- Email: [email protected]
High-dose chemotherapy in children with newly-diagnosed medulloblastoma
Reflection and Reaction
compounds as monotherapy or in combination with chemotherapeutic agents, but not combined with radiotherapy. In curative radiotherapy, success is not determined by the effect on the mass of the tumour cells, but by the effect on the subpopulation of tumour stem cells that, when they survive, can produce a recurrence.5 Several investigations5 have shown that the effects of molecular drugs combined with radiotherapy on the mass of tumour cells, which is measured by tumour regression or growth delay, often do not show that tumour stem cells are inactivated. Therefore, radiotherapy-specific preclinical research strategies are needed to identify suitable drugs.5 New drugs that are eventually included in clinical trials are usually tested only in combination with radiotherapy after they have shown promise alone or in combination with chemotherapy. Again, this selection could miss important opportunities. Finally, radiation dose is very important for tumour control and healthy tissue damage. Therefore, clinical trials on new molecular approaches combined with radiotherapy need high-quality and standardised radiotherapy approaches to generate valid results. Unfortunately, this important aspect is often not given enough focus in the design of clinical trial protocols. Ideally, molecular drugs would be designed specifically for combination with radiotherapy. To undertake pragmatic and fast approaches with an increased chance for success, radiation oncologists would need to participate early on in preclinical and
translational studies of new anticancer drugs. Drugs that have not been proven useful when given alone or in combination with chemotherapy would also need to be made available to researchers for exploring their potential in combination with radiotherapy. Michael Baumann Department of Radiation Oncology and OncoRay Centre for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscher 74, 01307 Dresden, Germany [email protected] I have received honoraria from Merck Pharma GmbH for lectures on EGFR inhibition during radiotherapy. 1 2
3
4 5
6
7
8
Bernier J, Hall EJ, Giaccia A. Radiation oncology: a century of achievements. Nat Rev Cancer 2004; 4: 737–47. Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003; 362: 933–40. Andreassen CN. Can risk of radiotherapy-induced normal tissue complications be predicted from genetic profiles? Acta Oncol 2005; 44: 801–15. Bentzen SM. Theragnostic imaging for radiation oncology: dose-painting by numbers. Lancet Oncol 2005; 6: 112–17. Krause M, Zips D, Thames HD, et al. Preclinical evaluation of moleculartargeted anticancer agents for radiotherapy. Radiother Oncol 2006; 80: 112–22. Baumann M, Krause M. Targeting the epidermal growth factor receptor in radiotherapy: radiobiological mechanisms, preclinical and clinical results. Radiother Oncol 2004; 72: 257–66. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–78. Bentzen SM, Heeren G, Cottier B, et al. Towards evidence-based guidelines for radiotherapy infrastructure and staffing needs in Europe: the ESTRO QUARTS project. Radiother Oncol 2005; 75: 355–65.
High-dose chemotherapy in children with newly-diagnosed medulloblastoma Medulloblastoma is a primitive neuroectodermal tumour of the cerebellum that arises mainly in children. This highly malignant tumour can spread via the cerebrospinal fluid intracranially or to the spinal cord. Therefore, adjuvant treatment of the entire CNS has been introduced first with craniospinal radiotherapy and more recently with chemotherapy. Use of chemotherapy resulted in improved event-free survival in high-risk groups (patients with metastases in the neuraxis or local residue after surgery, or both) and the possibility to apply reduced doses of radiation in the standard-risk groups. A 10-Gy reduction of craniospinal radiotherapy could lead to a ten-point increase in intelligence quotient (IQ)1 and a significantly decreased http://oncology.thelancet.com Vol 7 October 2006
risk of growth-hormone deficiency after pituitarygland radiotherapy.2 Tolerance of chemotherapy after craniospinal radiotherapy limits the dose intensity delivered with most of the drugs: ototoxic effects with cisplatin, neutropenia and thrombocytopenia with most alkylating agents such as nitrosoureas, and nutritional problems, among others. Use of so-called sandwich chemotherapy before radiotherapy, although better tolerated, could increase the treatment failures while delaying the use of reduced doses of craniospinal radiotherapy. However, the entire treatment duration needs to be accounted for, since most of the sandwich protocols are shorter than standard maintenance regimens used by US cooperative groups;
See Articles page 813
787
Reflection and Reaction
Spinal cord is common site of medulloblastoma spread
