- Email: [email protected]
In Reply to Drs. Maranzano and Trippa
314
I. J. Radiation Oncology
●
Biology
●
Physics
developed at the site of former tumor/SIB. In these 4 patients, ulcers healed 1, 3, 3, and 7 months later (see Table 4 in Studer et al. [2]). Thus, we consider SIB-IMRT with chemotherapy as described with single doses up to 2.2 Gy to planning target volume 1 to be safe and well tolerated. GABRIELA STUDER, M.D. CHRISTOPH GLANZMANN, M.D. Department of Radiation Oncology University Hospital Zurich Zurich, Switzerland doi:10.1016/j.ijrobp.2007.01.020 1. Garden AS, Morrison WH, Wong P-F, et al. Disease-control rates following intensity-modulated radiation therapy for small primary oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;67:438 – 444. 2. Studer G, Huguenin PU, Davis JB, et al. IMRT using simultaneously integrated boost (SIB) in head and neck cancer patients. Radiat Oncol 2006;1:7. 3. Studer G, Lutolf UM, Davis JB, et al. IMRT in hypopharyngeal tumors. Strahlenther Onkol 2006;182:331–335.
ADDENDUM TO: BASIC IMMUNOLOGY OF ANTIBODY TARGETED RADIOTHERAPY: IN REGARD TO WONG (INT J RADIAT ONCOL BIOL PHYS 2006;66: S8 –S14) To the Editor: This interesting review by Wong (1) has omitted some important data in its tables. Missing from the list of antibody/antigens in Table 1 is the melanoma-associated chondroitin sulfate proteoglycan, an antigen expressed by melanoma cells that is targeted by the monoclonal antibody 9.2.27. This benign murine antibody has a very low immune response and is not toxic to targeted melanoma cells. However, when labeled with 213Bi, an ␣-emitting radioisotope, the conjugate is highly cytotoxic to targeted melanoma cells. A phase I trial of this conjugate for intralesional targeted ␣-therapy for melanoma has been completed and published (2). Human anti-mouse antibody responses were not observed in the 16 subjects. However, single intralesional injections into subcutaneous melanomas caused massive cell death. An ongoing trial of systemic ␣-therapy for Stage 4 melanoma has reported partial responses for 10% of 33 subjects (personal communication, Raja C et al.). The unfortunate omission of 213Bi and 225Ac from Table 4 gives the wrong impression about the importance of these ␣-emitting radioisotopes. Bismuth-213 is milked from the 225Ac generator. It has a 46-min half life and emits an 8.35-MeV ␣ with an 80-m range. A 440-keV ␥-ray is also emitted that can be used for single photon emission tomography imaging with a high-energy collimator. Considerable preclinical data are available for 213Bi, which is undergoing clinical trials in Australia (personal communication, Raja C et al.), the United States (3), and Europe (4) for melanoma, myeloid leukemia, and lymphoma. The Memorial Sloan-Kettering Cancer Center is also running a phase I trial for 225Ac-labeled monoclonal antibody for myeloid leukemia. 225Ac has a 10-day half-life and decays by emission of four ␣-particles to stable 209 Bi. It is a highly cytotoxic agent. BARRY J. ALLEN, D.SC. Centre for Experimental Radiation Oncology St. George Cancer Care Centre Kogarah, NSW, Australia doi:10.1016/j.ijrobp.2007.01.036 1. Wong JYC. Basic immunology of antibody targeted radiotherapy. Int J Radiat Oncol Biol Phys 2006;66(Suppl.):S8 –S14. 2. Allen Barry J, Raja C, Rizvi SMA, et al. Intralesional targeted alpha therapy for metastatic melanoma. Cancer Biol Ther 2005;4:1318 –1324. 3. Jurcic JG, Larson SM, Sgouros G, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood 2002;100:1233–1239. 4. Schmidt D, Neumann F, Antke C, et al. Phase 1 clinical study on alpha-therapy for non-Hodgkin lymphoma. In: Morgenstern A, ed. Fourth alpha-immunotherapy symposium. ITU: Dusseldorf, Germany; pp 12.
