1162 I. J. Radiation Oncology 0 Biology 0 Physics

completely resected Stages II and IIIA squamous cell carcinoma of the lung had a S-year survival of approximately 34% without an apparent survival benefit from thoracic radiation therapy. Local-regional recurrence occurred in 15 of 29 (45%) patients who underwent surgery alone and in IO of 46 (22%) patients who received adjuvant thoracic radiation therapy. In the prospective trial of the Lung Cancer Study Group (LCSG) randomizing Stages II and IIIA patients with completely resected squa- mous cell carcinoma of the lung to observation or 5000 cGy thoracic radiation therapy (3), the 5-year survival was 36% for both the control arm and the thomcic radiation therapy arm. This prospective randomized trial, therefore, reinforced what was anticipated from Doctor Choi’s own retrospective analysis, that is, that thoracic radiation therapy does not improve survival in this group of patients. Several points of the LCSG study are worth reinforcing. Local failure occurred only in 19% of the control patients versus less than 1% of the treated patients. Therefore, Doctor Choi’s statement in his editorial that “5000 cGy in 25 fractions/ 5 weeks seems less than adequate” with respect to local control seems unwarranted, since over 99% of the radiated patients in the LCSG study had local control!

Doctor Choi’s earlier retrospective analysis also inferred a survival benefit with the addition of thoracic radiation therapy for patients with completely resected Stages II and IIIA adenocarcinoma of the lung (2). Two-year survival rates were approximately 60% for patients receiving adjuvant thoracic radiation therapy versus 40% without. Local failure occurred in 3 of 47 patients (6%) patients who received thoracic radiation therapy and 4 of 26 (15%) patients who had surgery alone. It is difficult to understand, therefore, with such low local failure rates in both groups, how radiation therapy could impact survival in a positive way. In the prospective surgical adjuvant therapy trial of the LCSG comparing che- motherapy to immunotherapy (4), local failure occurred in only 17% of patients (with a 2-year survival of approximately 36%) reinforcing the low incidence of local recurrence in these patients.

Weighing all the evidence, there is not a role for the routine or non- investigational administration of adjuvant thoracic radiation therapy following complete resection of a Stage II or IIIA (i.e., node positive) non-small cell lung cancer. Patients with close margins, multiple nodes, and extra nodal extension are likely to be those that benefit from adjuvant thoracic radiation therapy in terms of local control, but randomized trials are necessary to demonstrate such efficacy. Unfortunately, the bias of the radiation oncology community regarding the “benefit” that is derived from radiating the I in 5 or 6 patients who may locally benefit from such treatment will prevent such a trial from ever occurring in this country.

EDWARD G. SHAW, M.D. Division of Radiation Oncology Department of Oncology Mayo Clinic

1. Choi, N. C. Controversies in the role of postoperative radiotherapy in stages II and IIIA resected non-small cell lung carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 20: 1137-l 141; 1991.

2. Choi, N. C. H.; Grillo, H. C.; GardieIIo, M.; Scannell, J. G.; Wilkins, E. W. Basis for new strategies in postoperative radiotherapy of bron- chogenic carcinoma. Int. J. Radiat. Oncol. BioI. Phys. 6: 31-35; 1980.

3. The Lung Cancer Study Group. Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N. Engl. J. Med. 3 15: 1377-l 38 I; 1986.

4. Holmes, E. C.; Gail, M. Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma. J. Clin. Oncol. 4: 710-715; 1986.

RESPONSE TO DR. SHAW

To the Editor: With regard to the Comments by Dr. Shaw about my editorial on Controversies in Postoperative Radiation Therapy in Stage II and IIIA Resected Non-Small Cell Lung Cancer (I), it is critically important that interpretation of studies and data of others be accurate and correct. Dr. Shaw contended that the surgery alone group (S alone) of the Lung Cancer Study Group (LCSG) 773 study had only 19% of local failure rate and that postoperative radiation therapy (RT) is unlikely to improve the survival (8). Furthermore, Dr. Shaw misdirected the blame

Volume 22, Number 5, 1992

to the radiation oncology community for the difficulties that some co- operative study groups have had in running clinical trials in which surgery plus postoperative chemotherapy (S + CT) was going to be compared with S alone as if postoperative RT had no impact on the outcome in Stages II and IIIA non-small cell lung carcinoma (NSCLC).

