Cancer Treatment

Velcade for low grade lymphoma

Bortezomib is a drug that belongs to the class of drugs called proteasome inhibitors. The proteasome is a protein complex that breaks down rusty and modified proteins that cells are meant to dispose off. Its housekeeping job is very important for the cells to keep functioning. Research studies have shown that if the proteasome is inhibited (or stopped from functioning) some cancer cells, including some lymphoma cells may find it difficult to carry out normal functions and even die. Bortezomib (Velcade) is a type of drug that inhibits proteasomes. Theoretically it can be efective in a wide spectrum of malignancies.

It has shown great results in the treatment of relapsed multiple myeloma, another type of cancer that affects the bone marrow. Trials that have tried Velcade in relapsed lymphomas over the past few years have resulted in good responses in certain types of lymphoma, especially Mantle Cell Lymphomas. Bortezomib (Velcade) has been granted approval for the treatment of relapsed or refractory Mantle Cell Lymphoma by the FDA in December 2006. It represents an important step in the approach to second-line treatments in Mantle Cell Lymphoma, a potentially difficult to treat lymphoma.

A number of trials in low grade lymhomas are ongoing. For example, Millennium Pharmaceuticals and development partner Johnson & Johnson have initiated a phase III clinical trial of Velcade in non-Hodgkin's lymphoma. The trial will evaluate the drug in combination with rituximab in patients with relapsed or refractory follicular lymphoma, a subtype of non-Hodgkin's lymphoma (NHL). Anoterh study that Millenium is sponsoring is to determine if the combination of VELCADE and rituximab improves progression free survival relative to rituximab alone in patients with relapsed or refractory B-cell non-Hodgkin"s lymphoma (B-NHL) who never received rituximab or who have previously responded to rituximab. This is an international study being conducted in the United States and in many countries around the world.
An Italian study,NCT00509379,  A Phase II Multicenter Non-Randomized Study to Assess Safety, Toxicity and Clinical Activity of the Association of Bortezomib(VELCADE)With Rituximab in Relapsed/Refractory Indolent Non Follicular and Mantle-Cell Non-Hodgkin Lymphoma, is looking at activity in several low grade lymphoma types, including SLL.

Schenkein D. Proteasome inhibitors in the treatment of B-cell malignancies. Clin Lymphoma. 2002;3(1):49-55.

Cheson BD. Hematologic malignancies: New developments and future treatments. Semin Oncol. 2002;29(4 Suppl 13):33-45.

nccn.org, chronic lymphocytic leukemia

H. Pylori for lymphoma

H. pylori infection, one of the most common worldwide infections and an important factor linked to the development of peptic ulcer disease, gastric malignancy and dyspeptic symptoms occurs in an estimated 30 percent to 40 percent of the U.S. population. Diagnosis of infection is usually made by checking for dyspeptic symptoms and then doing tests which can suggest H. pylori infection. One can test noninvasively for H. pylori infection with a blood antibody test, stool antigen test, or with the carbon urea breath test.

Nearly all patients with gastric MALT lymphoma are infected with H. pylori, and the risk of developing this tumor is over six times higher in infected people than in uninfected people. Furthermore, up to 80 percent of patients with gastric MALT lymphoma achieve complete remission of their tumors after treatment with H. pylori-eradicating antibiotic therapy.

There are no guidelines that recommend testing for H. Pylori as screening for lymphoma. H. Pylori testing is appropriate for symptoms of peptic ulcer disease or lymphoma but nto screening.

Singapore Ministry of Health. Management of helicobacter pylori infection. Singapore: Singapore Ministry of Health; 2004 Sep. 25 p. [29 references]

Helicobacter pylori in peptic ulcer disease. NIH Consensus Statement Online Jan 7–9;12(1):1-23.

European Helicobacter Pylori Study Group. Current Concepts in the Management of Helicobacter pylori Infection. The Maastricht 2-2000 Consensus Report. Retrieved on September 30, 2006.

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.

Autologous stem cell transplant for follicular lymphoma

Lay Summary:

The role of AuSCT is not entirely clear in follicular lymphoma.

There are now 3 conflicitng studies of autologous transplant for follicular lymphoma.

Despite nearly identical eligibility criteria and the use of an anthracycline-based induction treatment in all studies, the results are quite different. The previous studies found a significant advantage to autologous stem cell transplantation (ASCT). The German Lymphoma Study Group (GLSG) reported that patients randomized to transplantation had a 64.7% progression-free survival (PFS) rate at 5 years versus 33% with conventional chemotherapy. The Groupe Ouest-Est d'Etude des Leucémies aigues et autres Maladies du Sang (GOELAMS) group reported 60% PFS for those randomized to autologous transplantation versus 48% with conventional chemotherapy. By contrast, the Groupe d'Etude des Lymphomes de l'Adulte (

GELA

) study does not show a significant PFS advantage for autologous transplantation.