thus, their poorer results cannot be explained only by radiotherapy delay. Gajjar and colleagues3 show a new approach that uses high-dose cyclophosphamide with stem-cell support to overcome haematological toxic effects after radiotherapy. Their results are excellent in terms of eventfree survival for both standard-risk and poor-risk groups, compared with most published trials. However, while limiting the duration of chemotherapy and the doses of vincristine and cisplatin, the researchers introduce a complex procedure with gonadal and neurological toxic effects. Indeed, the total doses of cyclophosphamide (16 g/m2) will lead to sterility in men and could lead to early gonadal failure in women. The same group has previously reported white-matter lesions in the posterior fossa after this regimen.4 The cumulative incidence at 1 year was 15%; a significant fall in estimated IQ was shown, and three patients developed permanent deficits. The radiosensitising effect of high-dose chemotherapy has been reported with several regimens, including busulfan, thiotepa, or carboplatin5 given before or after radiotherapy. We could thus encounter new toxic effects and the craniospinal radiotherapy dose spared will be at the expense of more chemotherapy-related toxic effects. Consequently, for patients at standard risk in whom good event-free survival can be obtained with different approaches, including some with hyperfractionated radiotherapy without chemotherapy,6 late toxic effects should be critically reappraised and cautiously investigated in future randomised studies. Indeed, 788
5-year event-free survival of about 80% can be obtained in most of the contemporary trials and substantial improvement of survival will be difficult to prove outside very large international trials. However, early and late toxic effects are probably quite different according to the various therapeutic approaches. For example, at the International Symposium on Pediatric NeuroOncology in 2004 in Boston, MA, USA, Colin Kennedy and co-workers7 reported a significant decrease in the health status of patients randomly assigned to receive conventional chemotherapy in addition to craniospinal radiotherapy in the SIOP PNET III trial.8 Consequently, further treatment sophistication will need precise and largely accepted methods to measure side–effects, especially on cognitive functions. However, the approach is certainly valid for patients at high risk, since the 63% (range 44–83) event-free survival at 5 years for the patients with overt metastases (M2 and M3 disease, according to Chang’s classification) seems to be higher than previous trials, which report survival at about 40%. Since these patients have a poor prognosis with current protocols, the side-effects could be regarded as acceptable in these settings. This study shows a clear benefit of high-dose chemotherapy in the firstline treatment of medulloblastoma. Other cooperative groups are exploring high-dose chemotherapy in highrisk medulloblastoma to confirm these findings. This study also confirms the prognostic effect of biological indicators on survival together with clinical characteristics. Medulloblastoma with β-catenin mutation or nuclear staining indicative of a mutation is a distinct entity with a more favourable outcome than other forms in this study as well as in the SIOP PNET III trial.8 These data are now mature enough and confirmed in independent studies, and can be used in the design of the next generation of trials aiming to further reduce the burden of treatment in this very good prognostic subgroup. In the near future, the pathological entity of medulloblastoma will undoubtedly be divided into several biological subgroups with risk-adapted and perhaps targeted treatments. *Jacques Grill, Christelle Dufour, Chantal Kalifa Brain Tumour Programme, Department of Paediatric and Adolescent Oncology, Gustave Roussy Institute, Villejuif 94805, France [email protected] We declare no conflicts of interest.
http://oncology.thelancet.com Vol 7 October 2006
Reflection and Reaction
1
2
3
4
Kieffer-Renaux V, Bulteau C, Grill J, et al. Patterns of neuropsychological deficits in children with medulloblastoma according to craniospatial irradiation doses. Dev Med Child Neurol 2000; 42: 741–45. Schmiegelow M, Lassen S, Poulsen HS, et al. Cranial radiotherapy of childhood brain tumours: growth hormone deficiency and its relation to the biological effective dose of irradiation in a large population based study. Clin Endocrinol (Oxf) 2000; 53: 191–97. Gajjar A, Chintagumpala M, Ashley D, et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results of a prospective, multicentre trial. Lancet Oncol 2006; 7: 813–20. Fouladi M, Chintagumpala M, Laningham FH, et al. White matter lesions detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 2004; 22: 4551–60.
