Abraham S. Kanate, Michael Craig, Jame Abraham, Wyndham H. Wilson and Elaine S. Jaffe
Hodgkin lymphoma (HL) is named after Thomas Hodgkin, who first described some neoplastic disorders of the lymphatic system in 1832. The 2008 World Health Organization (WHO) classification of hematologic neoplasms divides HL into two distinct types. Classical Hodgkin lymphoma (CHL) is characterized by the presence of multinucleated giant cells of B-cell origin, known as Reed-Sternberg (RS) cells, in a background of numerous reactive lymphocytes. HL is one of the few malignancies for which there is effective combination therapy with chemotherapy and/or radiation, which has translated to over 80% cure rates and a steady decline in mortality. The high cure rate for HL has led to more emphasis on regimen-related long-term toxicities in the recent years. CHL is considered a distinct clinicopathalogic entity from nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).
EPIDEMIOLOGY
Hodgkin lymphoma is among the most common cancer of young adults. HL constitutes approximately 1% of all malignancies and 18% of all lymphomas. In 2012, it is estimated that 9,060 new cases of HL will be diagnosed with 1,190 patient deaths in the United States.1 In Europe and North America, there is a bimodal age distribution, with an increasing frequency between the second and third decades, and a second peak after the fifth decade.
PATHOLOGIC CLASSIFICATION
Table 15.1 lists the World Health Organization Revised European American Lymphoma classifications, in comparison to older historical schemes.2
Classic HL.
Nodular sclerosis classic Hodgkin lymphoma (NSCHL).
Mixed cellularity classical Hodgkin lymphoma (MCCHL).
Lymphocyte-depleted classical Hodgkin lymphoma (LDCHL).
Lymphocyte-rich classical Hodgkin lymphoma (LRCHL).
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).
The immunophenotypes for CHL and NLPHL are described in Table 15.2.3
PATHOLOGY
Hodgkin lymphoma is unique among the malignant lymphomas in that the RS cells and variants, the malignant cells, constitute the minority of cells present in the tumor mass (Fig. 15.1). The neoplastic cells in CHL are associated with a rich inflammatory background of lymphocytes, eosinophils, neutrophils, histiocytes, and plasma cells in varying proportions. New molecular studies have provided evidence for the B-cell origin of the neoplastic cell in both CHL and NLPHL, as the cells have undergone somatic mutations in the immunoglobulin variable region. However, the tumor cells down regulate the B-cell program and are typically negative for most B-cell associated markers,4and they show constitutive activity of nuclear factor-kappa beta (NF-kB).
NSCHL requires the presence of a nodular growth pattern, broad bands of fibrosis, and a characteristic variant of the RS cell known as a lacunar cell. The lacunar cell has abundant clear cytoplasm with a sharply demarcated cell membrane. In formalin-fixed tissue a characteristic artifact often occurs; the cytoplasm of the cell retracts, leaving a clear space or lacuna. NSCHL is graded according to the proportion of neoplastic cells and the presence of necrosis, as well as depletion of normal lymphocytes. Two grades of NSCHL are identified in the WHO classification.2 This is the most common form of CHL, comprising 60% to 70% of cases, and has an equal distribution in males and females. NSCHL often involves mediastinal, supraclavicular, and cervical lymph nodes.
MCCHL is characterized by numerous classical RS cells in a rich inflammatory background, with fine reticular fibrosis but with the absence of distinct fibrous bands. MCCHL is more common in males and is the second most common type of CHL, affecting. MCCHL is frequently associated with disseminated disease at presentation, and B symptoms are also common. It is one of the variants of CHL that occurs with HIV infection and is the subtype most often positive for Epstein-Barr virus (EBV) sequences.2
FIGURE 15.1 Diagnostic Reed-Sternberg cell seen in classic types of Hodgkin lymphomas (mixed cellularity, nodular sclerosis, lymphocyte depletion). Neoplastic cells in nodular lymphocyte-predominant Hodgkin lymphomas are termed popcorn cells or L and H cells (lymphocytic or histiocytic predominance). Reed-Sternberg cells of the classic type generally are not seen in a nodular lymphocyte-predominant Hodgkin lymphoma.
