Cancer Treatment

BEACOPP and ABVD for Hodgkin's

The most widely accepted regimen for HD patients with advanced stage is ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). To improve on these results, time and/or dose intensified third-line protocols were investigated. Such a protocol developed by the German Hodgkin's Lymphoma Study Group (GHSG), BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) ahs been studied in various patient groups. THe results appear no better than with ABVD but also not worse.The HD9 randomized trial compared COPP/ABVD + RT with standard dose BEACOPP + RT and escalated dose BEACOPP + RT. Irradiation was given to approximately 70% of patients on all three arms based on presence of initial moderately bulky (> 5 cm) or residual nodal abnormalities. The most recent analysis, also with a median follow-up of 6.9 years, included 1195 evaluable patients and demonstrated superior freedom from treatment failure and overall survival for the patients treated with escalated dose BEACOPP + RT (Table 5).31,32 Escalated BEACOPP showed a higher but manageable rate of hematologic toxicity. Longer follow-up will be required to determine the true usefulness of escalated BEACOPP + RT. Whether the increased toxicity of this regimen (3% treatment induced mortality, 100% infertility in men, 100% infertility plus premature menopause in most women over the age of 25, increased risk of second neoplasms) can be justified remains to be determined. Of particular note is the fact that the increased efficacy of escalated BEACOPP only translated into a survival benefit in the 20% of patients with the poorest prognosis at diagnosis. The other 80% of patients with advanced Hodgkin lymphoma had the same overall survival whether initially treated with ABVD or escalated BEACOPP because of the availability of effective secondary treatment with high-dose chemotherapy and stem cell transplantation.

J. M. Connors, E. M. Noordijk, and S. J. Horning
Hodgkin's Lymphoma: Basing the Treatment on the Evidence
Hematology, January 1, 2001; 2001(1): 178 - 193.

V. Diehl, J. Franklin, M. Pfreundschuh, B. Lathan, U. Paulus, D. Hasenclever, H. Tesch, R. Herrmann, B. Dorken, H.-K. Muller-Hermelink, et al.
Standard and Increased-Dose BEACOPP Chemotherapy Compared with COPP-ABVD for Advanced Hodgkin's Disease
N. Engl. J. Med., June 12, 2003; 348(24): 2386 - 2395.

V. Ballova, J.-U. Ruffer, H. Haverkamp, B. Pfistner, H. K. Muller-Hermelink, E. Duhmke, P. Worst, M. Wilhelmy, R. Naumann, M. Hentrich, et al.
A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly)
Ann. Onc., January 1, 2005; 16(1): 124 - 131.

Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348:2386–2395.

Diehl V, Brillant C, Franklin J, et al. BEACOPP chemotherapy for advanced Hodgkin’s disease: Results of further analyses of the HD9- and HD12- trials of the German Hodgkin Study Group (GHSG)

How long to PET after remission of lymphoma

Although CT remains the gold standard for the staging and follow-up of malignant lymphomas, 18F-FDG PET has a potential role in accurately staging disease and in predicting response to therapy. This role has the potential to affect both the initial choice of chemotherapy and the decision to alter management based on the initial response to therapy . PET performed early in a chemotherapeutic regimen has demonstrated a role in identifying patients who will experience relapse and may require further treatment, but attention to the timing of the scan in relation to chemotherapy and growth factors is crucial.

In regard to followup, a recent study showed that a negative PET scan after completion of therapy does not exclude the presence of residual microscopic disease and does not indicate complete remission. The majority of studies evaluating FDG-PET in lymphoma include patients with diffuse large B-cell non-Hodgkin’s lymphoma (NHL) or Hodgkin’s disease. There are limited data available on the role of PET in other histologies.

A negative PET scan at the end of therapy appears to provide favorable prognostic information. Persistently positive PET scans at the end of therapy, or in follow-up, warrant close follow-up or additional diagnostic procedures, since some of those patients may remain in prolonged remission.

The Imaging Subcommittee of the International Harmonization Project (IHP) in Lymphoma developed guidelines for performing and interpreting positron emission tomography (PET) for treatment assessment in patients with lymphoma. The new recommendations, targeting both clinical practice and clinical trials, are published in the January 22 Early Release issue of the 2007 al of Clinical Oncology. They are based on experts' consensus and not randomized evidence.

