Font Size
A
A
A
...
7
...

Adult Non-Hodgkin Lymphoma Treatment (Professional) (cont.)

Indolent, Noncontiguous Stage II/III/IV Adult Non-Hodgkin Lymphoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Optimal treatment of advanced stages of low-grade lymphoma is controversial because of low cure rates with the current therapeutic options. Numerous clinical trials are in progress to settle treatment issues, and patients should be urged to participate. The rate of relapse is fairly constant over time, even in patients who have achieved complete responses to treatment. Indeed, relapse may occur many years after treatment. In this category, deferred treatment (i.e., watchful waiting until the patient becomes symptomatic before initiating treatment) should be given consideration.[1,2,3] Three randomized trials compared watchful waiting to immediate chemotherapy. All three trials showed no difference in cause-specific or overall survival (OS). For patients randomly assigned to watchful waiting, the median time to require therapy was 2 to 3 years and one-third of patients never required treatment with watchful waiting (half died of other causes and half remained progression-free after 10 y).[2,4];[5][Level of evidence: 1iiA] The PRIMA trial compared watchful waiting to immediate rituximab, the anti-CD20 monoclonal antibody, with or without maintenance doses. Numerous prospective clinical trials of interferon-alpha, including SWOG-8809, have shown no consistent benefit; the role of interferon in patients with indolent lymphoma remains controversial.[6,7,8,9,10,11,12,13,14,15,16,17]

Standard therapy includes rituximab, an anti-CD20 monoclonal antibody, either alone or in combination with purine nucleoside analogs such as fludarabine or 2-chlorodeoxyadenosine, oral alkylating agents (with or without steroids), or combination chemotherapy. Since none of these therapies are curative for advanced-stage disease, innovative approaches are under clinical evaluation. The approaches include intensive therapy with chemotherapy and total-body irradiation (TBI) followed by autologous or allogeneic bone marrow transplantation (BMT) or peripheral stem cell transplantation, and the use of idiotype vaccines and radiolabeled monoclonal antibodies. Currently, no randomized trials guide clinicians about the initial choice of watchful waiting, rituximab, nucleoside analogs, alkylating agents, combination chemotherapy, radiolabeled monoclonal antibodies, or combinations of these options.[18];[3] [Level of evidence: 1iiDiii]

However, four randomized prospective studies of previously untreated patients (involving more than 1,300 patients) and one Cochrane meta-analysis including both untreated and previously treated patients (involving almost 1,000 patients) have compared rituximab plus combination chemotherapy with chemotherapy alone. Rituximab plus chemotherapy was superior in terms of event-free or progression-free survival (ranging from 2–3 years) in all of the studies and in terms of OS in all but one study (absolute benefit ranging from 6%–13% at 4 years, P < .04 and hazard ratio = 0.63 [0.51–0.79] for the meta-analysis).[19,20,21,22];[23][Level of evidence: 1iiA] All of these trials were performed in symptomatic patients who required therapy. These results do not negate watchful waiting when appropriate. In a prospective randomized trial of 465 patients with relapsed follicular lymphoma, responders to R-CHOP or CHOP were further randomly assigned to rituximab maintenance (one dose every 3 months for 2 years) or no maintenance. At 6 years' median follow-up, rituximab maintenance was better for median progression-free survival (44 months vs. 16 months, P < .001) and borderline for 5-year OS (74% vs. 64%, P = .07).[24][Level of evidence: 1iiDiii] This benefit for maintenance was evident even for patients who received rituximab during induction therapy. Most patients in both arms received extensive rituximab during post-protocol salvage treatment.

For patients with indolent, noncontiguous stage II and stage III lymphoma, central lymphatic radiation therapy has been proposed but is not usually recommended as a form of treatment.[25,26]

Standard treatment options:

