1The Meyerstein Institute of Oncology, The Middlesex Hospital, London; 2Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, UK; 3Oncologica Clinica, Ospedale Regionale, Torrette di Ancona, Italy
Received 15 January 2001; revised 14 September 2001; accepted 17 September 2001.
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Abstract |
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Adjuvant therapy in osteosarcoma (OS) and Ewings sarcoma (ES) is primarily directed towards treatment of subclinical lung disease. Before the advent of modern intensive chemotherapy, lung irradiation was the only available adjuvant treatment. It has proven biological activity and low morbidity. There is, however, a wide variation in its application between centres. This systematic review aims to define the evidence to support the use of lung irradiation in these diseases.
Design
A review of trials published between 1966 and 2000 was undertaken to determine the evidence for the use of pulmonary irradiation in OS and ES.
Results
Several small series of prophylactic lung irradiation (PLI) have been reported, most from over 20 years ago. These studies support the theoretical basis for the use of PLI in both OS and ES. Few randomised studies have been performed which include PLI. In OS, studies demonstrated a trend in favour of PLI compared with no adjuvant treatment and, subsequently, a level of benefit similar to that achieved with chemotherapy, but no additive effect. No studies have used PLI in addition to current standard chemotherapy regimens, or evaluated its use after successful metastatectomy. In ES, only one randomised study has addressed the role of PLI, in a comparison with vincristine, actinomycin D and cyclophosphamide combination chemotherapy with or without doxorubicin. Prolonged follow-up favoured four-drug chemotherapy. Retrospective reports from large cooperative groups suggest that the addition of whole-lung radiotherapy (WLRT) improves outcome in ES patients presenting with pulmonary metastases. However, there are no randomised study data to support this.
Conclusions
Further randomised studies are necessary to clarify the role of PLI in addition to current standard chemotherapy regimens, or its use after successful metastasectomy in patients with OS. In patients with localised ES adjuvant chemotherapy appears to be superior to PLI alone, while there is little evidence to support treatment with WLRT in patients who present with pulmonary metastases.
Key words: Ewings sarcoma, osteosarcoma, pulmonary irradiation, pulmonary metastases
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Introduction |
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This paper reviews the available data and makes recommendations for evidence-based use of pulmonary irradiation in ES and OS.
The biological basis for prophylactic lung irradiation
The propensity of bone tumours to metastasise early, and often exclusively to the lungs, stimulated interest in the use of adjuvant therapies to prevent the development of pulmonary metastases. Prophylactic lung irradiation (PLI) is an attractive therapeutic proposition that offers a theoretical chance of curing patients at high risk of relapse using a non-toxic, well-tolerated adjuvant treatment.
The fundamental problem with thoracic irradiation is that pulmonary parenchymal tolerance is often exceeded before tumouricidal doses are achieved. Early irradiation is therefore imperative so that the minimum necessary dose can be applied early in the natural history of the disease, when subclinical metastases are likely to be at their smallest and most amenable to sterilisation.
Abbatucci et al. [1] provided the theoretical background upon which subsequent trials assessing the clinical efficacy of PLI were based. Working from radiobiological principles, they showed that the exponential kill of clonogenic cells produced by fractionated radiotherapy could, in principle, eradicate subvisual metastases. Assuming a D10 (the dose required to reduce the number of viable clonogenic cells in a tumour to 10%) of 4 Gy for OS, 20 Gy ought to prevent the growth of metastases containing <104 or <105 cells. Visible deposits detectable on chest X-ray, however, measure at least 6 mm to 10 mm and contain 108 or more tumour cells. An unacceptably high dose (~10 times the D10) would therefore be required to destroy such disease, exceeding significantly the tolerance of normal lung tissue.
Breur [2, 3] analysed 13 patients with microscopic pulmonary metastases and, by extrapolating backwards in time, showed that approximately one in four patients with subclinical metastases have tumours containing 105 cells, which are, in principle, curable by early adjuvant pulmonary irradiation at a dose well within lung tolerance.