The overall role of ASCT in follicular lymphoma continues to be debated. It is an excellent treatment option for the management of younger patients with recurrent disease. In advanced newly diagnosed lymphoma, a survival advantage has yet to be shown; with more prolonged follow-up it may still emerge in the GLSG study. An increased risk for therapy-related acute myeloid leukemia (t-AML) was observed in the GLSG and GOELAMS studies, but this risk may be minimized by modulation of induction and mobilization therapy preceding transplantation. Despite spectacular advances since the introduction of rituximab, many patients with advanced disease and a high Follicular Lymphoma International Prognostic Index (FLIPI) score have disease recurrences. For such patients, the continued study of autologous transplantation, possibly in combination with rituximab for in vivo purging, remains an important area of investigation.

In conclusion, there is no consensus regarding autologous stem ell transplantation for follicular lymphoma. Since some experts lukewarmy advocate it, it should not be considered "not medically necessary', even if it is arguably still investigational.

Koen van Besien Autologous transplantation for follicular lymphoma? Not too soon! Blood, 15 October 2006, Vol. 108, No. 8, pp. 2496-2497.

NCCN.ORG

Gemzar and Navelbine salvage for lypnoma

Gemcitabine, vinorelbine and prednisone or otehr drugs are being investigated to treat refractory or relapsed aggressive non-Hodgkin lymphomas (NHL).
Lay Summary: Gemcitabine and vinorelbine are somewhat effective but toxic when few options remain, but more investigation is needed.

The optimum therapy for patients with relapsed or refractory aggressive NHL not qualifying for platinum-based and/or high-dose chemotherapy is not known. In one  prospective phase II study evaluating a regimen consisting of gemcitabine (1 g/m2, days 1 and 8), vinorelbine (30 mg/m2, days 1 and 8) and prednisone (100 mg/day, days 1-8) (GVP) given every 21 days, there was substantial activity in poor prognosis relapsed or refractory aggressive lymphomas. It was generally well tolerated, but haematological toxicity is dose limiting. Several other studies yilded similar results.

One has to conclude that despite these results the treatment is still experimental as it is being studies in various studies with otehr agents added and a prospective phase III trial is necessary.

Efstathios S. Papageorgiou, Panagiotis Tsirigotis, Meletios Dimopoulos, Nikolaos Pavlidis, George Fountzilas, Sotirios Papageorgiou, Theofanis Economopoulos (2005)  Combination chemotherapy with gemcitabine and vinorelbine in the treatment of relapsed or refractory diffuse large B-cell lymphoma: a phase-II trial by the Hellenic Cooperative Oncology Group European Journal of Haematology 75 (2), 124–129.

A. Spencer, K. Reed and C. Arthur. (2007) Pilot study of an outpatient-based approach for advanced lymphoma using vinorelbine, gemcitabine and filgrastim. Internal Medicine Journal 37:11, 760–766

Fatih M. Uckun, Sanda Morar and Sanjive Qazi. (2006) Vinorelbine-based salvage chemotherapy for therapy-refractory aggressive leukaemias. British Journal of Haematology 135:4, 500–508

PET for lymphomas

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. Many studies have used subjective grading systems to assess response and have evaluated progression-free survival on the basis of negative or positive findings on follow-up scans. Further studies should focus on measuring response on the basis of SUV: Determining a cutoff value when assessing the percentage of change in SUV may improve the prognostic value of interim PET. Because most studies have shown variable SUVs among both aggressive and indolent lymphomas, the usefulness of a follow-up scan hinges on the existence of a pretherapy scan demonstrating 18F-FDG–avid disease. The role of 18F-FDG PET for indolent lymphomas, like CLL, remains unclear, and further studies have to be designed to investigate the role of PET for specific histologic types.

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

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

Revlimid for Chronic lymphocytic leukemia

Lay Summary: Revlimid is promising but still experimental for CLL.

Revlimid is an orally administered derivative of thalidomide, which is a very active agent for the treatment of multiple myeloma but has serious side effects, especially thromboembolism. Revlimid is reported to have less toxicity than thalidomide but retains antimyeloma effects. Revlimid has recently been approved by the FDA for review of treatment of myelodysplastic syndromes (MDS) wih a 5q- mutation and for first line treatmetn of multiple myeloma in conjunction with dexamethasone. Revlimid is in clinical trials for the evaluation of treatment for other hematologic cancers including CLL.

Researchers from the Roswell Park Cancer Center and the Toronto Sunnybrook Regional Cancer Center have reported that Revlimid  has significant activity in CLL. This study was also presented at the 2005 meeting of the American Society of Hematology in December 2005. Thalidomide has also demonstrated activity when combined with Fludara for initial treatment of CLL.This was a small study involving only 16 patients, but the complete response rate was over 50%.

The study presented at ASH 2005 and ASCO 2006 involved 29 patients with relapsed or refractory CLL. More than 50% has failed Rituxan combinations and more than 50% had failed fludarabine combinations. The complete response rate was 15%, the partial response rate was 53% and an additional 15% had stable disease. Two patients had complete molecular responses. The most common side effects reported were fatigue, neutropenia and thrombocytopenia. Approximately 60% had “flare reaction”—described as tender swelling of lymph nodes and rash—which was successfully treated with steroids. In-vitro studies showed an increased number of natural killer cells but no increase in apoptosis.