5
6
7
8
Grill J, Sainte-Rose C, Jouvet A, et al. Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 2005; 6: 573–80. Carrie C, Muracciole X, Gomez F, et al. Conformal radiotherapy, reduced boost volume, hyperfractionated radiotherapy, and online quality control in standard-risk medulloblastoma without chemotherapy: results of the French M-SFOP 98 protocol. Int J Radiat Oncol Biol Phys 2005; 63: 711–16. Kennedy C, Bull K, Walker D, et al. Effect of neoadjuvant chemotherapy on long-term health state and behavior in the PNET III randomised controlled trial of treatment for primitive neuroectodermal tumour (PNET). Proceedings of the 11th International Symposium on Pediatric NeuroOncology, Boston, MA, USA; June 13–16, 2004: 48 (abstr). Ellison DW, Onilude OE, Lindsey JC, et al. β-catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group Brain Tumour Committee. J Clin Oncol 2005; 23: 7951–57.
A better crystal ball to predict lung-cancer survival? One of the first questions patients ask their doctors after being diagnosed with cancer is “How much time do I have to live?”. The paper by Blanchon and colleagues1 in this issue of The Lancet Oncology provides a predictive model to answer this question in patients with non–small-cell lung cancer (NSCLC). Lung cancer has become the most common cause of cancer-related death worldwide.2 Risk stratification and prediction of death are essential for patients and families to plan for the future, for physicians to decide whether to intervene therapeutically or palliatively, for researchers to improve study design, and for administrators and policymakers to budget resources better. In view of the compelling need, it is surprising that no predictive model incorporating data other than cancer stage is widely used for NSCLC. Many studies have analysed prognostic factors in lung cancer, and although more than 150 risk factors have been identified, they have not been integrated into a simple and robust model. Focusing on readily accessible risk factors identified in previous studies, Blanchon and co-workers prospectively obtained data for 4479 patients with NSCLC diagnosed in 2000 in France.1 The study identified five independent predictors of time to death: age, sex, performance status, histological type, and cancer stage at time of diagnosis. Using Cox regression, the researchers developed an index that included these factors as predictors of death within 4 years in 2979 patients, and validated the findings in the remainder of the cohort. The index is simple to use, and its prognostic value is high, as indicated by analysis of the receiver operating characteristics of the model in both development and validation cohorts. Because of http://oncology.thelancet.com Vol 7 October 2006
the aggressive nature of lung cancer, prediction of death at earlier timepoints is also important for patients and their physicians, and the model was also shown to have a high predictive value at 1 and 2 years. Although these results are impressive, we wish to comment on several findings. First, most patients in this study (47%) were diagnosed with squamous-cell carcinoma, unlike countries such as Japan and the USA, where adenocarcinoma is the most common histology.3 Smoking was also found not to affect survival, whereas several studies4 from other countries have shown non-smokers to have better outcomes. However, the effects of such differences in populations, and possibly of cigarette composition, are modest, and should not greatly limit the relevance of the findings from this study.1 Notably, none of the therapeutic approaches affected survival, although other studies5 suggest that survival of some patients with NSCLC could improve with specific therapeutic interventions. This unexpected effect could have been because cancer stage so strongly determined treatment at the particular time and place of this study,1 but as patient-tailored treatment becomes available, future studies will need to revisit this issue. The forced expiratory volume in 1 sec (FEV1) has been validated extensively as a prognostic factor in chronic obstructive lung disease (COPD) and lung cancer.6 FEV1 was not measured in patients who were not surgical candidates, and hence was not included in this analysis. That this simple physiological test is not done routinely is unfortunate in a setting where it can be useful even in non-surgical patients. For example, many patients with lung cancer receive thoracic radiotherapy, and serial measurement of FEV1 can help assess dose-limiting
See Articles page 829
789