LDCHL is the rarest CHL, constituting approximately 1% of cases. Epidemiologically, it is seen in resource-limited regions of the world, and with increased frequency in HIV-infected individuals. LDCHL may represent a further evolution of MCCHL, with more frequent malignant cells, a depletion of normal lymphocytes, and greater fibrosis, which is often diffuse and reticular in nature. Patients can be elderly and present with B symptoms and at an advanced stage.
LRCHL is characterized by a cellular milieu of abundant normal lymphocytes, and a paucity of malignant cells that have the immunophenotype of classic RS cells. LRCHL may have a diffuse or nodular growth pattern, and especially in its nodular form may be mistaken for nodular lymphocyte-predominant HL. It tends to present in older individuals, often with isolated peripheral lymphadenopathy.
NLPHL differs from CHL in its immunophenotype, histologic characteristics, and clinical behavior.3 Classical RS cells are not seen. The neoplastic cells initially referred to as lymphocytic and histiocytic (L & H) cells are now called LP cells or more informally “popcorn cells.” They have a lobulated nuclear contour, dispersed chromatin, and inconspicuous nucleoli, and generally cluster within nodules associated with lymphocytes and histiocytes. Initially, the background lymphocytes are predominantly of B-cell phenotype, but T cells may predominate in later stages. The neoplastic cells, the LP cells, are positive for CD20, generally negative for CD15, and negative or weakly positive for CD30. NLPHL affects patients of all ages, and occurs more often in males than females. B symptoms are infrequent, and patients tend to have an indolent course but with multiple relapses over time, similar to low-grade non-Hodgkin lymphoma.
ETIOLOGY AND RISK FACTORS
EBV has been linked to many cases of CHL, but is absent in NLPHL. EBV is most commonly found in MCCHL and LDCHL but rarely in NSCHL. Infectious mononucleosis appears to be a predisposing risk factor for subsequent EBV-positive CHL but not EBV-negative CHL.5 NSCHL is most common in North America and is more prevalent among individuals of higher socioeconomic status, whereas MCCHL and LDCHL are seen in resource-limited regions of the world. The risk of CHL is increased 5- to 10-fold in HIV-positive patients. Familial cases of CHL have been reported, and siblings of CHL patients are at slightly increased risk. There is a weak association with certain HLA types.
CLINICAL FEATURES
Over 80% of patients have cervical lymph node enlargement, and more than 50% will have mediastinal adenopathy. Lymph nodes are usually nontender, firm, and rubbery.
Constitutional symptoms (“B” symptoms):
Unexplained fever (temperature >38°C, which may be cyclical).
Drenching night sweats.
Unexplained weight loss (>10% of body weight, over 6 months before the diagnosis).
Other symptoms include fatigue, weakness, anorexia, alcohol-induced nodal pain, and pruritus.
Staging (Ann Arbor/AJCC and Cotswold) is outlined in Table 15.3.6-8
PRETREATMENT EVALUATION
Excisional biopsy (and not needle biopsy) of a prominent node is highly recommended for diagnosis.
Detailed history with attention to unexplained fever, night sweats, and significant weight loss (constitutional symptoms).
Complete physical examination, including the lymph node examination and evaluation for hepatosplenomegaly.
Laboratory tests include
Complete blood count (CBC), erythrocyte sedimentation rate (ESR).
Biochemical tests of liver function, renal function, serum lactate dehydrogenase (LDH), and serum uric acid. Pregnancy test should be included for all women of child-bearing age. HIV testing is recommended if risk factors exist.
Radiologic studies
Chest radiograph and computed tomography (CT) scan of the chest, abdomen, and pelvis.
The use of positron emission tomography (PET) scan, often combined with CT has emerged as a powerful tool and is recommended in the initial staging and subsequent follow-up. 9
Bone marrow biopsy of the posterior iliac crest for those with abnormal CBC or clinical stage IIB, III, or IV.
Pulmonary function tests (PFT) with diffusion capacity for carbon monoxide and cardiac evaluation for the ejection fraction is useful prior to initiating therapy.
