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radiation fields previously used in Hodgkin's disease, mantle, para-aortic and inverted Y fields

Hodgkin Lymphoma    see video

 (see older reviews here , here ,here and E-medicine, an historical summary here and typical x-ray appearance here). With modern treatment the survival for early and advanced stages is better than 90% (go here).

As curative approaches to limited-stage and advanced-stage Hodgkin's lymphoma evolved through the 1990s, investigators appropriately focused on maximizing cure rates by intensifying the initial treatment. However, with very high cure rates for limited-stage Hodgkin's lymphoma now available, investigators have recently focused on reducing the intensiveness of the primary treatment. Just two cycles of the minimally toxic regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), followed by involved-field, moderate-dose radiation, cures almost all patients while avoiding staging laparotomy, infertility, and leukemogenesis. Even more to the point, properly selected patients can be cured with chemotherapy alone, completely eliminating the risks of radiation. There is more evidence for the need to limit the dose and field size if radiation is used along with chemotherapy (see here and here). Some of the data still favors radiation (here).

Images of the stages: stage 1, stage 2, stage 3, stage 4 and the node sites

The best web sites for information are below:

American Cancer Society Information,   ASCO Site
Medline Plus on Hodgkin's
NCCN Guidelines
NCI (CancerNet Information) esp Patient Information SIte
NIH Booklet, CancerConnect
Patient information from up to date: here
patient info #1 and #2


involved field radiation ports

In the past early stages would be treated with radiation alone or combined radiation plus chemotherapy. Studies comparing chemotherapy alone versus combination with radiation (CMT) often show the best results with the combination. (see table.) But there is evidence that adding radiation to chemotherapy may increase other cancers (see Aleman study and editorial by Connors.) We now tend to use small radiation fields which works as well as large fields with less side effects (see trial and study about safe lung doses.) More advanced stages are treated primarily with chemotherapy. New chemotherapy regimens are reporting even better results (see NEJM study.) Most clinicians follow the NCCN guidelines and they recommend most patients receive chemotherapy followed by low dose involved field radiation

Key Points
* Hodgkin's disease is a neoplastic disorder of the immune system with mounting evidence for a lymphocytic origin of the Reed-Sternberg cell.
* Clinical presentation can include a variety of constitutional symptoms including fever, weight loss, night sweats, and pruritus.
* The pattern of spread through the central axial lymph node system allows for curative radiation therapy for localized disease.
* Advanced disease can be cured in more than 50% of cases by combination chemotherapy.

  The largely successful treatment of Hodgkins disease is one of the triumphs of modern cancer therapeutics. The death rate in the last 30 years has decreased by two thirds because of the introduction of effective diagnostic and therapeutic modalities. It is fortunate that the majority of patients with the disease are young, with a median age of 26 to 30 years. There is a bimodal distribution, with a small peak of patients aged more than 50 years. Compared with non-Hodgkins lymphoma (41,000 new cases), Hodgkins disease is relatively rare, with 7900 new cases estimated to have occurred in 1994. The cause of Hodgkins disease is unknown, but the pattern of disease suggests a viral origin. There is some resemblance to the pattern of paralytic polio because children in Third World environments are more likely to develop the disease than are adults. The disease is more common in the adult age groups in the temperate areas. The role of the Epstein-Barr virus is uncertain, but genomic material of Epstein-Barr virus has been detected in at least 50% of the tumors. There is a male predominance in the incidence of Hodgkins disease through all age groups, with a 1.4-to-1 ratio seen in adults. Siblings of patients have an increased (sevenfold) risk for developing Hodgkins disease. Histocompatibility antigens associated with Hodgkins disease are A1, B5, and B18; the B18 antigen has the highest association.