Volume 68, Number 1, 2007 BE CAREFUL IN GETTING COST-EFFECTIVENESS CONCLUSIONS FROM A DEBATABLE TRIAL! To the Editor: In the article by Thomas et al., surgery plus radiotherapy results in a cost-effective treatment compared with radiotherapy alone in metastatic epidural spinal cord compression (MESCC) (1). This analysis is derived from the trial by Patchell et al., in which MESCC patients have a significantly better outcome if upfront surgery is done before radiotherapy (2). We have several comments regarding this latter trial. Only selected patients were recruited (i.e., patients with a good medical status, expected survival of at least 3 months, and nonradiosensitive tumors, and spinal cord compression restricted to a single area). These selection criteria caused a long-lasting accrual of only 101 valuable patients in more than 10 consecutive years (2). In fact, the population examined does not represent the majority of MESCC patients treated in the daily clinical practice where surgery is rarely indicated and radiotherapy alone remains the treatment of choice. The accrual was not homogeneous among the 7 participant institutions (1, 1, 1, 2, 12, 14, and 70 patients entered in the trial, respectively) and, probably, not all eligible patients were actually considered for this trial. This results in a possible patient selection bias. A tailored surgery was properly done, but this surgery approach can be given only where neurosurgery departments with large experience in this field are available. Only 45% of patients treated with radiotherapy recover or maintain the ambulatory function, with respect to the 75% of those undergoing surgery. In our and in other experiences about 60 –70% of patients respond to radiotherapy (3–5). Therefore, the scarce results obtained with radiotherapy alone could be due both to the exclusion of patients with radiosensitive tumor histologies and to an inappropriate patient selection in the radiotherapy-alone group. In fact, 18 of 51 (35%) patients treated without surgery had a spinal cord instability, a condition in which stabilization of the spine is considered mandatory in the majority of published trials as well as in good clinical practice. This foresaid criticism can escape the reader’s attention and convince him that all MESCC patients must be treated with surgery plus radiotherapy. Thomas et al., with an appropriate analysis, found evidence that treatment of MESCC with surgery plus radiotherapy is cost-effective, but their analysis is based on a population deriving from a debatable trial. There are selected situations in which surgery is surely indicated before radiotherapy, but in clinical practice radiotherapy alone remains the firstline approach for the majority of patients with MESCC (6). ERNESTO MARANZANO, M.D. FABIO TRIPPA, M.D. Department of Radiation Oncology S. Maria Hospital Terni, Italy doi:10.1016/j.ijrobp.2006.12.040 1. Thomas KC, Nosyk B, Fisher CG, et al. Cost-effectiveness of surgery plus radiotherapy versus radiotherapy alone for metastatic epidural spinal cord compression. Int J Radiat Oncol Biol Phys 2006;66:1212–1218. 2. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet 2005;366:643– 648. 3. Loblaw A, Perry J, Chambers A, et al. Systematic review of the diagnosis and management of malignant extradural spinal cord compression: The Cancer Care Ontario Practice Guidelines Initiative’s Neuro-oncology Disease Group. J Clin Oncol 2005;23:2028 –2037. 4. Rades D, Stalpers LJA, Veninga T, et al. Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol 2005;23:3366 –3375. 5. Maranzano E, Bellavita R, Rossi R, et al. Short-course versus split-course radiotherapy in metastatic spinal cord compression: Results of a Phase III, randomized, multicenter trial. J Clin Oncol 2005;23:8270 – 8272. 6. Maranzano E, Bellavita R, Rossi R. Radiotherapy alone or surgery in spinal cord compression? The choice depends on accurate patient selection. J Clin Oncol 2005;23:3358 –3365.
IN REPLY TO DRS. MARANZANO AND TRIPPA To the Editor: We believe that the results of the cost-effectiveness analysis by Thomas et al. (1) were produced using a study that was both internally and externally valid. We address each point of criticism in turn.
