Lymphomas of the Head and Neck Treatment & Management

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 is 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 [Adriamycin], etoposide, procarbazine, prednisolone, vincristine, and bleomycin with granulocyte colony-stimulating factor) are being investigated. However, ABVD remains the standard of care.

• HL - 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. ^[13]

    • 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 although 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 applied to bulky sites produces a progression-free survival of over 80%. The German Hodgkin Study Group investigated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). ^[14] Although this therapy was associated with increased toxicity, elevated-dose BEACOPP has shown promising results in terms of reduced induction failures and decreased rates of treatment failure and is an alternative to ABVD. 

  • 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, although regimens for aggressive NHL may be considered.

    • Rituximab has demonstrated good activity in this disease.

• HL - 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 rate 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). Augmented ICE (augICE) therapy is also an option but is an intensive regimen. ^[15]

  • 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 (ASCT) should also be seriously considered for patients with sensitive disease who have a relapse after 12 months. Complete responses on pre-ASCT PET scans are an indicator of better prognosis after ASCT. ^[15]

  • Patients with disease remaining after curative options have been exhausted are often still responsive to chemotherapy. Such patients may achieve lasting benefit from long-term treatment with single agents such as vinblastine, gemcitabine, or etoposide. Brentuximab vedotin, which targets CD30, has been approved for the treatment of patients with relapsed HL and has high response rates. ^[16] In addition, investigational therapies for HL include the use of monoclonal antibodies, radioimmunoconjugates, tumor vaccines, or immunotherapy, as well as allogeneic stem-cell transplantation.

  • Fifteen to 30 percent of patients with HL do not achieve long-term remission. Autologous stem-cell transplantation offers an additional, possibly curative treatment for those in whom initial combination chemotherapy fails, but this is only effective in about 50% of patients. CD30 is expressed on Hodgkin Reed-Sternberg cells, anaplastic large-cell lymphomas, embryonal carcinomas, and mature T-cell lymphomas and is a target for therapy.

  • The new drug brentuximab vedotin consists of the CD30-specific monoclonal antibody cAC10 attached to an antitubulin agent, monomethyl auristatin E (MMAE), for more effective antitumor activity. It is indicated in patients with CD30-positive tumors and relapsed or refractory disease. A multi-institutional study was performed with a total of 45 patients; it demonstrated an acceptable dose for its safety profile using a 1.8 mg/kg dose given every 3 weeks. The most common adverse effects, which were usually grade 1 or 2 in severity, were fatigue, pyrexia, diarrhea, neutropenia, nausea, and peripheral neuropathy. Complete regression was noted in 11 out of 17 patients with objective responses. Tumor regression observed on CT scan was noted in 36 out of 42 patients who could be evaluated at the end of the study. Thirteen patients with disease-related symptoms (out of 16 patients who reported them) had resolution of symptoms during treatment. The objective response had a median duration of 9.7 months or more, with median progression-free survival being 5.9 months. ^[2]

  • Brentuximab vedotin as a single agent or in combination with PD-1 blockade and other chemotherapy regimens prior to ASCT has been evaluated. In one study, patients with disease progression after initial treatment underwent single-agent brentuximab vedotin therapy. Those with complete or near-complete responses on PET scanning then underwent ASCT, and those who did not received more brentuximab vedotin with augICE treatment before undergoing ASCT. Of the 65 patients enrolled, 27% achieved complete response to brentuximab vedotin, and 83% achieved complete response to the brentuximab vedotin/augICE regimen. Sixty-four patients underwent ASCT, and 82% were progression-free at 3 years.

  • Brentuximab vedotin with bendamustine has been evaluated as well and shows promise, but it is associated with higher toxicities. Brentuximab vedotin with nivolumab is also showing promise as a treatment strategy, as it is effective, with more tolerability and, in one study with 62 patients, was associated with complete response rates approaching 61%. Research into brentuximab vedotin with pembrolizumab is also showing promising results, as has an investigation of brentuximab vedotin plus nivolumab and ipilimumab. ^[15]

  • Chimeric antigen receptor (CAR) T cells targeting CD30 are also being examined. ^[15]

  NHL

  • 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. Evidence has indicated that patients who are symptomatic and have untreated advanced-stage follicular lymphoma may benefit from receiving the combination of CHOP chemotherapy and 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 a regimen such as 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 alone, 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 (stage I or II) disease may be treated with combined modalities, although 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 age 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. A modified CHOP regimen, such as dose-dense CHOP (given every 2 wk) or etoposide plus CHOP (CHOEP) has also been evaluated, but no definitive and convincing evidence suggests that either should replace standard R-CHOP given on a 21-day schedule. Autologous stem-cell transplant consolidation in untreated DLBCL is under investigation, but most 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 ASCT, but 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. ^[17]

    • Primary CNS lymphoma (PCNSL) is a rare DLBCL usually confined to the CNS. Although these lymphomas 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 of 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 gastrointestinal tract, although it may involve the tonsils and head and neck nodes. Recently, bortezomib was found to be 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. ^{[18, 19]}

    • Lymphomas are also seen after solid-organ transplantation, when they are generally associated with an infection with 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, some do not fit into a specific subtype and are classified as peripheral T-cell lymphoma unspecified.

  • 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 peripheral T-cell lymphoma, not otherwise specified, also have poor outcomes, with a low incidence of cure. T-cell lymphoblastic lymphomas are highly aggressive and are treated with regimens that include intrathecal chemotherapy.

Surgery is performed only in select cases. Surgical intervention may be pivotal in obtaining biopsy specimens for histopathologic and immunophenotypic characterization of the lymphoproliferative disorder.

Medical oncologists work closely with radiation oncologists, head and neck oncologic surgeons, and pathologists to establish diagnoses and treatment courses and to provide follow-up care by means of multidisciplinary conferences.