References
1. Roswit B et al. Radiology 1968; 90: 688-697.
2. Perez C et al. Int J Radiat Oncol Biol Phys 1980; 6: 987-994.
3. Graham MV et al. Lung Cancer 1997; 18:124.
4. Emami B et al. Int J Radiat Oncol Biol Phys 1988; 15:1021-1025.
5. Medical Research Council. Clin Oncology 1996; 8:167-175.
6. Slawson R G et al. Int J Radiat Oncol Biol Phys 1988; 15: 61-68.
7. Holsti L et al. Int J Radiat Oncol Biol Phys 1980; 6: 977-981.
8. Cox J et al. Int J Radiat Oncol Biol Phys 1991; 20: 7-12.
9. Saunders M et al. Lancet 1997; 350:161-165.
10. Saunders M et al. Lung Cancer 1997; 18:123.
11. Sause WT et al. J Nat Cancer Inst 1995; 87:198-205.
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LONG-TERM SURVIVAL AFTER CLASSIC IRRADIATION THERAPY
P. VAN HOUTTE
Departement of radiotherapy, Institut Jules Bordet, Brussels, Belgium
Radiotherapy has often be considered the treatment of choice for inoperable non small cell lung cancer. Nevertheless, the practice varies widely from one country to another and from one center to another based on local tradition : some advocate an aggressive approach aiming at cure while others adopt a more conservative view with the main goal of relieving the patient of tumor-related symptoms. Indeed, only a few patients may apparently be cured with radiation therapy : the overall 5-year survival rates are below 10% in most series. If long term survival is one way to look to a treatment efficacy, it is also important to analyze the different factors influencing the survival as well as other parameters such as the local control, the pattern of failure...
Inoperable lung tumors treated with radiation therapy is a quite poor definition : it covers patients considered to be inoperable due to locoregional tumor extension or patients presenting with a "resectable" tumor but with compromised physiological functions. The table summarizes some of the survival observed after radiation for so called inoperable lung tumor. Different factors must be taken in consideration : the tumor extent (size, nodal spread), the patient status (performance status, weight loss, associated disease...), the quality of the radiation procedure (dose, fractionation, technique). A basic radiobiological principle of radiotherapy implies that a constant fraction of cells is destroyed by a given dose of radiation. Tumor volume is a critical factor for the success of a radiation course. When the tumor increases in size, the number of cells is higher requiring a higher radiation dose. This dose-volume relationship is well known for many epithelial cancers including head and neck cancers but also lung cancers. The RTOG trial 7301 compared different radiation total doses of 40 to 60 Gy with daily 2 Gy fraction. The higher radiation total dose led to better 2 and 3 year survival rates : 15% versus 6% for 40 Gy. Nevertheless, at 5 years, all three radiation schedules yield similar survival rates. This is partially due to the range of doses used in this trial. The data available from head and neck cancers showed that doses in excess of 70 Gy are required to control tumor larger than 3 cm with a high probability, a dose not used in conventional radiotherapy for lung cancers. Within the dose range of 40 to 60 Gy, the intrinsic radiosensitivity of the individual tumor may also influence directly the results.
Tumor size is an important factor not used in the staging system of lung cancer except for T1 and T2, tumors usually treated by surgery except for medically inoperable patient or in presence of extensive mediastinal involvement. Many series have outlined the importance of tumor size both for survival or local control. In the series of Dosoretz including 152 patients with medically inoperable NSC lung cancer without lymph node involvement, the 4-year actuarial risk of local relapse was 38% for T1 tumor and 80% for T2 and T3 tumors. In the series of Morita including 149 patients, the risk of local failure at 5 years was respectively 38% for tumor less than 3 cm, 45% for tumor between 3 and 5 cm and 68 % for tumor larger than 5 cm. Hazuka reported a 2 year local control progression free survival of 58% for T1 tumors compared to 23% for T4 treated with doses in excess of 60 Gy. Furthermore, achieving a local control of the disease had a direct impact on survival in the RTOG experience.
Last but not least, the quality of the radiation technique is an important crucial factor not only to prevent radiation induced severe damage to such vital organs as the lungs or the heart but also to control the disease and the patient survival. In the classical Dillman trial, a review showed that the tumor was not well covered in 22% of the patients!