Adequate counseling for semen/oocyte cryopreservation should be considered for certain treatment regimens and pelvic radiation therapy.
Prognostic Features
Unfavorable prognostic features for stage I/II disease include
Sedimentation rate of 50 or more in the absence of B symptoms.
Age greater than 50.
Presence of B symptoms (fever and loss of weight).
Greater than 3 sites of nodal involvement.
More than 1 area of extranodal involvement.
Bulky adenopathy including mediastinal disease more than one-third of the chest diameter on chest x-ray or tumor size >10 cm on CT scan.
The International Prognostic Factors Project on Advanced Hodgkin lymphoma prognostic score (for advanced disease only, 1 point for each positive factor):
Albumin level of less than 4.0 g/dL.
Hemoglobin level of less than 10.5 g/dL.
Male sex.
Age of 45 years or older.
Stage IV disease.
White blood cell count greater than 15,000/mm3.
Absolute lymphocyte count of less than 600/mm3 or a lymphocyte count less than 8% of the total white cell count.
The 5-year progression-free survival according to the international prognostic score are as follows: 0 factors 84%; 1 factor 77%; 2 factors 67%; 3 factors 60%; 4 factors 51%; and 5 or greater factors 42%.10
NLPHL histology portends a more indolent disease course. The presence of increased tumor-related CD68+ (>5%) macrophages has recently been shown to be associated with poorer disease-specific survival in multivariate analysis.11
MANAGEMENT OF NEWLY DIAGNOSED CLASSICAL HODGKIN LYMPHOMA
The goal of therapy for CHL is cure while limiting the early and delayed therapy related toxicity without compromising outcomes. Advances in the systemic treatment of CHL have dramatically improved the response rate and survival. This improvement is mainly due to careful staging, understanding of the pattern of spread, and advances in radiation and chemotherapy. In general, combination chemotherapy with or without radiation is used for most patients with CHL.12 Therapy with radiation consists of treating regions of known disease (especially if bulky) +/− adjacent nodal groups. Treatment selection is influenced by stage, prognostic factors, and short- and long-term toxicity. Response criteria for lymphoma, incorporating PET scan results, have been updated by a consensus panel.9
Radiation Therapy
Because of the availability of effective chemotherapy regimens, radiation as a single mode of treatment is rarely used in HL, except in some cases of early-stage NLPHL. Involved field radiation therapy (IFRT) was shown to have similar freedom from treatment failure and overall survival (OS), with better tolerabiltiy and toxicity profile compared to extended field radiation therapy (EFRT, including adjacent clinically negative nodal sites).13 Classically, radiation therapy was delivered to three major fields: the mantle, paraaortic, and pelvic or inverted-Y fields (Fig. 15.2). The appropriate dose of radiation is traditionally described as 25 to 30 Gy to clinically uninvolved sites, and 30 to 40 Gy to regions of initial nodal involvement. Newer treatment strategies/clinical trials aim to reduce or eliminate radiation exposure. Long-term sequelae of radiation include cardiopulmonary disease, lung cancer (especially in smokers), and breast cancer.
Chemotherapy Regimens
With combination chemotherapy long-term disease-free remissions are the norm, even in advanced CHL. The first “curative regimen” was mechlorethamine, Oncovin (vincristine), procarbazine, prednisone (MOPP), which resulted in about 70% complete remission in stage III–IV patients. Historically, MOPP was considered the standard treatment for advanced CHL. Subsequently many regimens that included Adriamycin (doxorubicin) were developed. The first of these was doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and hybrids of MOPP and ABVD. In a randomized study, the Cancer and Leukemia Group B (CALGB) compared three regimens (Table 15.4), the results showing that ABVD alone or MOPP/ABVD was superior to MOPP alone, in terms of remission, freedom from progression, and survival.14 An intergroup study of ABVD versus MOPP-ABV showed equivalency but higher hematologic and pulmonary toxicity with MOPP-ABV. Studies have consistently shown that ABVD is less toxic and more effective than MOPP, with better rates of freedom from progression and OS. At 10 years, the risk of developing treatment-related leukemia with the MOPP regimen is 2% to 3%, whereas it is 0.7% with ABVD.15 ABVD is considered the standard treatment option in North America.
