The Role of Radiation in the Management of Hodgkin's Disease: An Update

Cancer Investigation, 17(1), 47-55 (1999)

RADIATION ONCOLOGY

The Role of Radiation in the Management of Hodgkin’s Disease: An Update

Nancy Price Mendenhall, M.D.

Department of Radiation Oncology University of Florida College of Medicine Gainesville, Florida

INTRODUCTION

Hodgkin’s disease (HD) was considered to be a uni- versally fatal malignancy in the first half of this century; currently, as many as 80% of all patients (and 90% of all children) diagnosed with HD will be 5-year survivors, and are likely to be cured (1). In about half of the patients with HD, diagnosis occurs between the ages of 15 and 30 years. Because HD is, for the most part, a disease of the young, most patients are cured and late effects of therapy are a reality. Two effective treatment modalities for HD are chemotherapy (CT) and radiation therapy (RT), which differ in efficacy as well as acute and late toxicity. Each treatment modality can be used alone or in combined modality therapy regimens (CMT), providing the clinician with many possible treatment options. Unlike most other malignancies, there also is a real possibility of salvage in the event of disease recurrence after initial treatment. There also are choices in staging procedures that are related to different treatment approaches. The clinician’s initial staging and treatment decisions should be based not only on what approach will achieve the best freedom from disease relapse, as in most other malignancies, but also on the endpoints of overall survival, cause specific survival, subsequent functionality and freedom from late effects of therapy, and cost. In early and inter-

Copyright 0 1999 by Marcel Dekker, Inc.

mediate stage HD, the goal of therapeutic investigation is to achieve a reduction in acute and late toxicity without compromising the excellent survival rate already achieved. In advanced and recurrent HD, the goals are to improve survival and to decrease treatment toxicity. Paradoxically, the remarkable therapeutic success in HD has increased the complexity of decision making for the physician. It is in this setting that we review the role of RT in the management of HD.

SOURCES OF FAILURE AND TOXICITY AFTER TREATMENT FOR HD

The patterns of failure and toxicity are different after treatment with RT than after treatment with CT. Over- whelmingly, the majority of failures after CT are in sites of previous involvement, particularly in nodal sites with bulky (>6 cm) involvement (2,3). In contrast, the majority of failures after RT are in contiguous unirradiated nodal sites (2).

All toxicities from RT are field-dependent, occurring only if that particular area is treated. The acute effects of RT are transient and include dysphagia, dermatitis, nau- sea, and occasionally bone marrow suppression, depending on RT dose and the volume of marrow treated.

41

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48 Mendenhall

The major potential subacute and late effects of RT are dose-related and may include the following:

1.

2.

3.

4.

5.

6.

7.

Thyroid dysfunction [in 25-50%, depending on dose] (4). Pneumonitis (10%) or pulmonary fibrosis (<I%), depending on dose and volume of lung (5-7). Salivary dysfunction, depending on age, dose, and volume treated. Pericarditis (< 1%) or coronary artery disease, depending on dose and volume of heart (8). Impaired musculoskeletal development in children, depending on dose and age (9,lO). Sterility after pelvic treatment (< 1 % in males and 30% in females), depending on other therapies and age (11-14). Second malignancies, possibly dependent on dose (15-19).

The probability of the major potential late effects of irradiation is clearly related to the dose of RT administered with the possible exception of second malignancies, in which the effect of RT dose and the contribution of other etiologic factors are not yet well understood. In addition, the severity of the late effect, when observed, is also related to the dose administered in some cases, such as musculoskeletal effects in children and salivary dysfunction. It is clear, then, that to eliminate most of the late effects of RT, one need not entirely eliminate RT, but simply reduce the dose.

Less is known about the late effects of CT, in part because most 20- to 30-year survivors of HD had early stage disease and were treated with RT alone. It would appear, however, that many of the major late toxicities of CT are also related to the dose of specific agents, including the following:

Cardiotoxicity related to doxorubicin dose (20,21). Pulmonary fibrosis related to bleomycin dose (22,23). Sterility related to the dose of alkylating agents

Leukemia related to the dose of alkylating agents

The probability of other CT toxicities, such as major infectious events, may increase with the number of exposures. As with RT, therefore, many of the significant sequelae of CT could be eliminated by reducing the dose or number of exposures to a particular agent, rather than eliminating it entirely from the treatment regimen.

The patterns of failure as well as the relationship between the probability of toxicity and dose of therapeutic

1. 2.

3.

4. (24-30).

(17,31-36).

agents suggest that in many clinical settings, CMT can potentially improve disease control and reduce toxicity, if the use of one agent in low doses allows the reduction of dose in another agent.

