32 Radiotherapy for Hodgkin’s Disease
Chung K. K. Lee
Chung K.K. Lee, MD
University of Minnesota Medical School, MMC494, 420 Delaware St.S.E., Minneapolis, MN 55455, USA
Improved understanding of the biological mecha- nisms of Hodgkin’s disease, along with advances in staging and treatment, have made it one of the most successfully treated malignancies. This chap- ter focuses on the role of radiotherapy in the treat- ment of Hodgkin’s disease, particularly on modern radiation therapy techniques used in conjunction with combination chemotherapy in the treatment of early and advanced disease. Of emphasis is the need to individualize treatment to achieve optimal out- comes while minimizing long-term complications.
32.1
Diagnostic Evaluation and Staging
Critical for the successful treatment of Hodgkin’s disease is a careful evaluation of prognostic factors predictive of the ultimate outcome of the disease – factors such as disease stage, histopathology, per- formance status, bulk of disease, number and loca- tion of involved sites (including extra nodal sites), as well as age and gender of the patient.
A diagnostic work-up begins with a complete physical examination including documentation of any B symptoms (e.g., fever, night sweats, >10%
weight loss during previous 6 months) and other symptoms such as pruritus intolerance, fatigue, respiratory problems, and alcohol intolerance.
Evaluation of all nodal sites, including tonsillar and other lymphoid tissue-containing sites, is manda- tory. For patients who may need radiation therapy that includes the oral cavity, it is essential to have a pre-radiation evaluation of the teeth and complete oral cavity by a dentist. After a physical examina- tion, laboratory assessment is necessary and should include a complete differential blood count, eryth- rocyte sedimentation rate (ESR), serum electrolytes, liver and renal function tests, serum alkaline phos- phatase, and beta2-lactate dehydrogenase. Other optional blood tests that may be useful include serum copper, microglobulin, and various cell sur-
CONTENTS
32.1 Diagnostic Evaluation and Staging 805 32.2 Histopathological Classification 808 32.3 General Treatment Considerations 809
32.3.1 Treatment of Stage-I and -II Favorable Disease 809 32.3.2 Special Considerations for LMM 811
32.3.3 Delivery and Dose of CMT 811 32.3.4 Advanced Stage Hodgkin’s Disease 812 32.4 Radiation Therapy Techniques 814 32.4.1 Mantle Fields 815
32.4.2 Simulation of Mantle Field 815 32.4.2.1 Anterior Fields 818
32.4.2.2 Posterior Fields 819 32.4.3 Design Shielding 820 32.4.4 Subdiaphragmatic Fields 823
32.4.5 Preauricular and Waldeyer’s Ring Fields 823 32.4.6 Gap of Matching Fields 824
32.5 Limited Field (Involved Field/Regional Field) 824 32.6 Limited Field Above the Diaphragm 826 32.6.1 Cervical/Supraclavicular Region 826
32.6.1.1 Unilateral Cervical/Supraclavicular Region 826 32.6.1.2 Bilateral Cervical/Supraclavicular Region 827 32.6.2 Mediastinum/Hilar/Axillary Region 827
32.7 Limited/Regional Field Below the Diaphragm 828 32.7.1 Inguinal/Femoral/External Iliac
Lymph Node Area 828 32.7.2 Paraaortic Lymph Nodes 828 32.7.3 Spleen 829
32.8 Radiation Dose and Fractionation 829 32.8.1 Radiation Therapy Alone 829 32.8.2 Radiation Dose in CMT 829
32.8.3 Radiation Dose in Salvage Treatment 830 32.9 Normal Tissue Tolerance and Complications 830 32.9.1 Lung 830
32.9.2 Heart 830
32.9.3 Central Nervous System 830 32.9.4 Thyroid 831
32.9.5 Liver 831
32.9.6 Gastrointestinal Tract 831 32.9.7 Head and Neck 831 32.9.8 Reproductive Organs 831 32.9.9 Secondary Neoplasms 831 References 832
806 C. K. K. Lee
face cytogenetic analyses (Friedman et al. 1988;
Ray et al. 1973; Tubiana et al. 1984; Agnarsson and Kadin 1989).
To identify the extent of the disease, radiologi- cal studies are essential and should include a chest X-ray and computed tomography (CT) scans of the chest, abdomen, and pelvis. Magnetic resonance imaging (MRI) and positron emission tomography (PET) should be done as needed. PET-CT is a new tool to identify the active disease.
Over 60% of Hodgkin’s disease patients present with initial radiographic evidence of intrathoracic disease. Because of the ability of CT scans to detect small, unsuspected masses, determine the full extent of large masses, and detect involvement of the lung parenchyma, it is most often the test of choice (Castellino et al. 1986; Rostock et al. 1983). Eval- uation of the extent of mediastinal disease is nec- essary to quantify the potential for intrathoracic relapse; a greater risk of relapse, particularly in the intrathoracic area and transnodal sites, is seen in patients with large mediastinal masses (LMMs).
Several definitions are used to define a LMM. At the University of Minnesota, a large mass is defined as a mass with an MT ratio greater than 0.35. The MT ratio is defined as the largest transverse diameter of the mediastinal mass divided by the transverse diameter of the thorax at the level of T5-6 (Lee et al. 1980) (Fig. 32.1). Other institutions define a LMM as a mass whose greatest diameter is greater than one-third of the largest diameter of the thorax at the diaphragm on an upright posteroanterior chest radiograph (Mauch et al. 1988) or a mass 5–10 cm in size using the transverse diameter of the mass.
Despite improvements in diagnosis with inclu- sion of CT scans, detection of occult abdominal and pelvic disease remains challenging. Imaging stud- ies show a false-negative rate of 20–25% in detec- tion of occult disease in these areas. This is largely due to the difficulty of detecting occult disease in the spleen (Leibenhaut et al. 1989; Mauch et al.
1990). Available radiological studies that result in a much better yield in the detection of intra-abdomi- nal disease are MRI, PET, gallium scans combined with single photon-emission computed tomography (SPECT), and bipedal lymphangiography (Ng et al.
2002). The role of these ancillary tests is still under investigation. Some evidence suggests that gallium scans, particularly when combined with SPECT, are useful in assessing residual masses (Front and Israel 1995). Other studies suggest a continued role for bipedal lymphangiography to assess lymph node size and internal architecture, despite the increas-
ingly less frequent use of this procedure due to the diminishing skill of physicians in performing and interpreting the results of this test (Castellino et al. 1984). All of these imaging methods, however, remain limited in their ability to accurately identify occult abdominal disease. Whole-body PET using 18F-fluorodeoxy-glucose (FDG-PET) is a new imag- ing method currently under investigation and has shown some promise in improving overall diagnos- tic accuracy (Ng et al. 2002; Hueltenschmidt et al.
2001). It may also aid in evaluating response after systemic treatment in patients with a positive PET scan prior to treatment (de Wit et al. 2001; Spaepen et al. 2001; Schoder et al. 2001).
Although surgical staging with laparotomy and splenectomy was once relied on to provide the most precise way to determine abdominal involvement , this procedure is no longer used in most parts of the world because it does not greatly impact the eventual treatment strategy and involves an invasive procedure with possible morbidity in patients treated with combined modality. Surgi- cal staging may still play a role in selecting patients for treatment if the patient is to be treated with radi- ation therapy alone (Ng et al. 2002). Traditional his- torical surgical staging includes inspection, palpa- tion, and biopsy of nodes in the abdomen and pelvis;
wedge and needle biopsy of the liver; and the place-
Fig. 32.1. The MT ratio (largest transverse diameter of the medi- astinal mass divided by the transverse diameter of the thorax at the level of T5-6) is determined by measuring the mediastinal on the posteroanterior (PA) chest fi lm (Defi nition used at the University of Minnesota). (From Lee et al. 1980. Copyright © (1980) American Cancer Society. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)
ment of splenic pedicle clips. Premenopausal women also usually undergo a bilateral midline oophoro- pexy in anticipation of pelvic irradiation.