  The main clinical and laboratory feature of Hodgkins disease is painless lymphadenopathy, usually confined to one or two lymph node groups. Anemia is rare, except in advanced disease; when present, it may appear as the anemia of chronic disease, with a microcytic pattern, a low serum iron level, and a low iron-binding capacity. Granulocytic leukocytosis with eosinophilia may occur, usually in symptomatic patients with advanced disease. Thrombocytopenia is unusual, except in the presence of bone marrow involvement. Liver function studies do not predict the presence of liver involvement, but an elevated alkaline phosphatase level is the most common abnormality of advanced liver disease. Autoimmune phenomena are distinctly unusual, although rare instances of idiopathic thrombocytopenic purpura, cephrotic syndrome, and hemo-lytic anemia have been reported.The erythrocyte sedimentation rate is a nonspecific measure of disease activity and may be markedly elevated. Approximately 30% of patients have constitutional symptoms (B symptoms), which include fever, night sweats, and loss of 10% of body weight. Pruritus may also be noted. Manyif not allof the constitutional symptoms are thought to be related to the production of cytokines by the malignant cells. Clinically detected splenomegaly is unusual and is typically a later manifestation of advancing disease. Radiographic studies show a mediastinal mass, hilar adenopathy, or both in a high proportion of newly diagnosed patients. Nonspecific skin changes are rare. The diagnosis of Hodgkins disease requires the skill of an experienced pathologist or hematopathologist because the diagnosis can be difficult to make unless the Reed-Sternberg cell is easily seen. Debate over the immunologic lineag of the malignant cell of Hodgkins disease is controversial and this lineage remains the subject of considerable investigation. Surface marker studies suggest that the cell is of lymphocytic origin, but the malignant cell may be difficult to identify in the absence of the Reed-Sternberg cell. Recent investigations suggest that the cell of origin may be a B cell. This is especially true in the so-called lymphocyte-predominant type. The mixed component of eosinophils, lymphocytes, plasma cells, and fibroblasts suggests that a high percentage of the node may, in fact, not be neoplastic. Immunoperoxidase techniques permit a panel of stains to identify the Reed-Sternberg cell, especially by positive detection for the antigens Leu-M1 (CD15) and Ki-1 (CD30). T he histopathologic subtypes include lymphocyte predominant (<10%, usually with an indolent natural history), nodular sclerosis (approximately 60% to 80%), mixed cellularity (<10%), and lymphocyte depleted (<10%). The latter two may have an aggressive course [3,4].

  Most patients present with peripheral adenopathy, with 80% or more having the disease confined to above the diaphragm in the initial clinical assessmen Radiographic examination of the chest, including chest roentgenography and computed tomography (CT) of the chest and abdomen, and routine blood counts and chemistries are essential components of this staging process [6]. Bone marrow biopsy findings are more likely to be positive in advanced clinical disease, and biopsy is usually a routine component of staging. Gross clinical or radiographic involvement of para-aortic or iliac nodes does not require further abdominal staging. CT is noninvasive and is rapidly replacing lymphangiography [5]. Unfortunately, micronodular involvement of the liver and spleen still cannot be detected by CT. Gallium scanning is not widely used but its use is increasing, especially in the assessment of residual masses. All staging short of laparotomy is referred to as clinical staging. Postlaparotomy assessment is called pathologic staging. The staging classification as recently revised (Cotswolds classification.). In addition, it is apparent that wide field high-dose irradiation does have a higher likelihood of secondary radiation-induced malignancy, especially lung cancer and breast cancer in adolescent females. Recent practice has gone over to combined modality treatment, in which the fields of radiation are reduced after regression o masses by chemotherapy.

