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Radiation Therapy Can Still Be Used Safely in Combined Modality Approaches in Patients With Hodgkin's Lymphoma

Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Dallas, TX

In this issue of the Journal of Clinical Oncology, Heidenreich et al¹ provide important information that further quantifies the cardiovascular risks associated with wide-field, high-dose radiation that was once used in the management of Hodgkin's lymphoma. Their study suggests that Hodgkin's lymphoma survivors who were treated with older radiation techniques are at high risk for heart disease and may therefore benefit from screening for cardiovascular disease. However, it is important to note that the results of this study may not be extrapolated to modern-day radiation treatments. Clinical trials have indicated that modern-day radiation therapy can be delivered safely and offers significant advantages in preventing disease recurrence. Therefore, these data should not influence decisions to use radiation treatment in the combined modality treatment of Hodgkin's lymphoma. Unfortunately, it will take another generation of cured patients with Hodgkin's lymphoma treated with these current radiation techniques before reports on radiation-induced cardiac toxicities become part of a historical background.

The cardiovascular injury results presented in the Heidenreich et al¹ study needs to be understood in its appropriate historical context. The use of a radical approach of radiation therapy, which was pioneered in Stanford University in the 1960s by Henry Kaplan and Saul Rosenberg, offered patients with Hodgkin's lymphoma the first hope for cure.² To compensate for the lack of systemic treatment, which became available in the early 1970s, radiation therapy utilized large fields that treated the entire lymphatic system to relatively high radiation dosages. Oftentimes, the entire heart was included in a component of the radiation fields, and much higher biologic doses were delivered compared with contemporary treatment.

The cure rate of patients with Hodgkin's lymphoma was further increased after the addition of chemotherapy combinations like MOPP (mechlorethamine, vincristine, procarbazine, and prednisone).³ However, the toxicities from combining both modalities were significant. Many of the patients studied in the Heidenreich et al¹ report were treated in such a fashion. The realization of the high toxicity, including increased rates of cardiovascular injury and development of second malignancies, led to several randomized trials that shifted the practice of both medical and radiation oncologists. The toxic chemotherapy regimen, MOPP, was replaced by ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), which was found to be an equivalent, but less toxic, regimen. This was based on a study that compares six to eight cycles of MOPP with six to eight cycles of ABVD or to alternating ABVD and MOPP for 12 cylces.⁴

Radiation oncologists also began a series of studies aimed at minimizing the toxicity of radiation therapy treatment. German Hodgkin's Lymphoma Study Group (GHLSG) HD8 showed in a randomized trial that reducing the treatment volume from extended- to involved-field radiation therapy (IFRT), when combined with chemotherapy, is as effective as extended-field radiotherapy.⁵ Furthermore, the long-term results of the European Organisation for Research and Treatment of Cancer (EORTC) H7 trial also showed that in combined-modality treatment (CMT), IFRT could safely replace subtotal nodal radiation for patients with clinical stage I and II Hodgkin's lymphoma.⁶

The definition of IFRT remains unsettled. A recent publication by Girinsky et al⁷ suggested that fields that target only the involved lymph nodes, as defined by using modern imaging technologies, can be used to further reduce the field size of radiation from the current IFRT to involved-node radiation therapy. The authors based their suggestion on the fact that most of the recurrences occur in the original nodal sites. The later information was confirmed by Shahidi et al⁸ from Royal Marsden, who reported in a retrospective failure analysis of 61 patients with stage I and II Hodgkin's lymphoma treated without radiation that 83% of the recurrences developed in original sites of disease (45% as the only site).⁸

In addition to smaller radiation fields, the radiation dose used in modern-day therapy has also been reduced from 45 to 54 Gy to 30 Gy or even lower in the modern randomized trials. Koontz et al⁹ retrospectively compared CMT consisting of chemotherapy and low-dose IFRT (mean dose, 25.5 Gy) to definitive radiation with a mean dose of 37.9 Gy. The authors found the CMT to be equally effective in curing patients with early-stage Hodgkin's lymphoma (20-year overall survival, 83% for CMT v 70% for radiation alone) with fewer cardiac complications and second malignancies. The GHLSG HD10 again confirmed the safety of lowering the radiation dose. In this trial, 1,370 patients with favorable early-stage Hodgkin's lymphoma were randomly assigned to IFRT of 30 Gy or 20 Gy, and at their 4-year interim analysis, the freedom from treatment failure was similar.¹⁰

The data indicating equal efficacy when low-dose radiation is combined with chemotherapy are important because previous research concerning cardiac toxicities secondary to incidental radiation to the heart in patients with Hodgkin's lymphoma treated with radiation therapy have found that the risk is dependent on the total dose of radiation and the techniques used. In addition, the size of each individual fraction, the volume of the heart treated, relative weighting of radiation portals, method of blocking of the heart, the use of chemotherapy as well as the type of chemotherapy are also important. Finally, it is also essential to take into consideration patient factors including age, medical risk factors, and family history of heart diseases.

Hancock et al¹¹ published one of the first articles from Stanford University that concerned the risk of cardiac toxicities. This study analyzed 2,232 patients who received primary treatment for Hodgkin's lymphoma between 1960 and 1990.¹¹ The details of this article help to elucidate the difference between the early practices compared with ones in current use. A total of 1,609 patients in this study received mantle-field irradiation as part of their total nodal radiation therapy, whereas 369 received mediastinal irradiation, with the remaining patients not receiving mediastinal irradiation. Seventy-nine percent received doses of 40 Gy or more to the mediastinum, and most mantle fields were treated to more than 44 Gy. That daily fraction was 2.2 to 2.75 Gy before 1972, and anterior and posterior fields of radiation were treated on alternate days with minimal cardiac blockings until the mid- to late 1970s. The relative risk for cardiac death was 3.1 times that expected for the general population. Furthermore, the use of a heart block decreased the relative risk from 5.3 to 1.4. Most importantly, the patients who received a dose of less than 30 Gy had no increased risk. Using dosages of 30 Gy or less is now considered standard.