The use of staging laparotomy in Hodgkin’s dis- ease has resulted in a better understanding of the natural evolution of the disease. The disease appears to spread contiguously to adjacent lymph nodes first.
There is frequent extension to the spleen during the early course of the disease before it spreads to other visceral organs such as the liver. In 20–30% of clini- cal stage IA–IIA patients and 35% of IB–IIB patients, occult splenic or upper abdominal disease may be identified at staging laparotomy that is not detected on presurgical clinical staging studies (Leibenhaut et al. 1989; Mauch et al. 1990; Castellino et al.
1984; Front and Israel 1995; Brada et al. 1986;
Rutherford et al. 1980; Aragon de la Cruz et al. 1989). By removing the spleen during staging laparotomy, the volume of irradiation is reduced significantly and radiation to the left kidney can be avoided. In patients with negative laparotomy and other favorable prognostic factors, the radiation field can be confined to above the diaphragm (Tubiana et al. 1989; Haybittle et al. 1985; Sutcliff et al.
1985; Madelli et al. 1986; Mauch et al. 1995a).
Staging laparotomy has allowed for the selection of early-stage patients who could be treated with radia- tion alone and has helped identify the selective crite- ria for determining the low incidence of abdominal disease. These criteria include clinical stage-IA and -IIA female patients, patients younger than 26 years of age, and clinical stage-IA male patients with lym- phocyte predominance (LP) histology.
Staging laparotomy is associated with potential morbidity and mortality. Small-bowel obstruc- tion, development of wound or subdiaphragmatic abscess, and postoperative bleeding are the major complications but are as low as 3% (Tayor et al.
1985). Following splenectomy, patients are also at increased risk for infection with encapsulated bacte- ria (Molrine et al. 1995; Siber et al. 1986). Vaccina- tions against pneumococcus and meningococcus or prophylactic antibiotics should be used to decrease risk. An approximate twofold increased risk of leu- kemia following splenectomy has been reported in some studies, especially in patients who received chemotherapy following splenectomy (van der Velden et al. 1988). However, the mechanisms for this finding are poorly understood, and the increase is not recognized by all observers.
Table 32.1 summarizes the procedures recom- mended for proper work-up and staging of Hodg- kin’s disease.
Table 32.1. Diagnostic and staging procedure Mandatory
– Biopsy of any mass or lymph nodes History
– Age and gender
– Evaluation of systemic B symptoms
• Unexplained fever • Night sweats
• Weight loss >10% body weight in last 6 months – Other symptoms
• Alcohol intolerance
• Pruritus
• Respiratory problems
• Easily fatigued Physical examination
– Lymphadenopathy (note number, size, location, shape, consistency, and mobility of nodes)
– Palpable liver, spleen, and other masses Laboratory studies
– Standard
• Complete blood count including platelet counts
• Liver and renal function
• Blood chemistry
• Erythrocyte sedimentation rate – Optional
• Serum copper
• β2 microglobulin Radiographic
• Standard
Chest radiograph: posteroanterior and lateral
Thoracic, abdominal and pelvic computerized tomography
• Optional
Bipedal lymphogram
Gallium scan-67 (with high-dose SPECT) Technicium-99 bone scan
Magnetic resonance imaging Positron emission tomography scan Echo-cardiography
Special tests
– Pulmonary function test – Cardiac function test – Immunophenotyping – Molecular genetic analysis
– Morphological and immunophenotype features – Cytological examination of effusions, if present
– Bone marrow, needle biopsy (especially subdiaphragmatic disease of B symptoms)
– Optional
• Percutaneous or computed tomography-guided liver biopsy
• Peritoneoscopy
• Staging laparotomy with splenectomy, liver biopsy, selected lymph node biopsies, and open bone marrow biopsy
In 1971, the Ann Arbor classification for Hodg-
kin’s disease was established (Carbone et al. 1971)
(Table 32.2). This staging system was used for over
808 C. K. K. Lee
two decades for both clinical and pathological stag- ing of Hodgkin’s and non-Hodgkin’s lymphoma.
However, inadequacies of the Ann Arbor staging system, including failure to account for bulk and extent of disease and to precisely define extralym- phatic involvement, led to a modified classification system proposed at a 1989 international meeting at Cotswolds, England. The new classification relied on anatomic regions based on the knowledge that Hodgkin’s disease spreads along the lymphatic channel in an orderly fashion (Fig. 32. 2). The modi- fications incorporated some important prognostic factors, such as bulk of disease and a more precise definition of extralymphatic involvement (Lister et al. 1989) (Table 32.3).
32.2
Histopathological Classification
Histopathological classification of Hodgkin’s dis- ease includes four histological subtypes as defined by the Rye modification of the Lukes and Butler system: (1) LP, (2) nodular sclerosis (NS), (3) mixed cellularity (MC), and (4) lymphocyte depletion (LD) Hodgkin’s disease (Lukes and Butler 1966).
LP Hodgkin’s disease comprises 5–10% of all Hodgkin’s disease and is often localized to a single peripheral nodal region. Only 8% of these patients have mediastinal and abdominal involvement in early-stage disease (Mauch et al. 1993). This sub- type is found most often in male patients younger than 15 years of age or older than 40 years. It con- tains an abundance of benign-appearing cells and frequent variant lymphocytic and histiocytic cells with multilobulated nuclei (popcorn cells). Some
Table 32.2. Hodgkin’s disease staging classification Stage Definition
I Involvement of a single lymph node region (I) or of a single extralymphatic organ (IE)
II Involvement of two or more lymphatic regions on the same side of the diaphragm (II), or localized extralymphatic involvement as well as involvement of one or more regional lymphatic sites on the same side of the diaphragm III Involvement of lymphatic regions on both sides of the diaphragm (III); such involvement may include splenic involve-
ment (IIIS), localized extra lymphatic disease (IIIE), or both (IIISE)
IV Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without nodal involve- ment. The absence or presence of unexplained fever, night sweats, or loss of 10% or more of body weight in the 6 months preceding diagnosis are designated by the suffix letters A or B, respectively. Biopsy-proven involvement of extralymphatic sites is designated by letter suffixes: bone marrow M+; lung L+; liver H+; pleura P+; bone O+; skin and subcutaneous tissue D+
a Adopted at the workshop on the staging of Hodgkin’s disease held at Ann Arbor, MI in April, 1971 (reprinted with permis- sion from Carbone et al. 1971)
investigators have proposed classifying nodular LP histology as a separate clinically and histologically distinct entity (Mason et al. 1994).
Nodular sclerosis Hodgkin’s disease is the most common histology and accounts for 40–60% of all cases. It usually affects patients between the age of 15 years and 40 years, and affects males and females equally. It presents with central nodal regional involvement in 80–90% of cases (Lukes and Butler 1966).
Fig. 32.2. Clinical lymphoid regions, as defi ned by the Ann Arbor Staging System
About 25% of Hodgkin’s disease cases have MC histology. Patients with MC Hodgkin’s disease are older and more likely to present with systemic symptoms and advanced stages. Both malignant Reed-Sternberg cells and pleomorphic variant cells in an inflammatory background are seen more com- monly in this histology (Lukes 1971).
Only 5% of Hodgkin’s disease patients have LD his- tology. Generally, these patients have advanced dis- ease with systemic symptoms (Neiman et al. 1973).
In addition to the above four major subtypes of histopathology, interfollicular Hodgkin’s dis- ease presents with an uncommon pattern of focal involvement of a lymph node in the interfollicular zone. It may be easily confused with reactive hyper- plasia (Doggett et al. 1983).
