0360~?.016/90 $3.00 + .oO Copyright 0 I990 Pergamon Prss plc
Im. J. Radiarion Oncology Em/. Phys.. Vol. 18, PP. 485438 Printed in the U.S.A. All rights reserved.
??Editorial
DILEMMAS
AND DECISIONS
SEYMOURH. LEVITT,M.D. AND CHUNG K. K. LEE, M.D. Dept. of Therapeutic Radiology-Radiation Oncology, University of Minnesota Hospital and Clinics, Box 494 UMHC, Minneapolis, MN 55455 Tarbell et al. is indeed a retrospective and nonrandomized study, it is subject to a number of problems with retrospective or even pilot studies. The reader must always keep in mind the inherent biases which may be present in such studies. A recent article by Zelen provides a checklist which may be helpful (Table 1). One also needs to evaluate whether there was selection of patients and whether the treatment was appropriate and adequate (2 1). Also in evaluating recommendations in any scientific report, one needs to determine whether the recommendation is appropriate based on the results of the treatment and the complications thereof, that is the benefit/risk ratio.
In this issue of the journal is an article by Tarbell, et al. which relates the experience of the Joint Center in the treatment of Hodgkin’s disease patients with radiation therapy alone (RT), radiation plus whole-lung irradiation (RT + WLI), radiation therapy plus chemotherapy (RT + CT), and radiation therapy plus chemotherapy plus whole-lung irradiation (RT + CT + WLI), and radiation plus chemotherapy (RT + CT) (17). They retrospectively evaluate 590 patients with Stage IA to IIIB Hodgkin’s disease. For the most part, the patients were pathologically staged. The authors have come to a number of conclusions based on their experience. Among these they conclude that “the use of prophylactic whole-lung irradiation is no longer recommended since its use did not reduce pulmonary relapse, but did increase the risk of pneumonitis. Combined modality treatment is also associated with an increased risk of pneumonitis; however, its use in patients with large mediastinal adenopathy (LMA) appears justified.” We will confine our comments essentially to the WholeLung Irradiation aspect of the Tarbell report since their results are in conflict with ours. The Tarbell report thus presents a dilemma to readers as to how to account for the difference in results reported by the Joint Center for WLI patients compared to reports of the prospective nonrandomized experience at the University of Minnesota, Stanford University, and indeed earlier reports from the Joint Center itself (see table 5-reference 13) (8, 9, 13). Even more important, the reader is faced with the dilemma of how to treat patients with large mediastinal mass (LMM) or large mediastinal adenopathy (LMH) as defined by Tarbell et al. In a sense, this situation is similar to many other situations faced by the readers of scientific journals. It emphasizes the point that a physician’s decisions regarding the treatment of their own patients should not be based on reading the summary or indeed the article itself, but on carefully evaluating how the results are reported and conclusions researched. Since the article of
SELECTION The question of bias in selection for treatment is one which needs to be explained by Tarbell et al. More than half of the patients treated with whole-lung irradiation were patients with mediastinal masses less than i the diameter of the thorax (which we defined as an MT ratio less than f or SMM). The authors do not explain the treatment indication for these patients. We have treated 47 patients with WLI without CT. This number of patients is similar to the number treated at the Joint Center. We have confined our RT and WLI to patients with LMM and SMM with hilar disease (SMMH). We have not found an advantage to WLI for patients with SMM only. TREATMENT The authors treated the lungs with daily doses in excess of those recommended by both our Institution and Stanford. One of the patients was treated with 200 cGy/day. The authors do not state whether or not lung correction factors were used to determine the dose. If they were not, it is quite likely that the absorbed lung dose was significantly higher than reported. The actual dose to the lung may have been as much as 20-24s higher than that reported depending on patient thickness and photon energy (20). Accepted for publication 18 October 1989.
Reprint requests to: Seymour H. Levitt, M.D. 485
486
1. J.
Radiation Oncology 0 Biology0 Physics
Table 1. Checklist for biases in nonrandomized
studies
Physician selection Patient self-selection Diagnoses and staging Supportive care and management Patient evaluation Follow-up Prognostic factors Early termination
RESULTS
OF TREATMENT
There is an increased incidence of pulmonary relapse in those patients with small mediastinal mass (SMM) treated with RT + WLI relative to SMM patients treated with any other approach. The pulmonary relapse rate in the SMM patients treated by RT + WLI is similar to that in WLI treated LMM patients. On the other hand, LMM patients treated with RT + WLI, RT, or RT +CT have similar recurrence rates. It is only the LMM patients who receive RT + CT + WLI, who have a decreased pulmonary recurrence rate. This reported recurrence rate in LMM and SMM patients who receive RT + WLI, is greater than we or the Stanford group have reported in similar patients. (8-12, 14-16).