Letters to the editor
KENNETH C. THOMAS, M.D., M.H.SC., F.R.C.S.C. ROY A. PATCHELL, M.D. BOHDAN NOSYK, M.A. ASLAM ANIS, PH.D. Department of Health Care and Epidemiology Faculty of Medicine University of British Columbia Vancouver, BC, Canada doi:10.1016/j.ijrobp.2006.12.041 1. Thomas KC, Nosyk B, Fisher CG, et al. Cost-effectiveness of surgery plus radiotherapy vs. radiotherapy alone for treatment of metastatic epidural spinal cord compression. Int J Radiat Oncol Biol Phys 2006; 66:1212–1218. 2. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet 2005;366:643– 648. 3. Maranzano E, Bellavita R, Rossi R, et al. Short-course versus splitcourse radiotherapy in metastatic spinal cord compression: Results of a Phase III, randomized, multicenter trial. J Clin Oncol 2005;23:3358 – 3365. 4. Macloed RS, Wright JG, Solomon MJ, et al. Randomized controlled trials in surgery: Issues and problems. Surgery 1996;119:483– 486. 5. Loblaw A, Perry J, Chambers A, et al. Systematic review of the diagnosis and management of malignant extradural spinal cord compression: The cancer care Ontario practice guidelines initiative’s neurooncology disease group. J Clin Oncol 2005;23:2028 –2037. 6. Rades D, Stalpers LJA, Veninga T, et al. Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol 2005;23:3366 –3375.
IN REGARDS TO ALLEN ET AL. (INT J RADIAT ONCOL BIOL PHYS 2006;65:640 – 645) To the Editor: The Leuven Lung Cancer Group has a similar protocol for mesothelioma (cisplatin–pemetrexed induction chemotherapy, Extrapleural Pneumonectomy, 54 Gy/1.8 Gy thoracic radiotherapy). Seventeen patients were entered, of whom 11 were irradiated (1).
(a)
FEV1
100
percentile lung function
90 80 70
baseline
60
preop
50
est postop
40
6months postRT
30
1-1.5years postRT
20 10 0 patient 1
(b)
patient 2
patient 3
DLCO
100 90
percentile lung function
First, Patchell et al. (2) used inclusion criteria (good medical status, expected survival of ⱖ3 months, nonradiosensitive tumors, and spinal cord compression restricted to a single area of the spine) that are appropriate for the decision to offer surgery as a treatment option. Other studies have found that radiosensitive tumors occurred uncommonly (myeloma 7%, lymphoma 2%) and, further, multiple sites of spinal cord compression were observed in only 3% of patients (3). The results of the Patchell study were, in fact, representative for the vast majority of patients in clinical practice. Second, the long and uneven accrual across participating centers is a reflection of the difficulty in conducting randomized controlled trials, particularly when only 1 treatment arm includes an invasive treatment option (4). It remains that the study represents the best evidence available to guide treatment decisions. Third, the objective of Patchell et al. was to inform best clinical practice. Spinal decompression and stabilization of MESSC must only be delivered where surgical expertise exists. This would typically be at a tertiary care center with orthopedic or neurosurgical spine coverage. Fourth, although functional outcomes in the radiotherapy treatment arm were poorer than observed elsewhere (3, 5, 6) (likely due in part to exclusion of the above noted tumor types), probabilistic sensitivity analysis is designed to address such uncertainty by producing a credibility interval around the mean incremental cost-effectiveness ratio through variation of all parameter values (including measures of ambulation and survival time) within their given distributions. Results of the probabilistic sensitivity analysis showed support for our conclusions in this patient population. Finally, patients with spinal instability were stratified in the randomization to ensure equal distribution among treatment arms. Spinal instability was not associated with maintenance of continence, length of ambulation, or survival; it was positively associated with maintenance of ASIA scores and Frankel grade. We conclude that there is nothing “debatable” about the validity of the results of either the study by Patchell et al., or their application. While the conclusions may oppose the historical convention of radiotherapy as the standard of care for MESSC, we as medical practitioners must remain open to new evidence and the changes in practice that it may mandate.
315
80 70
baseline
60
preop
50
est postop
40
6months postRT
30
1-1.5years postRT
20 10 0 patient 1
patient 2
patient 3
Fig. 1. Evolution of the lung function parameters forced expiratory volume in 1 s (FEV1) (a) and diffusion capacity for carbon monoxide in the lung (DLCO) for 3 patients treated with intensitymodulated radiotherapy in the three-modality protocol for malignant mesothelioma. Preop ⫽ preoperative value; est postop ⫽ estimated postoperative value (calculated according to preoperative lung function and lung perfusion scan results); postRT ⫽ values after radiotherapy.