32.3
General Treatment Considerations
The goal of radiotherapy in treating Hodgkin’s disease is to treat all of the involved and potentially involved lymphatic chains with an adequate irradiation dose to increase the potential for tumor eradication while minimizing long-term treatment-related morbidity.
With increasing reliance on combined chemotherapy regimens to treat early as well as advanced disease, the role of radiation therapy has evolved from a single modality mainstay of treatment for early disease to its current role as combination therapy with chemo- therapy regimens. Use of radiation alone is currently reserved largely for patients who wish to avoid che- motherapy and a special category of patient with low risk factors as described previously. (Ng et al. 2002).
The current controversies surrounding radiotherapy in the treatment of Hodgkin’s disease are determi- nation of optimal radiation field size (involved or extended field?) and radiation dose (Ng et al. 2002).
32.3.1
Treatment of Stage-I and -II Favorable Disease
Radiation therapy alone. Although not commonly practiced, radiation alone, either by mantle field or subtotal nodal field plus splenic irradiation (STNI), can be used to treat stage-I and -II patients without the following features: LMM with or without hilar disease, bulky disease, systemic symptoms, four or more sites of involvement, advanced age (defined as older than 40 years), elevated ESR, male gender, and MC or LD histologies (Friedman et al. 1988;
Mauch et al. 1988; Somers et al. 1989; Crnkovich et al. 1987; Specht and Nissen 1988; Lee et al. 1990;
Henry -Amar et al. 1991; Tubiana et al. 1982; Hoppe et al. 1982b).
Historical data suggest that patients with patho- logical stage-IA and -IIA disease who were treated with sequential mantle and para-aortic fields or the mantle alone had an expected 10-year free-from- failure rate of 75–80% (Lee et al. 1990; Mauch et al.
1988; Hoppe et al. 1982a).
Most relapses occur within the first 3 years after radiation therapy, although up to 10% of patients relapse after 3 years. Prolonged late relapses beyond 5–10 years are uncommon. Following STNI, there is recurrence in the pelvis and inguinal femoral nodal region in 5–15% of patients.
In the past, the standard approach of most cen- ters in the United States was to require pathological staging of Hodgkin’s disease prior to recommend- ing radiation therapy alone. However, Canadian and European studies have shown excellent overall survival for patients who were selected for radiation therapy alone based on clinical staging. Therefore, clinically staged patients with favorable prognostic factors may be treated with radiation therapy alone.
The following subgroups have less than 10% risk of infradiaphragmatic involvement: clinical stage- IA females (6%), patients with involvement of the
Table 32.3. Cotswold modifications to Ann Arbor Staging Classification
I Suffix “X” to designate bulky disease as >1/3 widening of the mediastinum or >10 cm maximum dimension of nodal mass
II The number of anatomical regions involved should be indicated by a subscript (e.g., II3) III Stage III may be subdivided into:
III1: with or without splenic, hilar, celiac, or portal nodes III2: with para-aortic, iliac, mesenteric nodes
IV Staging should be identified as clinical stage (CS) or pathological stage (PS)
V A new category of response to therapy, unconfirmed/uncertain complete response (CR(U)) can be introduced because of the persistent radiological abnormalities of uncertain significance
(From CA-A Cancer Journal for Clinicians, Anonymous 1993)
810 C. K. K. Lee
mediastinum alone (0)%, stage-I males with LP his- tology (4%), and young (<27 years of age) females with limited (fewer than four supradiaphragmatic sites) stage-II disease (9%) (Specht and Nissen 1988). These patients may be treated effectively with a supradiaphragmatic field only. At the University of Minnesota Hospital, patients with clinical stage-I and -II disease with favorable features are selected for treatment with radiation therapy alone with- out staging laparotomy. Data from the European Organization for Research and Treatment of Cancer (EORTC) support the efficacy of this strategy. Treat- ing extended or total nodal field has become an almost historical approach. It is important however to know the evolution of the treatment approach.
Influence of pathological and clinical staging on the outcome of stage-I and -II Hodgkin’s patients following radiotherapy has been studied by the EORTC lymphoma cooperative group. Both groups of patients were treated with STNI with spleen included in clinical stage patients. At 10 years, there was no statistical difference in recurrence-free sur- vival (clinical stage 68% versus pathological stage 73%); however, a higher number of patients with positive findings at laparotomy relapsed compared with those with negative laparotomy (56% versus 83%, respectively) (Friedman et al. 1988).
Randomized trials conducted to define the proper fields for early-stage Hodgkin’s disease show better relapse-free survival for patients treated with extended field than for those treated with involved field irradiation (Rosenberg and Kaplan 1966;
Kaplan 1980). Results of mantle or limited field irradiation alone in early-stage Hodgkin’s disease have been disappointing with an increasing risk of relapse in the abdomen, except in patients who pres- ent with very favorable features (Specht and Nissen 1988).
Treatment for stage-I and -II infradiaphragmatic Hodgkin’s disease is less well studied than for supra- diaphragmatic disease. The prognosis of patients with clinical para-aortic lymph node involvement (stage II) is probably worse than those with a single site of peripheral nodal disease (stage I). The former patients are likely to have more disease in another site in the abdomen or have B-symptoms, or MC or LD histology. Staging laparotomy should be done if radiation therapy alone is carried out. Pathological stage-IA patients can be treated with radiation using an inverted-Y field only.
Radiation treatment alone using extended fields includes sequential mantle and para-aortic irra- diation, including the spleen if it is not removed
(STNI). The mantle field includes the cervical, axil- lary, infraclavicular, mediastinal, and hilar lymph node regions. Most of the lungs and part of the heart (mainly the left ventricles) are shielded in the mantle field. The infradiaphragmatic field includes the abdominal nodes and spleen. A 4-week break is usually given between the mantle and infradia- phragmatic treatment. Since clinical stage-I and -II disease may be associated with a 25% risk of occult abdominal involvement, the infradiaphragmatic field is treated prophylactically except in the very favorable group who have a less than 10% incidence of occult infradiaphragmatic involvement.
Combined modality therapy. Currently com- bined modality therapy (CMT) is the main treat- ment approach for most Hodgkin’s disease patients. Management of most patients with favor- able stage-I and -II disease will be based on clini- cal staging, CMT, and chemotherapy regimens that are less toxic. Several randomized trials show improved free-from-failure survival rates with the use of CMT in favorable early-stage Hodgkin’s patients (Zittoun et al. 1985; Cosset et al. 1992;
Bonadonna 1994; Fuller et al. 1988; Hoppe et al.
1982a). However, a survival benefit has not been definitively shown because of the good salvage rates following radiation failures.
Previous data from the review of randomized trials of more versus less extensive radiotherapy, with or without chemotherapy, suggested the use of less extensive radiation fields and resulted in simi- lar survival rates to those achieved with more inten- sive treatment (Specht et al. 1998). Recent evidence suggests that limited field irradiation in CMT is also feasible without compromising outcomes while reducing the risk of long-term toxicity. A study that examined the efficacy of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemother- apy followed by limited field irradiation showed a high 5-year actuarial overall survival (100%) and progressive-free survival (97%) with no observation of secondary malignancies and only mild pulmo- nary toxicity (Karmiris et al. 2003).
For the group of favorable patients, the overall
survival rates are good regardless of the treatment
modality used. Of importance in the choice of treat-
ment for these patients is the risk of long-term treat-
ment-related toxicities and side effects. Radiation
therapy has long been employed in the treatment of
Hodgkin’s disease, and its long-term toxicities are
well described. On the contrary, the long-term side
effects of chemotherapy and its combination with
radiation therapy have not been as well evaluated
or understood. If the long-term toxicities of CMT are demonstrated to be equal to or less than radia- tion therapy alone, CMT would be the treatment of choice even if the benefit in outcome is shown only in terms of free-from-failure rates. To reduce long- term toxicities, the field size and dose of the radia- tion may have to be reduced.