With regard to local-regional recurrence rate after so called “complete resection” for Stages II and IIIA squamous cell carcinoma in LCSG 773 study, the correct interpretation of the Table 3 of LCSG 773 data should be as follows: Local recurrence only as the site of first recurrence in S alone arm was 4 I % (2 l/5 1) instead of Dr. Shaw’s I9%, and the overall local recurrence rate-which includes not only local recurrence only as the site of first recurrence, but also the concurrent local and distant recurrences, as well as subsequent local recurrence after distant failure- would be much higher than 41% (8). Although Dr. Shaw contended that postoperative adjuvant RT following so called complete resection in Stages II and IIIA NSCLC is not indicated except for close margins, multiple nodes, and extranodal extension, this high rate of local recurrence over 4 I % after so called “complete resection” does not meet our patients’ and surgeons’ expectation and satisfaction of good cancer surgery. The term “complete resection” that was used in LCSG 773 report included an involvement of multiple mediastinal lymph nodes as long as a node proximal or cephalad to the highest mediastinal tumor-bearing node had to have been biopsied and found to be free of tumor. Dr. Shaw’s rec- ommendation of postoperative RT for the involvement of multiple me- diastinal lymph nodes does contradict his statement in the first paragraph. The use of such a term “complete resection” should be avoided in de- scribing the extent of surgery in Stages II and IIIA lung cancer. Instead, energy and time should be directed in providing sound data correlating local regional failure with the extent of primary lesion and regional lymph node status in terms of the number of involved nodes, extranodal ex- tension, and the location of involved nodes.

When Dr. Shaw stated that Massachusetts General Hospital (MGH) study showed no survival benefit by S + RT over S alone group in Stages II and IIIA squamous cell carcinoma (2, 3), he overlooked a very im- portant aspect of the data. In retrospective studies unlike prospective and randomized studies, the patient selection for postoperative RT is often done by surgeons. Therefore, S + RT group usually consists of patients with more advanced stage disease. Our study was not an excep- tion. There were 52% of patients with Stage IIIA disease in S + RT group, whereas only 27% of the control group (S only) had the same extent of disease (2). In spite of this unfavorable bias against S + RT, the 4-year actuarial survival rate was 42% and 33% for S + RT versus S groups.

In terms of radiation dose-tumor response in the setting of postop- erative RT, local recurrence was noted with radiation dose up to 50 Gy in 25 fractions over 5 weeks in MGH series (2). A reasonable radiation dose-tumor response relationship was also noted by Emami et al. in the context of postoperative RT (4). There was a trend of better local tumor control and survival by radiation dose over 50 Gy than less than 50 Gy. Several leading retrospective studies on this issue have also used a total dose of 55 to 60 Gy in 2 Gy of dose fractions, 5 days a week (5, 6, 7). Althouah LCSG 773 studv reported 3% rate of onlv local failure as the site of f;rst recurrence (overall local recurrence rate would be higher than this) using 50 Gy in 25 fractions over a period of 5 weeks, this is at the lower end of the range of radiation dose-tumor response relationship. Based on our radiation dose-tumor response data and others, our ap- proach has been to use a total dose of 54 to 56 Gy/1.8 to 2 Gy per fraction/5 days per week.

With regard to an issue of postoperative adjuvant therapies in Stages II and IIIA adenocarcinoma, Dr. Shaw stated an opinion without sup- porting data. Contrary to the Dr. Shaw’s view on this issue, postoperative RT has shown survival advantage over S alone in several leading ret- rospective studies, that is, Green et al., Kirsh et al., Martini et al., and Choi et al. (2, 5, 6, 7) The long term cure rate of S + RT for patients with Stages II and IIIA adenocarcinoma was even somewhat better than that of squamous cell carcinoma in the studies of Martini et al. and Choi et al. (2, 7) There should be a well-designed study of postoperative ad- juvant chemotherapy for Stage II and IIIA NSCLC. Such a study could compare S + RT with S + RT + CT.