In 4 right-sided cases, treatment with intensity-modulated radiotherapy (IMRT) was found to be essential to adequately cover the target volume while sparing the liver. This was, however, at the expense of the dose to the remaining lung (average mean lung dose [MLD], 10.3 Gy; average Vlung20, 12.4%). In 3 patients with a clinical follow-up of ⬎6 months, no major deterioration in lung function occurred: all 3 had better levels of diffusion capacity for carbon monoxide in the lung than expected from the calculated postoperative volumes (Fig. 1b), and 2 experienced an improvement in forced expiratory volume in 1 s (Fig. 1a). All left-sided mesotheliomas were treated with three-dimensional conformal radiotherapy: 45 Gy with inclined fields and table rotation, 9 Gy with off-cord tangential fields. Lung doses were negligible, except in 1 patient in whom an additional lateral field, given for optimization of the target dose, resulted in an MLD of 16.5 Gy. Our only radiotherapy-related Grade 5 toxicity occurred in this 72-year-old patient. He died of bronchiolitis obliterans organizing pneumonia 2 weeks after termination of radiotherapy. Were we just fortunate, or are there other reasons why we have not seen more fatal side effects? In general, lung doses in our IMRT patients were lower than those reported by Allen et al.; the liver doses, conversely, were higher. Comparison between both IMRT techniques might be instructive. The patient who died as a consequence of radiation-induced lung complications had the highest MLD in our series. He was also the oldest, but he had acceptable lung function. Although some published data suggest higher incidences of radiation pneumonitis in cases of older age and worse lung function, results are conflicting (2– 6). The Boston group irradiated patients up to 68 years of age, but it is unclear whether the oldest patients faired worse, or whether there was a correlation between the occurrence of radiation pneumonitis and lung function. A final explanation for their experience might be sought in the chemotherapy/radiotherapy scheduling. In addition to cisplatin, pemetrexed has been described as inducing radiosensitization. The clinical impact of sequencing and time interval between pemetrexed and radiotherapy, however, remains insufficiently understood (7–9). Whether the shorter chemo-
I. J. Radiation Oncology
●
Biology
●
Physics
developed at the site of former tumor/SIB. In these 4 patients, ulcers healed 1, 3, 3, and 7 months later (see Table 4 in Studer et al. [2]). Thus, we consider SIB-IMRT with chemotherapy as described with single doses up to 2.2 Gy to planning target volume 1 to be safe and well tolerated. GABRIELA STUDER, M.D. CHRISTOPH GLANZMANN, M.D. Department of Radiation Oncology University Hospital Zurich Zurich, Switzerland doi:10.1016/j.ijrobp.2007.01.020 1. Garden AS, Morrison WH, Wong P-F, et al. Disease-control rates following intensity-modulated radiation therapy for small primary oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;67:438 – 444. 2. Studer G, Huguenin PU, Davis JB, et al. IMRT using simultaneously integrated boost (SIB) in head and neck cancer patients. Radiat Oncol 2006;1:7. 3. Studer G, Lutolf UM, Davis JB, et al. IMRT in hypopharyngeal tumors. Strahlenther Onkol 2006;182:331–335.