COMPLICATIONS All complications of treatment should be evaluated, both acute and chronic. The authors reported the incidence of the acute complications of pneumonitis. There is an increased incidence of pneumonitis in patients with SMM treated with RT + WLI which is higher than that in LMM patients similarly treated. There is an increased pneumonitis rate in the WLI-SMM patients compared to all treatments to similar patients other than CT + RT + WLI. The authors have not given their definition of pneumonitis, that is, severity, extent, hospitalization, treatments. They have noted that 19 of the 35 patients who developed pueumonitis required treatment, 16 did not. They have not related the patients initial treatment to the development of pneumonitis requiring therapy. In addition, they have not reported their long-term pulmo-
February 1990, Volume 18. Number 2 nary complications. Addition of this information would be extremely helpful. We have carefully followed all of our treated patients, and we have found only one case of possible acute pneumonitis requiring therapy. This patient died within 2 weeks of completing whole-lung RT, but we did not see him and were informed he had some form of congestive failure. Autopsy was not available. This may or may not have been pneumonitis and occurred at a time which is quite early for the development of pulmonary fibrosis. We have only found long-term fibrosis in two patients and in five a questionable transient DOE, not requiring treatment. Our results with WLI are similar to those reported by Stanford using partial-lung block, and less than results reported by the Joint Center (9). Thus, we must conclude that the pneumonitis in the Joint Center series is related to their treatment technique. The authors also evaluated the cardiac and thyroid complications in the group of patients which they treated and found the results to be similar to those treated at other centers with large experience and with the utilization of modern techniques in the treatment of such patients. The authors unfortunately do not report the most serious complication other than recurrence and that is the development of second malignant neoplasms including solid tumors, lymphomas, and leukemias. This information is important for the reader in order to evaluate the long-term complications in relation to the treatment. The experience of Stanford and others would indicate that patients treated with chemotherapy or combined radiation therapy and chemotherapy suffer a higher incidence of second malignant neoplasms than patients treated with radiotherapy alone ( 1, 2, 6, 7, 18, 19). CONCLUSIONS The readers have the responsibility for resolving the dilemma due to conflicting reports in literature from major institutions which have differing experiences in treatment with whole-lung irradiation for large mediastinal mass. In order to do this, it is helpful for the reader to determine if there is evidence of bias. We do not have sufficient information from Tarbell et al. to determine whether bias is present in their selection of patients for WLI + RT, but the failure rate and com-
Table 2. Patients Stage I-IIIB treated with whole lung irradiation LMM UofM* Lung radiation therapy patients Pulmonary recurrence Pneumonitis
34 3 (9%) 3 (6%)
SMM
Total WLI
JTC*
U of M**
JTC
U of M***
JTC
22 3 (13%) 2 (9%)
11 1 (9%) 0
25 3 (12%) 4 (16%)
45 4 (8%) 2 (4%)
47 6 (13%) 6 (13%)
* U of M patients treated 1974- 1983. ** SMM patients at U of M all had hilar disease. *** Joint Center SMM patients hilar condition unknown. * JTC patients treated 1969-1984.
487
Dilemmas and Decisions 0 S. H. LEVITTAND C. K. K. LEE Hogkin’Disease s PSIA . IIIBwith Large
Hodgkin’s Disease PS IA - IIIBwith Large Mediastinal MassARerCurativeRadiotherapy Recurrence-Free SurvivalbyLow-Dose LungIrradiation
, n_ . ._ 0.8
(13)-
_o_ ---+--
(3)-
Mediastinal Mass and/or Hilar Disease
(0)
NoLungXRT(I&) LangXRT(1~34) P < om
I “.V
,
0
0.0 -
5b
GO Months
1;0
-1. 0
2;o
50
100
150
200
Months
Fig. 2.