Many studies are now underway to evaluate the activity of Revlimid in combination with rituximab in patients with lymphoma. The initial analysis of the first 46 patients of a 200 patient
phase-II, multi-center open-label clinical study, NHL-003, shows
encouraging results that are consistent with those of the earlier
NHL-002 trial (Abstract #2565). Responses were seen across all
sub-types of NHL. Furthermore, prognostic factors have been identified
that may be predictive of response to REVLIMID monotherapy. The study reported that overall response to single agent lenalidomide was 28%, with 6 responses in the diffuse large B-cell lymphoma group (21%) and 5 in the mantle cell lymphoma group (38%). Ten patients had stable disease (SD). This was reported at ASH in December 2007.

Miller K, Czuczman MS, Dimicli L, et al. Lenalidomide (L) induces high response rates with molecular remission in patients (pts) with relapsed (rel) refractory (ref) chronic lymphocytic leukemia (CLL). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. 2006. Abstract # 6605.

Chanan-Khan AA, Miller KC, DiMicheli L, et al. Results of a phase II study of lenalidomide (L) (Revlimid) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood 2005;135a, abstract # 447.

Chanan-Khan A, Miller KC, Takeshita K, et al. Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL). Blood. 2005;106:3348-3352.

Low Grade Follicular Lymphoma Treatment

Lay Summary: I review options for follicular lymphoma treatment.

Patients with low-grade non-Hodgkin's lymphoma (NHL) have a median survival of 4-8 years from diagnosis and a cause-specific survival of about 10 years. Radiotherapy can be curative in a small proportion of patients with very localized disease, but the majority of patients have advanced disease at diagnosis and it is not clear that any current therapy is curative in this situation. While in many instances patients with high-grade NHL are cured by chemotherapy, those with low-grade NHL, despite impressive response rates, almost invariably relapse. A 'watch-and-wait' strategy can therefore delay the onset of chemotherapy by 2-3 years, without affecting survival. Results with autologous stem cell transplantation have been similarly disappointing to date. Rituximab is a human-mouse chimeric monoclonal antibody that represents a novel approach to treatment of low-grade NHL, targeting malignant cells without the side effects associated with chemotherapy. A pivotal study has demonstrated a response rate of 56% in relapsed or refractory low-grade NHL. The relatively benign side-effect profile means rituximab can be used early in the disease process, and in combination with chemotherapeutic regimens and autologous transplantation. Ongoing and future studies will define the optimal role of rituximab in treatment of low-grade NHL.

Current treatment of follicular and low-grade non-Hodgkin's lymphoma. Anticancer Drugs. 2001 Jun;12 Suppl 2:S5-9.

Ha CS, Kong JS, McLaughlin P, Tucker SL, Fayad LE, Hess MA, Wilder RB, Cabanillas F, Cox JD, Stage III follicular lymphoma: long-term follow-up and patterns of failure.Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):748-54

http://www.lymphomation.org/chemoandradiostage3.pdf

Maintenance Rituxan

Lay Summary: Maintenance rituximab is becoming more common although questions remain.

The impact of maintenance treatment with rituximab on overall survival is one of the most important open questions for patients with indolent non-Hodgkin lymphoma. Recent randomized trials performed by the German Low Grade Lymphoma Study Group (GLSG) and by the EORTC demonstrated the superiority of rituximab maintenance after immunochemotherapy and after chemotherapy compared with observation alone.

A recent guidelines says this about maintenance rituximab for low grade lymphoma: "For previously treated patients with follicular or other indolent B-cell-histology lymphoma (such as mantle cell lymphoma, marginal zone lymphoma, and lymphoplasmacytoid lymphoma), excluding small lymphocytic lymphoma (SLL):
There is currently insufficient evidence to support or refute the additional use of rituximab as a maintenance therapy in patients who have completed chemotherapy plus rituximab." However, a Canadian guideline does recommend this approach and  it is becoming the predominant approach in clinical practice.NCCN also lists it as level 2B recommendation but strongly recommends that it be ina a context of a trial.
Another issue is how long maintenance should be continued. At this time, maintenance for more than two years would be very controversial.

NCCN.ORG, NHL

Imrie K, Stevens A, Meyer R, Hematology Disease Site Group. Rituximab in lymphoma and chronic lymphocytic leukemia: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Dec 22. 46 p. (Evidence-based series; no. 6-8). [65 references]

S. J. Horning
Optimizing Rituximab in B-Cell Lymphoma
J. Clin. Oncol., February 20, 2005; 23(6): 1056 - 1058.

John D. Hainsworth, Sharlene Litchy, Don W. Shaffer, Van L. Lackey, Manuel Grimaldi, F. Anthony Greco, 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
Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1088-1095