ADDENDUM TO: BASIC IMMUNOLOGY OF ANTIBODY TARGETED RADIOTHERAPY: IN REGARD TO WONG (INT J RADIAT ONCOL BIOL PHYS 2006;66: S8 –S14) To the Editor: This interesting review by Wong (1) has omitted some important data in its tables. Missing from the list of antibody/antigens in Table 1 is the melanoma-associated chondroitin sulfate proteoglycan, an antigen expressed by melanoma cells that is targeted by the monoclonal antibody 9.2.27. This benign murine antibody has a very low immune response and is not toxic to targeted melanoma cells. However, when labeled with 213Bi, an ␣-emitting radioisotope, the conjugate is highly cytotoxic to targeted melanoma cells. A phase I trial of this conjugate for intralesional targeted ␣-therapy for melanoma has been completed and published (2). Human anti-mouse antibody responses were not observed in the 16 subjects. However, single intralesional injections into subcutaneous melanomas caused massive cell death. An ongoing trial of systemic ␣-therapy for Stage 4 melanoma has reported partial responses for 10% of 33 subjects (personal communication, Raja C et al.). The unfortunate omission of 213Bi and 225Ac from Table 4 gives the wrong impression about the importance of these ␣-emitting radioisotopes. Bismuth-213 is milked from the 225Ac generator. It has a 46-min half life and emits an 8.35-MeV ␣ with an 80-m range. A 440-keV ␥-ray is also emitted that can be used for single photon emission tomography imaging with a high-energy collimator. Considerable preclinical data are available for 213Bi, which is undergoing clinical trials in Australia (personal communication, Raja C et al.), the United States (3), and Europe (4) for melanoma, myeloid leukemia, and lymphoma. The Memorial Sloan-Kettering Cancer Center is also running a phase I trial for 225Ac-labeled monoclonal antibody for myeloid leukemia. 225Ac has a 10-day half-life and decays by emission of four ␣-particles to stable 209 Bi. It is a highly cytotoxic agent. BARRY J. ALLEN, D.SC. Centre for Experimental Radiation Oncology St. George Cancer Care Centre Kogarah, NSW, Australia doi:10.1016/j.ijrobp.2007.01.036 1. Wong JYC. Basic immunology of antibody targeted radiotherapy. Int J Radiat Oncol Biol Phys 2006;66(Suppl.):S8 –S14. 2. Allen Barry J, Raja C, Rizvi SMA, et al. Intralesional targeted alpha therapy for metastatic melanoma. Cancer Biol Ther 2005;4:1318 –1324. 3. Jurcic JG, Larson SM, Sgouros G, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood 2002;100:1233–1239. 4. Schmidt D, Neumann F, Antke C, et al. Phase 1 clinical study on alpha-therapy for non-Hodgkin lymphoma. In: Morgenstern A, ed. Fourth alpha-immunotherapy symposium. ITU: Dusseldorf, Germany; pp 12.
Volume 68, Number 1, 2007 BE CAREFUL IN GETTING COST-EFFECTIVENESS CONCLUSIONS FROM A DEBATABLE TRIAL! To the Editor: In the article by Thomas et al., surgery plus radiotherapy results in a cost-effective treatment compared with radiotherapy alone in metastatic epidural spinal cord compression (MESCC) (1). This analysis is derived from the trial by Patchell et al., in which MESCC patients have a significantly better outcome if upfront surgery is done before radiotherapy (2). We have several comments regarding this latter trial. Only selected patients were recruited (i.e., patients with a good medical status, expected survival of at least 3 months, and nonradiosensitive tumors, and spinal cord compression restricted to a single area). These selection criteria caused a long-lasting accrual of only 101 valuable patients in more than 10 consecutive years (2). In fact, the population examined does not represent the majority of MESCC patients treated in the daily clinical practice where surgery is rarely indicated and radiotherapy alone remains the treatment of choice. The accrual was not homogeneous among the 7 participant institutions (1, 1, 1, 2, 12, 14, and 70 patients entered in the trial, respectively) and, probably, not all eligible patients were actually considered for this trial. This results in a possible patient selection bias. A tailored surgery was properly done, but this surgery approach can be given only where neurosurgery departments with large experience in this field are available. Only 45% of patients treated with radiotherapy recover or maintain