Nevertheless, even with the best technique and a classical radiation schedule, the results remain disappointing both in term of survival or local control. In the French trial, a precise pattern of failure analysis was performed using repeated fiberoptic bronchoscopies and restaging procedure for stage III disease. A dose of 65 Gy was delivered. The local control rate at 1 year was only 17% . This figure differs from several reports but reflects only differences in the definition of local control (first site of failure, in-field failure, ultimate control, absence of local evolution...), in the restaging procedure (repeated fiberoptic bronchoscopy, CT...) and the difficulties in differentiating fibrosis from tumor relapse. There is a clear need to search to new way of delivering the radiation either by modifying the fractionation, increasing the total dose (conformal radiation, brachytherapy) or combining radiation with drugs and even surgery.
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References
1. Arriagada R., Le Chevalier T., Quoix E., et al Effect of chemotherapy on locally advanced non-small lung carcinoma: a randomized study of 353 patients. Nt. J. Radiat. Oncol. Biol. Phys. 1991; 20: 1183-90
2. Dillman R. O., Seagren S L., Propert K J., et al randomized trial of induction chemotherapy plus high-dose versus radiation alone in stage III non-small cell lung cancer N. Engl. J. Med. 1990 ; 323 : 940-945
3. Dosoretz D. E. Katin M.J., Blitzer P. H., et al Radiation therapy in the management of medically inoperable carcinoma of the lung : results and implications for future treatment strategies Int. J. Radiat. Oncol. Biol. Phys 1992 ; 24 : 3-95.
4. Hazuka M. B., Turrisi A. T., Lutz S.T., et al Results of high-dose thoracic irradiation incorporating beam's eye view display in non-small cell lung cancer: A retrospective multivariate analysis. Int. J. Radiat. Oncol. Biol. Phys. 1993, 27: 273-284.
5. Morita K., Fuwa N., Suzuki Y., et al Radical radiotherapy for medically inoperable non-small cell lung cancer in clinical stage I : a retrospective analysis of 149 patients.
Radiother. Oncol. 1997; 42: 31-362.
6. Perez C. A., Stanley K., Grundy G., et al Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat cell carcinoma of the lung. Report by the Radiation Therapy Oncology Group Cancer 1982 ; 50 : 1091-1099.
7. Sause W., Scott C., Taylor S., et al Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588 Preliminary analysis of a phase III trial in regionally advanced unresectable non-small cell lung cancer. J. Nat. Cancer Inst. 1994; 87:198-205
8. Schaake-Koning C., van den Bogaert W., Dalesio O., et al Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer N.Engl.J.Med.1992;326 : 524-530
9. Würschmidt H., Bünemann H., Bünemann C., Beck-Bornholdt H. P., Heilmann H. P. Inoperable non-small cell lung cancer : a retrospective analysis of 427 patients treated with high-dose radiotherapy Int. J. Radiat. Oncol. Biol. Phys. 1994 ; 28 : 583-588.
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HIGH TECHNOLOGY RADIATION THERAPY FOR NON-SMALL CELL LUNG CANCER
W.T. SAUSE
M.D., FACR Salt Lake City, Utah 84143, USA
Technological advances in the delivery of radiation therapy are based primarily on the availability of sophisticated computerized planning systems. There have been very few, if any, major advances in the radiation beam quality. Although particle generating machines are sparsely available and worthy of investigation, it is unlikely that these machines will be universally applied to patients with epithelial tumors. The greatest advance in the technological aspects of external beam irradiation are those associated with sophisticated imaging techniques and sophisticated 3-dimensional, computerized planning techniques. The single most important scientific advance in radiation oncology has been the development and universal application of sophisticated imaging tools.