32.3.2
Special Considerations for LMM
For patients with stage-I and -II disease with unfa- vorable prognostic features, CMT is used. Altering treatment modalities may change the prognostic significance of some unfavorable factors.
Patients with a LMM require special therapeutic attention. Although the definition of large or bulky mediastinal disease varies, it is usually defined as a mass measuring greater than one-third of the larg- est transverse chest diameter (Mauch 1994) or the transverse diameter of the mass at the T5-6 level divided by the largest transverse diameter of the chest (Lee et al. 1980) (Fig. 32.1).
In patients treated with mantle field irradia- tion, the majority of failures occur outside or at the edge of the radiation port in the intrathoracic region (Mauch et al. 1988; Lee et al. 1990). This suggests that there are geometric difficulties in treatment volumes when trying to shield the lung parenchyma. This problem has led to modifications in treatment techniques, including low-dose lung irradiation to treat the microscopic disease and the use of a shrinking field technique as the size of the lung mass is reduced. The addition of low-dose (15–
18 Gy) whole or hemi-lung irradiation has resulted in excellent clinical outcomes with acceptable side effects (Mauch et al. 1983, 1988; Mai et al. 1991;
Mauch 1994; Rosenberg and Kaplan 1985; Lee et al. 1990).
The increased use of chemotherapy in the treat- ment of Hodgkin’s disease coupled with the greater risk of relapse after standard mantle field irradia- tion has led to the wide acceptance of CMT in the treatment of patients with LMM. CMT has lowered the local recurrence rate but has not significantly impacted overall survival. Chemotherapy treats sub-clinical disease and decreases the bulk of dis- ease. This allows for the use of smaller fields and lower doses of radiation.
Chemotherapy as the sole treatment for a poor- risk group of patients frequently fails to achieve complete response (CR) and results in greater relapse
than when radiation therapy is used alone (Zittoun et al. 1985; Biti et al. 1992). Therefore, radiation is absolutely needed to maximize local regional con- trol in this situation (Pavlovsky et al. 1988; Biti et al. 1992).
32.3.3
Delivery and Dose of CMT
Prior to the administration of chemotherapy, CT, gallium, and PET scans are recommended to permit evaluation of the post-treatment response and dis- cern the need for additional treatment.
The optimal regimen for CMT remains unsettled.
Multiple chemotherapeutic regimens with various numbers of cycles have been used. Largely based on the results of prospective trials in advanced Hodgkin’s disease, ABVD has become the stan- dard regimen for patients with stage-I or -II unfa- vorable prognosis. Other regimens used include MOPP (mechlorethamine, Oncovin, procarbazine, and prednisone), MOPP/ABV and BEACOPP (bleo- mycin, etoposide, adriamycin, cyclophosphamide, Oncovin, procarbazine, and prednisone). Most trials have incorporated four to six cycles of chemo- therapy (Somers et al. 1989).
Results from the German Hodgkin’s Study Group HD8 showed comparable outcomes among patients randomized to extended field irradiation versus involved field irradiation after two cycles of COPP/
ABVD, with reduced toxicity in the involved field treatment arm (Engert et al. 2001).
The Milan group recently presented the result of their trial comparing 4 cycles of ABVD with STNI and the same chemotherapy with involved field radi- ation therapy for stage I–II unfavorable Hodgkin’s disease (Bonfante et al. 2001). No difference was found between the two groups with regard to over- all survival and free-from-progression. Currently, the National Cancer Institute of Canada is conduct- ing an ongoing trial comparing two cycles of ABVD followed by either extended mantle or mantle plus para-aortic irradiation versus four to six cycles of ABVD with the same radiation regimen for those with stage I–II Hodgkin’s disease with unfavorable features.
Since the ABVD (doxorubicin, bleomycin, vin-
blastine, dacarbazine) era, combined modality (che-
motherapy and radiotherapy) has become almost
the standard approach in the treatment of disease
for unfavorable as well as favorable early-stage
Hodgkin’s disease.
812 C. K. K. Lee
To find the optimal dose and better regimen of che- motherapy and radiation port and dose, numerous studies are being carried out throughout the world.
The total radiation dose to the involved area of pre- chemotherapy region is 25–30 Gy with no detectable disease after chemotherapy, and 30–36 Gy with small residual disease. After chemotherapy, bulky residual disease receives a total radiation dose of 40 Gy. Estab- lishing the extent of the disease prior to receiving chemotherapy is important for RT planning.
Multiple trials and studies have provided evi- dence that radiation fields may be safely limited to an involved or regional field in most combined modality programs if four to six or fewer cycles of chemotherapy are given. Table 32.4 aims to iden- tify appropriate radiation volume for unfavorable Hodgkin’s lymphoma. The treatment of stage-I and -II unfavorable Hodgkin’s disease with CMT should result in a survival in the range of 90%. The long- term toxicities of CMT are not fully defined because of the relatively short follow-up.
At the University of Minnesota, unless the patient is being treated in a particular study, irradiation of
the modified mantle or involved field with doses of 25–36 Gy is used following four to six cycles of sys- tematic therapy. The site of initial bulky disease such as LMM is boosted up to 30–36 Gy if a CR is achieved, and to a dose of 40 Gy if a CR is not achieved. In patients with initial pericardial invasion, the initial field includes the entire heart with a cone-down to a mantle field after 15 Gy (Fig. 32.3). For patients with chest wall invasion, 25–30 Gy is given to the pre-che- motherapy volume in patients achieving CR. A total dose of 36–40 Gy is given if there is residual dis- ease. Whenever possible, shrinking field techniques should be used (Fig. 32.3, 32.4)
Table 32.5 reveals some recommendations for primary treatment outside clinical trials.
32.3.4
Advanced Stage Hodgkin’s Disease
Chemotherapy is the primary treatment modality for advanced stage Hodgkin’s disease (ASHD). The role of radiation in these patients is a controversial
Table 32.4 Randomized clinical trials in unfavorable-prognosis stage-I and -II Hodgkin’s lymphoma: trials to identify the appropriate radiation volume (used with permission from de Vita et al. 2005). ABV doxorubicin (Adriamycin), bleomycin, vinblastine; ABVD doxorubicin, bleomycin, vinblastine, dacarbazine; COPP cyclophosphamide, vincristine (Oncovin), procar- bazine, prednisone; CS clinical stage; DFS disease-free survival; EFRT extended-field radiotherapy; EORTC European Orga- nization for Research and Treatment of Cancer; ESR erythrocyte sedimentation rate; FFP freedom from progression; FFTF freedom from treatment failure; GELA Groupe d’Etude des Lymphomes de l’Adulte; GHSG German Hodgkin Study Group;
IFRT involved-field radiotherapy; MOPP mechlorethamine, vincristine (Oncovin), procarbazine, prednisone; NS not signifi- cant; RFS relapse-free survival; STLI subtotal nodal irradiation; SV survival
Trial Eligibility Treatment regimens No. of
patients
Outcome
French Cooperative, 1976–1981
CS I–II without age >45 years;
≥ 3 involved areas; bulky disease A: 3 MOPP + IFRT (40 Gy) + 3 MOPP
82 DFS, 87%; SV (6 years), 92%
B: 3 MOPP + EFRT (40 Gy) + 3 MOPP
91 DFS, 93%; SV (6 years), 91%
(DFS: P=NS; SV: P=NS)
Istituto Nazionale Tumori, Milan, 1990–1997
All CS I–II A: 4 ABVD + STLI 65 FFP, 96%; SV (5 years), 93%
B: 4 ABVD + IFRT 68 FFP, 94%; SV (5 years), 94%
(FFP: P=NS; SV: P=NS)
EORTC/GELA H8U, 1993–1998
CS IA–IIB with age ≥ 50 y; ESR
≥ 50 mm/h in A, ≥ 30 mm/h in B;
≥ 4 involved sites; large mediasti- nal disease
A: 6 MOPP/ABV + IFRT (36 Gy)
335 RFS, 94%; SV (4 years), 90%
B: 4 MOPP/ABV + IFRT (36 Gy)
333 RFS, 95%; SV (4 years), 95%
C: 4 MOPP/ABV + STLI 327 RFS, 96%; SV (4 years), 93%
(RFS: P=NS; SV: P=NS)
GHSG HD8, 1993–1998
CS IA–IIB with ESR ≥ 50 mm/
h in A, ≥ 30 mm/h in B;
≥ 3 involved sites; large mediasti- nal disease
A: 4 COPP/ABVD + EFRT 532 FFTF, 86%; SV (5 years), 91%
B: 4 COPP/ABVD + IFRT 532 FFTF, 84%; SV (5 years), 92%
(FFTF: P=NS; SV: P=NS)
Fig. 32.3a–c. A 19-year-old female patient with clinical stage 2a, nodular sclerosis Hodgkin’s disease with a large mediastinal mass extending left pericardial border. Positron emission tomography (PET) scans became negative after receiving six cycles of adriamy- cin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy with remaining soft tissue density in the mediastinum. a Radiation port including left cardial border up to 1500 cGy with 100 cGy per day, treated anteroposterior–posteroanterior (AP–PA) fi elds.