the ambulatory function, with respect to the 75% of those undergoing surgery. In our and in other experiences about 60 –70% of patients respond to radiotherapy (3–5). Therefore, the scarce results obtained with radiotherapy alone could be due both to the exclusion of patients with radiosensitive tumor histologies and to an inappropriate patient selection in the radiotherapy-alone group. In fact, 18 of 51 (35%) patients treated without surgery had a spinal cord instability, a condition in which stabilization of the spine is considered mandatory in the majority of published trials as well as in good clinical practice. This foresaid criticism can escape the reader’s attention and convince him that all MESCC patients must be treated with surgery plus radiotherapy. Thomas et al., with an appropriate analysis, found evidence that treatment of MESCC with surgery plus radiotherapy is cost-effective, but their analysis is based on a population deriving from a debatable trial. There are selected situations in which surgery is surely indicated before radiotherapy, but in clinical practice radiotherapy alone remains the firstline approach for the majority of patients with MESCC (6). ERNESTO MARANZANO, M.D. FABIO TRIPPA, M.D. Department of Radiation Oncology S. Maria Hospital Terni, Italy doi:10.1016/j.ijrobp.2006.12.040 1. Thomas KC, Nosyk B, Fisher CG, et al. Cost-effectiveness of surgery plus radiotherapy versus radiotherapy alone for metastatic epidural spinal cord compression. Int J Radiat Oncol Biol Phys 2006;66:1212–1218. 2. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet 2005;366:643– 648. 3. Loblaw A, Perry J, Chambers A, et al. Systematic review of the diagnosis and management of malignant extradural spinal cord compression: The Cancer Care Ontario Practice Guidelines Initiative’s Neuro-oncology Disease Group. J Clin Oncol 2005;23:2028 –2037. 4. Rades D, Stalpers LJA, Veninga T, et al. Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol 2005;23:3366 –3375. 5. Maranzano E, Bellavita R, Rossi R, et al. Short-course versus split-course radiotherapy in metastatic spinal cord compression: Results of a Phase III, randomized, multicenter trial. J Clin Oncol 2005;23:8270 – 8272. 6. Maranzano E, Bellavita R, Rossi R. Radiotherapy alone or surgery in spinal cord compression? The choice depends on accurate patient selection. J Clin Oncol 2005;23:3358 –3365.
IN REPLY TO DRS. MARANZANO AND TRIPPA To the Editor: We believe that the results of the cost-effectiveness analysis by Thomas et al. (1) were produced using a study that was both internally and externally valid. We address each point of criticism in turn.
Letters to the editor
KENNETH C. THOMAS, M.D., M.H.SC., F.R.C.S.C. ROY A. PATCHELL, M.D. BOHDAN NOSYK, M.A. ASLAM ANIS, PH.D. Department of Health Care and Epidemiology Faculty of Medicine University of British Columbia Vancouver, BC, Canada doi:10.1016/j.ijrobp.2006.12.041 1. Thomas KC, Nosyk B, Fisher CG, et al. Cost-effectiveness of surgery plus radiotherapy vs. radiotherapy alone for treatment of metastatic epidural spinal cord compression. Int J Radiat Oncol Biol Phys 2006; 66:1212–1218. 2. Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet 2005;366:643– 648. 3. Maranzano E, Bellavita R, Rossi R, et al. Short-course versus splitcourse radiotherapy in metastatic spinal cord compression: Results of a Phase III, randomized, multicenter trial. J Clin Oncol 2005;23:3358 – 3365. 4. Macloed RS, Wright JG, Solomon MJ, et al. Randomized controlled trials in surgery: Issues and problems. Surgery 1996;119:483– 486. 5. Loblaw A, Perry J, Chambers A, et al. Systematic review of the diagnosis and management of malignant extradural spinal cord compression: The cancer care Ontario practice guidelines initiative’s neurooncology disease group. J Clin Oncol 2005;23:2028 –2037. 6. Rades D, Stalpers LJA, Veninga T, et al. Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol 2005;23:3366 –3375.
IN REGARDS TO ALLEN ET AL. (INT J RADIAT ONCOL BIOL PHYS 2006;65:640 – 645) To the Editor: The Leuven Lung Cancer Group has a similar protocol for mesothelioma (cisplatin–pemetrexed induction chemotherapy, Extrapleural Pneumonectomy, 54 Gy/1.8 Gy thoracic radiotherapy). Seventeen patients were entered, of whom 11 were irradiated (1).
