side effects during and immediately after treatment, and late damage, which may not become apparent until months or years later. It is dependent on the volume (how much of the body is treated), the dose delivered per fraction (treatment session), the overall treatment time, and the type of radiation. In simple terms, the larger the volume, the lower the dose tolerated. The dose per fraction has an important inftuence on late normal tissue damage. For radical curative treatments, a large number of small fractions will be delivered to a small- or medium-sized volume, and a standard treatment regime might be 6Q Gy in 36 fractions over 6 weeks of daily treatment (2 Gy per fraction). For palliative end points, a small number of larger doses per fraction are often adequate, e.g., 20 Gy in 5 fractions over I week of daily treatment; sometimes a large single fraction of 6-8 Gy may be used. Some common palliative fractionation prescriptions are summarized in Table 1. For more information on radiobiology. the reader is referred to two readable and accessible reviews.“.”
If only the tumor and a margin around it are treated, then this is termed invo&f f;eti t. If a larger area is treated or a whole region is irradiated, then this may be referred to It is possias loca-regional or u&tej&Mtrmtment.
Dose per fraction (GyI Number of”reactions Overall time Number of fractions” Per day Per week
35 2.33
30 3
20 4
6-8 tL-8
::
10 12
5 5
I 1
1 5
1 5
1 1
1 5
S’reatment session or visit to the RT department.
ble to treat the whole body or half body. The volume is defined by a process of treatment plameing, that may require simulation (the use of a dwagnostic X ray unit specially constructed for radiotherapy planning) and computerized tomography assistance. For radical treatment, this may be a complicated, highly technical, and precise pmcess. However, for palliative work, planning citn often be kept to a minimum to ensure as little inconvenience and discomfort to the patient as possible. side E&?&s There is no doubt that radiotherapy gives rise to significant side effects, although every effort is made to minimize these in the palliative scenario. These may be divided into two groups: those that are confined to the irradiated volume, and systemic effects. Early normal tissue damage toxicity is summarized in Table 2. Most are transient and mild. and are alleviated by simple remedies. It is significant that acute skin reactions are often referred to perjoratively as burns, when, in fact, they represent a transient depopulation of the basal cells of the skin. Although this may be a description close to the truth, it implies a lack of care or misadventure, which is unfortunate. Severe skin reactions may occur in radical treatment, but they are rarely a significant cause of morbidity in palliative treatment. It is sometimes also feared that hair loss will occur even when the volume does no: include the scalp. Counselling and education are required to dispel these myths. Late normal tissue damage is a phenomenon of slowly or nondividing cell lines. Structures, such as the central nervous system (particularly the spinal cord), lung, kidney, the lens of the eye, and microvasculature everywhere, are especially sensitive. Late normal tissue damage is
Systemic-not confined to irradiation volume Malaise Nausea or vomiting
Pain relief
Anorexia Fatigue Specific-confined to irradiation volume Skin Redness Itching Breakdown Abdomen and pelvis Nausea Vomiting Diarrhea Frequency, dysuria, hematuria (cystitis) Head and Neck Dysphagia (murositis) Dry mouth
Control of bleeding (Hemoplysis. vaginal bleeding, hematuria, and rectal bleeding) Control of fungation and ulceration Dyspnea Oncological emergencies (Superior vena cava obstruction. spinal cord compression, cerebral mm*-qlases causing raised intracranial pressuS:) Relief of blockage of hollow viscera Shrinkage of tumor masses causing symptoms by
Taste aheralion Chest Painful dysphagia Head Alopecia Bone Marrow Myelosuppression
virtue of site or spare occupancy
ihe (esophagitis)
not often a significant problem for palliative patients, as the majority do not live long enough to be at risk of developing such damage. However, sound practice usually dictates that all treatments are within safe, late, normal damage limits, although on occasion these constraints may be waived for short-term comfort when it is clear that survival will be very short.
The main indications are summarized in Table 3. It is important that a radiation oncologist be consulted, to prevent inappropriate a priori decisions. It is particularly unfortunate that patients are not referred when it is considered that a tumor is not “radiosensitive.” Radiownsitivily is a radiobiological term referring to the intrinsic response of a given cell line to radiation. Radioresponsiveness is the clinical counterpart. In fact, most tumors “respond” to radiotherapy, although there is a quite marked variation in this response. For palliative end points, even the so-called “radioresistant” tumors will respond favorably, often without measurable tumor regression.