The German Hodgkin Study Group (GHSG) developed the bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide, Oncovin (vincristine), procarbazine, and prednisone (BEACOPP) regimen to improve treatment outcomes in HL. The HD9 clinical trial for patients with advanced-stage CHL using COPP/ABVD, BEACOPP, or increased-dose BEACOPP, and consolidative radiation therapy to sites of initial bulky (5 cm or larger) or residual disease, showed a 5-year OS of 83% for COPP/ ABVD, 88% for BEACOPP, and 91% for increased-dose BEACOPP.16 The actuarial rate of secondary acute leukemia 5 years after diagnosis of HL was 0.4% for COPP/ABVD, 0.6% for BEACOPP, and 2.5% for increased-dose BEACOPP (P = 0.03). Although this study suggests that dose intensity improves the survival of Hodgkin lymphoma, the improvement must be balanced against the increased toxicity and risk of leukemia.17 BEACOPP is considered unsuitable for patients over age 65, associated with significant noted, the primary end point of this trial was freedom from first progression and secondary end points included OS and freedom from second progression and EFS after initial therapy.
Results: BEACOPP superior to ABVD in freedom from first progression, however when salvage therapy with auto-transplant is included BEACOPP and ABVD where equal with regards to OS and freedom from second progression, suggesting patients who relapse after ABVD can be effectively salvaged with HDT and auto-HCT, shielding the majority of patients from the toxicity profile of using upfront BEACOPP.
The abbreviated 12-week chemoradiotherapy regimen, Stanford V, was developed to increase chemotherapy dose intensity by alternating myelosuppresive and non-myelosuppressive treatments weekly, and is given in combination with radiation to sites of disease.19 Radiation therapy (to nodal sites >5 cm and macroscopic splenic disease) is an integral part of the regimen. The Eastern Cooperative Oncology Group clinical trial E2496 (published in abstract form) compared ABVD to Stanford V. Disease-specific and survival outcomes were similar in both groups at 5 years. There was more grade 3 lymphopenia and sensory neuropathy in the Stanford V arm.20 Another randomized trial showed Stanford V to be inferior to ABVD if the prescribed radiation treatment is modified.21
FIGURE 15.2 Radiation therapy fields used in treating Hodgkin disease.When the fields shown in C and D are combined, this is commonly called total nodal irradiation (TNI). (From Haskell CM. Cancer Treatment. 4th ed. Philadelphia, PA: WB Saunders; 1995:965)
Commonly used regimens include
ABVD: doxorubicin + bleomycin + vinblastine + dacarbazine.
BEACOPP: bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone.
COPP/ABVD: cyclophosphamide + vincristine + procarbazine + prednisone/doxorubicin + bleomycin + vinblastine + dacarbazine.
MOPP: mechlorethamine + vincristine + procarbazine + prednisone.
MOPP/ABV hybrid: mechlorethamine + vincristine + procarbazine + prednisone/doxorubicin + bleomycin + vinblastine.
Stanford V: doxorubicin + vinblastine + mechlorethamine + etoposide + vincristine + bleomycin + prednisone. Radiation therapy is added to the involved field.
CHOOSING A TREATMENT REGIMEN
For treatment selection, patients may be divided into three major groups:
Stages IA and IIA without the poor prognostic factors detailed above are considered “favorable early stage” and are at low risk for recurrence. Cure rate is >90%.
Stages IB–IIB and stages I–II with poor-risk features are considered “unfavorable early disease.” Cure rate is >80%.
Stages III and IV are considered “advanced stage” and are at significant risk for recurrence. Cure rate is about 60% to 70%.
Treatment Recommendations for Classical Hodgkin Lymphoma
In addition to the following information, Table 15.5 details commonly used treatment regimens.