Baeza et al. [4] theorised that there was no convincing evidence that sterilisation of OS metastases in the lung could be achieved with a lower dose than that required for the primary site. They therefore recommended that whole-lung radiotherapy (WLRT) should only be considered in conjunction with the development of more effective adjuvant therapies such as radioprotectors (which improve lung tolerance), radiosensitisers (to selectively sensitise the tumour) or more effective chemotherapy regimens.
WLRT has been extensively used in the past to palliate successfully pulmonary metastases from musculoskeletal tumours [5], but very few data on the effectiveness of adjuvant PLI have been published. When considering palliative WLRT for metastatic disease, it is important to balance the morbidity and risk of parenchymal injury from the high doses required against the possibility of achieving valuable clinical benefit.
WLRT technique
Bilateral pulmonary irradiation is a straightforward radiotherapy technique. Parallel opposed antero-posterior fields encompassing the apices and posterior costophrenic angles are applied to the whole thoracic cavity. Customised anterior cardiac lead shielding may be used, particularly if concurrent cardiotoxic chemotherapy is administered. The two lungs may be treated simultaneously or sequentially.
Lung tissue tolerates high-dose irradiation poorly. When planning treatment, care must be taken not to exceed total doses of 18 to 20 Gy in 1.8 to 2.0 Gy fractions in order to respect lung tolerance.
Many early studies did not make dose corrections for the increased transmission of radiation through healthy lung tissue. In others, it is not clear whether correction factors were used or not. Uncorrected prescriptions, based on the inaccurate assumption that the lungs have the same density as normal tissue, underestimate the actual dose given to the centre of the lungs by ~14%. Dose fractionation is also important, since the doses delivered during WLRT are often close to tolerance. Consequently, significant pulmonary parenchymal injury may be sustained if the lungs are irradiated to a high dose per fraction without taking transmission factors into account.
Cobalt or megavoltage photons fractionated daily to a total midplane dose (MPD) of 5.5 to 25 Gy have been employed in the studies described when lung correction factors have been indicated.
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Study design |
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Results |
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Early descriptive studies of WLRT as part of the management of OS are of limited value because of the small numbers of patients, heterogeneity of timing and type of treatment of the primary and short follow-up. In total, they suggest some biological activity of WLRT in OS. The limited information from randomised studies once again indicates a therapeutic gain from PLI that is lost when adjuvant systemic therapy is added. The value of PLI in patients receiving current standard chemotherapy regimens has not been tested in controlled studies.
The role of adjuvant radiotherapy: evidence from non-randomised studies. Lougheed et al. [6] were the first to propose that elective PLI of clinically normal lungs might delay the development of pulmonary metastases in OS. Prophylactic irradiation was delivered to a single lung field (15 Gy over 12 days) in combination with actinomycin D chemotherapy. Four of eight patients developed metastases in the untreated lung, but only one case progressed in the irradiated lung field.
Newton [7] reported that fewer patients developed pulmonary secondaries in early follow-up after elective pulmonary irradiation than non-irradiated controls. Only four of 13 irradi-ated patients progressed after prophylactic irradiation. The effect was, however, short-lived and late relapses rendered the long-term benefit insignificant.
Caldwell [8] performed sequential elective bilateral WLRT on a series of 38 patients with a variety of tumours including seven with OS. Seventeen had no detectable metastases; 21 with pulmonary nodules received WLRT followed by either surgical resection or a boost to a higher dose. The dose delivered ranged from 16 to 20 Gy, uncorrected, in 2.0 Gy fractions. Three of the four OS patients with no demonstrable metastases at presentation were alive and well with no active disease at between 2 and 4 years.
In the small prospective series of Caceres et al. [9], 17 evaluable patients from Peru received PLI with or without doxorubicin. All were treated to a dose of 20 Gy over 2128 days; 10 also received adjuvant doxorubicin. After only 13 months of follow-up, three of seven irradiated patients were free of disease, compared with six of 10 in the chemotherapy arm.
The retrospective review of 62 OS patients from The Princess Margaret Hospital, Toronto, by Jenkin et al. [10] included six cases who received 15 Gy PLI and simultaneous actinomycin. All six developed diffuse pulmonary metastases within 2 to 6 months, with no demonstrable disease-free survival (DFS) benefit over untreated historical controls.