Pain. The role oI’ radiotherapy in t management of pain due to rPlalignant bone metastases is unquestioned, and this indicatic~n (mainly for patients with lung, breast, and prostate primaries) constitutes approximat 20% iation of the total numbers referred to most oncology departments. ‘-’ The pathogenesis of metastatic hone pain and the mechanism of action of radiotherapy are not understood. The similar results achieved with a very wide range of doses and fractionation schedules, with overall responses usually in the region of 70%-SO%, indicate a dissociation between tumor regression and pain relief. The rapidity of action, usually within 24 hr, which is achieved after singlefraction local or hemibody irradiation, is similar to that observed after pituitary ablation.“’ It has often been proprosed that an effect on chemical mediators of the inflammatory response may be operative. A randomized study from Tokyo emphasized patient factors rather than fractionation in achieving pain control,” and a retrospective study from Rome showed lower response rates for adenocarcinoma of the kidney and non-small-cell lung cancer primary histologies, and limb sites of metastases. A dose response was described for total absorbed radiation dose, but not for fraction size,‘2 Retrospective dose response data must, however, be viewed with caution. Higher doses for the palliation of renal cell carcinoma have been adThe key issues revolve vocated elsewhere.” around questions of what dose, fractionation, and field size are required to produce an acceptable irjcidence of sustained pain relief with tnin-
imal toxicity and inconvenience to patients and their families. There has been considerable interest in the administration of large single fractions for bone metastases. In a randomized study” at the Royal Marsden Hospital, a single fraction of 8 Cy was compared with a fractionated course of 30 Gy in 10 daily fractions. No difference was found in the speed of onset or duration of pain relief, which was independent of the histology of the primary tumor. A subsequent study from the same group looked at 4&y single fractions. ts the further expiuration of lowand fractions.“S This is supported by a dose small study from Bxfotd, which also observed that there was a 25% retreatment need in the
8..Gy group and a higher incidence, albeit short duration, of gastrointestinal side effects,” Thus, there is a growing body of ~dence to show that pragmatic treatment of bone me(repeatable) ftactions is safe, ceptable to patients. Crellin and colleagues have discussed the possible reasons many radiation oncologists in the United Kingdom have been reluctant to change their prescribing habits. They emphasize the fact that an apprenticeship training system has more influence than the published literature on practice, and discuss the difficulties of study methodology and the lack of information on late normal tissue damage for large fractions.” The justification of higher total fractionated courses for the prevention of pathological fracture or vertebral fracture due to lyric metastases in the presence of neurological involvement, has wide acceptance, but there is no evidence in favor of these arguments,n*t” The use of hemibody irradiation for bone pain is the subject of increasing interest.“-“’ This may be either the superior or lower half, or both in sequence (usually separated by an interval of 4-6 wk). The tnain indications have been for widespread disease such as a very advanced stage of multiple myeloma or prostatic carcinoma. No difference in terms of response is noted between the two histologies in one comparative evaluation, ‘a but significant toxicity is described using the doses that are widely used at pnxent: 8 Cy to the lower, and 6 Gy to the upper half. An exploration of lower doses is recommended to reduce toxicity while retaining igh wed response rates, in the region of There is also considerable interest in the
use of sequential hemibody irradiation as a systetnic therapy for widespread God-Hodgki~s Iymphoma, breast cancer, or small-cell lung cancer which has failed chemotherapy.“-‘” With refinements in terms of selection, indications, technique, and fractionation, this approach shows considerable promise, and may have a small but definite place in the palliation of these, and possibly othe,? tumors. There has been some recent increase in the idea of the systemic use of radioisotopes for bone pain.’ It is present y regarded as suitable for comparison with hemibody irradiation, but appears to have major disadvantages in terms of late onset of pain relief at Z-4 wk compared with 24-48 hr for hemibody irradiation, and unpredictable differential isotope distribution between normal and tumor-bearing bone. Furthrr evaluation ij clearly required, and its use in combination with external beam radiotherapy may be interesting.
Radiotherapy is often helpful in situations where tumor directly infiltrates into nervous or soft tissues. It is usually administered in combination with steroids or nonsteroidal antinflammatory drugs. Higher doses of radiation may be required for these indications than for bone pain. Careful planning of treatment to include known neurological pathways is important. This is particularly the case for head and neck tumors where there is a propensity for perineurat spread, and in situations where spread into the spinal canal might have occurred. Caution with fractionation is required where large volumes of nervous system tissue are irradiated, such as in brachial and lumbosacral plexus invasion, where late normal tissue damage may be a particular danger. Apical lung cancers may give rise to brachial plexus invasion, or produce the classical Pancoast’s syndrome, and radical irradiation may give worthwhile and sustained loco-regional control and symptom relief.