compounds as monotherapy or in combination with chemotherapeutic agents, but not combined with radiotherapy. In curative radiotherapy, success is not determined by the effect on the mass of the tumour cells, but by the effect on the subpopulation of tumour stem cells that, when they survive, can produce a recurrence.5 Several investigations5 have shown that the effects of molecular drugs combined with radiotherapy on the mass of tumour cells, which is measured by tumour regression or growth delay, often do not show that tumour stem cells are inactivated. Therefore, radiotherapy-specific preclinical research strategies are needed to identify suitable drugs.5 New drugs that are eventually included in clinical trials are usually tested only in combination with radiotherapy after they have shown promise alone or in combination with chemotherapy. Again, this selection could miss important opportunities. Finally, radiation dose is very important for tumour control and healthy tissue damage. Therefore, clinical trials on new molecular approaches combined with radiotherapy need high-quality and standardised radiotherapy approaches to generate valid results. Unfortunately, this important aspect is often not given enough focus in the design of clinical trial protocols. Ideally, molecular drugs would be designed specifically for combination with radiotherapy. To undertake pragmatic and fast approaches with an increased chance for success, radiation oncologists would need to participate early on in preclinical and
translational studies of new anticancer drugs. Drugs that have not been proven useful when given alone or in combination with chemotherapy would also need to be made available to researchers for exploring their potential in combination with radiotherapy. Michael Baumann Department of Radiation Oncology and OncoRay Centre for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscher 74, 01307 Dresden, Germany [email protected] I have received honoraria from Merck Pharma GmbH for lectures on EGFR inhibition during radiotherapy. 1 2
3
4 5
6
7
8
Bernier J, Hall EJ, Giaccia A. Radiation oncology: a century of achievements. Nat Rev Cancer 2004; 4: 737–47. Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003; 362: 933–40. Andreassen CN. Can risk of radiotherapy-induced normal tissue complications be predicted from genetic profiles? Acta Oncol 2005; 44: 801–15. Bentzen SM. Theragnostic imaging for radiation oncology: dose-painting by numbers. Lancet Oncol 2005; 6: 112–17. Krause M, Zips D, Thames HD, et al. Preclinical evaluation of moleculartargeted anticancer agents for radiotherapy. Radiother Oncol 2006; 80: 112–22. Baumann M, Krause M. Targeting the epidermal growth factor receptor in radiotherapy: radiobiological mechanisms, preclinical and clinical results. Radiother Oncol 2004; 72: 257–66. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–78. Bentzen SM, Heeren G, Cottier B, et al. Towards evidence-based guidelines for radiotherapy infrastructure and staffing needs in Europe: the ESTRO QUARTS project. Radiother Oncol 2005; 75: 355–65.
High-dose chemotherapy in children with newly-diagnosed medulloblastoma Medulloblastoma is a primitive neuroectodermal tumour of the cerebellum that arises mainly in children. This highly malignant tumour can spread via the cerebrospinal fluid intracranially or to the spinal cord. Therefore, adjuvant treatment of the entire CNS has been introduced first with craniospinal radiotherapy and more recently with chemotherapy. Use of chemotherapy resulted in improved event-free survival in high-risk groups (patients with metastases in the neuraxis or local residue after surgery, or both) and the possibility to apply reduced doses of radiation in the standard-risk groups. A 10-Gy reduction of craniospinal radiotherapy could lead to a ten-point increase in intelligence quotient (IQ)1 and a significantly decreased http://oncology.thelancet.com Vol 7 October 2006
risk of growth-hormone deficiency after pituitarygland radiotherapy.2 Tolerance of chemotherapy after craniospinal radiotherapy limits the dose intensity delivered with most of the drugs: ototoxic effects with cisplatin, neutropenia and thrombocytopenia with most alkylating agents such as nitrosoureas, and nutritional problems, among others. Use of so-called sandwich chemotherapy before radiotherapy, although better tolerated, could increase the treatment failures while delaying the use of reduced doses of craniospinal radiotherapy. However, the entire treatment duration needs to be accounted for, since most of the sandwich protocols are shorter than standard maintenance regimens used by US cooperative groups;
See Articles page 813
787
Reflection and Reaction
Spinal cord is common site of medulloblastoma spread