b Shielded left cardial border and lower mediastinum carried up to 2550 cGy. c Final boost fi eld carried up to 3600 cGy b
a c
Fig. 32.4a–d. A 27-year old male with clinical stage 2a treated with six cycles of adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy. a Field designed to include pre-chemotherapy sites and volume except mediastinum, which is designed using post-chemotherapy remaining soft tissue width. Treated up to 1650 cGy using 150-cGy daily dose. b Shielded low medi- astinum and carried up to 2550 cGy. c,d Field design using post-chemotherapy volume carried up to 3600 cGy at the central axis point using 180 cGy daily dose. Neck, superclavicular, and axillary regions were shielded as off-axis calculation points accumulated up to desired total dose by the Clarkson off-axis calculation point
b
d a
c
issue. With combination chemotherapy, about 20%
of patients fail to achieve CR and about one-third of patients who achieve a CR will eventually relapse (Longo et al. 1986; Raemaekers et al. 1997). The
majority (80–90%) of failure occurs in previous dis-
ease sites, especially bulky and nodal disease areas
(Fabian et al. 1994). For these reasons, radiation
therapy has been added in ASHD patients, espe-
814 C. K. K. Lee
cially those with bulky disease. Several phase-II and -III studies have explored whether adding radiation treatment improves disease-free or overall survival in these patients. Controversy still exists over proper total radiation dose and field size because of the questionable efficacy and the toxicity of consolida- tive RT. The type, intensity, duration, and dose of chemotherapy add difficulty to the assessment of the efficacy of RT in this setting.
Radiation therapy is employed in three different clinical settings in ASHD: (1) as consolidative treat- ment after CR post-chemotherapy; (2) as an inte- grated part of a CMT program, possibly with reduced dose chemotherapy; and (3) as a non-cross-resistant agent for treatment after partial response from che- motherapy. Most large prospective trials include radiation therapy in the treatment program.
Many retrospective studies suggest that, com- pared with chemotherapy alone, low-dose (20–
30 Gy) consolidative RT increases survival benefits with the use of CMT (Fabian et al. 1994; Diehl et al. 1995). Since these studies are all retrospective they are subject to potential selection bias. Some of the studies used chemotherapy consolidation instead of radiotherapy. The potential contribu- tion of radiotherapy is dependent on several factors such as patient characteristics, various prognostic factors, and response and duration of the chemo- therapy program.
The guidelines for the dose and volume of radia- tion therapy in CMT are not well defined. Low-dose irradiation (15–30 Gy) has been employed based on the hypothesis that a lower dose of radiation may be all that is needed in the adjuvant setting. Table 32.6 summarizes randomized clinical trials in ASHD treatment combined modality radiation and chemo- therapy. At the University of Minnesota institution,
patients with ASHD receive a dose of 25–30 Gy to the involved field if there is bulky disease (defined as mass >3–5 cm) but a CR is achieved. If there is less than a CR, a boost to 30–40 Gy will be given to the residual tumor mass.
32.4
Radiation Therapy Techniques
There has been a gradual evolution in concept and application in the use of radiation therapy to treat Hodgkin’s disease since Gilbert proposed “segmen- tal roentgen therapy” in 1939 (Gilbert 1939) and Peters proposed “radical radiation” in 1950 (Peters 1950). Knowledge of the predictable patterns of relapse, the contiguous character of regional lymph node involvement, and the availability of megavolt- age beam techniques have led to the development of current techniques and reasonably standardized radiation fields for the treatment of Hodgkin’s dis- ease (Kaplan 1962). Rosenberg and Kaplan demon- strated in 1966 that in the vast majority of untreated patients with disease limited to lymph nodes only contiguous areas were involved, which proved the orderly progression in which Hodgkin’s disease spreads (Rosenberg et al. 1966).
Widely accepted terms to denote treatment fields – such as mantle, para-aortic, inverted Y field, pelvic field, Waldeyer’s ring, preauricular field, spade- shape field, extended field (mantle and para-aortic fields), total nodal irradiation (mantle and inverted Y fields), and involved field – reflect the variation and growing standardization of these fields. Despite this apparent standardization, differences exist in the actual techniques used by different institutions.
Table 32.5. Recommendations for primary treatment outside clinical trials (used with permission from de Vita et al. 2005).
CS clinical stage; CT chemotherapy; EFRT extended-field radiotherapy; IFRT involved-field radiotherapy; RF risk factors (see Table 41.5-7); RT radiotherapy
Group Stage Recommendation
Early stages (favorable) CS I–II A/B no RF EFRT (30–36 Gy) or 4–6 cycles CTa + IFRT (20–36 Gy) Early stages (unfavorable) CS I–II A/B + RF 4–6 cycles CTb + IFRT (20–36 Gy)
Advanced stages CS IIB + RF; CS III A/B; CS IV A/B 6–8 cycles CTc + RT (20–36 Gy) to residual lymphoma and bulk
aABVD [doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine], EBVP (epirubicin, bleomycin, vinblastine, and prednisone), or VBM (vinblastine, bleomycin, and methotrexate)
bABVD, Stanford V (mechlorethamine, adriamycin, vinblastine, vincristine, etoposide, bleomycin, and prednisone), or MOPP/
ABV [mechlorethamine, vincristine (Oncovin), procarbazine, and prednisone/Adriamycin, bleomycin, vinblastine]
cABVD, MOPP/ABV, ChlVPP/EVA (chlorambucil, vinblastine, procarbazine, and prednisone/etoposide, vincristine, and Adriamy- cin), or BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) escalated
An example of the techniques used at the Univer- sity of Minnesota for extended field and total nodal field with liver irradiation are shown in Figures 32.3 and 32.4. Differences in treatment technique may account for different outcomes reported in the lit- erature. A Pattern of Care survey of 163 treatment facilities found that recurrence significantly corre- lated with technique (involved field versus extended field), treatment machine (less than 80 cm cobalt-60 [
60Co] versus greater than 80 cm
60Co, linear accel- erator), simulation, and presence of splenic pedicle clips (Hanks et al. 1983).
