All-Oral Chemotherapy in Lymphoma

With the advent of hospice and palliative medicine more attention is given to palliative chemotherapy. New chemotherapy regimens are being designed to ‘heal’ rather than ‘cure’, to alleviate symptoms while maintaining the patient’s quality of life.

In the early 1990s the University of Florida developed an ‘all-oral’ protocol for use in refractory / recurrent Hodgkin’s disease. (1) This protocol was based on an earlier European regimen CEP but, as Prednimustine was unavailable in the United States, cytoxan and prednisone were substituted.(2) The resultant all-oral protocol, CCEP, was used with success not only in Hodgkin’s disease but also in refractory / recurrent non-Hodgkin’s lymphoma.(1,3) The protocol is as follows;

Cytoxan 100 mg PO day 1  10
CCNU 80 mg/m2 PO day 1
Etoposide 100 mg/m2 PO day 1  5
Prednisone 60 mg/m2 PO day 1  14

The chemotherapy was cycled every 28 days.

Several palliative lymphoma regimens were developed since but few were ‘all-oral’. A CCEP regimen (using Procarbazine instead of Prednisone) was used in AIDS-related non-Hodgkin’s lymphoma at 6 week intervals. (4) The response rate was 61% with a 39% complete response rate. However the treatment related mortality was high at 11% with myelosuppression being the most frequent and severe toxicity. Similarly, a study in Africa utilizing these agents on different schedules revealed an overall response rate of 78% with an overall survival time of 12.3 months. 33% of these patients with AIDS-related non-Hodgkin’s lymphoma survived 5 years.(5) Another protocol, PEPC, used Procarbazine in place of CCNU and was administered as metronomic therapy.(6,7) The overall response rate was 69% with a 36% complete response rate and a 33% partial response rate. No treatment related deaths were reported though myelosuppression was still a significant factor.

All-oral chemotherapy is useful both in the home and the outpatient setting. A cost analysis of the oral regimen reveals that the oral Etoposide is very expensive making the overall costs seems higher with CCEP when compared to a common intravenous (lymphoma) regimen like CHOP. However, unlike CHOP, CCEP requires no costs of pharmacy preparation, intravenous administration nor the OCN staff / facility necessary to administer it. CCEP also requires no intravenous (port) access and, by dose titration, tumor-effects can be maximized and quality-of-life maintained with myelosuppression and other toxicities kept to a minimum.

The CCEP (Cytoxan, CCNU, Etoposide and Prednisone) protocol shows great promise and should be considered by academic palliative services for study both in Hodgkin’s and non-Hodgkin’s lymphoma. Its efficacy in Hodgkin’s disease is noted in the literature however the results from the University of Florida, for Non-Hodgkin’s lymphoma, were never published. I am an affiliate of the Moffitt Cancer Center (University of South Florida) and have been told by a senior professor that since the agents in CCEP are so commonplace no drug company would ever supply the funding needed for university-level testing. How do you see this protocol proceeding on its own faith and merit? Is there any academic palliative program willing to put forward its own effort, independent of the pharmaceutical industry, to investigate this regimen further?

1. Miller AM, Moreb J, Killeen RB: All-oral chemotherapy in refractory Hodgkin’s disease. Lancet 1991; 337:1408.

2. Santoro A, Viviani S, Valagussa P, Bonfante V, Bonadonna G: CCNU, Etoposide and Prednimustine (CEP) in refractory Hodgkin’s disease. Sem Onc 1986; 13 (suppl 1):23-26.

3. Killeen RB, Marsh RL: 1991. unpublished.

4. Remick SC, McSharry JJ, Wolf BC, Blanchard CG, Eastman AY, Wagner H, Portuese E, Wighton T, Powell D, Pearce T, Horton J, Ruckdeschel JC: Novel oral combination chemotherapy in the treatment of intermediate-grade and high-grade AIDS-related non-Hodgkin’s lymphoma. J Clin Oncol 1993; 11:1691-1702.

5. Mwanda WO, Orem J, Fu P, Banura C, Kakembo J, Onyango CA, Ness A, Reynolds S, Johnson JL, Subbiah V, Bako J, Wabinga H, Abdallah FR,
Myerson HJ, Whalen CC, Lederman MV, Black J, Ayers LW, Katongole-
Mbidde E, Remick SC: Dose-modified oral chemotherapy in the treatment
of AIDS-related non-Hodgkin’s lymphoma in East Africa. J Clin Oncol 2009;

6. Coleman M, Ruan J, Furman RR, Niesvizky R, Martin P, Leonard JP: Oral combination chemotherapy for refractory / relapsed lymphoma with the PEP-C (C3) regimen (daily prednisone, etoposide, procarbazine, cyclophosphamide): low dose continuous metronomic multidrug therapy. Proc Am Soc Clin Onc 2007; 25: 457s (abst 8064).

7. Coleman M, Martin P, Ruan J, Furmann R, Niesvizky R, Elstrom R, George P,
Kaufman TP, Leonard JP: Prednisone, etoposide, procarbazine and
cyclophosphamide (PEP-C) oral chemotherapy regimen for recurring / refractory
lymphoma: Low-dose metronomic multidrug therapy. Cancer 2007; 112(10):2228-2232.

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