thus, their poorer results cannot be explained only by radiotherapy delay. Gajjar and colleagues3 show a new approach that uses high-dose cyclophosphamide with stem-cell support to overcome haematological toxic effects after radiotherapy. Their results are excellent in terms of eventfree survival for both standard-risk and poor-risk groups, compared with most published trials. However, while limiting the duration of chemotherapy and the doses of vincristine and cisplatin, the researchers introduce a complex procedure with gonadal and neurological toxic effects. Indeed, the total doses of cyclophosphamide (16 g/m2) will lead to sterility in men and could lead to early gonadal failure in women. The same group has previously reported white-matter lesions in the posterior fossa after this regimen.4 The cumulative incidence at 1 year was 15%; a significant fall in estimated IQ was shown, and three patients developed permanent deficits. The radiosensitising effect of high-dose chemotherapy has been reported with several regimens, including busulfan, thiotepa, or carboplatin5 given before or after radiotherapy. We could thus encounter new toxic effects and the craniospinal radiotherapy dose spared will be at the expense of more chemotherapy-related toxic effects. Consequently, for patients at standard risk in whom good event-free survival can be obtained with different approaches, including some with hyperfractionated radiotherapy without chemotherapy,6 late toxic effects should be critically reappraised and cautiously investigated in future randomised studies. Indeed, 788
5-year event-free survival of about 80% can be obtained in most of the contemporary trials and substantial improvement of survival will be difficult to prove outside very large international trials. However, early and late toxic effects are probably quite different according to the various therapeutic approaches. For example, at the International Symposium on Pediatric NeuroOncology in 2004 in Boston, MA, USA, Colin Kennedy and co-workers7 reported a significant decrease in the health status of patients randomly assigned to receive conventional chemotherapy in addition to craniospinal radiotherapy in the SIOP PNET III trial.8 Consequently, further treatment sophistication will need precise and largely accepted methods to measure side–effects, especially on cognitive functions. However, the approach is certainly valid for patients at high risk, since the 63% (range 44–83) event-free survival at 5 years for the patients with overt metastases (M2 and M3 disease, according to Chang’s classification) seems to be higher than previous trials, which report survival at about 40%. Since these patients have a poor prognosis with current protocols, the side-effects could be regarded as acceptable in these settings. This study shows a clear benefit of high-dose chemotherapy in the firstline treatment of medulloblastoma. Other cooperative groups are exploring high-dose chemotherapy in highrisk medulloblastoma to confirm these findings. This study also confirms the prognostic effect of biological indicators on survival together with clinical characteristics. Medulloblastoma with β-catenin mutation or nuclear staining indicative of a mutation is a distinct entity with a more favourable outcome than other forms in this study as well as in the SIOP PNET III trial.8 These data are now mature enough and confirmed in independent studies, and can be used in the design of the next generation of trials aiming to further reduce the burden of treatment in this very good prognostic subgroup. In the near future, the pathological entity of medulloblastoma will undoubtedly be divided into several biological subgroups with risk-adapted and perhaps targeted treatments. *Jacques Grill, Christelle Dufour, Chantal Kalifa Brain Tumour Programme, Department of Paediatric and Adolescent Oncology, Gustave Roussy Institute, Villejuif 94805, France [email protected] We declare no conflicts of interest.
http://oncology.thelancet.com Vol 7 October 2006
Reflection and Reaction
1
2
3
4
Kieffer-Renaux V, Bulteau C, Grill J, et al. Patterns of neuropsychological deficits in children with medulloblastoma according to craniospatial irradiation doses. Dev Med Child Neurol 2000; 42: 741–45. Schmiegelow M, Lassen S, Poulsen HS, et al. Cranial radiotherapy of childhood brain tumours: growth hormone deficiency and its relation to the biological effective dose of irradiation in a large population based study. Clin Endocrinol (Oxf) 2000; 53: 191–97. Gajjar A, Chintagumpala M, Ashley D, et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results of a prospective, multicentre trial. Lancet Oncol 2006; 7: 813–20. Fouladi M, Chintagumpala M, Laningham FH, et al. White matter lesions detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 2004; 22: 4551–60.