  1. For asymptomatic patients, deferred therapy with careful observation.[2,27]
  2. Rituximab may be considered as first-line therapy.
    • Rituximab alone, as shown in the ECOG-E4402 trial, for example.[28,29,30,31,32]
    • R-F: rituximab plus fludarabine.[33]
    • R-CVP: rituximab plus cyclophosphamide plus vincristine plus prednisone.[21,34]
    • R-CHOP: rituximab plus cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[20,35,36]
    • R-FM: rituximab plus fludarabine plus mitoxantrone.[37]
    • R-FCM: rituximab plus fludarabine plus cyclophosphamide plus mitoxantrone.[38]
  3. Purine nucleoside analog:
    • Fludarabine.[18,39,40]
    • 2-chlorodeoxyadenosine.[41,42]
  4. Oral alkylating agents (with or without steroids):
  5. Combination chemotherapy alone:
    • CVP: cyclophosphamide plus vincristine plus prednisone.[18,45]
    • CVP followed by rituximab maintenance.[46]
    • C-MOPP: cyclophosphamide plus vincristine plus procarbazine plus prednisone.[47,48]
    • CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[43,49]
    • FND: fludarabine plus mitoxantrone plus or minus dexamethasone, as evidenced in the SWOG-9501 trial, for example.[50,51]
  6. Yttrium-90-labeled ibritumomab tiuxetan and iodine-131-labeled tositumomab are available for previously untreated and relapsing patients with minimal (<25%) or no marrow involvement with lymphoma, as was shown in the SWOG-9911 trial, for example.[52,53] Randomized prospective studies are required to determine the optimal utilization of this modality.[54]
  7. Intensive therapy with chemotherapy with or without TBI or high-dose radioimmunotherapy followed by autologous or allogeneic BMT or peripheral stem cell transplantation is under clinical evaluation.[55,56,57,58,59,60,61,62,63,64,65]
  8. Phase III trials comparing chemotherapy alone versus chemotherapy followed by anti-idiotype vaccine.[66,67,68]
  9. Extended-field radiation therapy (stage III patients only).[69]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with indolent, noncontiguous stage II adult non-Hodgkin lymphoma, indolent, stage III adult non-Hodgkin lymphoma and indolent, stage IV adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Eek R, Falkson G: The low-grade lymphoproliferative disorders. Oncology 54 (6): 441-58, 1997 Nov-Dec.
  2. Ardeshna KM, Smith P, Norton A, et al.: Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 362 (9383): 516-22, 2003.
  3. Gribben JG: How I treat indolent lymphoma. Blood 109 (11): 4617-26, 2007.
  4. Brice P, Bastion Y, Lepage E, et al.: Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15 (3): 1110-7, 1997.
  5. Longo DL: Idiotype vaccination in follicular lymphoma: knocking on the doorway to cure. J Natl Cancer Inst 98 (18): 1263-5, 2006.
  6. Smalley RV, Andersen JW, Hawkins MJ, et al.: Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. N Engl J Med 327 (19): 1336-41, 1992.
  7. Solal-Céligny P, Lepage E, Brousse N, et al.: Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial. J Clin Oncol 16 (7): 2332-8, 1998.
  8. Andersen JW, Smalley RV: Interferon alfa plus chemotherapy for non-Hodgkin's lymphoma: five-year follow-up. N Engl J Med 329 (24): 1821-2, 1993.
  9. Hagenbeek A, Carde P, Meerwaldt JH, et al.: Maintenance of remission with human recombinant interferon alfa-2a in patients with stages III and IV low-grade malignant non-Hodgkin's lymphoma. European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 16 (1): 41-7, 1998.
  10. Aviles A, Duque G, Talavera A, et al.: Interferon alpha 2b as maintenance therapy in low grade malignant lymphoma improves duration of remission and survival. Leuk Lymphoma 20 (5-6): 495-9, 1996.
  11. Arranz R, García-Alfonso P, Sobrino P, et al.: Role of interferon alfa-2b in the induction and maintenance treatment of low-grade non-Hodgkin's lymphoma: results from a prospective, multicenter trial with double randomization. J Clin Oncol 16 (4): 1538-46, 1998.
  12. Fisher RI, Dana BW, LeBlanc M, et al.: Interferon alpha consolidation after intensive chemotherapy does not prolong the progression-free survival of patients with low-grade non-Hodgkin's lymphoma: results of the Southwest Oncology Group randomized phase III study 8809. J Clin Oncol 18 (10): 2010-6, 2000.
  13. Cole BF, Solal-Céligny P, Gelber RD, et al.: Quality-of-life-adjusted survival analysis of interferon alfa-2b treatment for advanced follicular lymphoma: an aid to clinical decision making. J Clin Oncol 16 (7): 2339-44, 1998.
  14. Ozer H, Wiernik PH, Giles F, et al.: Recombinant interferon-alpha therapy in patients with follicular lymphoma. Cancer 82 (10): 1821-30, 1998.