Fig. I.
plication rate in these patients would lead us to believe it is. We also assume that the pulmonary complication rate is related to their technique. Our experience with RT + WLI for LMM + SMMH has indicated a significantly decreased incidence of recurrences both pulmonary and extrapulmonary, a significantly increased recurrence-free survival, and a minimal incidence of pneumonitis and an acceptable complication rate (Table 2). We have recently evaluated our results in overall survival (OS) and recurrence-free survival (RFS) in LMM, and we have found them equivalent to the results of others using chemotherapy or (combined modality treatment. A recent review of our Stage I-RIB LMM patients treated with WLI demonstrated a RFS of approximately 80% at IO years (Fig. 1 & 2). These results are equal to or better than the reports of CT or CMT (3,4). Unfortunately, the authors have not included in this article an analysis of survival of their LMM Ipatients treated by all of the modalities. However, a recent report from both Stanford and
the Joint Center cited a 79%, 7-year FFR for LMM patients treated with CMT (3). Despite the authors recommendations of chemotherapy rather than WLI for LMM, their best results in preventing recurrence were in patients who had RT + WLI + CT. The results in LMM patients treated with CT + RT were inferior to RT + WLI + CT and the pneumonitis rate was more than twice as high. We continue to recommend RT + WLI for patients with SMM plus hilar disease, and for patients with LMM. Based on our experience, we contend that our approach to RT + WLI is one which is therapeutically effective and which when appropriately delivered produces minimal pneumonitis and other acute complications, and diminishes the risk of the more serious complications of second malignant neoplasms found with the use of CT and adjuvant CT. To further improve results in patients with LMM, modifications of CT + RT similar to those recommended by Fuller et al. may be indicated (5).
REFERENCES 1. Boivin, J.-F.; Hutchison, G. B. Leukemia and other cancers
after radiotherapy and chemotherapy for Hodgkin’s disease. JNCI 67(4):751-759; 1981. 2. Boivin, J.-F.; O’Brien., K. Solid cancer risk after treatment of Hodgkin’s disease. Cancer 61:2541-2546; 1988. 3. Cmkovich, M. 3.; Leopold, K.; Hoppe, R. T.; Mauch, P. M. Stage I to IIB Hodgkin’s disease: the combined experience at Stanford University and the Joint Center for Radiation Therapy. J. Clin. Oncol. 5(7):1041-1049; 1987. 4. Ferrant, A.; Hamoir, V.; Binon, J.; Michaux, J-L.; Sokal, G. Combined modality therapy for mediastinal Hodgkin’s disease. Cancer 55:3 1’7-322; 1985. 5. Fuller, L. M.; Hagemeister, F. B.; North, L. B.; McLaughlin, P.; Velasquez, W. S.; Cabanillas, F. The adjuvant role of two cycles of MOPP and low-dose lung irradiation in stage IA through IIB Hodgkin’s disease: preliminary results. Int. J. Radiat. Oncol. Biol. Phys. 14683-692; 1988. 6. Henry-Amar, M. Seoond cancers after radiotherapy and
chemotherapy for early stages of Hodgkin’s disease. JNCI 71(5):91 l-916; 1983. Henry-Amar, M. Quantitative risk of second cancer in patients in first complete remission from early stages of Hodgkin’s disease, NC1 Monographs 6:65-72; 1988. Hoppe, R. T. The management of stage II Hodgkin’s disease with a large mediastinal mass: a prospective program emphasizing irradiation. Int. J. Radiat. Oncol. Biol. Phy. 11: 349-355; 1985. Kaplan, H. S. Complication of radiation therapy: respiratory system. Hodgkin’s Disease, Cambridge, Massachusetts: Harvard University Press; 1980:42 l-429. 10. Lee, C. K. K.; Aeppli, D. M.; Bloomfield, C. D.; Levitt, S. H. Hodgkin’s disease: a reassessment of prognostic factors following modification of radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 13:983-991; 1987. 11. Lee, C. K. K.; Bloomfield, D. C.; Goldman, A. I.; Levitt, S. H. Prognostic significance of mediastinal involvement in
488
12.
13.
14.
15.
16.