  Surgical staging (laparotomy) is intended to show the presence of microscopic involvement in abdominal lymph node sites, liver, and especially, spleen. The spleen is the most common site of abdominal involvement. Patients who have had splenectomies have a higher incidence of serious infections with encapsulated organisms such as Streptococcus pneumoniae. Patients should therefore be vaccinated with polyvalent pneumococcal vaccine or trivalent vaccine. Laparotomy is not needed unless therapy will be influenced by the findings. An increasing body of data confirms that laparotomy per se does not influence survival, and therefore it has been abandoned in many countries. In favorable presentations, such as localized, asymptomatic (CS/IIA) without bulky disease, normal sedimentation rate, and with fewer than four sites of involvement, limited radiation (mantle field for supradiaphragmatic presentations) will suffice for three fourths of the patients. Laparotomy staging will detect 10% to 15% abdominal involvement in favorable patients; thus, the progression-free rate for radiation therapy only will be even higher, in the range of 85% to 90%. The likelihood of abdominal involvement in patients presenting with asymptomatic Hodgkins disease that is clinically confined to above the diaphragm is 30%. The incidence rises in symptomatic (B symptom) patients and is proportional to the number of involved nodal sites. Patients with massive mediastinal tumors (more than one third of the chest diameter) require systemic therapy and thus do not require laparotomy. Patients with very favorable presenting features (eg, female, <26 years, with stage IA nodular sclerosis) do not require laparotomy because the likelihood of abdominal disease is less than 5%.In many institutions in which the policy is to offer combined-modality therapy routinely, laparotomy may be deferred. Some of the prognostic variables associated with an unfavorable natural history, early dissemination, or both are shown in Table 3. Hodgkins disease is known to be associated with a defect in delayed hypersensitivity reactivity. Advanced stages may have a marked lymphopenia. Cutaneous anergy is common but may be reversed in patients who have achieved long-term cure. The immune defect is attributed to suppression of normal T-lymphocyte function.. Humoral immunity is usually intact, except in patients who have had splenectomies and combined chemotherapy and radiation therapy.

Early-Stage Disease (IA or IIA)
  Disease limited to nodes on one side of the diaphragm is usually treated with radiation therapy directed to the involved fields plus contiguous uninvolved lymph  groups. This is commonly delivered as a mantle alone or with extension over the para-aortic area to L-2 (Fig. 1). Total nodal irradiation is rarely required for localized disease. Primary radiation therapy alone is offered to patients who are shown to have disease confined to stage I or II and are considered on a clinical basis to have a low likelihood of abdominal involvement (eg, stage I disease, female, <26 years, with a nodular sclerosis or lymphocyte-predominant subtype, or those shown to have negative findings on staging laparotomy). The tendency is to limit the field to the mantle if the disease is confined to the upper chest (above the carina) The long-term side effects of radiation therapy include hypothyroidism, radiation fibrosis, effusions, and late-occurring solid tumors in the field of irradiation. Patients who present with bulky mediastinal masses or otherwise extensive disease, such as pericardial involvement, require chemotherapy before radiation therapy

Advanced-Stage Disease (IIIA2, IIIB, or IV)
  Radiation therapy is still an option in some patients with minimal splenic, splenic hilar, or celiac node involvement (stage IIIA1). It is possible to effect a cure in 60% to 70% of patients with total nodal irradiation, but those with more than four gross nodules in the spleen will require systemic therapy because of the higher rate of recurrence with radiation therapy alone. There is a greater tendency now to offer such patients combined modality therapy because it is associated with the lowest recurrence rate The more advanced stages, such as IIIA2, IIIB, and IV, will require combination chemotherapy as primary therapy, with the possibility of radiation therapy for residual masses or sites of previous bulk disease. The role of systemic therapy has increased over the last 10 years as data have accumulated on the superiority of combined modality therapy over radiation therapy alone in patients with any but the most favorable prognostic features.