Others have also reported significant increases in the risk of ischemic heart disease with high-dose therapy. Glanzmann et al¹² reported on 352 patients treated with mantle radiation with a dose ranging from 30 to 45 Gy, with the majority of patients receiving a dose of 40 to 41 Gy. The risk was increased when a large volume of the heart was included in the radiation field and in patients with known risk factors.

Heidenreich et al^13,14 reported several times on cardiac toxicities using the same population of patients with Hodgkin's lymphoma treated with mantle irradiation at Stanford University between 1964 and 1994. In 2003, the authors reported on an increased risk of valvular disease (detected by echocardiography) in 294 patients who received mantle irradiation to mean dose of 43 Gy.¹³ In 2005, these authors reported high rates of diastolic dysfunction in the same population.¹⁴ In their current article, we see another aspect of cardiovascular adverse effects in this particular population of patients. This time the authors performed stress echocardiography, and radionuclide perfusion imaging with angiography if appropriate. After excluding all patients who were already diagnosed with heart diseases, signs of possible stress induced ischemia were identified in 18.4% of subjects (54 of 294). Coronary angiography performed on 40 patients showed coronary artery stenosis exceeding 50% in 22 patients and narrowing exceeding 70% in 16 patients. With a median follow-up of 6.5 years, 23 patients developed coronary events. The authors concluded that stress-induced testing can identify asymptomatic individuals at high risk for acute myocardial infarction and sudden death, especially in patients more than 10 years beyond mediastinal irradiation.

This study adds valuable information to the knowledge accumulated over the last 15 years on the risk of cardiac toxicity after mantle irradiation in patients with Hodgkin's lymphoma. It should encourage oncologists to perform the adequate screening to detect coronary artery diseases for surviving patients who received treatment for Hodgkin's lymphoma with these abandoned radiation techniques and doses.

The experience of cardiac injury associated with radiation treatments of Hodgkin's lymphoma parallels the experiences of radiation treatments for left-sided breast cancer. Initial techniques used in the 1960s and 1970s were associated with an increased risk of death as a result of cardiovascular disease. However, after this risk became appreciated and techniques for using radiation in breast cancer were changed, this increased risk was overcome. For example, a study that analyzed breast cancer data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program¹⁵ found that patients who received radiation in the 1970s (1973-1979) for a left-sided breast cancer had a significantly higher 15-year mortality from ischemic heart disease compared to those with right-sided disease, but this difference was not seen for patients treated in either the early or late 1980s.

One of the most difficult problems radiation oncologists face is educating patients and other oncology specialists that as radiation techniques evolve, previously described adverse effects associated with the treatment can be overcome. The high risk of cardiac toxicities from older eras of treatment should not discourage the use of modern-day radiation therapy. In the appropriate setting and with greatly revised techniques, the more recent randomized trials discussed in this editorial indicate that radiation should continue to play an important role in Hodgkin's lymphoma treatment.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Manuscript writing: Bouthaina S. Dabaja, James D. Cox, Thomas A. Buchholz

Final approval of manuscript: Bouthaina S. Dabaja, James D. Cox, Thomas A. Buchholz

REFERENCES

1. Heidenreich PA, Schnittger I, Strauss HW, et al. Screening for coronary artery disease after mediastinal irradiation for Hodgkin's disease. J Clin Oncol 25:43-49, 2007[Abstract/Free Full Text]

2. Kaplan HS: The radical radiotherapy of regionally localized Hodgkin's disease. Radiology 78:553-561, 1962[Medline]

3. Devita VT Jr, Serpick AA, Carbone PP: Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann Intern Med 73:881-895, 1970[Abstract/Free Full Text]

4. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478-1484, 1992[Abstract]

5. Engert A, Schiller P, Josting A, et al: Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: Results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 21:3601-3608, 2003[Abstract/Free Full Text]

6. Noordijk EM, Carde P, Dupouy N, et al: Combined-modality therapy for clinical stage I or II Hodgkin's lymphoma: Long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials. J Clin Oncol 24:3128-3135, 2006[Abstract/Free Full Text]

7. Girinsky T, van der Maazen R, Specht L, et al: Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: Concepts and guidelines. Radiother Oncol 79:270-277, 2006[CrossRef][Medline]

8. Shahidi M, Kamangari N, Ashley S, et al: Site of relapse after chemotherapy alone for stage I and II Hodgkin's disease. Radiother Oncol 78:1-5, 2006[CrossRef][Medline]

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10. Diehl V, Brillant C, Engert A, et al: Investigating reduction of combined modality treatment intensity in early stage Hodgkin's lymphoma: Interim analysis of a randomized trial of the German Hodgkin's Study Group (GHSG). J Clin Oncol 23:561s, 2005 (suppl; abstr 6506)

11. Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 270:1949-1955, 1993[Abstract/Free Full Text]

12. Glanzmann C, Huguenin P, Lutolf UM, et al: Cardiac lesions after mediastinal irradiation for Hodgkin's disease. Radiother Oncol 30:43-54, 1994[CrossRef][Medline]

13. Heidenreich PA, Hancock SL, Lee BK, et al: Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol 42:743-749, 2003[Abstract/Free Full Text]

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15. Giordano SH, Kuo YF, Freeman JL, et al: Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97:419-424, 2005[Abstract/Free Full Text]

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