One way to ensure quality control in the treat- ment of Hodgkin’s disease is by routine field simu- lation and frequent film verification to verify that involved tissues are adequately treated and sensitive structures properly shielded. Portal films examined in the Patterns of Care Study demonstrated and increased overall recurrence rate (54% versus 14%, P<0.001) and an infield or marginal recurrence rate (33% versus 7%, P<0.001) between patients treated with inadequate margins between the protective lung and cardiac blocks and the tumor, and patients treated with adequate margins.
Careful follow-up of patients in large-scale clini- cal trials has permitted a rapid advance in our knowl- edge and optimal treatment of Hodgkin’s disease.
Radiation therapy planning involves the radiation oncologist, radiation physicist, medical dosimetrist, and radiation therapist. The patient undergoes a simulation procedure where treatment parameters are set. Films are taken for the design of customized blocks and the points for dose measurements are marked. After the measurements are obtained, com- puterized planning determines the dose delivered to each reference point. A compensator is computer generated if necessary to achieve a uniform dose dis- tribution to different reference points. If treatment to both the mantle and the para-aortic area is nec- essary, extra caution is exercised to match the two fields and avoid overdosing areas, especially spinal cord, as a result of the possible field overlap.
Radiation therapy will be delivered by stan- dard megavoltage (4–10 MV) techniques, utiliz- ing shaped fields with blocks individualized to the specific patient. In general, parallel opposed fields will be most appropriate. The minimum source- skin distance or source-axis distance should be 80 cm. Radiation treatments are administered in 150- to 180-cGy fractions, 5 days a week. There has been controversial data and opinion regard- ing total radiation dose in Hodgkin’s disease. Dose has been strongly influenced by data from Stanford
that initially used 40–44 Gy (1 Gy=100 cGy). This recommendation was derived from a retrospec- tive analysis of in-field control in the early 1960s.
Subsequent reports demonstrated excellent results with 30–36 Gy. Data from another comprehensive retrospective study on dose–response showed that a 98% in-field control rate could be achieved with 37.5 Gy. With megavoltage radiotherapy, the doses required for 98% in-field control for subclinical dis- ease and disease of less than 6 cm and greater than 6 cm are 32.4 Gy, 36.9 Gy, and 37.4 Gy, respectively.
Data from German Hodgkin’s Disease Study Group showed that 30 Gy was adequate for the control of subclinical disease. In our institution, 30 Gy in 20 to 24 fractions is delivered to subclinical disease and 36–40 Gy to clinically detectable disease sites with special attention given to the placement of a subcari- nal block to protect the heart. The para-aortic area and spleen receive a dose of 30 Gy in 150- to 180-cGy fractions.
32.4.1 Mantle Fields
Mantle fields were first used at Stanford in 1956 and since then modifications to mantle fields have been adopted by various institutions. Typical mantle fields include all the major lymph node bearing areas above the diaphragm, neck, axilla, medias- tinal, and occipital. Preauricular lymph nodes and Waldeyer’s ring area are included if needed. The mantle field is used to treat the major supradia- phragmatic nodal chains that are at high risk for the involvement of Hodgkin’s disease, while maximally shielding the lungs. Preauricular lymph nodes are treated when there is high neck disease. Optimal design of the mantle field relies on imaging studies.
A chest CT scan for patients with significant medi- astinal adenopathy provides important information on disease extension to the lung, pericardium, chest wall, and internal mammary or pericardial lymph node. Incorporation of the CT scan into treatment planning decisions for patients treated with radio- therapy alone results in treatment field changes in about 15% of patients (Somers et al. 1989).
32.4.2
Simulation of Mantle Field
The following techniques are used at the University
of Minnesota to simulate mantle fields.
816 C. K. K. Lee
Table 32.6. Randomized clinical trials in advanced-stage Hodgkin’s lymphoma: major trials for which results have been recently published or not yet published (used with permission fromde Vita et al. 2005). ABV doxorubicin (Adriamycin), bleomycin, vinblastine; ABVD doxorubicin, bleomycin, vinblastine, dacarbazine; ASCT autologous stem cell transplantation; BEACOPP bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine (Oncovin), procarbazine, prednisone; BEACOPP-14 BEACOPP regimen with 14-day interval between courses; ChlVPP chlorambucil, vinblastine, procarbazine, and prednisone; COPP cyclophosphamide, vincristine (Oncovin), procarbazine, prednisone; CR complete response; CS clini- cal stage; CT computed tomography; ECOG Eastern Cooperative Oncology Group; EFS event-free survival; EORTC European Organization for Research and Treatment of Cancer; EPO erythropoietin; EBMT European Bone Marrow Transplant Registry; EVA etoposide, vincristine, and doxorubicin; FFS failure-free survival; FFTF freedom from treatment failure; GELA Groupe d’Etude des Lymphomes de l’Adulte; GHSG German Hodgkin Study Group; HDCT high-dose chemotherapy; IFRT involved-field radiotherapy; IPS international prognostic score (International Prognostic Factors Project); MOPP mechlorethamine, vincristine (Oncovin), procarbazine, prednisone; OS overall survival; PABlOE prednisolone, doxorubicin, bleomycin, vincristine, etoposide; PET positron emission tomography; PR partial response; PVACEBOP prednisolone, vinblastine, doxorubicin, chlorambucil, etoposide, bleomycin, vincristine (Oncovin), procarbazine; resid residual; RT radiotherapy; SNLG Scotland and Newcastle Lymphoma Group; Stanford V mechlorethamine, doxorubicin, vinblastine, predni- sone, vincristine, bleomycin, VP-16; SV survival; SWOG Southwest Oncology Group; TTF time to treatment failure; UKLG (BNLI) United Kingdom Lymphoma Group (British National Lymphoma Investigation); VAPEC-B doxorubicin, cyclophosphamide, etoposide, vincristine, bleomycin, prednisolone TrialEligibilityTreatment regimensNo. of patientsOutcome Manchester (Radford et al.)—A: 6 ChlVPP/EVA ± RT (bulk/resid) 144FFTF, 82%; SV (5 years), 89% B: 11 VAPEC-B ± RT (bulk/resid)138FFTF, 62%; SV (5 years), 79% (FFTF: P=0.006; SV: P=0.04) GHSG HD9 (Diehl)CS IIB with large mediastinal involve- ment, massive splenic involvement, or E lesions; CS III, IV
A: 8 COPP/ABVD ± RT (bulk/resid)260FFTF, 69%; SV (5 years), 83% B: 8 BEACOPP baseline ± RT (bulk/resid) 469FFTF, 76%; SV (5 years), 88% C: 8 BEACOPP escalated ± RT (bulk/resid) 466FFTF, 87%; SV (5 years), 91% (P<0.0001; A versus C: P<0.002) GHSG HD12 (Diehl)CS IIB with large mediastinal involve- ment or E lesions; CS III, IV A: BEACOPP (escalated ×8) ± RT (bulk/resid) Began 01/1998; planned: n=1200Final analysis planned for 2006 B: BEACOPP (escalated × 8) C: BEACOPP (escalated × 4 + baseline × 4) ± RT (bulk/resid) D: BEACOPP (escalated × 4 + baseline × 4) GHSG HD15 (Diehl)CS IIB with large mediastinal involve- ment or E lesions; CS III, IV A: 8 BEACOPP escalated + EPO/placebo + IFRT (30 Gy for PET-positive PR) Opened 01/2003Open B: 6 BEACOPP escalated + EPO/placebo + IFRT (30 Gy for PET-positive PR) C: 8 BEACOPP-14 + EPO/placebo + IFRT (30 Gy for PET-positive PR)
