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Postoperative radiotherapy in non-small-cell lung cancer
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE
Postoperative radiotherapy in non-small-cell lung cancer Sir—Meta-analyses should be seen as hypothesis-generating and not only as providing the last word in a particular argument. In the systematic review and meta-analysis of postoperative radiotherapy in non-small-cell lung cancer (NSCLC) (PORT) (July 25, p 257)1 the greatest determinant of radiotherapy was evident in those with the least risk of relapse. The hypothesis is that there are two effects in play here: one is a detrimental effect that affects all patients and the other a protective effect from which only patients with a higher risk of relapse stand to gain. Only in stage II (N2) disease do the two seem to balance out without the appearance of either benefit or determinant from the addition of radiotherapy. In his accompanying commentary, Alastair Munro2 suggests that the early appearance of this detrimental effect favours lung damage as the most likely explanation and he goes on to show a dose-relation between detriment and radiotherapy dose. Although I support lung damage as the most likely explanation, to relate lung damage solely to the dose delivered is an oversimplification. The extent of symptomatic or radiological lung damage is related not only to the dose delivered and fractionation schedule but also to the volume of lung irradiated. 3 Radiation fields for mediastinal irradiation generally extend from the suprasternal notch to 5–6 cm below the carina, and in one trial even included the supraclavicular fossae. Inevitably, this wide range means that a substantial amount of normal lung is treated. Cardiac morbidity is more difficult to quantify and may have been an additional factor; it is now recognised as an important factor in morbidity after older techniques of breast irradiation.4 Three-dimensional (3D) radiotherapy planning techniques now used in most centres more clearly delineate normal tissues at risk and facilitate the use of shielding. By contrast, the use of spinal shielding in all but one trial (well before the advent of 3D planning), though not affecting lung
1384
dose, will have shielded midline structures with the result that the dose received by areas at risk will have been somewhat less than the dose prescribed. An alternative way to reduce lung dose would be to decrease the dose prescribed. Although such reduction might seem prudent from Munro’s figure, it ignores progress in other areas of NSCLC radiotherapy in which we now know that for patients with well localised disease and good performance status better outcome follows the use of higher dose or more intensive regimes.5 To suggest that 45 Gy in 20 daily fractions would be appropriate ignores this evidence and uses a fraction size greater than 2 Gy which may be prejudicial to normal tissue sparing. A common feature in the included trials is that the sites at risk were not clearly defined. It has long been recognised that certain nodal sites are at greater risk of recurrence for primary tumours in particular locations (eg, lower-lobe tumours are less likely to involve upper paratracheal nodes than upper lobe tumours). An appropriate radiotherapy technique would recognise this fact and not aim to include sites with a low risk of recurrence in a rather blunderbuss whole-mediastinum approach. This overview points strongly to the need for a further postoperative trial in N2 disease. In such a trial (surgery versus surgery plus radiotherapy), radiotherapy would be directed with modern techniques to areas known to be at high or medium risk of recurrence according to the location of the primary tumour and would use more intensive regimens than have been used in the past (eg, 60 Gy in 30 daily fractions or CHART 5). These three factors would enhance the likelihood of benefit while reducing the risk of detriment N P Rowell Clinical Oncology, The Churchill, Headington, Oxford OX3 7LJ, UK 1
PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small cell
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lung cancer: systematic review of individual patient data from nine randomised trials. Lancet 1998; 352: 257–63. Munro AJ. What now for postoperative radiotherapy for lung cancer? Lancet 1998; 352: 250–51. Graham MV, Purdy JA, Ememi B, Matthews JW, Harms WB. Preliminary results of a prospective trial using three dimensional radiotherapy for lung cancer. Int J Radiat Biol Phys 1995; 33: 993–1000. Gagliardi G, Lax I, Ottolenghi A, Rutqvist LE. Long-term cardiac mortality after radiotherapy of breast cancer— application of the relative seriality model. Br J Radiol 1996; 69: 839–46. Saunders M, Dische S, Barrett A, Harvey A, Gibson D, Parmar M. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: a randomised multicentre trial. Lancet 1997; 350: 161–65.
