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Lymphomas of the Head and Neck Treatment & Management

  • Author: Kieron M Dunleavy, MD; Chief Editor: Arlen D Meyers, MD, MBA  more...
 
Updated: Aug 04, 2015
 

Medical Care

In the past, the standard chemotherapeutic regimen used for HL was mechlorethamine (nitrogen mustard), vincristine, procarbazine, and prednisolone (MOPP). However, this regimen was associated with infertility, a 2% incidence of myelodysplasia/acute leukemia at 4-6 years after treatment, and a 3% incidence of fatal febrile neutropenia. ABVD is a regimen of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine. ABVD is superior to MOPP alone and now considered the standard of care in HL. The incidence of infertility is lower with ABVD than with MOPP, but fatal pulmonary toxicity can occur with bleomycin.

In advanced HL, intensified regimens such as the escalated BEACOPP (ie, cyclophosphamide, doxorubicin, etoposide, procarbazine, prednisolone, vincristine, and bleomycin with granulocyte colony-stimulating factor) are being investigated. However, ABVD remains the standard of care.

  • Hodgkin lymphoma - Initial therapy
    • Classic HL: For the purpose of selecting therapy, the European Organization for Research and Treatment of Cancer (EORTC) divides patients with early-stage (I or II) classic HL into favorable or unfavorable groups based on the presence of at least 1 of the following adverse factors: large mediastinal mass, age > 50 years, elevated ESR, and involvement of 4 or more lymph-node regions. Advanced stages are III and IV.
      • Stage I or II favorable disease: Although extended-field radiotherapy alone was the standard of care for several years, most groups now favor combined chemotherapy and radiation or combined chemotherapy alone, and a recent study has demonstrated a better overall survival for patients who receive chemotherapy alone.[3]
      • Stage I and II unfavorable disease: Chemotherapy with or without radiation is standard of care.
      • Stage III or IV disease: For advanced disease, combination chemotherapy, such as ABVD, is the standard of care. Patients generally receive 2 cycles of therapy beyond complete remission (for a minimum of 6 and maximum of 8 cycles). Patients with bulky mediastinal disease often receive consolidative irradiation. Radiation therapy is sometimes omitted in select patients who have complete remission and negative PET scans.
      • Although the outcome with ABVD in these stages is good (event-free survival of about 70%) and though it remains the standard of care, intensive regimens are being investigated. The Stanford V regimen, which combines chemotherapy (mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone) with consolidative radiotherapy to bulky sites produces a progression-free survival of over 80%. The German Hodgkin Lymphoma study group investigated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). Although this therapy was associated with increased toxicity, elevated-dose BEACOPP has shown promising results in terms of reducing induction failures and decreased rates of treatment failure.
    • In contrast to classic HL, nodular lymphocyte predominant HL is a rare subtype that is biologically similar to indolent B-cell lymphoma.
      • The 10-year survival rate for patients with early-stage disease without treatment is greater than 80%; therefore, the role of therapy in asymptomatic patients is unclear, nevertheless radiation or rituximab alone is often used.
      • Advanced-stage disease is usually treated like HL in patients with an unfavorable prognosis, though regimens for aggressive NHL may be considered.
      • Rituximab has demonstrated good activity in this disease.
  • Hodgkin lymphoma - Therapy for relapsing or refractory disease
    • For patients who have had early-stage disease and relapse after receiving radiation therapy alone, regimens such as ABVD are highly effective and result in high relapse-free survival rates of about 70% at 10 years.
    • For patients who have relapse after receiving combined-modality therapy or chemotherapy alone, the same or another combination chemotherapeutic regimen can be used if the duration of remission exceeds 12 months. The relapse-free survival at 5 years is 50%.
    • Regimens used for salvage therapy in HL include ABVD; etoposide, methylprednisolone, high-dose cytarabine, and cisplatin (ESHP); ifosfamide, cisplatin, and etoposide (ICE); and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and hydroxy-daunorubicin (DA-EPOCH).
    • For patients in whom induction fails or who have a relapse within a year of initial chemotherapy, the outcome with standard chemotherapy is poor. High-dose chemotherapy (with or without radiotherapy) followed by autologous hematopoietic stem-cell transplantation is the standard therapy for patients with responsive disease.
    • Autologous stem-cell transplantation should also be seriously considered for patients with sensitive disease who have a relapse after 12 months.