Combination chemotherapy

The original MOPP (mustargen, oncovin, procarbazine, and prednisone) protocol was the pioneer regimen that demonstrated that advanced Hodgkins disease could be cured by chemotherapy alone. Its toxic side effects included a marked myelosuppression in some patients, and sterilizationespecially in males, but also in females aged more than 25 years. In addition, especially in conjunction with radiation therapy, the alkylating agents contribute to a small but finite incidence of myelodysplasia or leukemia (approx 3%). The risk is higher in patients with splenectomy and in those aged more than 40 years. A nonalkylating agentcontaining regimen previously used as a second-line protocol, ABVD, has been shown to be equivalent (in some trials, superior) to MOPP, without the previously mentioned toxicity. The body of data now supports the use of ABVD as the first-line chemotherapeutic approach because it has been shown to be equivalent to all other standard dose regimens and less toxic. Alkylating agentcontaining regimens may be used effectively in patients who relapse from treatment with ABVD. Variations of MOPP and ABVD, including the hybrid regimen, MOPP-ABV, have also been used. It is controversial whether hybrid chemotherapy will be superior to ABVD. The alternation of cycles of MOPP with ABVD is superior to MOPP used alone but not superior to ABVD alone. The major toxic effect of ABVD is the rare serious pulmonary reaction to bleomycin. The likelihood of cure in patients with advanced-stage disease with chemotherapy alone is 50% to 60%.Systemic therapy should be used in almost all patients who present with clinical or pathologic evidence of stage III and IV disease and in those who present with bulky (>one third of the diameter of the chest) thoracic stage II disease; extensive infradiaphragmatic stage II disease; four or more sites involved above th daphragm; or marked constitutional (B) symptoms, especially fever and weight loss, regardless of clinical stage. The extent of radiation therapy, if used, can be reduced to those areas of bulk disease only.

Radiation therapy

In general, radiation therapy is not added to regimens in patients who have very extensive nodal or extranodal disease such as hepatic or bone marrow involvement. Curative therapy is well tolerated, but a number of nonmalignant chronic toxicities may occur as long-term medical problems. These toxicities include sterilization in males, especially after MOPP or pelvic radiation therapy, and premature ovarian failure with early menopause in women.Radiation therapy may result in chronic pulmonary pneumonitis and fibrosis, especially in the presence of bleomycin, with decreased carbon monoxide diffusion and restrictive changes. Cardiomyopathy is rare but has occasionally been noted in patients treated with conventional doses of doxorubicin as well as in those who have received left ventricular irradiation. Rarely, premature coronary artery disease has been noted. Improvements in radiation technique have minimized such problem but hypothyroidism continues to be problem following radiation treatment.

High-Dose Therapy
  Lymphomas, in general, are the most drug-responsive neoplasms. Hodgkins disease in relapse may still retain sensitivity to cytotoxic agents, especially alkylating agents. The latter can be escalated to doses that necessitate transplantation of autologous bone marrow or peripheral stem cells for the patient to tolerate the extent and duration of myelosuppression. The clinical features that predict a more favorable response to high-dose therapy are similar to those that predict a response to second-line conventional-dose chemotherapy: good performance status, chemotherapy-sensitive relapse, no more than two previous chemotherapeutic regimens, and absence of residual bulk disease. The timing of high-dose therapy is still uncertain because second-line chemotherapy can effect a high order of response in patients whose first remission lasts longer than 1 year, with 30% to 50% of patients remaining in a durable second remission at 5 years High-dose therapy carries a potential risk for toxic death in the range of 10%, and the immunosuppressive effect is likely to be additive; late serious infections may therefore occur. Most trials have shown that allogeneic transplantation offers no advantage over autologous transplantation. The toxicity of the former approach in heavily treated immunosuppressed patients is limiting. Patients who achieve only a partial initial remission or who relapse within 1 year represent a major challenge for salvage therapy and could be considered for a high-dose program. Both of the major regimensCBV (cyclophosphamide, carmustine, and etoposide) and BEAM (carmustine, etoposide, cytarabine, and melphalan)contain carmustine, which should be used with caution in patients with pulmonary compromise or in those who have had extensive irradiation to the chest. The long-term (approximately 5-year) disease-free benefit from high-dose therapy is determined by the patient mix and can vary between 20% and 40%. The introduction of hematopoietic growth factors has shortened the duration of neutropenia. The impact of modern therapy has been such that almost 75% of all patients who present with Hodgkins disease may be cured. Patients should continue to be monitored for recurrence, late infections, and neoplastic complications.. The majority of relapses occur by 3 years, but a few late recurrences will be noted with continued follow-up. Infectious diseases should be treated aggressively because residual impairment of immune function persists despite remission or cure of the disease.