I. J. Radiation Oncology 0 Biology 0 Physics
Hodgkin’s disease treated with curative radiotherapy. Cancer 46:2403-2409; 1980. Lee, C. K. K.; Bloomfield, C. A.; Goldman, A. I.; Nesbit, M. E.; Levitt, S. H. The therapeutic utility of lung irradiation for Hodgkin’s disease patients with large mediastinal masses. Int. J. Radiat. Oncol. Biol. Phys. 7:151-154; 1981. Leslie, N. T.; Mauch, P. M.; Hellman, S. Stage IA to IIB supradiaphragmatic Hodgkin’s disease. Cancer 55:20722078; 1985. Levitt, S. H.; Lee, C. K. K.; Aeppli, D. M.; Bloomfield, C. D. Radical treatment of Hodgkin disease with radiation therapy: results of a 15-year clinical trial. Radiology 162: 623-630; 1987. Levitt, S. H.; Lee, C. K. K.; Aeppli, D. M.; Bloomfield, C. D. The role of radiation therapy in Hodgkin’s disease: Experience and controversy, in press. Levitt, S. H.; Lee, C. K. K.; Bloomfield, C. D. Radical radiation therapy in the treatment of laparotomy staged
February 1990, Volume 18, Number 2 Hodgkin’s disease patients. Int. J. Radiat. Oncol. Biol. Phys. 10:265-274; 1984. 17. Tarbell, N. J.; Thompson, L.; Mauch, P. Thoracic irradiation in Hodgkin’s disease: Disease control and long-term complications. Int. J. Radiat. Oncol. Biol. Phys., 1989. in press. 18. Tester, W. J.; Kinsella, T. J.; Wailer, B.; Makuch, R. W.; Kelley, R. A.; Glatstein, E.; DeVita, V. T. Second malignant neoplasms complicating Hodgkin’s disease: The National Cancer Institute Experience. J. Clin. Oncol. 2(7):762-769; 1984. 19. Tucker, M. A.; Coleman, C. N.; Cox, R. S.; Varghese, A.; Rosenberg, S. A. Risk of second cancers after treatment for Hodgkin’s disease. N. Engl. J. Med. 318(2):76-8 1; 1988. 20. Van Dyk, J. Magna-field irradiation: physical considerations. Int. J. Radiat. Oncol. Biol. Phys. 9:1913-1918; 1983. 21. Zelen, M. The reporting of clinical trials: counting easy. J. Clin. Oncol. 7(7):827-828; 1989.
is not
Im. J. Radiarion Oncology Em/. Phys.. Vol. 18, PP. 485438 Printed in the U.S.A. All rights reserved.
??Editorial
DILEMMAS
AND DECISIONS
SEYMOURH. LEVITT,M.D. AND CHUNG K. K. LEE, M.D. Dept. of Therapeutic Radiology-Radiation Oncology, University of Minnesota Hospital and Clinics, Box 494 UMHC, Minneapolis, MN 55455 Tarbell et al. is indeed a retrospective and nonrandomized study, it is subject to a number of problems with retrospective or even pilot studies. The reader must always keep in mind the inherent biases which may be present in such studies. A recent article by Zelen provides a checklist which may be helpful (Table 1). One also needs to evaluate whether there was selection of patients and whether the treatment was appropriate and adequate (2 1). Also in evaluating recommendations in any scientific report, one needs to determine whether the recommendation is appropriate based on the results of the treatment and the complications thereof, that is the benefit/risk ratio.