The French Bone Tumour Study Group [11] published studies on a non-randomised series of 41 evaluable cases of extremity OS treated with six cycles of intensive combination chemotherapy including mitomycin C, vincristine, methotrexate, doxorubicin, dacarbazine and cyclophosphamide with PLI (20 Gy in 12 fractions), intercalated between the first two cycles. The overall survival rate of 66% and a 5-year DFS of 58% compared well with historical controls but at the cost of unacceptably high toxicity, which was not seen with lung irradiation alone. They observed marked impairment of lung function tests resulting in restrictive ventilatory defects, five life-threatening infections and one death from Pneumocystis carinii pneumonia.
A study at the Mayo Clinic (dose and fractionation schedule not given) [12] in which pulmonary micrometastases in OS were evaluated suggested no therapeutic advantage from prophylactic pulmonary irradiation.
Evidence from randomised studies. Rab et al. [13] published the first randomised trial assessing elective WLRT in 1976. Fifty-three patients from the Mayo Clinic were randomised to receive PLI while breathing 100% oxygen with intravenous actinomycin D administered 1 h before each fraction. An MPD of 15 Gy, uncorrected, was delivered (the dose per fraction was not stated). The control group did not undergo PLI. Although the study revealed a trend towards improved median survival time with PLI (42 months compared with 25 months), after a median of 32 months follow-up there was no statistically significant difference in overall survival or DFS.
In January 1970, the European Organisation for Research and Treatment of Cancer (EORTC) initiated the first multicentre, randomised, controlled clinical trial of adjuvant PLI after radical treatment of primary OS in the so-called O2 trial [14]. One hundred and twenty patients with localised extremity tumours were recruited. The experimental group received 17.5 Gy MPD in 10 fractions over 12 days to both lung fields, delivering a total dose of ~20 Gy with lung correction. Control patients received no adjuvant treatment. Unfortunately, early enthusiasm from the adjuvant chemotherapy trials of the 1970s [1517] reduced clinical interest in the trial, resulting in its premature closure in 1975, with 86 evaluable cases.
Three-year DFS was better in the irradiated group (43% compared with 28%). The difference was not, however, statistically significant (P = 0.059). Overall 5-year survival was improved in the irradiated group (55% compared with 40%), although this difference also failed to reach statistical significance (P = 0.18).
Early subgroup analysis revealed a significant 3-year DFS advantage in patients under 17 years old (48% compared with 28%; P = 0.028). Subsequent re-examination of the mature trial data showed that this advantage was lost with longer follow-up. The updated 5-year DFS for the 60 patients under 16 years old dropped to 31% and 50% in the observed and treated groups, respectively (P = 0.074). No significant long-term advantage from PLI could be demonstrated.
In the light of increasing evidence that adjuvant chemotherapy was beneficial in OS, the EORTC and the International Society of Paediatric Oncology jointly launched the O3 trial in 1978 to compare the value, toxicity and effectiveness of adjuvant chemotherapy and/or PLI [18]. Two hundred and forty patients younger than 30 years were randomised to three groups: group 1 (adjuvant chemotherapy), 3 months of induction combination chemotherapy (vincristine, methotrexate and leucovorin rescue alternating with doxorubicin) followed by 6 months of consolidation (including doxorubicin and cyclophosphamide); group 2 (elective PLI) 20 Gy in 10 fractions over 14 days, with lung correction; group 3, induction chemotherapy (as in group 1) followed by PLI.
The type of adjuvant treatment did not significantly alter the overall survival, DFS or metastasis-free survival. Moreover, the pattern of relapse was no different between the three groups (62% developed lung metastases and 24% bone metastases as their first site of distant disease). Overall survival and DFS at 4 years were 43% and 24%, respectively.
As expected, acute toxicity was greater with chemotherapy and resulted in three deaths. PLI was well tolerated, although more irradiated patients developed a late, but asymptomatic, deterioration in pulmonary function on spirometric criteria compared with those receiving chemotherapy (14% compared with 5%).