RADIOTHERAPY FIELDS

To understand the principles of radiotherapy fields and treatment volumes in HD, one must understand the con- cepts of “contiguous” nodal spread and “subclinical” disease. The patterns of involvement in early stage HD are not random throughout all nodal areas, but contiguous, involving adjacent lymphatic regions, implying spread of disease through the lymphatic channels. The first reports of cure in HD with radiotherapy followed treatment of not only the areas of involvement but also “complementary” fields that included the areas where disease tended to recur (37,38). In later staging studies, contiguous patterns of involvement were described, the presence of subclinical disease in clinically negative contiguous areas was documented, and standard fields of radiotherapy were defined to include not only the nodal region with obvious clinical involvement, but also the contiguous nodal regions at risk for subclinical disease and subsequent treatment failure (39,40). When RT is the sole treatment for HD, therefore, the RT fields include not only the involved nodal regions, but also elective fields covering contiguous nodal regions known to be at risk for subclinical disease. Standard RT field prescrip- tion also includes elective treatment of extranodal areas known to be at risk, if CT is not given for control of subclinical disease. These extranodal sites include the ip- silateral lung parenchyma in patients with bulky mediastinal disease (>6 cm) or hilar adenopathy and the liver in patients with spleen involvement.

The following is a list of terminology used to describe standard radiotherapy fields in HD.

Involved Field (IF)

IF is treatment of a standard field encompassing the area(s) of involvement without elective treatment of adjacent or next-echelon nodal areas. An example would be treatment of the entire right neck in a patient with one clinically involved right low neck node. IF does not refer to treatment of only the involved node.

Extended Field (EF)

EF refers to treatment of the standard field(s) encompassing all nodal regions with involvement plus elective

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Radiation in the Management of Hodgkin’s Disease 49

treatment of clinically negative contiguous nodal region(s). An example would be treatment of a standard right femoral node field and a right pelvic field in a patient with involvement of a solitary right femoral node. In a patient with a right low neck node and an axillary node, a mantle field would not constitute an EF, because not all of the contiguous nodes, which in this case include the upper abdominal nodes, are treated (40).

Mantle

The mantle is one of the most commonly used standard RT treatment fields. It includes both necks (upper border being the tragus), supraclavicular and infraclavic- ular fossae, axillae, the superior and inferior mediasti- num, and both hilae. When indicated, the mantle may be extended to include the entire cardiac silhouette, and one or both lungs.

Inverted Y Field

The inverted Y field includes femoral, inguinal, and pelvic nodal areas, as well as the paraaortic nodes. It may be extended to include the spleen.

Subtotal Nodal Irradiation (STNI)

STNI refers to treatment of the mantle, spleen (if present), and paraaortic fields. STNI constitutes an extended field in laparotomy stage I and I1 HD patients. If at laparotomy there is involvement of the spleen, but not the upper abdominal nodes, STNI would constitute treatment of an extended field, but if there is paraaortic node involvement, STNI would only constitute treatment of involved fields.

Total Nodal Irradiation (TNI)

TNI refers to treatment of all standard nodal fields in HD including mantle, spleen (if present), paraaortic, pelvic, and femoral fields. In stage I11 disease with upper abdominal nodal involvement, this constitutes an extended field; in stage I11 disease with pelvic and femoral node involvement, it constitutes only involved fields. Be- cause of the significant risk of subclinical disease in the upper abdomen in clinical stage I and I1 patients, TNI may in reality constitute an extended field in clinical stage I and I1 disease.

RT DOSE

The doses of RT required for disease control in HD are very modest compared with doses required for carci- noma and sarcoma. The volume of normal tissue that must be exposed in standard RT fields for HD, however, is substantial. There has been some debate over the opti- mal dose of RT in HD. In the early reports of radiotherapy cure in HD, doses of 35 Gy were used (38). A study from Stanford University, Stanford, CA, in the 1960s suggested that disease control could be improved with increasing doses of RT (41) and recommended doses of 40-44 Gy. A study from M.D. Anderson Cancer Center, Houston, TX, argued that the dose-response curve in HD was sigmoid rather than linear and disease control would not improve with doses greater than 30 Gy, but normal tissue complications would increase significantly with higher doses (42). Subsequent studies in the last decade failed to demonstrate evidence of increased disease control with doses in excess of 30 Gy (43-47); however, there is a substantial in-field recurrence rate in bulky tumors treated with RT alone. The standard doses used at the University of Florida are 35 Gy for clinically evident disease treated with RT alone and 30 Gy for subclinical disease. A higher rate of in-field disease control can be achieved in bulky tumors by adding adjuvant CT; whether higher doses of RT in bulky tumors would result in better in-field disease control is unclear.