NOAH C. CHOI, M.D. Department of Radiation Oncology Massachusetts General Hospital Harvard Medical School Boston, MA 02 114

Correspondence 1163

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Choi, N. C. Controversies in the role of postoperative radiotherapy in Stages II and IIIA resected non-small cell lung carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 20: 1137-l 141; 1991. Choi, N. C. H.; Grille, H. C.; Gardiello, M.; Scannell, J. G.; Wilkins, Jr., E. W. Basis for new strategies in postoperative radiotherapy of bronchogenic carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 6: 31- 35; 1980. Choi, N. C.; Kanarek, D. J.; Grille, H. C. Effect of postoperative radiotherapy on changes in pulmonary function in patients with stage II and IIIA lung carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 18: 95-99; 1990. Emami, B.; Kim, T.; Roper, C.; Simpson, J.; Pilepich, M.; Hederman, M. Postoperative radiation therapy in the management of lung can- cer. Radiology 164: 25 1-253; 1987. Green. N.: Kurohara. S. S.: Georae. III. F. W.: Crews. Jr.. 0. E. Postresection irradiation for prim& lung cancer. Radiology -116: 405-407; 1975. Kirsh, M. M.; Sloan, H. Mediastinal metastases in bronchogenic carcinoma: Influence of postoperative irradiation, cell type, and lo- cation. Ann. Thorac. Surg. 33: 459-463; 1982. Martini, N.; Flehinger, B. J.; Bains, M. S.; McCormack, P. Man- agement of stage III disease: Alternative approaches to the manage- ment of mediastinal adenopathy. In: Delarue N. C., Eschapasse H. ed. International trends in general thoracic surgery, vol 1, lung cancer. Philadelphia: W. B. Saunders Co., 1985: 108-120. The Lung Cancer Study Group: Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N. Engl. J. Med. 3 15: 1377-8 1; 1986.

RESPONSE TO LINDSTROM AND FOWLER’S “THE INFLUENCE OF DOSE AND TIME ON LOCAL CONTROL

OF CARCINOMA OF THE LARYNX BY RADIATION THERAPY”

To the Editor: In a recent paper, Lindstrom and Fowler reanalyzed the time factor in data on local control of carcinoma of the larynx pre- viously reported by Maciejewski et al. (1, 2). Lindstrom and Fowler’s regression analysis, which was performed without making any radiobi- ological assumptions, fits Maciejewski’s data excellently; however, a good fit does not necessarily prove the validity of a model. Beside the extraor- dinary steep loss of 20% local tumor control per I .75 days, which is comprehensively discussed by the authors, the model also predicts a high local tumor control rate at a total dose of 0 Gy (l), whereas local tumor control is minimal at 52 Gy. We think that this unrealistic prediction, which is caused by a negative contribution of dose between 0 and I 10 Gy on tumor control probability, may severely limit the applicability of Lindstrom and Fowler’s model.

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MICHAELBAUMANN, M.D. HANS-PETERBECK-BORNHOLDT,PH.D. University Hospital Hamburg-Eppendorf Dept. of Radiation Therapy and-institute

of Biophysics and Radiation Biology Martinistr. 52 D-2000 Hamburg 20 Germany

Lindstrom, M. J.; Fowler, J. F. Re-analysis of the time factor in local control by radiotherapy of T3T4 squamous cell carcinoma of the larynx. Int. J. Radiat. Oncol. BioI. Phys. 2 I : 8 13-8 17; I99 I. Maciejewski, R.; Preuss-Bayer, G.; Trott, K. R. The influence of the number of fractions and of overall treatment time on local control and late complication rate in squamous cell carcinoma of the larynx. Int. J. Radiat. Oncol. Biol. Phys. 9: 321-328; 1983.