The O3 study therefore showed that survival for patients receiving elective PLI was equivalent to that of patients receiving the current best standard adjuvant chemotherapy. Combined chemotherapy and irradiation, however, offered no advantage over single modality treatment.
No further randomised studies of the role of PLI in OS have been carried out. These three trials failed to demonstrate a clear advantage for PLI. All are small, however, and any benefit of PLI in addition to a full course of chemotherapy would be obscured by the design of the O3 study.
WLRT in advanced disease. Although only 20% of patients with OS present, with detectable metastatic disease, long-term survival with widespread pulmonary deposits rarely exceeds 15% [19].
Thoracotomy offers the only realistic chance of cure from metastatic disease with survival rates of 20% to 40% in patients undergoing pulmonary metastatectomy after recurrence confined to the lung [2022]. Several favourable prognostic factors have been described (including fewer than four lesions completely removed at first thoracotomy, unilateral disease and a disease-free interval of at least 18 months) [22]. The addition of WLRT after metastatectomy, however, has too infrequently been applied to feature in such analyses.
The report by Giritsky et al. [23] of 12 patients, while providing further evidence that thoracotomy and resection should be undertaken aggressively whenever lung deposits appear operable, failed to show any benefit for pre- or post-thoracotomy irradiation (dose and fractionation schedule not given).
The O3 data [18] suggested that successful metastatectomy was more frequently possible following previous PLI than after adjuvant chemotherapy (14 of 19 compared with eight of 15). Survival was better after metastatectomy compared with other approaches (P = 0.0002).
Pulmonary irradiation may also be used for the palliation of advanced disease. Complete remission after low-dose palliative irradiation has been reported. Caldwell [8] described one patient with a single demonstrable pulmonary nodule who received elective WLRT (20 Gy in 10 fractions) plus a boost to the nodule (25 Gy in 10 fractions) and remained free of disease at 5 years. Two other patients with pulmonary metastases died despite WLRT.
Published data assessing survival after irradiation of pulmonary metastases are scarce and the use of WLRT for metastatic OS, even in the palliative setting, remains the exception rather than the rule.
In summary, WLRT has activity against metastatic OS but does not confer any advantage when added to conventional adjuvant chemotherapy. Perhaps the most interesting unanswered question is whether WLRT might have a role in reducing further recurrence in those patients deemed at very high risk after metastatectomy. Unfortunately, there are no published data to support this and a randomised study is unlikely.
Ewings sarcoma
Since James Ewing first described this malignant small round-cell tumour in 1921, it has become apparent that most patients with apparently localised disease have micrometastases at diagnosis. Without systemic treatment, more than 80% die from metastatic disease. As with OS, the lungs are the most common site for secondary spread. Survival has increased considerably, however, with the realisation that ES is the most chemo- and radiosensitive of the bone tumours.
Adjuvant radiotherapy in ES. In 1976 Mintz et al. [24] reported that WLRT could inhibit the development of pulmonary metastases. In a case report of ES of the scapula, the whole left hemithorax was irradiated during treatment of the primary tumour to a dose of 30 Gy in 10 daily fractions. Despite rapidly aggressive disease and metastatic invasion of the untreated right lung within 10 months, the left lung remained free of tumour. A transient self-limiting left-sided radiation pneumonitis was observed.
The series reported by Caldwell [8] included 10 patients with ES who received elective WLRT. Six of the patients underwent PLI; the remaining four received WLRT for pulmonary metastases. Eight remained disease-free in the lungs at the time of analysis or death, including complete remission in one patient presenting with pulmonary disease. Three patients were alive between 3 and 7 years after irradiation. Only two of the six metastases-free cases survived.