In this issue of the journal is an article by Tarbell, et al. which relates the experience of the Joint Center in the treatment of Hodgkin’s disease patients with radiation therapy alone (RT), radiation plus whole-lung irradiation (RT + WLI), radiation therapy plus chemotherapy (RT + CT), and radiation therapy plus chemotherapy plus whole-lung irradiation (RT + CT + WLI), and radiation plus chemotherapy (RT + CT) (17). They retrospectively evaluate 590 patients with Stage IA to IIIB Hodgkin’s disease. For the most part, the patients were pathologically staged. The authors have come to a number of conclusions based on their experience. Among these they conclude that “the use of prophylactic whole-lung irradiation is no longer recommended since its use did not reduce pulmonary relapse, but did increase the risk of pneumonitis. Combined modality treatment is also associated with an increased risk of pneumonitis; however, its use in patients with large mediastinal adenopathy (LMA) appears justified.” We will confine our comments essentially to the WholeLung Irradiation aspect of the Tarbell report since their results are in conflict with ours. The Tarbell report thus presents a dilemma to readers as to how to account for the difference in results reported by the Joint Center for WLI patients compared to reports of the prospective nonrandomized experience at the University of Minnesota, Stanford University, and indeed earlier reports from the Joint Center itself (see table 5-reference 13) (8, 9, 13). Even more important, the reader is faced with the dilemma of how to treat patients with large mediastinal mass (LMM) or large mediastinal adenopathy (LMH) as defined by Tarbell et al. In a sense, this situation is similar to many other situations faced by the readers of scientific journals. It emphasizes the point that a physician’s decisions regarding the treatment of their own patients should not be based on reading the summary or indeed the article itself, but on carefully evaluating how the results are reported and conclusions researched. Since the article of
SELECTION The question of bias in selection for treatment is one which needs to be explained by Tarbell et al. More than half of the patients treated with whole-lung irradiation were patients with mediastinal masses less than i the diameter of the thorax (which we defined as an MT ratio less than f or SMM). The authors do not explain the treatment indication for these patients. We have treated 47 patients with WLI without CT. This number of patients is similar to the number treated at the Joint Center. We have confined our RT and WLI to patients with LMM and SMM with hilar disease (SMMH). We have not found an advantage to WLI for patients with SMM only. TREATMENT The authors treated the lungs with daily doses in excess of those recommended by both our Institution and Stanford. One of the patients was treated with 200 cGy/day. The authors do not state whether or not lung correction factors were used to determine the dose. If they were not, it is quite likely that the absorbed lung dose was significantly higher than reported. The actual dose to the lung may have been as much as 20-24s higher than that reported depending on patient thickness and photon energy (20). Accepted for publication 18 October 1989.
Reprint requests to: Seymour H. Levitt, M.D. 485
486
1. J.
Radiation Oncology 0 Biology0 Physics
Table 1. Checklist for biases in nonrandomized
studies
Physician selection Patient self-selection Diagnoses and staging Supportive care and management Patient evaluation Follow-up Prognostic factors Early termination
RESULTS
OF TREATMENT
There is an increased incidence of pulmonary relapse in those patients with small mediastinal mass (SMM) treated with RT + WLI relative to SMM patients treated with any other approach. The pulmonary relapse rate in the SMM patients treated by RT + WLI is similar to that in WLI treated LMM patients. On the other hand, LMM patients treated with RT + WLI, RT, or RT +CT have similar recurrence rates. It is only the LMM patients who receive RT + CT + WLI, who have a decreased pulmonary recurrence rate. This reported recurrence rate in LMM and SMM patients who receive RT + WLI, is greater than we or the Stanford group have reported in similar patients. (8-12, 14-16).
COMPLICATIONS All complications of treatment should be evaluated, both acute and chronic. The authors reported the incidence of the acute complications of pneumonitis. There is an increased incidence of pneumonitis in patients with SMM treated with RT + WLI which is higher than that in LMM patients similarly treated. There is an increased pneumonitis rate in the WLI-SMM patients compared to all treatments to similar patients other than CT + RT + WLI. The authors have not given their definition of pneumonitis, that is, severity, extent, hospitalization, treatments. They have noted that 19 of the 35 patients who developed pueumonitis required treatment, 16 did not. They have not related the patients initial treatment to the development of pneumonitis requiring therapy. In addition, they have not reported their long-term pulmo-