The high tech radiation therapy or 3-D treatment planning is radiation therapy which is made to conform to the target volume. Inherent in this statement, is the accurate definition of the target volume and the ability to deliver non-co-planar radiation beams adequate to conform to the volume and eliminate treatment to normal tissue.(10)(13) Our current 2-D systems often lack an appreciation of tumor volume and normal tissues surrounding the tumor volume.(7)(9) The current 2-D systems are universally limited to co-planar beams and these 2-dimensional plans fail to define the tumor volume in all dimensions. The availability of modern computer systems give us the ability to overcome these 2-dimensional shortcomings and apply a more sophisticated beam to the area of interest. The biological assumptions required to apply this technologically sophisticated treatment include: dose response relationship to ionizing irradiation, failure to control the epithelial tumors with standard techniques, and limitations of standard irradiation based on normal tissue tolerance.(12)(4)
There is no doubt that a dose-response relationship of external beam radiation therapy to the control of lung cancer exists. RTOG data suggests a short term survival and improvement in local control with doses up to 60 Gy.(11) Continuous hyperfractionated, accelerated radiation therapy delivered in Great Britain in a randomized trial suggest an improvement in local control and an improvement in survival with the application of the more aggressively delivered radiation.(15) An MRC trial which randomized patients to several schedules of hypofractionated irradiation was also able to demonstrate a dose-response relationship between external beam irradiation and survival.(16) Although in most instances survival is poor, there appears to be a well-defined dose-response relationship of external beam irradiation therapy to the temporal control of epithelial neoplasms of the lung. Ultimately, local failure is a substantial problem.(14)(2)
Bronchoscopic data from the French Multi-Institutional Trial suggests that only 15% of patients with advanced lung cancer are controlled with standard doses of external beam radiation therapy. RTOG 73-01, also suggested that ultimate survival (five year), was poor irrespective of the transient improvement in local control seen with 60 Gy. Although there appears to be a dose-response relationship to epithelial cancers of the lung, the response is often transient and local failure remains a difficult problem. Normal tissue toxicity also remains a substantial problem in the management of lung cancer. Graham, et. al, have reported normal tissue toxicities in 20 patients treated with 3-D technology.(6) They have been able to correlate the incidence in radiation pneumonitis with the radiation dose given to the percent of normal lung. When 60% of the ipsilateral lung exceeded 3500 cGy, or 50% of the lung volume exceeded 2000 cGy, the incidence of grade III and IV pneumonitis was substantially increased. Mediastinal structures, such as the spinal cord, esophagus and heart are also those limiting structures in the management of lung cancer. As external beam radiation therapy is combined with cytotoxic chemotherapy, the esophagus has become the dose-limiting organ in the mediastinum. Any contribution of radiotherapy planning to reduce the total volume of esophagus treated would result in better patient tolerance to treatment.
Although no large multi-institutional trials have been conducted, preliminary evidence from Memorial Sloan-Kettering and University of St. Louis, suggest that as the dose of 3-D radiation is increased, median survival of those patients is also improved.(1)(3)(5)(8) The Radiation Therapy Oncology Group has also embarked on a large multi-institutional trial which will randomize patients to several dose levels of 3-D conformal therapy. Those patients who have less than 25% of the lung volume in the treatment beam will be randomized to 4-dose levels from 70.9 Gy in 33 fractions in 7 to 8 weeks, to 90.3 Gy in 42 fractions in 9 to 10 weeks. Those patients who have 25-37% of the lung volume in the treatment beam, will be randomized to 3-dose levels from 70.9 Gy in 33 fractions in 7 to 8 weeks, to 83.8 Gy in 39 fractions in 8 to 9 weeks. Those patients who have greater than 37% of the lung volume in the beam, will be randomized from 64.5 Gy in 30 fractions in 6 weeks to 77.4 Gy in 36 fractions in 7 to 8 weeks.
In summary, bronchogenic cancer is a malignancy in which we can define a dose response relationship of external beam irradiation to tumor control, ultimate tumor control is poor, and structures in the mediastinum limit our ability to deliver adequate doses of irradiation with and without chemotherapy. Theoretically, patients with lung cancer would benefit from sophisticated treatment planning which would allow greater and superior doses of radiation. The availability of commercial planning computers will allow the hypothesis to be tested.
Bibliography
1. Armstrong JG, Burman C, Leibel S, Fontenla D, Kutcher G, Zelefsy M, Fuks Z. Three-dimensional conformal radiation therapy may improve the therapeutic ratio of high-dose radiation therapy for lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 26:685-689; 1993.
2. A. Effect of chemotherapy on locally advanced non-small cell lung carcinoma: A randomized study of 353 patients. Int. J. Radiat. Oncol. Biol. Phys. 20:1183-1190; 1991.
3. Emami B, Purdy J, Harms W, Manolis J, Wong J, Drzymala R, Simpson JR. Three-dimensional treatment planning for lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 21:217-227; 1991.
4. Fuks Z, Leibel SA, Wallner KE, Begg CB, Fair WR, Anderson LL, Hilaris BS, Whitmore WF. The effects of local control on metastatic dissemination in carcinoma of the prostate: Long-term results in patients treated with 125 implantation. Int. J. Radiat. Oncol. Biol. Phys. 21:537-547; 1992.
5. Graham MV, Matthews JW, Harms WB, Emami B, Purdy JA. 3-D radiation treatment planning study for patients with carcinoma of the lung. Int. J. Radiat. Oncol. Biol. Phys. 29:1105-1117; 1994.
6. Graham MV, Shiue K, Emami B, Purdy JA. Dose-volume correlations with early pneumonitis for 3D treatment planning of non-small cell lung cancer patients. International Journal of Radiation Oncology Biology Physics (in press).