(a)
FEV1
100
percentile lung function
90 80 70
baseline
60
preop
50
est postop
40
6months postRT
30
1-1.5years postRT
20 10 0 patient 1
(b)
patient 2
patient 3
DLCO
100 90
percentile lung function
First, Patchell et al. (2) used inclusion criteria (good medical status, expected survival of ⱖ3 months, nonradiosensitive tumors, and spinal cord compression restricted to a single area of the spine) that are appropriate for the decision to offer surgery as a treatment option. Other studies have found that radiosensitive tumors occurred uncommonly (myeloma 7%, lymphoma 2%) and, further, multiple sites of spinal cord compression were observed in only 3% of patients (3). The results of the Patchell study were, in fact, representative for the vast majority of patients in clinical practice. Second, the long and uneven accrual across participating centers is a reflection of the difficulty in conducting randomized controlled trials, particularly when only 1 treatment arm includes an invasive treatment option (4). It remains that the study represents the best evidence available to guide treatment decisions. Third, the objective of Patchell et al. was to inform best clinical practice. Spinal decompression and stabilization of MESSC must only be delivered where surgical expertise exists. This would typically be at a tertiary care center with orthopedic or neurosurgical spine coverage. Fourth, although functional outcomes in the radiotherapy treatment arm were poorer than observed elsewhere (3, 5, 6) (likely due in part to exclusion of the above noted tumor types), probabilistic sensitivity analysis is designed to address such uncertainty by producing a credibility interval around the mean incremental cost-effectiveness ratio through variation of all parameter values (including measures of ambulation and survival time) within their given distributions. Results of the probabilistic sensitivity analysis showed support for our conclusions in this patient population. Finally, patients with spinal instability were stratified in the randomization to ensure equal distribution among treatment arms. Spinal instability was not associated with maintenance of continence, length of ambulation, or survival; it was positively associated with maintenance of ASIA scores and Frankel grade. We conclude that there is nothing “debatable” about the validity of the results of either the study by Patchell et al., or their application. While the conclusions may oppose the historical convention of radiotherapy as the standard of care for MESSC, we as medical practitioners must remain open to new evidence and the changes in practice that it may mandate.
315
80 70
baseline
60
preop
50
est postop
40
6months postRT
30
1-1.5years postRT
20 10 0 patient 1
patient 2
patient 3
Fig. 1. Evolution of the lung function parameters forced expiratory volume in 1 s (FEV1) (a) and diffusion capacity for carbon monoxide in the lung (DLCO) for 3 patients treated with intensitymodulated radiotherapy in the three-modality protocol for malignant mesothelioma. Preop ⫽ preoperative value; est postop ⫽ estimated postoperative value (calculated according to preoperative lung function and lung perfusion scan results); postRT ⫽ values after radiotherapy.
In 4 right-sided cases, treatment with intensity-modulated radiotherapy (IMRT) was found to be essential to adequately cover the target volume while sparing the liver. This was, however, at the expense of the dose to the remaining lung (average mean lung dose [MLD], 10.3 Gy; average Vlung20, 12.4%). In 3 patients with a clinical follow-up of ⬎6 months, no major deterioration in lung function occurred: all 3 had better levels of diffusion capacity for carbon monoxide in the lung than expected from the calculated postoperative volumes (Fig. 1b), and 2 experienced an improvement in forced expiratory volume in 1 s (Fig. 1a). All left-sided mesotheliomas were treated with three-dimensional conformal radiotherapy: 45 Gy with inclined fields and table rotation, 9 Gy with off-cord tangential fields. Lung doses were negligible, except in 1 patient in whom an additional lateral field, given for optimization of the target dose, resulted in an MLD of 16.5 Gy. Our only radiotherapy-related Grade 5 toxicity occurred in this 72-year-old patient. He died of bronchiolitis obliterans organizing pneumonia 2 weeks after termination of radiotherapy. Were we just fortunate, or are there other reasons why we have not seen more fatal side effects? In general, lung doses in our IMRT patients were lower than those reported by Allen et al.; the liver doses, conversely, were higher. Comparison between both IMRT techniques might be instructive. The patient who died as a consequence of radiation-induced lung complications had the highest MLD in our series. He was also the oldest, but he had acceptable lung function. Although some published data suggest higher incidences of radiation pneumonitis in cases of older age and worse lung function, results are conflicting (2– 6). The Boston group irradiated patients up to 68 years of age, but it is unclear whether the oldest patients faired worse, or whether there was a correlation between the occurrence of radiation pneumonitis and lung function. A final explanation for their experience might be sought in the chemotherapy/radiotherapy scheduling. In addition to cisplatin, pemetrexed has been described as inducing radiosensitization. The clinical impact of sequencing and time interval between pemetrexed and radiotherapy, however, remains insufficiently understood (7–9). Whether the shorter chemo-