Specific recommendations related to followup are:

After treatment completion, PET should be performed at least 3 weeks, and preferably 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Noncontrast PET/CT can be used instead of contrast-enhanced diagnostic CT to follow-up patients with lymphoma, although patients with hepatic or splenic involvement should continue to receive contrast-enhanced diagnostic CT. Attenuation-corrected PET is much preferred over nonattenuation-corrected scans.

In regard to this case, I consider the PET to be medically necessary ONCE. This is because PET after the initial post-therapy PET is not recommended by NCCN, is not recommended specifically for T-cell histology and the duration of PET followup after remission is not well defined in guidelines.

Freudenberg LS, Antoch G, Schutt P, et al. FDG-PET/CT in re-staging of patients with lymphoma. Eur J Nucl Med Mol Imaging. 2004;31:325–329

Yuliya S. Jhanwar and David J. Straus The Role of PET in Lymphoma Journal of Nuclear Medicine Vol. 47 No. 8 1326-1334, 2006

Lavely WC, Delbeke D, Greer JP, Morgan DS, Byrne DW, Price RR, Hallahan DE, G PET in the follow-up management of patients with newly diagnosed Hodgkin and non-Hodgkin lymphoma after first-line chemotherapy.Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):307-15.

Jonathan W. Friedberg, Vaseem ChengaziPET Scans in the Staging of Lymphoma: Current Status The Oncologist, Vol. 8, No. 5, 438–447, October 2003

J. W. Fletcher, B. Djulbegovic, H. P. Soares, B. A. Siegel, V. J. Lowe, G. H. Lyman, R. E. Coleman, R. Wahl, J. C. Paschold, N. Avril, et al.
Recommendations on the Use of 18F-FDG PET in Oncology
J. Nucl. Med., March 1, 2008; 49(3): 480 - 508.

Donor Lymphocyte Infusions (DLI) for CLL

Lay Summary: DLI is well studied in chronic myelogenous leukemia but less so in other hematological conditions.

DLI induces complete remissions in the majority of patients with chronic myeloid leukemia (CML) in early-stage relapse and in less than 30% of patients with relapsed acute leukemia, myelodysplasia, and multiple myeloma. DLI-induced remissions of chronic phase CML are durable, but as many as half of patients with other diseases ultimately relapse. Complications of DLI include acute and chronic graft-vs-host disease (GVHD) and aplasia, which induce profound immunosuppression and susceptibility to opportunistic infections. There is a strong correlation of GVHD and disease response.
Other hematologic malignancies do not respond to DLI as well as early-stage CM. In general, less than 30% of patients with relapsed acute leukemia,myelodysplasia, and multiple myeloma achieve complete responses to DLI. As many close to half or more of patients who do achieve a complete response may be expected to relapse after DLI. DLI has been researched as a treatment for a variety of hematologic malignancies, including most prominently chronic myeloid leukemia, but also acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, myelodysplastic syndromes, chronic lymphocytic leukemia, Hodgkin’s disease, and non-Hodgkin’s lymphoma. Studies are limited due to small numbers but they have provided evidence that DLI can establish a graft-versus-leukemia/lymphoma effect.

Chronic lymphocytic leukemia (CLL) also appears to be responsive to allogeneic donor T cells.However, clinical expereince is limited.  Some patient have obtained a remission following DLI as treatment of persistent disease following alloBMT. Other CLL patients have obtained complete remissions, including molecular complete remissions, following discontinuation of posttransplant immunosuppression. However, there is not much literature credibly supporting routine use of DLI for CLL.

PET to"fish" for a diagnosis

Lay Summary: PET should not be used to "fish" for a diagnosis. On the other hand, when a pathological diagnosis is already established, PET can be useful for follow-up, staging and reassessment after therapy.

PET scanning is an excellent modality to assess tumor size and metabolic activity and it is coming into wider use as supporting data becomes avaialble for various tumor types. Unfortunately, there is no literature to support use of PEt to "fish" for diagnosis when no histologic diagnosis has been obtained. Since lymphadenopathy can be caused by a variety of conditions with different degree of gadolinium uptake and different specificites, sensitivities and accuracies, PET is potentially msileading and even harmful when used in this fashion. A NCT00068146 study is looking at a related question:  the usefulness of FDG-PET scanning in distinguishing autoimmune lymphoproliferative syndrome (ALPS) from lymphoma. Much more investigation will neeed to be done before PET can be used to disitnguish different types of lymphadenopathies.