EORTC 20884 (09/1989–03/2000)CS III and IV6–8 MOPP/ABV + (if CR after 6 cycles):Total: 736 →A: IFRT (24–30 Gy) 172EFS, 79%; SV (5 years), 91% →B: No further treatment 161EFS, 84%; SV (5 years), 85% (EFS: P=0.35; SV: P=0.10) Not randomized85 PR250EFS, 79%; SV, 87% GELA (Fermé & Diviné)IPS 0–2A: 6 ABVD ± RT (bulk)nene B: Intensified conventional CT ± RT (bulk) GELA/EBMT H96-1 (Fermé & Diviné)IPS 3+A: Brief intensified CT then HDCT + ASCT ± RT (bulk)83FFS, 75%; SV (5 years), 86% B: 8 ABVD ± RT (bulk)80FFS, 82%; SV (5 years), 88% (FFS: P=0.4; SV: P=0.6) UKLG (BNLI) LY09 (Hancock)Disease requiring systemic therapy: CS I–II with bulk or >3 sites; CS III–IV A: 6–8 ABVD ± RT (bulk/resid)Recruitment: 04/1997– 09/2001; n=807SV (3 years), 91% B: 6–8ChlVPP/PABlOE ± RT (bulk/resid)or 6–8 ChlVPP/EVA ± RT (bulk/resid)
SV (3 years), 88% UKLG (BNLI) phase II study (Hancock)CS IIB, III, IV with large mediastinal involvement or ≥2 extranodal sites A: 6–8 ABVD ± RT (bulk)Began 03/1998; planned: n=80End point: response; phase-III trial to follow B: Stanford V ± RT (bulk) SNLG HDIII (Proctor et al.193) SNLG index <0.5 (high risk)3 PVACEBOP ± RT (bulk) + (if response):n=107, randomized n=65Median follow-up, 6 years OS, 78% (all patients) TTF (5 years), arms not different →A: Melphalan,VP-16 then HDCT + ASCT TTF, 79±11% →B: 2 PVACEBOP TTF, 85±7% (TTF: P=0.35) SWOG/ECOG 2496 (Horning & Coltman)CS II with bulk and III and IV; IPS 0–2 A: 6–8 ABVD ± RT (bulk) B: Stanford V ± RTOpenOpen Global study, EORTC 20012CS III and IVA: 8 ABVDOpened 01/2003Open B: 4 BEACOPP escalated + 4 BEACOPP baseline No radiation SWOG/ECOGCS II with bulk and III and IV; IPS 3+A: ABVD—— B: ABVD then HDCT (BCNU, VP-16, cyclophos- phamide) + ASCT
818 C. K. K. Lee
32.4.2.1 Anterior Fields
1. Patients are placed in a supine position with arms above the shoulder. The arm position is 90º from the axilla and should eliminate any skin folds of the axilla. Others have used various arm posi- tions as shown in Figure 32.5. Different arm posi- tions may be used but attention must be paid to how the lymph nodes move in relation to the arm position for a given situation. Upper extremity lymphangiograms show that the elevation of the arms results in changes to the location of the axil- lary lymph nodes (Crnkovich et al. 1987; Grant and Jackson 1973; Weisenberger and Juillard 1977). When the hands are over the head with a greater than 90º angle at the axillae, axillary lymph nodes are moved away from the lung area, which allows for the design of lung and shoulder shielding.
2. The head position should allow the mandible to be perpendicular to the table top to avoid the pos- sibility of unnecessary radiation through the oral cavity and mandible Figure 32.6.
3. Palpable lymph nodes can be outlined with a thin wire at the time of simulation to help design the fi eld.
4. Field boundaries are placed superiorly to the level of mastoid tip through the chin line and inferi- orly at T9–10 or T10–11 vertebral interspace. Infe- rior border should be extended as needed to the level of T11–12, to include the mediastinum. In patients with an intact spleen, special consider- ation should be given to the inferior border of the mantle because the spleen is usually included in
the para-aortic fi eld. In this situation, lung and diaphragmatic movement by respiration should be watched. In patients who receive whole lung irradiation, lower margins of the mantle fi eld are inferior to the diaphragm to include the lung parenchyma.
5. Laterally, the fi eld includes the axillae as deter- mined clinically.
6. The central axis is defi ned at the center of the treatment and lies usually close to or at the sternal notch. Simulation radiographs are taken includ- ing all borders. This will often require two radio- graphs to show all the fi eld margins. If the fi eld size to cover the treatment area is too large, an extended source-skin distance may be used.
7. Mark the fi eld boundaries and central axis on the patient. A tattoo may be placed at the central axis and inferior border to help daily setup and for future reference when the infraradiodiaphrag- matic fi eld is setup. Tattoos may also be placed about 10 cm lateral to the right and left of the central axis line, which helps to confi rm the arm position relative to the central axis line.
8. When all the fi eld borders and the central axis positions have been determined, a mantle mea- surement sheet for irregular fi eld calculations is prepared. Patient separation is taken at the central axis, axillae, midneck, supraclavicular, midmediastinum, and low mediastinum, about 3 cm above the bottom of the fi eld (Fig. 32.7). An irregular fi eld point dose calculation is performed at midseparation for each point using a computer- ized Clarkson method. These point dose calcula- tions help to achieve the desired cumulative dose to all areas of interest (Fig. 32.8).
Fig. 32.5a–c. Arm positions for mantle fi elds. a Arm positions bring axillary lymph nodes medially close to the lateral part of the lung. Shielding the lung properly can be diffi cult. b Arm extension position makes the lymph nodes move over the shoulder area. Shielding the humeral head and shoulder joint can be diffi cult. c Right angle position gives reasonable room to shield the shoulder and place the lung block without including too much lateral strip of lung
b
a c
Fig. 32.6. Proper chin extension prevents excess dose to the oral cavity and mandible
Fig. 32.7. Measurement sheet for mantle fi elds for various cal- culations is completed at the time of simulation
Fig. 32.8. Computer output sheet showing cumulative midthickness doses for mantle fi elds
32.4.2.2
Posterior Fields
If the treatment machine and the table permit, ante- rior and posterior treatments should be delivered in the same positions. The patient should remain in the supine position and the beam rotated 180º from the anterior field to set up the posterior field.
In this case, a posteroanterior Beam’s eye view will include more of the oral cavity, which requires spe- cial attention to shield the excess oral cavity in the field (Fig. 32.9). Treating the patient in the supine position, however, makes it difficult to evaluate pos-
Irregular Field Daily Dose, Output for: on: 3-Apr-90
Point # 1 2 3 4 5 6
75.6% 72,5% 69.2% 87.3% 79.0% 75.1%
CA Mid Media Low Media Neck S. Clav. Axilla RX #
1 150 144 137 173 157 149 2 300 288 275 346 313 298 3 450 432 412 520 470 447 4 600 575 549 693 627 596 5 750 719 687 866 784 745 6 900 863 824 1039 940 894 7 1050 1007 961 1213 1097 1043 8 1200 1151 1098 1386 1254 1192 9 1350 1295 1236 1559 1411 1341 10 1500 1438 1373 1732 1567 1490 11 1650 1582 1510 1905 1724 1639 12 1800 1726 1648 2079 1881 1788 13 1950 1870 1785 2252 2038 1937 14 2100 2014 1922 2425 2194 2086 15 2250 2158 2060 2598 2351 2235 16 2400 2302 2197 2771 2508 2384 17 2550 2445 2334 2945 2665 2533 18 2700 2589 2471 3118 2821 2682 19 2850 2733 2609 3291 2978 2831 20 3000 2877 2746 3464 3135 2980 21 3150 3021 2883 3687 3292 3129 22 3300 3165 3021 3860 3448 3278 23 3450 3309 3158 3984 3605 3427 24 3600 3452 3295 4157 3762 3576 25 3750 3596 3433 4330 3919 3725 26 3900 3740 3570 4504 4075 3874 27 4050 3884 3707 4677 4232 4023 28 4200 4028 3844 4850 4389 4172 29 4350 4172 3982 5023 4546 4321 30 4500 4315 4119 5196 4702 4470 31 4650 4459 4256 5370 4859 4619
upper Neck Department of Radiation Oncology
Mantle Field Measurement Sheet Name Hosp. No.