February 1990, Volume 18. Number 2 nary complications. Addition of this information would be extremely helpful. We have carefully followed all of our treated patients, and we have found only one case of possible acute pneumonitis requiring therapy. This patient died within 2 weeks of completing whole-lung RT, but we did not see him and were informed he had some form of congestive failure. Autopsy was not available. This may or may not have been pneumonitis and occurred at a time which is quite early for the development of pulmonary fibrosis. We have only found long-term fibrosis in two patients and in five a questionable transient DOE, not requiring treatment. Our results with WLI are similar to those reported by Stanford using partial-lung block, and less than results reported by the Joint Center (9). Thus, we must conclude that the pneumonitis in the Joint Center series is related to their treatment technique. The authors also evaluated the cardiac and thyroid complications in the group of patients which they treated and found the results to be similar to those treated at other centers with large experience and with the utilization of modern techniques in the treatment of such patients. The authors unfortunately do not report the most serious complication other than recurrence and that is the development of second malignant neoplasms including solid tumors, lymphomas, and leukemias. This information is important for the reader in order to evaluate the long-term complications in relation to the treatment. The experience of Stanford and others would indicate that patients treated with chemotherapy or combined radiation therapy and chemotherapy suffer a higher incidence of second malignant neoplasms than patients treated with radiotherapy alone ( 1, 2, 6, 7, 18, 19). CONCLUSIONS The readers have the responsibility for resolving the dilemma due to conflicting reports in literature from major institutions which have differing experiences in treatment with whole-lung irradiation for large mediastinal mass. In order to do this, it is helpful for the reader to determine if there is evidence of bias. We do not have sufficient information from Tarbell et al. to determine whether bias is present in their selection of patients for WLI + RT, but the failure rate and com-
Table 2. Patients Stage I-IIIB treated with whole lung irradiation LMM UofM* Lung radiation therapy patients Pulmonary recurrence Pneumonitis
34 3 (9%) 3 (6%)
SMM
Total WLI
JTC*
U of M**
JTC
U of M***
JTC
22 3 (13%) 2 (9%)
11 1 (9%) 0
25 3 (12%) 4 (16%)
45 4 (8%) 2 (4%)
47 6 (13%) 6 (13%)
* U of M patients treated 1974- 1983. ** SMM patients at U of M all had hilar disease. *** Joint Center SMM patients hilar condition unknown. * JTC patients treated 1969-1984.
487
Dilemmas and Decisions 0 S. H. LEVITTAND C. K. K. LEE Hogkin’Disease s PSIA . IIIBwith Large
Hodgkin’s Disease PS IA - IIIBwith Large Mediastinal MassARerCurativeRadiotherapy Recurrence-Free SurvivalbyLow-Dose LungIrradiation
, n_ . ._ 0.8
(13)-
_o_ ---+--
(3)-
Mediastinal Mass and/or Hilar Disease
(0)
NoLungXRT(I&) LangXRT(1~34) P < om
I “.V
,
0
0.0 -
5b
GO Months
1;0
-1. 0
2;o
50
100
150
200
Months
Fig. 2.
Fig. I.
plication rate in these patients would lead us to believe it is. We also assume that the pulmonary complication rate is related to their technique. Our experience with RT + WLI for LMM + SMMH has indicated a significantly decreased incidence of recurrences both pulmonary and extrapulmonary, a significantly increased recurrence-free survival, and a minimal incidence of pneumonitis and an acceptable complication rate (Table 2). We have recently evaluated our results in overall survival (OS) and recurrence-free survival (RFS) in LMM, and we have found them equivalent to the results of others using chemotherapy or (combined modality treatment. A recent review of our Stage I-RIB LMM patients treated with WLI demonstrated a RFS of approximately 80% at IO years (Fig. 1 & 2). These results are equal to or better than the reports of CT or CMT (3,4). Unfortunately, the authors have not included in this article an analysis of survival of their LMM Ipatients treated by all of the modalities. However, a recent report from both Stanford and
the Joint Center cited a 79%, 7-year FFR for LMM patients treated with CMT (3). Despite the authors recommendations of chemotherapy rather than WLI for LMM, their best results in preventing recurrence were in patients who had RT + WLI + CT. The results in LMM patients treated with CT + RT were inferior to RT + WLI + CT and the pneumonitis rate was more than twice as high. We continue to recommend RT + WLI for patients with SMM plus hilar disease, and for patients with LMM. Based on our experience, we contend that our approach to RT + WLI is one which is therapeutically effective and which when appropriately delivered produces minimal pneumonitis and other acute complications, and diminishes the risk of the more serious complications of second malignant neoplasms found with the use of CT and adjuvant CT. To further improve results in patients with LMM, modifications of CT + RT similar to those recommended by Fuller et al. may be indicated (5).