Table 15.5 Commonly Used Treatment Regimen
ABVD
Doxorubicin, 25 mg/m2 per dose IV push for two doses, days 1 and 15 (total dose/cycle, 50 mg/m2)
Bleomycin, 10 U/m2 per dose IV push for two doses, days 1 and 15 (total dose/cycle, 20 U/m2)
Vinblastine, 6 mg/m2 per dose IV push for two doses, days 1 and 15 (total dose/cycle, 12 mg/m2)
Dacarbazine, 375 mg/m2 per dose IV infusion for two doses, days 1 and 15 (total dose/cycle, 750 mg/m2)
Treatment cycle repeats every 28 d
MOPP
Mechlorethamine, 6 mg/m2 per dose IV push for two doses, days 1 and 8 (total dose/cycle, 12 mg/m2)
Vincristine, 1.4 mg/m2 per dose IV push for two doses, days 1 and 8 (total dose/cycle, 2.8 mg/m2)
Procarbazine, 100 mg/m2/d orally for 14 doses, days 1–14 (total dose/cycle, 1400 mg/m2)
Prednisone, 40 mg/m2/d orally for 14 doses, days 1–14 (cycles 1 and 14 only) (total dose/cycle, 560 mg/m2)
Treatment cycle repeats every 28 d.
Alternating MOPP/ABVD
Alternate MOPP and ABVD cycles by 28 d
MOPP/ABV Hybrid
Mechlorethamine, 6 mg/m2 IV push day 1 (total dose/cycle, 6 mg/m2)
Vincristine, 1.4 mg/m2 IV push day 1 (total dose/cycle, 1.4 mg/m2; maximal dose, 2 mg)
Procarbazine, 100 mg/m2/d orally for 7 doses, days 1–7 (total dose/cycle, 700 mg/m2)
Prednisone, 40 mg/m2/d orally for 14 doses, days 1–14 (total dose/cycle, 560 mg/m2)
Doxorubicin, 25 mg/m2 IV push day 8 (total dose/cycle, 25 mg/m2)
Hydrocortisone, 100 mg IV day 8, before bleomycin (total dose/cycle, 100 mg)
Bleomycin, 10 U/m2 IV push day 8 (total dose/cycle, 10 U/m2)
Vinblastine, 6 mg/m2 IV push day 8 (total dose/cycle, 6 mg/m2)
Treatment cycle repeats every 28 d
BEACOPP Standard Dose
Bleomycin, 10 mg/m2 (day 8); etoposide, 100 mg/m2 (days 1–3); doxorubicin, 25 mg/m2 (day 1); cyclophosphamide, 650 mg/m2 (day 1); vincristine, 1.4 mg/m2 (day 8); procarbazine, 100 mg/m2 (days 1–7); and prednisone 40 mg/m2 (days 1–14)
Regimen was repeated on day 22
The maximum dose of vincristine is 2 mg
Increased-Dose BEACOPP
Bleomycin, 10 mg/m2 (day 8); etoposide, 200 mg/m2 (days 1–3); doxorubicin, 35 mg/m2 (day 1); cyclophosphamide, 1250 mg/m2 (day 1); vincristine, 1.4 mg/m2 (day 8); procarbazine, 100 mg/m2 (days 1–7); and prednisone 40 mg/m2 (days 1–14)
Regimen was repeated on day 22
G-CSF starting on day 8 until count recovery
The maximum dose of vincristine is 2 mg
Stanford V
Mustard, 6 mg/m2 IV weeks 1, 5, 9
Vincristine, 1.4 mg/m2 IV weeks 2, 4, 6, 8, 10, 12 (maximal dose, 2 mg)
Prednisone, 40 mg/m2/d orally every other day, weeks 1–9, taper
Doxorubicin, 25 mg/m2 IV weeks 1, 3, 5, 7, 9, 11
Bleomycin, 5 U/m2 IV weeks 2, 4, 6, 8, 10, 12
Vinblastine, 6 mg/m2 IV weeks, 1, 3, 5, 7, 9, 11
Etoposide, 60 mg/m2 IV daily for 2 d, weeks 3, 7, 11
—The maximum dose of vincristine is 2 mg
—All drugs are administered on day 1, except for VP-16, which is given on days 1 and 2
—Taper prednisone by 10 mg of the total dose qod (every other day) on weeks 10 and 11
—Reduce the dose of vinblastine to 4 mg/m2 on weeks 9 and 11 for patients over the age of 50 yr
—Reduce the dose of vincristine to 1 mg on weeks 10 and 12 for patients over the age of 50 yr
—If mustard is unavailable, cyclophosphamide 650 mg/m2 IV on weeks 1, 5, 9 may be substituted
ABVD, doxorubicin (Adriamycin), bleomycin, vinblastin, and dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; G-CSF, granulocyte colony-stimulating factor; IV, intravenous; MOPP, mechlorethamine, Oncovin, procarbazine, and prednisone.