Sir—The aim of a meta-analysis is to compile data from similarly designed trials that are individually statistically underpowered to answer an important controversy in medicine. The recent meta-analysis by the PORT Metaanalysis Trialists Group on postoperative radiotherapy after surgery for NSCLC1 raises far more questions than answers. Patients with pathological stage I NSCLC have a low risk of local recurrence and cannot reasonably expect the benefit from postoperative radiotherapy. 2 Radiation oncology residents and fellows know that they would immediately fail the boards examination if they recommended routine postoperative radiotherapy for completely resected stage I NSCLC. Since there is no controversy about stage I disease, these cases (26% of the meta-analysis’ sample size) should have been excluded. By contrast with wrongly including all the stage I patients, the PORT group has inexplicably excluded two randomised trials that seem to slightly favour postoperative radiotherapy.3,4 One is excluded from the metaanalysis with only the nebulous statement “. . . whether it is indeed randomised is not clear . . .”.4 Why were these trials excluded? Many of the trials in the metaanalysis, including some so-called
THE LANCET • Vol 352 • October 24, 1998
COMMENTARY
CORRESPONDENCE
Postoperative radiotherapy in non-small-cell lung cancer Sir—Meta-analyses should be seen as hypothesis-generating and not only as providing the last word in a particular argument. In the systematic review and meta-analysis of postoperative radiotherapy in non-small-cell lung cancer (NSCLC) (PORT) (July 25, p 257)1 the greatest determinant of radiotherapy was evident in those with the least risk of relapse. The hypothesis is that there are two effects in play here: one is a detrimental effect that affects all patients and the other a protective effect from which only patients with a higher risk of relapse stand to gain. Only in stage II (N2) disease do the two seem to balance out without the appearance of either benefit or determinant from the addition of radiotherapy. In his accompanying commentary, Alastair Munro2 suggests that the early appearance of this detrimental effect favours lung damage as the most likely explanation and he goes on to show a dose-relation between detriment and radiotherapy dose. Although I support lung damage as the most likely explanation, to relate lung damage solely to the dose delivered is an oversimplification. The extent of symptomatic or radiological lung damage is related not only to the dose delivered and fractionation schedule but also to the volume of lung irradiated. 3 Radiation fields for mediastinal irradiation generally extend from the suprasternal notch to 5–6 cm below the carina, and in one trial even included the supraclavicular fossae. Inevitably, this wide range means that a substantial amount of normal lung is treated. Cardiac morbidity is more difficult to quantify and may have been an additional factor; it is now recognised as an important factor in morbidity after older techniques of breast irradiation.4 Three-dimensional (3D) radiotherapy planning techniques now used in most centres more clearly delineate normal tissues at risk and facilitate the use of shielding. By contrast, the use of spinal shielding in all but one trial (well before the advent of 3D planning), though not affecting lung
1384
dose, will have shielded midline structures with the result that the dose received by areas at risk will have been somewhat less than the dose prescribed. An alternative way to reduce lung dose would be to decrease the dose prescribed. Although such reduction might seem prudent from Munro’s figure, it ignores progress in other areas of NSCLC radiotherapy in which we now know that for patients with well localised disease and good performance status better outcome follows the use of higher dose or more intensive regimes.5 To suggest that 45 Gy in 20 daily fractions would be appropriate ignores this evidence and uses a fraction size greater than 2 Gy which may be prejudicial to normal tissue sparing. A common feature in the included trials is that the sites at risk were not clearly defined. It has long been recognised that certain nodal sites are at greater risk of recurrence for primary tumours in particular locations (eg, lower-lobe tumours are less likely to involve upper paratracheal nodes than upper lobe tumours). An appropriate radiotherapy technique would recognise this fact and not aim to include sites with a low risk of recurrence in a rather blunderbuss whole-mediastinum approach. This overview points strongly to the need for a further postoperative trial in N2 disease. In such a trial (surgery versus surgery plus radiotherapy), radiotherapy would be directed with modern techniques to areas known to be at high or medium risk of recurrence according to the location of the primary tumour and would use more intensive regimens than have been used in the past (eg, 60 Gy in 30 daily fractions or CHART 5). These three factors would enhance the likelihood of benefit while reducing the risk of detriment N P Rowell Clinical Oncology, The Churchill, Headington, Oxford OX3 7LJ, UK 1
PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small cell
2
3
4
5
lung cancer: systematic review of individual patient data from nine randomised trials. Lancet 1998; 352: 257–63. Munro AJ. What now for postoperative radiotherapy for lung cancer? Lancet 1998; 352: 250–51. Graham MV, Purdy JA, Ememi B, Matthews JW, Harms WB. Preliminary results of a prospective trial using three dimensional radiotherapy for lung cancer. Int J Radiat Biol Phys 1995; 33: 993–1000. Gagliardi G, Lax I, Ottolenghi A, Rutqvist LE. Long-term cardiac mortality after radiotherapy of breast cancer— application of the relative seriality model. Br J Radiol 1996; 69: 839–46. Saunders M, Dische S, Barrett A, Harvey A, Gibson D, Parmar M. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: a randomised multicentre trial. Lancet 1997; 350: 161–65.
Sir—The aim of a meta-analysis is to compile data from similarly designed trials that are individually statistically underpowered to answer an important controversy in medicine. The recent meta-analysis by the PORT Metaanalysis Trialists Group on postoperative radiotherapy after surgery for NSCLC1 raises far more questions than answers. Patients with pathological stage I NSCLC have a low risk of local recurrence and cannot reasonably expect the benefit from postoperative radiotherapy. 2 Radiation oncology residents and fellows know that they would immediately fail the boards examination if they recommended routine postoperative radiotherapy for completely resected stage I NSCLC. Since there is no controversy about stage I disease, these cases (26% of the meta-analysis’ sample size) should have been excluded. By contrast with wrongly including all the stage I patients, the PORT group has inexplicably excluded two randomised trials that seem to slightly favour postoperative radiotherapy.3,4 One is excluded from the metaanalysis with only the nebulous statement “. . . whether it is indeed randomised is not clear . . .”.4 Why were these trials excluded? Many of the trials in the metaanalysis, including some so-called
THE LANCET • Vol 352 • October 24, 1998