Hem~ptysis,vaginal bkeding, hmnaturia,and rectul Radiotherapy has a long track record bkding of controlling hemorrhage from exophytic bleeding tumors. It has been known for sometime that vaginal bleeding from cervical carcinoma may be arrested by intracavitary isotope
Equally, external bea irradiation is e ctive eitber as a s ve course, or where indicated, in a high-dose radicai treatment context. In advanced disease, there is now good experience of using a few large fracinsertion.
tjons.2’.25
Control ~fi%ngatim and ?Jlceratim Most disfiguring and distressing cases of superficial tumor fungation and ulceration can be helped by radiotherapy. The most common of these tumors encountered in oncological practice are breast cancer on the chest wall, fungating bead and neck cancer, and both melanoma and nonmclanoma skin cancer. High doses may be required where the clinical situation warrants this, but a few large fractions may also be helpful fat elderly patients, or those wit91 a very poor prop;.. nosis.“” L$@rtea The most common tumor causing shortness of breath is lung cancer, although metastases from other primary sites may, and frequently do produce respiratory symptoms. The mechanisms of dyspnea are not completely understood, may be multifactorial, and often coexist with significant levels of established chronic lung damage-most commonly, chronic obstructive airways disease. Radiotherapy can give excellent palliation for dyspnea due to endobronchial obstruction or extrinsic nodal compression of the bronchi, and for hemoptysis, cough, chest pain, superior venal caval obstt-uction, and dysphagia due to extrinsic esophageal compression. A British consensus document sets out a pragmatic treatment guide for lung cancer, and emphasizes that there is no evidence of a benefit for early treatment ofasymptomatic incurabie patients and that short courses of radiotherapy are usually as effective as more protracted fractionation schedules for palliative end
oncologkd
Emgencies
Su@rior vma cava obstruction The treat men t of superior vena cava obstruction with radiotherapy and steroids is well established, particularly when associated with other features of mediastinal obstruction. The urgency of commencing treatment may have been slightly overemphasized in the past. The use of high-dose steroids, opioid analgesics, anxiolytics, and oxygen (if indicated) in the acute situation can often produce
S@al cord compression Metastatir spinal cord com93res.G~ is a devastating complica(jon 09 malignant disease. Considerable clinical vigilance is required to ensure early diagnosis and the prompt institution of emergency lreatment. Clinical signs ant9 syrnpfoms may 91esubtle and atypical,and levels of‘ compression may i)e mu!tiplt!. assyn~etric-a9, dllcl of Inixetl upper and lower motor neutrons. Vague complaims of back pain. leg weakness. shooting pains, d~~3sthesias, anc9 sphillcrer clisturbance should always be taken seriously. Early delecliotl rather t91an tumor cell type a9,pears to be important in determining the functional outcome.‘!’ A full clinical arid radiologic
assessmem
is essential,
anti
either computerized tomography, myelography, or magnetic resonance imaging if available, is indicated,“” together with the early commencement of high-dose corticosteroids. Consultation with a neurosurgicai service is always advisable. Result:; obtained with radiotherapy or with surgery appear to be similar,“’ and Findlay has suggested a useful a9gorithmic approach to the problem.‘” Further work is required to identify subgroups who may benefit from one modality rather than the other. The poor prognosis of patients with cord compression should not obscure the itnportance of obtaining the best palliative functional result, and patients who are thought to be unsuitable for surgical intervention should usually immediately commence a course of radiotherapy to the compression site. The results for patients with evidence of established complete cord “section” who fail to respond to steroids are so poor that it is questionable if they should be subjected to treatment, although radiotherapy is always indicated for pain control if pain is present.
melashes causing raised id pressure Irradiation of the whole brain for cerebral metastases has an important role in tbe pa99iation of this common and inevitably fatal cosn919L cation of malignancy, but documentation of indications and results could be better. The role
of steroids in the emergency control of raised intracranial pressure is undisputed, but much remains to be understood about the mechanism of action, optimal preparation, dose. and scheduling. sp This review stresses the importance of trying to reduce and tail off the steroids as soon as neurological function is stable. There is considerable scope for more clinical research, particularly with regard to selection criteria for radiotherapy, Failure to respond to steroids, impaired conscious level, and neuropsychiatric presentations seem unfavorable prognostic factors for response to radiotherapy, whereas motor neu~lo~~cal deficits that respond to steroids tter, The use of radiotherapy in the acute situation for critically raised intracranial pressure together with steroids may sometimes produce impressive results in the short term. For solitary metastases, there is evidence that surgical excision is of value both tn itirrns of quality and quandty of lifee.sWs Some controversy surrounds the issue of whether higher doses of radiotherapy produce better results, either to multiple or solitary metastases, with the balance of opinion pointing towards a negative conclusion,Y~’ Several studies have addressed malignant melanoma as an entity of special interest. There are conflicting reports about the role of chemotherapy, with one study showing a few longterm survivors,s” and another a negative conclusion. Despite suggestions that large-dose-perfraction treatment is beneficial for radiobioul reztsons, Chai and colleagues conclude a short overall treatment time is more important?” The overall picture is gloomy for most patients with cerebral metastases. However, short palliative courses of cerebral radiotherapy should always be considered, although more information concerning prognostic selection factors would be helpful. Most studies seem to focus too much on survival, and more focus on palliative issues is required. Patients with solitary metastases should have the benefit of a neutosurgical opinion, and stereotactic radiosury may he a promising avenue for selected
lumen, wall, or extrinsic compression to the helpstructure. Palliative radiotherapy may ful in many of these situations, although more information on outcomes would be helpful. Examples include the bronchi, esophagus, upper airway or digestive tract, bile ducts, ureters, lymphatic channels, and blood vessels.