The first Intergroup Ewings Sarcoma Study (IESS-I), a large randomised trial of adjuvant therapy in localised ES, compared the addition of doxorubicin or bilateral pulmonary radiotherapy (15 Gy uncorrected in 10 fractions) with standard vincristine, actinomycin D, cyclophosphamide (VAC) chemotherapy. All patients received radiotherapy to the primary lesion. In the first IESS-I report, Razek et al. [25] reported a reduction in lung metastases of 38% with VAC alone compared with 10% with vincristine, actinomycin D, cyclophosphamide, Adriamycin (VACA) and 20% with PLI. The addition of Adriamycin (doxorubicin) improved survival and reduced the incidence of overt lung metastases more than prophylactic bilateral pulmonary irradiation, but the difference between treatments was not statistically significant. Prolonged follow-up of 342 patients [2628] demonstrated that lung deposits developed more frequently after PLI (20%) than VACA (15%), although the difference was not significant (P = 0.35). There was a statistically significant 5-year relapse-free survival advantage with VACA (60%) over VAC plus PLI (44%; P <0.05) and VAC alone (24%; P <0.001). A similar improvement in overall survival at 5 years was evident (65% with VACA compared with 53% with VAC plus PLI; P = 0.001) indicating that the addition of doxorubicin was superior to adjuvant PLI.
The IESS-I did not study the addition of PLI to doxorubicin-based chemotherapy, but as similar rates of recurrence in the lungs were observed in all three arms, it seems unlikely that PLI would confer a significant additional benefit.
WLRT in advanced disease. Since the early 1970s, WLRT has occasionally been employed in conjunction with chemotherapy in patients who present with lung metastases [29, 30]. This has not been tested in randomised trials. Although studies of metastatic disease by large cooperative groups such as IESS and the Cooperative Ewings Sarcoma Study (CESS) have employed WLRT, non-uniform selection of patients obscures any conclusions.
Rosen et al. [29] reported the use of WLRT in metastatic ES during an early trial of adjuvant synchronous chemotherapy and radiotherapy in 1972. Two of 12 patients presented with pulmonary metastases and received WLRT (20 Gy in 10 fractions) in addition to adjuvant VACA combination chemotherapy. Both remained clinically and radiographically free of disease after 20 and 21 months, respectively. This was compared with a group of historical controls that received no additional treatment in which less than 10% were alive at 20 months.
Jaffe et al. [30] reported 14 patients, including five with metastatic disease at diagnosis treated with VAC. Of four cases with pulmonary secondaries, there were one partial and three complete responses. One of the three developed recurrent lung metastases at 9 months, prompting the use of elective WLRT (15 Gy in 10 fractions) in the two remaining patients in an attempt to consolidate the response. Both remained in remission for 6 months before eventually dying of widespread disease. It was claimed that survival was prolonged compared with that of historical controls.
Evidence favouring routine pulmonary irradiation in patients who achieve a complete remission with chemotherapy remains scarce. Margolis and Phillips [5] irradiated seven patients with pulmonary metastases from ES. Doses in the series ranged from 5.5 to 30 Gy, uncorrected. Only two achieved permanent control of the lung lesions. Both also received actinomycin D. One died of other causes after 18 months and the other remained well at 8 years.
The Intergroup Ewings Sarcoma Studies of Metastatic Disease (I and II) [31] employed pulmonary irradiation in patients with lung metastases. Overall, 30% remained in remission at 3 years, simply confirming that some patients presenting with haematogenous metastases can be cured using combination chemotherapy and radiotherapy.
The German CESS studies [3236] retrospectively analysed the impact of bilateral thoracic irradiation on survival in ES patients with pulmonary metastases at diagnosis. Complete radiographic remission was achieved in 29 of 30 evaluable cases after either chemotherapy (n = 25) or chemotherapy plus resection of pulmonary metastases (n = 4). Of these 29 patients, 22 also had WLRT (12 to 21 Gy in 1.5-Gy fractions). Nine of the 10 patients who remained in complete remission at the time of analysis had undergone WLRT. A strong doseresponse relationship was suggested: remission was achieved in one of six patients without WLRT compared with four of 10 receiving 12 to 16 Gy and five of six treated with 18 to 21 Gy. Relapsed patients had received significantly lower doses than complete responders (P = 0.028).