Ref: http://clinicaltrials.gov/show/NCT00068146

Cook GJR, Fogelman I, Maisey MN. Normal physiological and benign pathological variants of 18-FDG PET scanning: potential for error in interpretation. Sem Nucl Med 1996;26:308–14

Umbilical cord stem cells

Lay summary: Cord stem cells have been shown to be equivalent to other allogeneic cells for transplantation in leukemia but not yet for other diagnoses.

Cord blood transplatation ifs a fairly recent but rapidly becoming established technique for transplnatation in leukemia. The first unrelated cord blood transplantations were performed in children. The first 25 unrelated cord blood transplantations were reported in 1996. Since then a number of reports appeared. This work has been followed by several studies, showing similar results in children. The New York Blood Center reported on 562 cases, 82% children, who underwent transplantation in a variety of centers with differing conditioning regimens and graft-versus-host disease prophylaxis. However, there have been retrospective matched pair analyses. Two studies in the New England Journal of Medicine reinforce the role of cord-blood transplantation in the treatment of leukemia in adults. Although this treatment is not recommended over HLA-matched donors from unrelated donor sources, it is a viable alternative that can be effective. (N Engl J Med. 2004;351:2255-2265, 2276, 2328). Although guidelines ahve not yet listed this alternative, more recent review articles and an editorial state that it is an equivalently effective approach, even in adults. Both reports reinforce the role of cord-blood transplantation in the treatment of adults with leukemia. It is realistic to anticipate that the current results for cord-blood transplantation in adults with hematologic cancers will contribute to more extended use in the coming years.

J. Aschan Allogeneic haematopoietic stem cell transplantation: current status and future outlook Br. Med. Bull., October 5, 2006; (2006)

Karen K. Ballen New trends in umbilical cord blood transplantation
Blood, 15 May 2005, Vol. 105, No. 10, pp. 3786-3792

Vikram Mathews, MD and John F. DiPersio, MD, PhD Stem Cell Transplantation in Acute Myelogenous Leukemia in First Remission: What Are the Options? Current Hematology Reports 2004,

Autologous and allogeneic transplant for Hodgkin's

Some 20-30 % of patients with Hodgkin's lymphoma achieve a remission and then relapse.  In general, the longer the initial complete remission, the better the outlook with any form of salvage therapy.
A variety of treatment regimens have been used for patients with relapsed Hodgkin's disease. In addition to MOPP or ABVD in patients who received the opposite regimen initially, a number of other treatments have been used. Unfortunately, the number of patients achieving extended survival free of Hodgkin's disease is quite poor, although patients with no adverse risk characteristics (see above) have been reported to have 5-year failure-free survivals as high as 50%. For this reason a variety of hifh dose approaches have been studies. Autologous bone marrow transplantation can patients with multiply relapsed Hodgkin's disease. Because of the superior results in patients treated early in the course of the disease, most advocates of bone marrow transplantation would prefer to use it as part of the treatment of the initial relapse following any effective initial chemotherapy regimen. In this setting, patients who receive an alternate standard chemotherapy regimen and achieve at least a partial remission then undergo autologous transplantation. Rerfractory patients also benefit from ASCT. The results in this setting have yielded durable remissions in 47% to 85% of patients. In a randomized trial conducted in Europe, patients with relapsed, chemosensitive Hodgkin's disease had a significantly better failure-free survival with transplantation rather than continuing standard dose chemotherapy.

In some patients in whom HDC fails, allogeneic HSC transplantation may be a viable option. In this method, myeloablative therapy (chemotherapy and sometimes RT) is followed by the infusion of HSCs from a genetically matched donor. This offers the potential for an immunological antitumor effect from T-cells provided by the HSC donor, which may improve the chances for cure of the disease. Historically, allogeneic transplantation for Hodgkin disease has been considered too high risk for most patients due a high transplant-related mortality. However, evolution of transplant protocols to include less toxic conditioning regimens will likely expand the utility of this option for patients with refractory Hodgkin disease. Allogeneic transplantation for Hodgkin disease should ideally be performed in the context of a clinical trial but is considered standard of care already at this time.