    • Patients with disease after curative options have been exhausted are often still responsive to chemotherapy. Such patients may achieve long-term benefit from chronic treatment with single agents, such as vinblastine, gemcitabine, or etoposide. Recently, brentuximab, which targets CD30, was approved for the treatment of patients with relapsed HL and has high response rates.[4] In addition, investigational therapies for HL include use of monoclonal antibodies, radioimmunoconjugates, tumor vaccines, or immunotherapy and also allogeneic stem-cell transplantation.
  • Non-Hodgkin lymphoma
    • Indolent B-cell lymphoma: These lymphomas include multiple subtypes, such as follicular and small lymphocytic lymphoma, and they are generally considered incurable with conventional therapy. The tumors are characterized by an indolent course, and because patients can remain well for several years without therapy, a watch-and-wait strategy is often used. When this is the case, indications for therapy include symptomatic or aggressive disease, bulky lymphadenopathy, hypersplenism, or bone-marrow infiltration causing cytopenias. Recently, evidence has shown that patients who are symptomatic and have untreated advanced stage follicular lymphoma, may benefit from receiving the combination of CHOP chemotherapy with rituximab.
      • In select patients with early-stage follicular lymphoma, irradiation alone is associated with a 10-year disease-free survival rate of over 60%. Although no prospective study has been performed to compare irradiation with observation, findings from a recent retrospective analysis from Stanford University suggest that irradiation may not improve the survival of patients with early disease over observation alone.
      • Several drugs are effective. Fludarabine has high response rates and is useful in untreated and previously treated patients, as are alkylating agents such as cyclophosphamide and prednisone. Anti-CD20 monoclonal antibody is increasingly used; it is effective in treated patients and in up to 73% of untreated patients. In combination with fludarabine or regimens such as cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone (CHOP), rituximab is effective and may have a role in maintenance therapy. A phase III study showed that rituximab and CHOP (R-CHOP) improved survival compared with CHOP, raising the issue of whether R-CHOP should be the new standard.
      • Radioimmunotherapy is a relatively new treatment for relapsing follicular lymphoma. It involves radiotherapy targeted to tumor tissue by conjugating anti-CD20 antibody to yttrium-90 or iodine-131. Ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar) are approved for relapsing or refractory follicular lymphoma and have an overall response rate of up to 80%. Their role in previously untreated disease has still not been established and remains under investigation.
      • Both autologous and allogeneic stem-cell transplantation are being evaluated in follicular lymphoma. Idiotype vaccination, made by conjugating and immunologically manipulating tumor-specific antigen for in vitro and bcl-2 antisense therapy is aimed at decreasing bcl-2 oncoprotein.
    • Aggressive B-cell lymphomas: These include DLBCL, Burkitt lymphoma, mantle-cell lymphoma, and lymphoblastic lymphoma. With the exception of mantle-cell lymphoma, these tumors are potentially curable.
      • DLBCL is the most common histologic subtype. All stages of disease require systemic chemotherapy; irradiation alone is inadequate. Early-stage (I or II) disease may be treated with combined modalities, though the benefit of irradiation is controversial and it adds the problem of long-term toxicities which can be very serious.
      • Chemotherapy followed by consolidation radiotherapy has 5-year overall survival and progression-free survival rates of up to 80%. Rituximab-based chemotherapy and the observation that radiation does not improve overall survival strengthen the case for immunochemotherapy alone.
      • Primary mediastinal DLBCL (PMBCL) is a potential exception in that consolidation radiotherapy appears to be necessary after standard chemotherapy. However, results with DA-EPOCH and rituximab (DA-EPOCH-R) suggest that this regimen may obviate the need for radiation treatment in most patients. This is particularly important in this disease, considering that it typically occurs in young women who have a much higher risk of developing breast and other cancers after receiving mediastinal radiation.
      • Stage III or IV DLBCL is treated with combination chemotherapy. CHOP, developed more than 25 years ago, remains the standard combination and cures about one third of all cases. In a randomized study, the addition of rituximab improved event-free and overall survival and has led to the emergence of R-CHOP as the de facto standard in DLBCL.