In CMT, lower doses of RT have been used with excellent in-field disease control. At Stanford University, excellent results have been achieved in children with doses of 15-25 Gy for clinically evident disease in conjunction with six cycles of CT (10).

ROLES OF RADIOTHERAPY

The possible roles of RT in HD are outlined in Table 1, including the doses and treatment volumes typically used in given settings, the contribution of CT, and ex- pected outcome.

RT may be used alone or in conjunction with varying amounts of different CT regimens. If it is used alone, RT must treat clinically involved areas as well as all areas at risk for subclinical disease, and staging studies must identify or predict all areas of probable subclinical involvement.

In different CMT regimens, the role of RT may be eradication of all clinical and moderate risk subclinical disease, all clinical and high risk subclinical disease, all clinically evident disease, only bulky disease, or only dis-

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Tabl

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Rol

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r clin

ical

ly

invo

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; 30

Gy

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; 15

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25-7

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>50%

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PF

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, PR

: pa

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ease that has not responded completely to CT. In general, in CMT regimens, the more CT used, the less RT needed and vice versa. If RT is used, the dose of CT can probably be reduced; and if CT is used, the dose of RT can probably be reduced. It is important to clarify the goals of each modality in designing a combined treatment regimen, to ensure that the appropriate (minimum necessary) dose of each modality is given.

EARLY STAGE DISEASE

RT alone is considered the treatment of choice in adults with early stage HD. It has been compared with CT alone in two prospective randomized trials (2,48,49). In comparable patients with early stage disease (no large mediastinal adenopathy or other bulky disease, no B symptoms, pathologic stage I and IIA), disease control results for CT are similar to those for RT; however, there is less acute toxicity (2) and a higher suc- cessful salvage rate after recurrence (49), leading to a better ultimate survival rate with RT in adult early stage HD. If RT is used as the sole agent in HD, the standard treatment is extended fields, thus including not only all clinically evident disease, but also subclinical disease for success. In a patient with supradiaphragmatic, laparotomy stage I or IIA HD, the standard treatment would therefore be STNI using 35-36 Gy in clinically involved areas and 30 Gy in areas at risk for subclinical disease (50). In a clinical stage I or I1 patient, the extent of subclinical disease is somewhat uncertain, so an alternative is TNI (14). In special circumstances or in an IRB approved by the Institutional Review Board, one may elect not to treat extended fields, thus incurring a higher risk of treatment failure, to avoid RT exposure in a given area (51-54). Examples of this approach include IF for a stage IA lymphocyte-predominant upper neck or femoral node presentation or a mantle field only in a female with laparotomy stage I or IIA disease with a normal erythrocyte sedimentation rate, and no more than two sites of involvement with lymphocyte-predominant or nodular sclerosis histology.

In preadolescent children, doses historically used in HD patients treated with RT alone produce significant soft tissue sequelae; thus, treatment with RT alone in children is reserved for the rare patient with localized lymphocyte-predominant disease who is treated with only an IF, or the musculoskeletally mature (Tanner stage IV/V) teenager. Most children with early stage HD are treated with two to four cycles of CT with reduced doses of RT (15-25 Gy) or six cycles of CT.

INTERMEDIATE RISK HD

Intermediate risk HD includes stage I and I1 with poor prognostic factors (more than three sites of involvement, B symptoms, and bulky disease >6 cm, including large mediastinal adenopathy) and early stage 111 disease. These patients are candidates for single modality therapy with RT alone or CT alone or CMT with minimal or full dose CT. Most institutions prefer CMT for these patients, because of the lower relapse rate.

RT Alone

RT alone may be used in intermediate risk HD without apparent loss of survival in retrospective series (18), but there is a relatively high rate of relapse approaching 50% in some subsets. In stage I11 disease, several series have identified prognostic factors that are useful in selecting patients for treatment with RT; these include the absence of B symptoms, minimal or no spleen involvement, disease confined to the upper abdomen without pelvic or femoral node involvement, and fewer than five sites of involvement (55-58). Given the high relapse rate with RT alone in these patients, the use of RT alone should be justified by avoidance of specific complications antici- pated with CT.