7. Langer M, Kijewski P, Brown R, Ha C. The effect on minimum tumor dose of restricting target-dose inhomogeneity in optimized three-dimensional treatment of lung cancer. Radiother. And Oncol. 21:245-256; 1991.
8. Leibel SA. Clinical experience with 3D conformal radiation therapy for non-small cell lung cancer at the Memorial Sloan-Kettering Cancer Center. In: J. Meyer (eds). Frontiers in Radiation Therapy (in press). Basel, Switzerland: S. Karger; 1994.
9. Martel MK, Ten Haken RK, Hazuka MB, Turrisi AT, Fraass BA, Lichter AS. Dose-volume histogram and 3D treatment planning evaluation of patients with pneumonitis. Int. J. Radiat.
10. Martel MK, Strawderman M, Hazuka MB, Turrisi AT, Fraass BA, Lichter AS. Volume and dose parameters for survival of non-small cell lung cancer patients. Radiother. And Oncol. 44:23-29, 1997.
11. Perez CA, Bauer M, Edelstein S, al, e. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int. J. Radiat. Oncol. Biol. Phys. 12:539-547; 1986.
12. Suit HD. Local control and patient survival. Ing. J. Radiat. Oncol. Biol. Phys.
13. Vijayakumar S, Myrianthopoulos L, Rosenberg I, Halpern H, Low N, Chen G. Optimization of radical radiotherapy with beam’s eye view techniques for non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 21:779-788; 1991.
14. LeChevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, Tarayre M, Lacombe-Terrier MJ, Douillard JY, Laplanche A. Radiotherapy alone versus combined chemotherapy and radiotherapy in non-resectable non-small cell lung cancer: First analysis of a randomized trial in 353 patients. Journ. of the Natnl. Ca. Inst. 83 #6: 417-423; 1991
15. Sanders MI, et al, J of Nat Canc, 73, 1455-1462, 1996.
16. Macbeth FR, Bolger JJ, Hopwood P, Bleehen NM, Cartmell J, Girling DJ, Machin D, Stephens RJ, Bailey AJ. Randomized trial of palliative two-fraction versus more intensive fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Clin. Oncol. 8:167-175, 1996.
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RADIOTHERAPY VERSUS BEST SUPPORTIVE CARE IN LOCALLY ADVANCED NSCLC
A. GREGOR, FRCP FRCR
Department of Clinical Oncology Western General Hospital ,NHS Trust Crewe Rd Edinburgh EH4 2XU - Scotland
Critical assessment of the individual contribution of thoracic radiotherapy (TR) to the overall management of locally advanced Non small cell lung cancer (NSCLC) is hampered by both the quantity and quality of available evidence. There are only four reported trials which have specifically addressed this question.
Two are historical studies of the Veterans Administration (1) and the Oxford Trials (2) and can be open to criticism regarding technical quality of the radiation treatment, staging methodology and patient selection and reporting standards.
More recently the West of Scotland Lung Cancer Group -WSLCG (3) set out to perform in collaboration with the Finsen Institute a trial which closed without reaching its planned sample size. There is a current Medical Research Council Trial - LU17 (4) which is ongoing.
When evaluating the role of TR the selection of endpoints determines the character of the intervention and to certain extent predetermines the outcome. Studies such as the LU17 comparing palliative TR with BSC are unlikely to show a survival difference and appropriately concentrate on symptom control and QOL. Selection of patients is also critical. Populations with advanced disease and high frequency of subclinical metastatic involvement cannot readily benefit from local therapy. Choice of radiation dose and quality of TR technique is likely to influence local control and therefore outcome. Local control as a principal endpoint is difficult to assess in previously irradiated intrathoracic field and even with sophisticated radiological and endoscopic techniques remains disappointingly low in clinical practice.
Sample size needs to be much larger than has been the case in situation where differences are likely to be small.
It is mandatory to take these constraints into account, if our interpretation of the available evidence is to be valid.
The VA study (1) did show a survival advantage for TR 22% v 16% survival at 1 year which has been interpreted as "no appreciable benefit". Expecting greater gain may have been naive. The Oxford Trials (2) were ambitious in their aspirations to test whether any treatment of inoperable lung cancer brings benefit. The sample size was small -148 patients "randomised" into 3 treatment categories. Only 38 patients received TR. NSCLC represented 50% and 23% had metastatic disease at entry. The results were equivocal.