      • Several other regimens are used to treat DLBCL. In patients with a poor prognosis over 60 years, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ADVBP) is associated with improved overall and event-free survivals compared with CHOP. DA-EPOCH-R has progression-free and overall survival rates of approximately 80% at 2-year follow-up. Modified CHOP regimen, such as dose-dense CHOP (given every 2 wk) and etoposide plus CHOP (CHOEP) have also been evaluated, but no definitive and convincing evidence suggests that they should replace standard R-CHOP given on a 21-day schedule. Autologous stem-cell transplant consolidation in untreated DLBCL is under investigation, but most previous results do not suggest any benefit over standard approaches.
      • Relapsing DLBCL should be treated with salvage chemotherapy, such as rituximab and ICE (R-ICE), ESHAP, or DA-EPOCH-R. Patients with responsive disease are often treated with autologous stem-cell transplantation, though cure rates are relatively low. In patients who have a chemosensitive relapse without marrow involvement of the bone, high-dose therapy usually offers the best opportunity for a response and remission. The value of autologous transplantation at relapse may diminish because more patients are being cured with R-CHOP (compared with CHOP in the past) given as initial therapy.[5]
      • Primary CNS lymphoma (PCNSL) is a rare DLBCL usually confined to the CNS. Although they have DLBCL histology, their clinical behavior is distinct from systemic DLBCL, a feature that indicates different biology. Several important drugs used for the treatment of systemic DLBCL achieve low CNS concentrations because they do not cross the blood-brain barrier. Methotrexate, which has excellent CNS penetration, is the core of chemotherapeutic regimens for PCNSL; alone, it produces response rates up to 50%. Irradiation is also effective, but responses are short lived. New treatment paradigms combine several drugs with good CNS penetration and rituximab, with or without irradiation.
    • Other aggressive B-cell lymphomas
      • Burkitt lymphoma is a highly aggressive B-cell lymphoma that can cause disease in the head and neck region. It is curable with systemic chemotherapy. Intensive regimens are typically used and include intrathecal chemotherapy. Lymphoblastic lymphoma is usually of the T-cell phenotype and usually affects the mediastinum; this is curable with aggressive chemotherapy.
      • Mantle-cell lymphoma is a B-cell lymphoma that has a moderately aggressive clinical course. Current treatments are rarely curative, and patients have a median survival of 3-5 years. Treatments range from aggressive combination chemotherapy to allogeneic transplantation. In asymptomatic patients, particularly in older patients, a watch-and-wait approach is reasonable. The disease has a high predilection for the GI tract, though it may involve the tonsils and head and neck nodes. Recently, bortezomib was found to be very effective in the treatment of relapsed and refractory mantle cell lymphoma and is being evaluated in the up-front setting.
    • Aggressive B-cell lymphomas in patients with immunocompromise
      • Patients with HIV infection have a significantly increased incidence of lymphoma. The risk is increased approximately 1000-fold for Burkitt lymphoma and 400-fold for aggressive lymphoma. Many of these lymphomas are highly curable and should be treated with systemic chemotherapy. Recent studies show excellent outcomes with EPOCH-R chemotherapy.[6, 7]
      • Lymphomas are also seen after solid-organ transplantation, when they are generally associated with an infection with Epstein-Barr virus (EBV).
      • The spectrum of disease is wide, and treatment options include the withdrawal of immunosuppression, rituximab, and chemotherapy. Whether combination antiretroviral therapy (cART) should be suspended during chemotherapy is controversial
  • T-cell lymphomas: Patients with T-cell lymphoma can present with disease in the head and neck region, but these tumors are less common than B-cell lymphomas. In general, T-cell lymphomas involve the nodal regions, but skin involvement with cutaneous T-cell lymphomas can also occur. Extranodal NK/T-cell lymphomas specifically involve the nasal sinuses. These lymphomas are derived from mature T-cells and have been subdivided into a number of distinct pathologic entities. However, a portion does not fit into a specific subtype and are classified as peripheral T-cell lymphoma unspecified (PTCL-U).
    • Extranodal NK/T-cell lymphoma, nasal type: The sites of predilection for this particular disease are the nasal cavity, nasopharynx, and palate. Patients with this are variable, but localized disease can be treated very effectively with radiation. The prognosis for those with disseminated disease is poor.
    • Other peripheral T-cell lymphomas: Anaplastic large-cell lymphoma (ALCL) tends to occur in young patients, and the outcome with systemic chemotherapy is good. The long-term survival rate is approximately 70% with chemotherapy. Angioimmunoblastic T-cell lymphoma is usually associated with immunodeficiency. It tends to be aggressive, and results of standard therapy are poor. Those with PTCL-NOS also have poor outcomes, with a low incidence of cure. T-cell lymphoblastic lymphomas are highly aggressive and treated with regimens that include intrathecal chemotherapy.
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Surgical Care