The most recently published survival analysis of 171 evaluable patients registered with the European Intergroup Cooperative Ewings Sarcoma Studies suggested a benefit from WLRT in disseminated Ewings disease [37]. Bilateral WLRT (15 to 18 Gy) improved outcome in 41 cases presenting with isolated pulmonary metastases (0.40 compared with 0.19 4-year event-free survival; P <0.05). In addition, WLRT improved EFS in patients with both lung and bone metastases from 0.05 to 0.30 (P <0.001). Retrospective analysis of 94 patients with isolated lung secondaries showed a 10% benefit from lung irradiation after 5 years (log rank P <0.05). These non-randomised comparisons must be interpreted with great caution, however, since the basis upon which patients were selected for WLRT is unknown.
In summary, although WLRT has been widely applied in patients presenting with pulmonary metastases, no firm conclusions can be drawn from the reported data. Even in large cooperative group experience, patient-selection factors confound interpretation, so as to make these reports almost valueless. No randomised trial data have been published.
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Pulmonary toxicity |
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Radiation pneumonitis was first described in 1922 by Groover et al. [39]. Symptoms usually begin between 1 month and 4 months after radiotherapy to the lung but may be delayed for as long as 6 months. The acute reaction comprises cough, dyspnoea and fever, and may subside leaving no clinical or radiological sequelae. A minority of patients progress to a state of irreversible fibrosis with a chronic restrictive deficit, loss of lung volume and interstitial shadowing.
Many variables may influence the development of pneumonitis, especially radiation dose, fractionation, lung volume, coexisting infection and administration of drugs, particularly actinomycin D [40].
Clinically apparent pneumonitis is rare at doses below 15 Gy and prolongation of overall treatment time reduces both the risk and severity. Various fractionation schedules have been proposed. Newton and Spittle [41] found that treatment-related complications were rare after a dose of 22.5 Gy in 13 fractions. Abbatucci [38] recommended a dose of 15 Gy in four fractions followed by a boost or surgical resection of any sites of demonstrable metastases.
The efficacy of thoracic irradiation may be enhanced with concomitant chemotherapy. This might allow the radiation dose to be kept to a minimum, thereby reducing post-irradiation morbidity [38]. Certain agents potentiate lung toxicity (e.g. actinomycin D and doxorubicin), however. In spite of this, doses at the limit of tolerance are usually employed.
Wara et al. [42] published the University of California experience of irradiating 92 lung fields in 51 patients with doses ranging from 5.5 to 66 Gy. They showed that concurrent actinomycin D lowered the threshold for the onset of clinical radiation pneumonitis. This concurred with the finding of Cohen et al. [40] finding that actinomycin D can reduce the radiation tolerance of the lung by as much as 20%. The incidence of pneumonitis increased with radiation dose and was much greater at lower total doses with chemotherapy than with radiation alone. They recommended 15 Gy in 10 fractions with actinomycin or 25 Gy over 20 fractions as a safe dose with an acceptably low risk (<5%) of pulmonary complications.
None of the larger studies to date (O2, O3 and IESS) has reported a significant incidence of radiation pneumonitis. Two prospective studies evaluating pulmonary function after adjuvant lung radiation and doxorubicin in OS have been published. In 1980 Carcelen et al. [43] provided the first data on lung function tests after elective WLRT (20 Gy in 2128 days). Baseline and follow-up spirometry was performed on six patients, four of whom also received subsequent doxorubicin chemotherapy. No significant changes in pulmonary function were observed at 6 or 20 months.
In an earlier report, respiratory symptoms in 18 patients treated with WLRT were studied; 11 also received doxorubicin chemotherapy. Four exhibited cardiorespiratory symptoms and three became dyspnoeic, but none of the 18 subjects displayed radiological signs of fibrosis or pneumonitis after 20 Gy prophylactic irradiation. Spirometric data were not provided, however [9].