In a recent review, Mink and Armitage (2001) stated that autologous stem cell transplantation has proven to be beneficial in selected patients with HD. Transplantation appeared to increase event-free survival in patients who failed to enter complete remission with initial therapy. When a patient relapses after a complete remission, transplantation is probably the best option and particularly so if the remission lasted less than 1 year. Transplantation as part of primary therapy for very high-risk patients may be beneficial, but is not standard therapy at this time. Lazarus et al (2001) reviewed data from the Autologous Blood and Marrow Transplant Registry (n = 414) to determine relapse, disease-free survival, overall survival, and prognostic factors in patients with relapsed HD. They concluded that autologous hematopoietic stem cell transplantation (autotransplantation) should be considered for patients with HD in first relapse or second remission.

Mink SA, Armitage JO. High-dose therapy in lymphomas: A review of the current status of allogeneic and autologous stem cell transplantation in Hodgkin's disease and non-Hodgkin's lymphoma. Oncologist. 2001;6(3):247-256.

Lazarus HM, Loberiza FR Jr, Zhang MJ, et al. Autotransplants for Hodgkin's disease in first relapse or second remission: A report from the autologous blood and marrow transplant registry (ABMTR). Bone Marrow Transplant. 2001;27(4):387-396.

Reece DE. Hematopoietic stem cell transplantation in Hodgkin disease. Curr Opin Oncol. 2002;14(2):165-170.

Hodgkin's Lymphoma and Rituxan

Lay Summary: Rituxan is a promising drug for Hodgkin's but more studies need to be done.

According to results recently published in the journal Blood, Rituxan® (rituximab) appears to be a promising agent in the treatment of some patients with recurrent Hodgkin's. Monoclonal antibodies have recently emerged as therapeutic strategies for various cancers, particularly non-Hodgkin’s lymphomas. Monoclonal antibodies are proteins that are designed through laboratory processes to recognize and bind to specific protein and/or carbohydrate sequences (antigens) of a cell, such as a cancer cell. The binding of monoclonal antibodies to a cell often stimulates the immune system to initiate an attack against the cell and/or may cause the cell to die. Rituxan® is a monoclonal antibody approved for treatment of non-Hodgkin’s lymphoma (NHL) and binds to an antigen called CD 20. A small subset of patients with Hodgkin’s lymphoma (3% to 8%) has a type of cancer called CD 20 lymphocyte predominant Hodgkin’s lymphoma, characterized by a large proportion of their cancer cells expressing CD 20. Patients with CD 20 lymphocyte predominant Hodgkin’s lymphoma tend to have a higher rate of recurrence following standard therapy than other patients with Hodgkin’s lymphoma. 

Researchers from Germany recently conducted a clinical trial to evaluate the effectiveness of Rituxan® in the treatment of recurrent Hodgkin’s lymphoma. The trial involved 14 patients with CD 20 lymphocyte predominant Hodgkin’s lymphoma, or Hodgkin’s lymphoma with over 30% of their cancer cells expressing CD 20. Patients were on average 9 years from diagnosis and had stopped responding to at least one prior therapy. Overall, 12 patients had an anti-cancer response to Rituxan®, with 8 patients achieving a complete disappearance of detectable cancer and 4 patients achieving a partial anti-cancer response. Two patients had progressive disease. One year following therapy, 9 of the 12 responding patients demonstrated no signs of cancer progression. Furthermore, at over 20 months following therapy, the average duration of responses has not yet been reached. Side effects were generally mild and moderate, allowing for the majority of patients to receive treatment on an outpatient basis.

The researchers concluded that Rituxan® is a viable treatment option for patients with relapsed Hodgkin’s lymphoma that expresses the CD 20 antigen clinical trials.

In summary, there are two Phase II trials that demonstrate some effectiveness in a specific subset of Hodgkin’s Lymphoma. First, it needs to be determined if the patient has lymphocyte predominant disease. Most plans will consider this therapy to be investigational but where coverage is availble it is certainly an interesting and promising option.

Update 1/20/08 - no significant new infromation has been published since the date of this post. 

Rationale:

Rehwald U, Schultz H, Reiser M, et al. Treatment of relapsed CD20+ Hodgkin lymphoma with monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood. 2003;101:420-424.

Rehwald U, Schulz H, Reiser M, et al. German Hodgkin Lymphoma Study Group (GHSG): treatment of relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood. 2003;101: 420-424.

D. Re, R. K. Thomas, K. Behringer, and V. Diehl
From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential
Blood, June 15, 2005; 105(12): 4553 - 4560.