Surgery is only performed in select cases.

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Contributor Information and Disclosures
Author

Kieron M Dunleavy, MD Investigator/Attending Physician, National Cancer Institute

Kieron M Dunleavy, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

Coauthor(s)

Erik Kass, MD Chief, Department of Clinical Otolaryngology, Associates in Otolaryngology of Northern Virginia

Erik Kass, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Medical Association, American Association for Cancer Research, American Rhinologic Society

Disclosure: Nothing to disclose.

Wyndham Wilson, MD, PhD Senior Investigator, Division of Clinical Sciences, National Institutes of Health National Cancer Institute

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Karen H Calhoun, MD, FACS, FAAOA Professor, Department of Otolaryngology-Head and Neck Surgery, Ohio State University College of Medicine

Karen H Calhoun, MD, FACS, FAAOA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Head and Neck Society, Association for Research in Otolaryngology, Southern Medical Association, American Academy of Otolaryngic Allergy, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Medical Association, American Rhinologic Society, Society of University Otolaryngologists-Head and Neck Surgeons, Texas Medical Association

Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine

Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;SymbiaAllergySolutions<br/>Received income in an amount equal to or greater than $250 from: Symbia<br/>Received from Allergy Solutions, Inc for board membership; Received honoraria from RxRevu for chief medical editor; Received salary from Medvoy for founder and president; Received consulting fee from Corvectra for senior medical advisor; Received ownership interest from Cerescan for consulting; Received consulting fee from Essiahealth for advisor; Received consulting fee from Carespan for advisor; Received consulting fee from Covidien for consulting.

Additional Contributors

Daniel J Kelley, MD Consulting Staff, Eastern Shore ENT and Allergy Associates and Peninsula Regional Medical Center

Daniel J Kelley, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Head and Neck Society, The Triological Society

Disclosure: Nothing to disclose.

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CT scan of a patient with a natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus.
CT scan 6 months after treatment with 4 cycles of DA-EPOCH (ie, infused etoposide, doxorubicin, and vincristine with bolus cyclophosphamide and prednisone).
CT scan of a patient with a recurrence of stage I-AE angiocentric lymphoma of the left maxillary sinus, treated 7 years earlier with 4 cycles of ProMACE-MOPP (ie, prednisone, methotrexate, Adriamycin, cyclophosphamide, etoposide–mechlorethamine [nitrogen mustard], vincristine, procarbazine, and prednisone) and 3960 cGy of radiation.
CT scan 2 years after salvage therapy.
Fiberoptic nasal examination of a patient with natural killer (NK)/T-cell lymphoma of the right nasal cavity and maxillary sinus.
 
 
 
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