CMT with Adjuvant CT and Standard RT

In CMT for intermediate risk HD, a minimal amount of CT (two to three cycles) may be used as an adjuvant to RT with the goal of improving the disease control or toxicity achieved with RT alone. In this case, the role of RT is still to control all sites at risk for subclinical disease and clinically evident disease. The full dose of RT is given, and the treatment volume is EF. This approach, with two to three cycles of CT followed by STNI or TNI, has been used extensively in adults with intermediate risk HD at several institutions (1859-61) with excellent results-better than those achieved historically with single modality therapy and comparable to results achieved with CMT regimens using more CT. There appears to be no significant additional toxicity with the exception of an increased risk of male infertility when two cycles of mechlorethamine, vincristine, procarbazine, prednisone (MOPP) were used. An additional advantage of this approach is that the tumor shrinkage achieved with CT in patients with bulky mediastinal adenopathy permits significant reductions in the amount of normal pulmonary

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52 Mendenhall

tissue exposed to full dose irradiation, which should result in decreased acute and late pulmonary toxicity. This approach is appropriate for adults with intermediate risk HD, including stage I and I1 with bulky disease (>6 cm), B symptoms, or four or more sites of involvement (1839). Stage 111 candidates for this approach include all those without pelvic or femoral node involvement, but the best results were achieved in patients with only upper abdominal involvement without B symptoms or large mediastinal disease (60).

CMT with CT and Consolidative RT

A second role of RT in CMT is to control all sites of clinically evident disease, whereas CT is used for control of areas at risk for subclinical disease. This approach has the potential for greater disease control than what would be achieved with CT because it reduces failures in sites of known involvement, and has the potential for less toxicity by reducing the CT dose for control of clinically evident disease to a CT dose sufficient for control of subclinical disease. An example would be the use of four to six cycles of CT in conjunction with RT delivered to all involved fields. This approach has been used in early and intermediate stage HD in the Pediatric Oncology Group, with the delivery of 4 months of MOPP/doxorubicine, bleomycine, vinblastine, dacarbazine (ABVD), or doxorubicine, bleomycine, vinblastine, etoposide (ABVE) in conjunction with 25.5 Gy to involved fields; the doses of RT and CT were both reduced by one-third from what would be used with either modality alone. It is hoped that there will be a significant reduction in toxicity with this approach.

ADVANCED DISEASE

Patients with advanced HD are treated with CT or CMT. Retrospective experiences from several institutions including Memorial Sloan-Kettering Cancer Center, New York, NY (62) and the University of Florida (63) demonstrated that disease control and survival rates are better in patients with advanced disease treated with CMT using RT in all sites of clinical involvement than in concurrent patients treated with CT alone. Although the patterns of relapse after CT alone suggest that consolidative radiotherapy to sites of involvement should decrease recurrences and thus improve survival, the prospective randomized trials testing the role of radiotherapy in advanced disease have not conclusively proven the

benefit of RT. These trials have been difficult to interpret, however; in the most recently reported trial from the Southwest Oncology Group (SWOG) (64), it appears that relapses are reduced with the addition of RT, and there may be survival benefits in subsets of patients with nodular sclerosis histology, but not in the overall group. Com- pliance with RT guidelines in this trial was problematic; many patients randomized to receive RT either did not receive RT or had major field violations that may have confounded interpretation of the results. At the Univer- sity of Florida, we recommend consolidative RT to all sites of involvement after six cycles of CT in patients with advanced disease (IIIB and IV). When the bone marrow is involved, it is not treated, but all other involved nodal or extranodal sites are, including cortical bone me- tastases, the liver, and the lung.

Another role of RT in CMT is as an adjuvant to aid in control of sites of bulky disease or partial response to dose-intense CT in advanced disease. This approach is currently being tested at Stanford University (65).

RECURRENT DISEASE

The treatment for recurrent disease must be individu- alized, based on the patient’s sites of recurrent and previous disease, all previous therapy, and the likelihood of tolerance of the salvage treatment. Patients who have limited recurrences after initial radiotherapy alone have an excellent chance of survival. The best approach appears to be CMT, with six cycles of a doxorubicin-containing CT regimen and RT given to all involved areas not previously irradiated (66-69).

In patients with recurrent disease after CT alone, with recurrence limited to nodal sites, excellent results have been achieved with aggressive RT (70-73). It is impera- tive that RT be delivered to all sites (nodal and extranodal) at risk for subclinical disease as well as all involved sites, if this approach is to be effective.

In patients with extensive or extranodal sites of involvement at recurrence after CT alone or in patients with recurrence after CMT in an area previously irradiated, standard CT for salvage has yielded very disap- pointing results: at best, 20% survival at 5 years. These patients are considered candidates for high-dose therapy with stem cell rescue at most institutions; preliminary results with transplant approaches are promising, but long- term data are necessary to determine the long-term success rates of these approaches.