REFERENCES 1. Boivin, J.-F.; Hutchison, G. B. Leukemia and other cancers
after radiotherapy and chemotherapy for Hodgkin’s disease. JNCI 67(4):751-759; 1981. 2. Boivin, J.-F.; O’Brien., K. Solid cancer risk after treatment of Hodgkin’s disease. Cancer 61:2541-2546; 1988. 3. Cmkovich, M. 3.; Leopold, K.; Hoppe, R. T.; Mauch, P. M. Stage I to IIB Hodgkin’s disease: the combined experience at Stanford University and the Joint Center for Radiation Therapy. J. Clin. Oncol. 5(7):1041-1049; 1987. 4. Ferrant, A.; Hamoir, V.; Binon, J.; Michaux, J-L.; Sokal, G. Combined modality therapy for mediastinal Hodgkin’s disease. Cancer 55:3 1’7-322; 1985. 5. Fuller, L. M.; Hagemeister, F. B.; North, L. B.; McLaughlin, P.; Velasquez, W. S.; Cabanillas, F. The adjuvant role of two cycles of MOPP and low-dose lung irradiation in stage IA through IIB Hodgkin’s disease: preliminary results. Int. J. Radiat. Oncol. Biol. Phys. 14683-692; 1988. 6. Henry-Amar, M. Seoond cancers after radiotherapy and
chemotherapy for early stages of Hodgkin’s disease. JNCI 71(5):91 l-916; 1983. Henry-Amar, M. Quantitative risk of second cancer in patients in first complete remission from early stages of Hodgkin’s disease, NC1 Monographs 6:65-72; 1988. Hoppe, R. T. The management of stage II Hodgkin’s disease with a large mediastinal mass: a prospective program emphasizing irradiation. Int. J. Radiat. Oncol. Biol. Phy. 11: 349-355; 1985. Kaplan, H. S. Complication of radiation therapy: respiratory system. Hodgkin’s Disease, Cambridge, Massachusetts: Harvard University Press; 1980:42 l-429. 10. Lee, C. K. K.; Aeppli, D. M.; Bloomfield, C. D.; Levitt, S. H. Hodgkin’s disease: a reassessment of prognostic factors following modification of radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 13:983-991; 1987. 11. Lee, C. K. K.; Bloomfield, D. C.; Goldman, A. I.; Levitt, S. H. Prognostic significance of mediastinal involvement in
488
12.
13.
14.
15.
16.
I. J. Radiation Oncology 0 Biology 0 Physics
Hodgkin’s disease treated with curative radiotherapy. Cancer 46:2403-2409; 1980. Lee, C. K. K.; Bloomfield, C. A.; Goldman, A. I.; Nesbit, M. E.; Levitt, S. H. The therapeutic utility of lung irradiation for Hodgkin’s disease patients with large mediastinal masses. Int. J. Radiat. Oncol. Biol. Phys. 7:151-154; 1981. Leslie, N. T.; Mauch, P. M.; Hellman, S. Stage IA to IIB supradiaphragmatic Hodgkin’s disease. Cancer 55:20722078; 1985. Levitt, S. H.; Lee, C. K. K.; Aeppli, D. M.; Bloomfield, C. D. Radical treatment of Hodgkin disease with radiation therapy: results of a 15-year clinical trial. Radiology 162: 623-630; 1987. Levitt, S. H.; Lee, C. K. K.; Aeppli, D. M.; Bloomfield, C. D. The role of radiation therapy in Hodgkin’s disease: Experience and controversy, in press. Levitt, S. H.; Lee, C. K. K.; Bloomfield, C. D. Radical radiation therapy in the treatment of laparotomy staged
February 1990, Volume 18, Number 2 Hodgkin’s disease patients. Int. J. Radiat. Oncol. Biol. Phys. 10:265-274; 1984. 17. Tarbell, N. J.; Thompson, L.; Mauch, P. Thoracic irradiation in Hodgkin’s disease: Disease control and long-term complications. Int. J. Radiat. Oncol. Biol. Phys., 1989. in press. 18. Tester, W. J.; Kinsella, T. J.; Wailer, B.; Makuch, R. W.; Kelley, R. A.; Glatstein, E.; DeVita, V. T. Second malignant neoplasms complicating Hodgkin’s disease: The National Cancer Institute Experience. J. Clin. Oncol. 2(7):762-769; 1984. 19. Tucker, M. A.; Coleman, C. N.; Cox, R. S.; Varghese, A.; Rosenberg, S. A. Risk of second cancers after treatment for Hodgkin’s disease. N. Engl. J. Med. 318(2):76-8 1; 1988. 20. Van Dyk, J. Magna-field irradiation: physical considerations. Int. J. Radiat. Oncol. Biol. Phys. 9:1913-1918; 1983. 21. Zelen, M. The reporting of clinical trials: counting easy. J. Clin. Oncol. 7(7):827-828; 1989.
is not