RESPONSE TO DRS. BAUMANN AND BECK-BORNHOLDT

To the Editor: The comments of Baumann and Beck-Bomholdt point to a common confusion over the various roles a model may play in the analysis of data. A distinction must be made between (I) empirical models made up of flexible, mathematically convenient functions interpretable only within the boundaries of the data and, (2) radiobiological or mech-

anistic models derived from prior assumptions about processes and re- lationships. These two types of models have entirely different uses [see Box, Hunter, and Hunter (1) Chapters 9 and 16 for an informative dis- cussion of this issue]. In the analysis presented in Lindstrom and Fowler (2) our goal was to obtain an accurate parsimonious summary of the empirical relationships between the predictor variables and the outcome without making any prior assumptions as to what these relationships should be. Thus, we were able to fit an empirical model.

The criticism that this model predicts nonsensical, results for dose = 0 implies either that we consider the model mechanistic or that we plan to use it to predict results for doses near zero. Neither of these is the case. The only claim we make about this model is that it fits these data (a point on which we and Baumann and Beck-Bomholdt agree). Likewise, the only use we make of the model is as a representation of the data. In particular, it tells us nothing about the relationshipk between predictor variables and outcome for values of the predictor variables outside the range of the data. It was not intended to do so.

The aspect of our empirical model which bothers Baumann and Beck- Bornholdt most is the increase in local control for small doses, toward the right of Figure 1 (2). In contrast, we consider this result an example of the advantage of the empirical modeling process. the increase in local control for low doses is a real feature of this data set and is not caused by one or two influential data bins (or even all the bins at the lowest dose). Since our goal is to find a model which describes the data, we feel that we have succeeded. If we had used a mechanistic model, we would have missed this feature of the data completely since no radiobiological model would allow this behavior. The important question is, of course, what caused this unexpected result. We suspect physician selection and conclude that randomized, controlled clinical trials are required to obtain accurate estimates of both the effect of dose and ofloverall time.

While there is certainly a place for mechanistic modeling in biology, it is also true that models with no such pretensions can be equally useful. We wish to stress the point that unlike most data apalyses presented in this field, ours is not intended to advocate any specific model as appro- priate for future data. Rather, we wish to advocate thelmethod of empirical modeling as appropriate for clinical, radiobiological data.

MAR$J.LINDSTROM,PH.D. JOHN F. FOWLER, PH.D., DSc. University of Wisconsin-Madison Biostatistics Center and Department of Human Oncology 1300 University Ave., Madison. WI 53706

I. Box, G. E. P.; Hunter, W. G.; Hunter, J. S. Statistics for experi- menters, NY: John Wiley & Sons, Inc.; 1978.

2. Lindstrom, M. J.; Fowler, J. F. Reanalysis ofthe time factor in local control by radiotherapy of T,T, squamous cell carcinoma of the larynx. Int. J. Radiat. Oncol. Biol. Phys. 2 I: 8 13-8 17; 199 I.

NEED FOR COMMON NOMENCLATURE AND DEFINITIONS IN 3-D CONFORMAL R&DIOTHERAPY

To the Edifor: A recent paper by Vijayakumar et al. (I) described their experience in treating 198 patients with limited technique 3D ra- diotherapy. After reading their manuscript and reviewing most of the recently published articles on 3D conformal radiotherapy, I would like to make the following comments and suggestions. In their article, Vi- jayakumar ef al. have termed their technique “beam’s eye view” radio- therapy (BEV RT). I would like to point out that ‘beam’s eye view” is one of the tools used in 3D conformal radiotherapy and by itself, does not constitute a different form of radiotherapy. In ;fact, using this kind of nomenclature will lead to more confusion in the future. For example, if one uses a multi-leaf collumator in 3D conformal radiotherapy, then the possibility of different nomenclatures such as “multi-leaf collumator radiotherapy” (MLCRT) may come forward. Againb all of these are tools in 3D conformal radiotherapy, and I would suggestithat institutions and investigators working on this new technology keep in mind that all of these are 3D conformal radiotherapy with very strict definition. Beam’s eye view, room’s view, multi-leaf collumator, independent jaws, etc. are different tools in 3D conformal radiotherapy.

Vijayakumar et al. have used terminologies in their article such as: “TIM” for tumor; and “TGT” for target: and “LGT” for large target and so on and so forth. Similar individually-preferred terminologies are also prevelent in recent 3D literature. Again, it appears that a commonly