  15. Allen IE, Ross SD, Borden SP, et al.: Meta-analysis to assess the efficacy of interferon-alpha in patients with follicular non-Hodgkin's lymphoma. J Immunother 24 (1): 58-65, 2001 Jan-Feb.
  16. Cheson BD: The curious case of the baffling biological. J Clin Oncol 18 (10): 2007-9, 2000.
  17. Rohatiner AZ, Gregory WM, Peterson B, et al.: Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol 23 (10): 2215-23, 2005.
  18. Hagenbeek A, Eghbali H, Monfardini S, et al.: Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin's lymphoma. J Clin Oncol 24 (10): 1590-6, 2006.
  19. Herold M, Haas A, Srock S, et al.: Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol 25 (15): 1986-92, 2007.
  20. Hiddemann W, Kneba M, Dreyling M, et al.: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106 (12): 3725-32, 2005.
  21. Marcus R, Imrie K, Solal-Celigny P, et al.: Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 26 (28): 4579-86, 2008.
  22. Salles GA, Mounier N, de Guibert S, et al.: Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: final analysis of the GELA-GOELAMS FL2000 study with a 5-year follow-up. [Abstract] Blood 110 (11): A-792, 2007.
  23. Schulz H, Bohlius J, Skoetz N, et al.: Combined immunochemotherapy with rituximab improves overall survival in patients with follicular and mantle cell lymphoma: updated meta-analysis results. [Abstract] Blood 108 (11): A-2760, 2006.
  24. van Oers MH, Tönnissen E, Van Glabbeke M, et al.: BCL-2/IgH polymerase chain reaction status at the end of induction treatment is not predictive for progression-free survival in relapsed/resistant follicular lymphoma: results of a prospective randomized EORTC 20981 phase III intergroup study. J Clin Oncol 28 (13): 2246-52, 2010.
  25. Jacobs JP, Murray KJ, Schultz CJ, et al.: Central lymphatic irradiation for stage III nodular malignant lymphoma: long-term results. J Clin Oncol 11 (2): 233-8, 1993.
  26. Mendenhall NP, Million RR: Comprehensive lymphatic irradiation for stage II-III non-Hodgkin's lymphoma. Am J Clin Oncol 12 (3): 190-4, 1989.
  27. Portlock CS, Rosenberg SA: No initial therapy for stage III and IV non-Hodgkin's lymphomas of favorable histologic types. Ann Intern Med 90(1): 10-13, 1979.
  28. Ghielmini M, Schmitz SF, Cogliatti SB, et al.: Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 103 (12): 4416-23, 2004.
  29. Witzig TE, Vukov AM, Habermann TM, et al.: Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol 23 (6): 1103-8, 2005.
  30. Hainsworth JD, Litchy S, Shaffer DW, et al.: Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (6): 1088-95, 2005.
  31. Williams ME: ECOG 4402: randomized phase III-trial comparing two different rituximab dosing regimens for patients with low tumor burden indolent non-Hodgkin's lymphoma. Curr Hematol Rep 3 (6): 395-6, 2004.
  32. Buske C, Hiddemann W: Rituximab maintenance therapy in indolent NHL: a clinical review. Leuk Res 30 (Suppl 1): S11-5, 2006.
  33. Czuczman MS, Koryzna A, Mohr A, et al.: Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol 23 (4): 694-704, 2005.
  34. Marcus R, Imrie K, Belch A, et al.: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105 (4): 1417-23, 2005.
  35. Czuczman MS, Weaver R, Alkuzweny B, et al.: Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol 22 (23): 4711-6, 2004.
  36. Hainsworth JD, Litchy S, Morrissey LH, et al.: Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23 (7): 1500-6, 2005.
  37. Zinzani PL, Pulsoni A, Perrotti A, et al.: Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol 22 (13): 2654-61, 2004.
  38. Forstpointner R, Dreyling M, Repp R, et al.: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104 (10): 3064-71, 2004.
  39. Whelan JS, Davis CL, Rule S, et al.: Fludarabine phosphate for the treatment of low grade lymphoid malignancy. Br J Cancer 64 (1): 120-3, 1991.
  40. Solal-Céligny P, Brice P, Brousse N, et al.: Phase II trial of fludarabine monophosphate as first-line treatment in patients with advanced follicular lymphoma: a multicenter study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 14 (2): 514-9, 1996.
  41. Saven A, Emanuele S, Kosty M, et al.: 2-Chlorodeoxyadenosine activity in patients with untreated, indolent non-Hodgkin's lymphoma. Blood 86 (5): 1710-6, 1995.
  42. Fridrik MA, Jäger G, Kienzer HR, et al.: Efficacy and toxicity of 2-Chlorodeoxyadenosine (Cladribine)--2 h infusion for 5 days--as first-line treatment for advanced low grade non-Hodgkin's lymphoma. Eur J Cancer 34 (10): 1560-4, 1998.
  43. Peterson BA, Petroni GR, Frizzera G, et al.: Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol 21 (1): 5-15, 2003.
  44. Robinson KS, Williams ME, van der Jagt RH, et al.: Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol 26 (27): 4473-9, 2008.