Favorable Early Disease
Combined modality therapy with chemotherapy (ABVD 2–4 cycles) + radiation was considered standard. Abbreviated therapy with 2 cycles of ABVD followed by 20 Gy IFRT is equally effective and far less toxic in suitable patients.22 The exclusion criteria for the trial were bulky mediastinal mass, large splenic involvement, >2 sites of disease, and elevated ESR.
In a randomized controlled trial, 4 cycles of ABVD without radiation therapy were recently shown to have superior 12-year DFS and OS, compared to radiation therapy as a treatment strategy.23Notwithstanding the radiation protocol in the trial, which involved administering 35 Gy of subtotal nodal irradiation (no longer considered standard), chemotherapy alone with ABVD alone likely represents an effective alternative. The ongoing HD16 trial by GHSG compares ABVD for 2 cycles with or without radiation (20 Gy IFRT), guided by functional PET/CT imaging. Chemotherapy alone may be considered for patients with early-stage disease.
Unfavorable Early Disease
ABVD 4–6 cycles followed by IFRT. Restaging PET/CT after 2 cycles of ABVD can guide therapy, 2 additional cycles after a complete response is considered followed by consolidative IFRT 30 to 36 Gy. Alternatively, patients may be treated with ABVD × 6 cycles without radiation.
Massive mediastinal disease (defined as a mediastinal mass width greater than one-third of the maximum chest diameter or 10 cm mass) is usually treated with combined modality therapy. However, chemotherapy alone is curative in over half of patients; clinical trials are now assessing if radiation can be omitted in patients who have negative FDG-PET scans post-chemotherapy. Regimens such as ABVD should be considered for this patient group.
Advanced Disease
ABVD for 6 cycles is the current standard. Treatment is usually continued 2 cycles after resolution of disease is confirmed by imaging studies.
Increased-dose BEACOPP for patients with or without radiation treatment for poor prognosis disease (IPS score >4) may be considered in younger patients, but will likely not impact OS.
Addition of IFRT is usually considered, particularly for bulky disease. Some evidence suggests that there may be no need to add radiation, if a complete response can be achieved with combination chemotherapy.
Stanford V, if administered in the described manner, is a viable alternative in selected patients.
Role of Positron Emission Tomography Scan
PET scanning has emerged as a powerful tool in the management of HL. Integrated PET/CT scanning is invaluable in the initial evaluation and staging of the disease. Interim imaging with PET scan after 2 cycles of chemotherapy that is negative is a strong, positive prognostic factor implying better disease-free survival (DFS) and OS in multivariate analysis.25 Incorporating interim PET results to guide further therapy—example: dose reduction of chemotherapy or withholding IFRT in PET-negative patients after 2 cycles of therapy—are under evaluation. Posttreatment PET/CT is useful in identifying residual disease versus fibrosis/necrosis, but the standard for evaluation of residual/progressive disease remains biopsy and pathologic evaluation.
Lymphocyte-Predominant Hodgkin Lymphoma
This subtype is associated with the propensity for multiple relapses, even up to 15 years after presentation. Early stages of NLPHL without risk factors are treated with radiation alone or, in some cases, with observation following complete surgical resection. Advanced stages are rare at diagnosis and may have a poor prognosis. While such cases are usually treated like CHL, the unique biology of NLPHL raises the question of whether it should be treated like an aggressive B-cell lymphoma.3 Indeed, phase II trials show high single agent activity of rituximab in NLPHL, the tumor cells of which are almost always CD20 positive. The use of rituximab combined with chemotherapy in the frontline setting is still considered investigational and affected patients should be referred for trials due to the rarity of the disease.