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SUMMARY of testicular function following radiation therapy for early-stage Hodgkin’s disease. J Clin Oncol 7:718-724, 1989. Pedrick TJ, Hoppe RT: Recovery of spermatogenesis following pelvic irradiation for Hodgkin’s disease. Int J Radiat Oncol Biol

Mendenhall NP, Taylor BW Jr, Marcus RB Jr, et al: The impact of pelvic recurrence and elective pelvic irradiation on survival and treatment morbidity in early-stage Hodgkin’s disease. Int J Radiat Oncol Biol Phys 21:1157-1165, 1991. Hancock SL, Tucker MA, Hoppe RT: Breast cancer after treatment of Hodgkin’s disease. J Natl Cancer Inst 85(1):25-31, 1993. Van Leeuwen FE, Klokman WJ, Hagenbeek A, et al: Second cancer risk following Hodgkin’s disease: A 20-year follow-up study. J Clin Oncol 12(2):312-325, 1994. Biti G, Cellai E, Magrini SM, et al: Second solid tumors and leukemia after treatment for Hodgkin’s disease: An analysis of 1121 patients from a single institution. Int J Radiat Oncol Biol Phys

Mendenhall NP, Cantor AB, Barre DM, et al: The role of prognostic factors in treatment selection for early-stage Hodgkin’s disease. Am J Clin Oncol 17(3):189-195, 1994. Bhatia S, Robison LL, Oberlin 0, et al: Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N Engl J Med 334(12):745-751, 1996. Kreuser ED, Voller H, BeNes C, et al: Evaluation of late cardiotoxicity with pulsed Doppler echocardiography in patients treated for Hodgkin’s disease. Br J Haematol 84(4):615-622, 1993. Lipshultz SE, Lipsitz SR, Mone SM, et al: Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer, N Engl J Med 332(26):1738-1743, 1995. Brice P, Tredaniel J, Monsuez JJ, et al: Cardiopulmonary toxicity after three courses of ABVD and mediastinal irradiation in favor- able Hodgkin’s disease. Ann Oncol 2 (Suppl 2):73-76, 1991. Cosset J, Henry-Amar M, Crade T, et al: Increased pulmonary toxicity in the ABVD arm of the EORTC H6-U trial. Proc Annu Meet Am Soc Clin Oncol 8(985):253, 1989 (abstract). Bokemeyer C, Schmoll H, van Rhee J, et al: Long-term gonadal toxicity after therapy for Hodgkin’s and non-Hodgkin’s lym- phoma. Ann Hematol 68(3):105-110, 1994. Dhabhar BN, Malhotra H, Joseph R, et al: Gonadal function in prepubertal boys following treatment for Hodgkin’s disease. Am J Pediatr Hematol Oncol 15(3):306-310, 1993. DaCunha MF, Meistrich ML, Fuller LM, et al: Recovery of spermatogenesis after treatment for Hodgkin’s disease: Limiting dose of MOPP Chemotherapy. J Clin Oncol 2(6):571-577. 1984. DeLena M, Ditonno P, Lorusso V, et al: Bulky mediastinal Hodg- kin’s disease: Results of a combined modality approach (ABVDI MOPP alternating chemotherapy plus radiation therapy). Haema- tologica 78(4):230-235, 1993. Charak BS, Gupta R, Mandrekar P, et al: Testicular dysfunction after cyclophosphamide-vincristine-prccarbazine-predniso- lone chemotherapy for advanced Hodgkin’s disease. A long-term follow-up study. Cancer 65(9): 1903-1906, 1990. Shafford E, Kingston JE, Malpas JS, et al: Testicular function following the treatment of Hodgkin’s disease in childhood. Br J Cancer 68(6):1199-1204, 1993. Viviani S , Santoro A, Ragni G, et al: Gonadal toxicity after combination chemotherapy for Hodgkin’s disease. Comparative re-

Phys 12(1):117-121, 1986.

29(1):25-31, 1994.

RT is the most effective single agent in HD, and it has many roles in the management of this disease. These roles include RT as the sole curative agent in early stage HD in adults and in limited nodal recurrences in patients previously treated with CT alone; RT as the primary treatment for clinical and subclinical disease in CMT regimens using minimal adjuvant CT; RT as an integral part of standard and high-dose CMT regimens used to consol- idate CT responses in all sites of clinical involvement; and RT as an adjuvant to CT for areas of bulky disease or incomplete CT response. Its effectiveness depends on the clinical expertise of the treating physician, the ade- quacy of the staging studies, and the accuracy of the treatment technique.

Address correspondence to: Dr. Nancy Price Mendenhall, Department of Radiation Oncology, University of Florida Health Science Center, P.O. Box 100385,2000 SW Archer Road, Gainesville FL 32610-0385.

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Documents

The Role of Radiation in the Management of Hodgkin's Disease: An Update