5
6
7
8
Grill J, Sainte-Rose C, Jouvet A, et al. Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 2005; 6: 573–80. Carrie C, Muracciole X, Gomez F, et al. Conformal radiotherapy, reduced boost volume, hyperfractionated radiotherapy, and online quality control in standard-risk medulloblastoma without chemotherapy: results of the French M-SFOP 98 protocol. Int J Radiat Oncol Biol Phys 2005; 63: 711–16. Kennedy C, Bull K, Walker D, et al. Effect of neoadjuvant chemotherapy on long-term health state and behavior in the PNET III randomised controlled trial of treatment for primitive neuroectodermal tumour (PNET). Proceedings of the 11th International Symposium on Pediatric NeuroOncology, Boston, MA, USA; June 13–16, 2004: 48 (abstr). Ellison DW, Onilude OE, Lindsey JC, et al. β-catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group Brain Tumour Committee. J Clin Oncol 2005; 23: 7951–57.
A better crystal ball to predict lung-cancer survival? One of the first questions patients ask their doctors after being diagnosed with cancer is “How much time do I have to live?”. The paper by Blanchon and colleagues1 in this issue of The Lancet Oncology provides a predictive model to answer this question in patients with non–small-cell lung cancer (NSCLC). Lung cancer has become the most common cause of cancer-related death worldwide.2 Risk stratification and prediction of death are essential for patients and families to plan for the future, for physicians to decide whether to intervene therapeutically or palliatively, for researchers to improve study design, and for administrators and policymakers to budget resources better. In view of the compelling need, it is surprising that no predictive model incorporating data other than cancer stage is widely used for NSCLC. Many studies have analysed prognostic factors in lung cancer, and although more than 150 risk factors have been identified, they have not been integrated into a simple and robust model. Focusing on readily accessible risk factors identified in previous studies, Blanchon and co-workers prospectively obtained data for 4479 patients with NSCLC diagnosed in 2000 in France.1 The study identified five independent predictors of time to death: age, sex, performance status, histological type, and cancer stage at time of diagnosis. Using Cox regression, the researchers developed an index that included these factors as predictors of death within 4 years in 2979 patients, and validated the findings in the remainder of the cohort. The index is simple to use, and its prognostic value is high, as indicated by analysis of the receiver operating characteristics of the model in both development and validation cohorts. Because of http://oncology.thelancet.com Vol 7 October 2006
the aggressive nature of lung cancer, prediction of death at earlier timepoints is also important for patients and their physicians, and the model was also shown to have a high predictive value at 1 and 2 years. Although these results are impressive, we wish to comment on several findings. First, most patients in this study (47%) were diagnosed with squamous-cell carcinoma, unlike countries such as Japan and the USA, where adenocarcinoma is the most common histology.3 Smoking was also found not to affect survival, whereas several studies4 from other countries have shown non-smokers to have better outcomes. However, the effects of such differences in populations, and possibly of cigarette composition, are modest, and should not greatly limit the relevance of the findings from this study.1 Notably, none of the therapeutic approaches affected survival, although other studies5 suggest that survival of some patients with NSCLC could improve with specific therapeutic interventions. This unexpected effect could have been because cancer stage so strongly determined treatment at the particular time and place of this study,1 but as patient-tailored treatment becomes available, future studies will need to revisit this issue. The forced expiratory volume in 1 sec (FEV1) has been validated extensively as a prognostic factor in chronic obstructive lung disease (COPD) and lung cancer.6 FEV1 was not measured in patients who were not surgical candidates, and hence was not included in this analysis. That this simple physiological test is not done routinely is unfortunate in a setting where it can be useful even in non-surgical patients. For example, many patients with lung cancer receive thoracic radiotherapy, and serial measurement of FEV1 can help assess dose-limiting
See Articles page 829
789