COMPLICATIONS OF THERAPY
While the disease-specific mortality in HL has improved greatly due to the advances made in combination chemotherapy, therapy-related long-term toxicity is quite significant. It is extremely important that patients be followed by an oncologist even years after the completion of therapy.
Radiation Therapy Early Complications
Mantle field radiation may cause mouth dryness, pharyngitis, cough, and dermatitis.
Subdiaphragmatic radiation may cause anorexia and nausea.
Radiation can cause myelosuppression or thrombocytopenia.
Late Complications
Hypothyroidism.
Pericarditis and pneumonitis.
Lhermitte sign: 15% of the patients receiving mantle radiation may experience electric shock sensation radiating down the back of the legs when the head is flexed, 6 to 12 weeks after the treatment. The pathophysiology may be transient demyelinization of the spinal cord, and the syndrome usually resolves spontaneously.
Coronary artery disease (CAD): Increased risk in patients who receive cardiac radiation. Patients should be monitored and evaluated for other risk factors for CAD.
Secondary neoplasms (lung, breast, stomach, and thyroid).
Lung cancer: Twofold to eightfold increase in lung cancer is observed more than 5 years after the radiation treatment and persists through the second decade. The increased risk is greatest in inhaled tobacco users.
Breast cancer risk is inversely proportional to the age at radiation treatment. The relative risk (RR) is 136 if the patient is younger than 15 years. RR is 19 for age group 15 to 24 years. RR is 7 for age group 24 to 29 years. The high risk is restricted to women irradiated before age 30 years. Average interval between radiation and diagnosis of breast cancer is 15 years. Breast examination should be part of follow-up for women at risk; routine mammography should begin about 8 years after completion of the radiation.
Chemotherapy
Early Complications
Nausea and vomiting
Alopecia
Myelosuppression
Infection
Late Complications
Sterility (primarily with MOPP-based regimens)
Neuropathy (primarily with vincristine)
Cardiomyopathy (doxorubicin)
Pulmonary fibrosis (bleomycin)
Secondary leukemia (esc. BEACOPP, MOPP ± radiation)
RELAPSED/REFRACTORY HODGKIN LYMPHOMA
If the relapse is due to inadequate initial treatment, retreatment with chemotherapy or radiation is considered. Based on the results of two randomized trials that showed improved DFS and no difference in OS, high-dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) is considered standard. About 60% to 65% of patients can be salvaged with AHCT, but time to relapse <12 months, primary refractory disease, extranodal site of relapse, and B symptoms each portends a worse outcome. Cytoreduction with salvage chemotherapy regimen has important ramifications on the outcome of AHCT. Chemo-sensitive disease to second-line chemotherapy tends to have better outcome with AHCT. Brentuximab vedotin (SGN35) is an antibody-drug conjugate targeting CD30 + cells that was recently approved for use in relapsed HL after AHCT.24 AHCT is considered investigational therapy but may be employed in clinical research trials in refractory/progressive disease.
SALVAGE CHEMOTHERAPY REGIMENS
Non–Anthracycline-Containing Regimens
ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin).
ICE (ifosfamide, carboplatin, and etoposide).
DHAP (dexamethasone, high-dose cytarabine, and cisplatin).
EIP (etoposide, ifosfamide, and cisplatin).
Anthracycline-Containing Regimens
Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin).
EVA (etoposide, vincristine, doxorubicin).
ASHAP (doxorubicin, cisplatin, high-dose cytarabine, and methylprednisolone).
PALLIATIVE TREATMENT
Palliative treatment includes investigational treatment, radiation treatment, sequential single-agent chemotherapy (gemcitabine or vinblastine).
References
15.Swerdlow AJ, Douglas AJ, Hudson GV, et al. Risk of second primary cancers after Hodgkin’s disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation. BMJ. 1992;304:1137-1143.