  45. Hoppe RT, Kushlan P, Kaplan HS, et al.: The treatment of advanced stage favorable histology non-Hodgkin's lymphoma: a preliminary report of a randomized trial comparing single agent chemotherapy, combination chemotherapy, and whole body irradiation. Blood 58 (3): 592-8, 1981.
  46. Hochster H, Weller E, Gascoyne RD, et al.: Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol 27 (10): 1607-14, 2009.
  47. Anderson T, DeVita VT Jr, Simon RM, et al.: Malignant lymphoma. II Prognostic factors and response to treatment of 473 patients at the National Cancer Institute. Cancer 50 (12): 2708-21, 1982.
  48. Longo DL, Young RC, Hubbard SM, et al.: Prolonged initial remission in patients with nodular mixed lymphoma. Ann Intern Med 100 (5): 651-6, 1984.
  49. Dana BW, Dahlberg S, Nathwani BN, et al.: Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol 11 (4): 644-51, 1993.
  50. Tsimberidou AM, McLaughlin P, Younes A, et al.: Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regimen in patients with stage IV indolent lymphoma. Blood 100 (13): 4351-7, 2002.
  51. Velasquez WS, Lew D, Grogan TM, et al.: Combination of fludarabine and mitoxantrone in untreated stages III and IV low-grade lymphoma: S9501. J Clin Oncol 21 (10): 1996-2003, 2003.
  52. Kaminski MS, Tuck M, Estes J, et al.: 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 352 (5): 441-9, 2005.
  53. Press OW, Unger JM, Braziel RM, et al.: Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin's lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 24 (25): 4143-9, 2006.
  54. Morschhauser F, Radford J, Van Hoof A, et al.: Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 26 (32): 5156-64, 2008.
  55. Apostolidis J, Gupta RK, Grenzelias D, et al.: High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: long-term clinical and molecular follow-up. J Clin Oncol 18 (3): 527-36, 2000.
  56. van Besien K, Sobocinski KA, Rowlings PA, et al.: Allogeneic bone marrow transplantation for low-grade lymphoma. Blood 92 (5): 1832-6, 1998.
  57. Gopal AK, Gooley TA, Maloney DG, et al.: High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis. Blood 102 (7): 2351-7, 2003.
  58. van Besien K, Loberiza FR Jr, Bajorunaite R, et al.: Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 102 (10): 3521-9, 2003.
  59. Schouten HC, Qian W, Kvaloy S, et al.: High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. J Clin Oncol 21 (21): 3918-27, 2003.
  60. Deconinck E, Foussard C, Milpied N, et al.: High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood 105 (10): 3817-23, 2005.
  61. Sebban C, Mounier N, Brousse N, et al.: Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 108 (8): 2540-4, 2006.
  62. Lenz G, Dreyling M, Schiegnitz E, et al.: Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 104 (9): 2667-74, 2004.
  63. Rohatiner AZ, Nadler L, Davies AJ, et al.: Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: long-term follow-up. J Clin Oncol 25 (18): 2554-9, 2007.
  64. Gopal AK, Rajendran JG, Gooley TA, et al.: High-dose [131I]tositumomab (anti-CD20) radioimmunotherapy and autologous hematopoietic stem-cell transplantation for adults > or = 60 years old with relapsed or refractory B-cell lymphoma. J Clin Oncol 25 (11): 1396-402, 2007.
  65. Gyan E, Foussard C, Bertrand P, et al.: High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood 113 (5): 995-1001, 2009.
  66. Bendandi M, Gocke CD, Kobrin CB, et al.: Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med 5 (10): 1171-7, 1999.
  67. Neelapu SS, Gause BL, Nikcevich DA, et al.: Phase III randomized trial of patient-specific vaccination for previously untreated patients with follicular lymphoma in first complete remission: protocol summary and interim report. Clin Lymphoma 6 (1): 61-4, 2005.
  68. Inogès S, Rodrėguez-Calvillo M, Zabalegui N, et al.: Clinical benefit associated with idiotypic vaccination in patients with follicular lymphoma. J Natl Cancer Inst 98 (18): 1292-301, 2006.
  69. Ha CS, Kong JS, Tucker SL, et al.: Central lymphatic irradiation for stage I-III follicular lymphoma: report from a single-institutional prospective study. Int J Radiat Oncol Biol Phys 57 (2): 316-20, 2003.
eMedicineHealth Public Information from the National Cancer Institute

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER

This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information.

Some material in CancerNet™ is from copyrighted publications of the respective copyright claimants. Users of CancerNet™ are referred to the publication data appearing in the bibliographic citations, as well as to the copyright notices appearing in the original publication, all of which are hereby incorporated by reference.





Medical Dictionary