Ellis et al. [44] evaluated the changes in spirometry, lung volumes and diffusing capacity (DLCO) in 28 patients with no known metastatic disease after pulmonary irradiation to a dose of 16 Gy in 10 fractions. Minimal impairment of lung forced vital capacity and forced expiratory volume was seen after 6 months, which then improved and remained normal after the second year after treatment. Lung volumes (total lung capacity, residual volume and functional residual capacity) decreased slightly after 6 months and failed to improve considerably thereafter. DLCO deteriorated markedly at the first post-irradiation assessment, but improved steadily and virtually returned to baseline after 5 years. No patient reported any significant respiratory symptoms or developed pneumonitis during a mean of 42 months of follow-up (range from 6 to 77 months). Diffusing capacity, which indirectly measures the ability of oxygen to cross the alveolar capillary membrane, was the parameter most affected. This reflects the radiation fibrosis seen on histological examination of the capillary membrane and is probably the most important pathophysiological effect of radiation lung damage. Overall, the work of Ellis et al. demonstrated a mild, asymptomatic restrictive ventilatory deficit at 6 to 12 months after radiation, which reversed rapidly leaving little or no residual functional disability.
Baeza et al. [4] published results from a series of 62 patients with pulmonary secondaries from a variety of malignant tumours treated with WLRT at the MD Anderson Hospital. A variety of uncorrected dose fractionation schedules were administered, most commonly 15 Gy in 10 fractions or 20 Gy in 15 daily treatments. Overall, 71% developed pulmonary metastases within 12 months; 23% of those who received in excess of 15 Gy developed pneumonitis; and 25% of those treated with concurrent actinomycin D developed the complication. Three of the 13 cases of pneumonitis were fatal; two had been treated with concomitant chemotherapy. The 10 survivors had no residual clinical or radiological sequelae but did display persistent ventilatory defects on spirometry.
Margolis and Phillips [5] irradiated a selection of patients with metastatic disease from various tumours and confirmed that actinomycin D sensitises the lungs to fractionated radiotherapy. Ten of 35 irradiated lungs (29%) developed pneumonitis compared with five of 11 (46%) of those treated with concurrent actinomycin D.
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Conclusions |
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Assessment of the value of PLI has lagged behind the considerable advances that have been made with the use of adjuvant chemotherapy in bone tumours. The few randomised and retrospective series made comparisons with chemotherapy regimens, most of which have been superseded. No studies have been carried out in patients receiving modern intensive chemotherapy protocols. Consequently, in future trials it will be even harder to demonstrate a worthwhile clinical benefit from WLRT.
There is little doubt that adjuvant prophylactic pulmonary irradiation using fractionated courses of ~20 Gy can delay the onset of lung metastases in localised primary bone tumours. There is no evidence, however, for an additive survival benefit when used together with combination chemotherapy.
In OS, PLI has been shown, at best, to be as effective as the early adjuvant chemotherapy regimens. Combination chemotherapy and radiation increases toxicity but appears to offer no additional benefit over single modality treatment.
For metastatic OS, surgical resection remains the treatment of choice. The role of radiotherapy post-metastatectomy is not established and has not been thoroughly addressed. It is unrealistic to attempt randomised studies of WLRT after pulmonary metastatectomy, but carefully designed and reported descriptive studies may inform us further.
In apparently localised ES, adjuvant chemotherapy appears to be superior to PLI alone in terms of local control, inhibition of lung relapse and overall survival.
WLRT continues to be used in selected patients, particularly those with lung metastases at diagnosis. No controlled studies supporting its use in this context exist. In contrast to OS, however, up to one-third of patients with advanced disease at presentation may be potentially cured with intensive cytotoxic therapy with or without whole-lung radiation. The recently initiated European cooperative group study of ES includes randomisation between conventional chemotherapy plus WLRT, or peripheral blood stem cell-supported high-dose chemotherapy for such patients, even though the role of WLRT in this setting remains to be defined clearly.
In summary, pulmonary irradiation is a therapeutic modality for bone tumours that, although introduced 30 years ago, has been insufficiently evaluated to determine clearly its benefits. Modern intensive chemotherapy regimens have superseded its use. Despite this, WLRT is used in certain centres to treat bone tumours, but indications appear to vary widely. Finally, there remain subgroups of patients with both OS and ES for whom even a small additional benefit from WLRT may be worthwhile, and future studies should be aimed at detecting these indications.
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Footnotes |
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References |
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