Date
Point #1: Central Axia Point #2: Mid- Mediastinum
Point #3: Lower
Mediastinum (3 cm above the lower border of the field) Point #4: Neck (midway
from upper border to base of neck at anterior border of sterno-cleidomas- toid muscle)
Point #5: Supraclavicular (1-2 cm medial to mid-clavicular
line and just superior to the clavicle Point #6: Upper axilla
(apex of axilla)
Reference Point Perpendicular Source-skin
Distance at Ref. Point AP/PA Thickness at Ref. Point
1. Central Axis 2. Mid-Mediastinum 3. Lower Mediastinum 4. Neck 5. Supraclavicular 6. Axilla
Aterior Posterior Ant. Post. Ant. Post
Gap Gap Separation Separation
Overall Field-size at Surface = Source-Film Distance: Anterior =
Posterior = Source-Tray Distance: Anterior =
Posterior =
(Mantle Field Measurement (10/97)
820 C. K. K. Lee
Fig. 32.9a,b. Techniques used at the University of Minnesota. a Anterior mantle fi eld. b Posterior mantle fi eld
a b
terior neck nodes and posterior beam exit. Using the same superior border for the posterior field, as in the anterior radiograph, may miss the posterior neck node.
If simulation is done in the prone position for the posterior field, the same steps are followed as described above. Since the junction point for the anterior and posterior field is at the midthickness point, the posterior field border in the prone posi- tion will usually fall at one vertebrate higher than the anterior field, as seen in the simulation radio- graph because the spine is located in the posterior part of the body relative to the middle of the antero- posterior thickness.
32.4.3
Design Shielding
The key to good mantle field setup is in the place- ment of lung blocks. Lung blocks must protect as much lung and heart as possible while irradiating macroscopic and microscopic disease to minimize the risk of treatment failure. The most important aspect of the mantle field design is the individu- alization that is needed in shaping lung blocks to conform to the specific contours of a given patient.
Careful design and placement of shielding blocks protects the pulmonary parenchyma from the effects of excessive dose.
On simulation film, or port film, individualized diversion blocks should be designed for both anterior and posterior films that are not necessarily identical but that include identical nodal groups. The actual blocks are custom designed by following the outline
of the block as drawn on the simulation film as well as by the additional use of thoracic CT scans. For uncomplicated cases, the anterior field lung blocks should allow about 2 cm below the medial end of the clavicle to include the infraclavicular lymph node and leave the strip of the lateral part of the lung to include the axillary lymph node with adequate mar- gins. To include the axillary lymph node in the strip, one should pay attention to the patient’s arm posi- tion (Grant and Jackson 1973). Posteriorly, the lung block can be higher than the anterior field and leaves less strip of lung in the infraclavicular area since the lymph nodes in this area are anteriorly located. To include the axilla, there should be falloff outside of the lateral chest wall. It is also necessary to shield soft tissue of the lower lateral chest wall below the level of the fourth intercostal space, unless there is low axillary lymph node involvement.
In the design of lung blocks, medially at least a 1- to 1.5-cm margin should be allowed for any medi- astinal shadow – except for the heart – or any mass shadow. The hilum is hard to define radiographi- cally as its anatomical delineation. Therefore, the medial edge of the lung blocks around the hilum can be a source of variation among different institutions.
Stanford advocates whole pericardial irradiation to the lower prophylactic doses (15 Gy) for mediasti- nal disease (Carmel and Kaplan 1976; Page et al.
1970). This practice is not universally followed.
If there is no gross midline neck disease, trap-
ezoidal or ovoid anterior larynx and posterior cer-
vical spine blocks in addition to lung blocks are
recommended. Stanford also recommends an entire
posterior thoracic spine block after the delivery of
2000–2500 cGy, as well as a subcarinal block. At
the University of Minnesota, a 2-cm-wide posterior cervical block placed above the level of the thoracic inlet after delivery of 2000 cGy to the central axis is used (Fig. 32.10). If there is no presence of sub- carinal disease, the subcarinal block can be used after the delivery of 3000 cGy. Radiation dose at each off axis point provides information on when to shield each necessary region. The subcarinal block is placed at the lower edge of the field extending cephalad to within 6 cm of the carina. This appears to significantly reduce the risk of radiation-induced heart disease. When the humeral head is shielded in patients with bulky axillary disease, extreme cau- tion must be used.
After all of the blocks have been drawn, dosi- metric calculations should be made at the multiple points of interest. Doses received in these areas can vary considerably because of varying patient thick- ness in the large field and in the different scatter contributions from the blocks. For example, nodes in the axilla and the high neck receive a greater dose than nodes in the lower mediastinum. Therefore, the dose differences at each site should be calcu- lated (Fig. 32.7) and compensation should be pro- vided by placing the shielding block earlier for the particular anatomic area or by using compensators (Fig. 32.11).
In the presence of inferior mediastinal disease or pericardial extension, the entire cardiac silhouette is irradiated to 15 Gy and then changed to shield the apex of the heart. After a dose of 30–35 Gy is deliv- ered, a block is placed about 5 cm below the carina to provide more cardiac and pericardial protection.
However, in no instance do we treat areas of clini- cal involvement of Hodgkin’s disease with doses of less than 36 Gy if radiotherapy alone is planned.
Figure. 32.12 represents examples of field modifica- tions and shielding of the extended field which has been used in the CALGB and SWOG inter-group study.
Patients with massive mediastinal disease and/or hilar disease who are treated with radiation alone require further modifications to the lung blocks.
When hilar adenopathy is present, there is sub- stantial risk of subclinical Hodgkin’s disease in the lung. There is also an increased risk of subsequent pulmonary relapse; therefore, low-dose lung irradi- ation has been recommended using thin lung blocks that transmit 37% of the total 1650-cGy dose deliv- ered to the central axis (Page et al. 1970; Lee et al.
1979).
In patients with LMM, locoregional recurrence is the major cause of failure (Lee et al. 1980). These
patients are treated with low-dose bilateral or unilat- eral lung irradiation to eliminate microscopic lung disease as well as to shrink tumor mass (Fig. 32.13).
Total dose to the lung parenchyma of 1000–1600 cGy in daily doses of 100 cGy is given (Lee et al. 1979).
The shrinking field technique should be used several times during the treatment course. One can consider a 10- to 14-day treatment break during the course of radiation treatment to allow for tumor shrinkage, as Stanford originally introduced (Johnson et al. 1976) (Fig. 32.14). The technique of reshaping and enlarg- ing lung blocks as the mass responds to treatment reduces the risk of pulmonary toxicity.
Although historically whole lung irradiation was the best radiation treatment to provide optimal sur- vival rates for patients with LMM, most patients currently receive CMT with modifications to the radiation fields and dose to deliver less aggressive treatment (Leopold et al. 1989). An unresolved issue is what volume should be used in patients with LMM
Fig. 32.10. Posterior mantle fi eld port fi lm with posterior cer- vical spine block
Fig. 32.11. Schematic fi gure for the shielding of the off-axis areas according to cumulative dose output
822 C. K. K. Lee
Fig. 32.14a,b. Reduction in size of large mediasti- nal mass after 1500 cGy to the whole lung using 100- cGy daily fractions b
a
Fig. 32.13a,b. Unilateral lung irradiation for a patient with protruding mediastinal disease on the right side
a b
Fig. 32.12. Example of modi- fi ed mantle and para-aortic spleen fi elds used in CALGB
#9497 and SWOG #9133