oftumor tm.sS@S calcsing syvnptom ty
drMost tumors can be e of radiotherapy, reor histology. The important question to be posed in each case is whether a volume reduction will have a favorable effect on symptom control and quality of life. Where gains in terms of palliative end points are either likely to be small or nonexistent, it may be best not to embark on treatment. Such individual decisions may be difficult, and there is often no literature to act as a guide. Very large masses adjacent to critical normal tissues, particularly those that respond less favqrably, such as sarcoma and melanoma. may be best not treated.
Owing to disappointing results in the aggressive management of most of the common solid tumors.41 the focus of oncology has shifted in recent years. Communities. patients, and their fam!lies have requested that more interest be shown in palliative care issues. Research into palliative radiotherapy methods and outcomes has been largely neglected until recently, but changes in practice are already apparent. Radiation oncologists have a duty to communicate what they have to offer patients with advanced incurable cancer. and at a time when more and more such patients are being managed in nononcological settings, such as hospices or at home, it is important for their caregivers to know when to call the radiation oncologist.
1. Fletcher GH. Regaud lecture and perspectives on the history of radiotherapy. Kadiother Oncol 1988;12:253-271. 2. Editorial. Strontium 1990;335:38+-385.
c$ lrollow visceru Any hollow ay be partially or completely obstructed by the presence of a tumor in the
and bone
pain.
Lancet
3. Ashby M, Stoffell B. Therapeutic ratio and defined phases: proposal of ethical framework for palliative care. Br Med J 1991;302:1322-1324.
4. P~l~~l~on~.The rcspvns~bjl~ty of ~adiologis~5 in tbc
~~se~vatio~l of breast and rectum in cancer treatment. Clin Radio1 1986:37:303-309. 5. Suit HD. Radiation biology: The conceptual and practical impact on radiation therapy. Radiat 1983:94: 10-40. 6. Hall EJ. Basic radiobiology. 1988;11(3):220-258.
Am J Clin Oncol
7. Coia LR. Hanks GE, Martz K. Steinfeld A. Diamond jJ, Kramer 5. Practice patterns of palliative care for the United States 19X4-1985. lnt J Radiat Oncol Biol Phys 1988;14: 1261-1269. 8. Crellin AM, Marks A. Maher EJ. Why don’t British radiotherapists give single fractions of radiotherapy for bone metastases? Clin Oncol 1989; 1:63-66. 9. Pouhen HS. Nielsen OS. Klee M, Korth M. Palliative irradiation of bone metastases. Cancer Treat Rev 1989:16:41-48. IO. Bates ‘I‘. Kadiotherapy Oncol 1989; I :57-58.
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Il. Okawa ‘1‘.Kita M. Goto M. Nishijima H, Miy;rji N. Randomized prospective clinical study of small, large and twice-a-day fraction radiotherapy for painful bone metastases. Radiother Oncol 1988:13:99-104.
isonl of single dose and fractionared re~~~~eI~s. Int ,j Rihlt Olld Biol Phys 19H9: 17: 128 1-i 28.5. 21. LJrtasun R(Z. B&b A, Rodoar 1). Hemi diation: An XtiW herapeutic modaliy for the ~~~tYll~ll1 Of ptk~ltS With small cell lurlg cancer. Kadiat Oncol Biol Phys I9H3;9: I.i75-157#.
m
Ir
2% Jullien D. Vilcoq JR, Campana F. irradiations hCmlcorporelles: Kesultats chez 92 patientes porteuses de cancer du scin polymetastatique trairees i l’lnstitut Curie. Agence lnternationale de 1’Eneqrie Atomique. Colloque International sur la Kadiotberapie dans les I’ays en D&eloppement ---Situations et Tendances. Vienne 1986347: 1-7. 23. Duchesne GM. Harmcr (IL. emibody irradiatiou in lymphomas and related malignancies. lilt .j Kadiat Onto1 Biol Phys 19X5: I 1:2003-2006. ?4. Ha11cJS. K~senman .j(;, Varia MA, For&r W(:, Walton LA, (:urrie JL. 1000 c