The WSLCG trial (3) set out to resolve the issue comparing again in a 3 arm study (BSC, radical TR alone or with neoadjuvant Cisplatin chemotherapy). Only 118 patients could be randomised in 5 years and the trial stopped prematurely. Survival was the principal endpoint and although not statistically significant due to the small sample size the median survival of TR patients of 53 weeks (95% CI 32-59) compared to 34 weeks (95% CI 22-57) for the BSC arm. Interestingly the 2 year survival was similar at 20% for TR and 15% for BSC. It is a pity that the study sample size is inadequate and that we don’t have enough comparable data for a meaningful metanalysis.
Future studies addressing the issue of TR against BSC are unlikely, so what practical conclusions are possible?
Local control remains a prerequisite for cure in NSCLC. Evidence of radiation dose response is available and technical innovations as well as radiobiological advances offer a real prospect for safe and meaningful dose escalation. Advances in chemotherapy contribute possibilities for both bulk reduction and radiosensitisation of tumours. In disease such as NSCLC we need all the available help to influence the outcome.
References
1. Roswit et al Radiology;90,688-697; 1968
2. Durrant et al Lancet;I,715-719,1971
3. Gregor et al; J Nat Canc Inst, 85,12,997-999,1993
4. MRC LCWP personal communication
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RANDOMIZED STUDIES OF RADIOTHERAPY VERSUS CHEMOTHERAPY
S. KAASA Professor MD, Palliative Medicine Unit and Unit for Applied Clinical Research, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
There is a lack of consensus regarding the treatment policy of local advanced non small cell lung cancer (NSCC) despite a large amount of completed and ongoing clinical trials. The majority of patients with locally advanced disease usually develop distant metastases. At this stage of the disease, patients may suffer from a series of symptoms, such as pain, dyspnoea, anorexia, cachexia, nausea, fatigue etc. At the time of diagnosis, a majority of the patients are symptomatic. Chest radiotherapy has been the standard treatment for many years. It seems to be a general disagreement about the primary aim of the treatment of locally advanced NSCLC. The aim the treatment of this type of patients can either be life prolonging, symptom preventive, symptom relieving or combinations.
There are very few randomized clinical trials comparing radiotherapy with chemotherapy (Table 1). Only three published randomized trials were identified in the literature. One study published in 1977 (1) was a late report of two British trials published in the 70-ies (2,3) designed to assess the effect of immediate treatment of inoperable NSCLC. In these series 148 patients were included, allocated to radiotherapy, single agent chemotherapy with prokarbazin or combination chemotherapy with nitrogen mustard, vinblastin and prednisone. No difference in survival was reported. Quality of life was evaluated by a simple physician assessed instrument. The group of patient included in this study is heterogeneous, even with some small cell lung cancer patients. The chemotherapy regimen, is today considered to be sub optimal. Furthermore, the patients in this study had a short life expectancy.
Johnson et al (4) published a study including 319 patients in 1990. The aim of the study was to compare the survival of NSCLC patients treated with single agent chemotherapy, vincristin, thoracic radiotherapy (60Gy) or a combination of both treatment modalities. In this publication only data comparing radiotherapy with chemotherapy is reported. No statistically significant difference was found in survival, however, the response rate was higher (30%) in radiotherapy arm as compared with the single agent chemotherapy (10%). The median survival in this study is more than two longer compared to the previous study. One major limitation also in this study, is the use of a single agent chemotherapy. Another limitation is the cross over design between vincristin and radiotherapy performed in all patients who progressed after the first treatment modality.
In 1988 (5) Kaasa and colleagues published data from a randomised trial comparing radiotherapy (42Gy) with a modern chemotherapy regimen, containing cisplatin and etoposide. Furthermore the cross over between the arms was limited. No difference was found in survival with a median survival of 45/46 weeks in the two treatment arms respectively. Patients receiving radiotherapy showed a doubling of tumour response, 42%, as compared to 21% in the chemotherapy arm. Quality of life data in a sub cohort is found in separate publications (6,7,8). Treatment related side effects were more pronounced in the chemotherapy group than in the radiotherapy group.
When data are interpreted the survival advantage of a few individuals must be weighted against the potential harm to those patients who do not experience any survival benefit. Assessment of quality of life in these types of studies should therefore be mandatory, using standard instruments such as the EORTC QLQ-C30 (9) combined with a lung cancer specific module (10).
In conclusion the evidence concerning the direct comparison of radiotherapy versus chemotherapy in randomised trials is scares. Only one study has included cisplatin-based treatment which is considered to be the optimal drug in combination for NSCLC(11). Furthermore, data on symptom control and quality of life in general is limited. Therefore it is reasonable to conclude that there is no real answer to the question whether radiotherapy or chemotherapy is superior to one another.
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