The Cambridge University Hospitals and Anglia Regional Experience of Using PEP-C As Palliative Chemotherapy in Lymphoma

PEP-C (prednisolone, etoposide, procarbazine, and cyclophosphamide) is an orally administered chemotherapy regimen used with palliative intent in relapsed or refractory lymphoma. To our knowledge no data on PEP-C have been reported since the original group described the regimen (Coleman et al., (2008) Leuk & Lymph 49, 447). Here we present a cohort from 3 centres describing our use of PEP-C over an 8 year period. Within the limitations of a retrospective cohort we find that PEP-C can give sustained responses and is well tolerated.

PEP-C is usually administered as daily oral medication in three phases (Coleman et al., as above). Firstly, there is an induction phase where PEP-C is given daily until the white cell count falls below 3.0x10⁹/L; then there is a break in treatment whilst the marrow recovers; and finally, PEP-C is re-started with the number of days per week on which it is given being titrated to keep the white cell count above 3.0x10⁹/L. Variations to this schedule are possible.

We identified 70 patients who received PEP-C at our centres and data from all is included. To achieve meaningful group sizes for analysis we classified patients as having high grade (43/70 (61%), mainly diffuse large B-cell) or low grade (27/70 (39%), mainly mantle cell) lymphoma.

The median age when starting PEP-C was 74 years. Ninety three percent of patients had stage 3 or 4 disease, and 26% had a performance status of 3 or 4. Our cohort was therefore relatively frail.

Of the 70 patients treated, 39% had a complete or partial response, and 44% had stable or progressive disease. In the remainder of cases there was no suitably objective measure by which to assess response. We assessed predictors of response by multivariate logistic regression and found the significant predictors to be whether disease was low or high grade, and whether or not a patient had responded to the line of chemotherapy prior to PEP-C (chemosensitive versus chemoresistant). Eleven out of 43 patients (26%) with high grade disease responded to PEP-C compared to 16 out of 27 (59%) with low grade disease (odds ratio=0.15 [95% CI 0.04 to 0.61]; p=0.008). Similarly, 5 out of 26 patients (19%) with chemoresistant disease responded to PEP-C compared to 19 out of 38 (50%) with chemosensitive disease (odds ratio=0.15 [95% CI 0.03 to 0.69]; p=0.014). There was no interaction between the predictors.

As might be expected, whether or not a patient responded to PEP-C translated into a difference in overall survival. Patients who did not respond to PEP-C had a median overall survival from starting PEP-C of 70 days versus 599 days in patients who did respond (hazard ratio 4.9 [95% CI 2.4 to 9.9]; log rank p<0.001).

Whether or not a patient responds to PEP-C cannot, however, be used a priori to make a decision about whether a patient might benefit from treatment. We therefore built Cox regression models to find other predictors of overall survival and found the significant predictor to be whether or not a patient was 'chemosensitive' as defined above. Chemosensitive patients had a median overall survival of 465 days compared to 77 days for chemoresistant patients (hazard ratio 0.47 [95%CI 0.26 to 0.85]; log rank p=0.011). For high versus low grade lymphoma the overall survivals were 116 and 411 days respectively but this trend did not reach statistical significance (p=0.050). For all patients the median overall survival was 167 days.

The median time spent on treatment with PEP-C was 62 days, but there was considerable variation (range 4 to 1237 days). Interestingly, whilst chemosensitive patients had a median overall survival of 465 days from starting PEP-C (see above), they only spent a median of 90 days on treatment. This suggests that the optimum duration of treatment needs to be better defined as a shorter course may confer some ongoing benefit.

Twenty two out of 70 patients (31%) discontinued PEP-C due to toxicity (uncomplicated marrow suppression in 10, non-neutropenic sepsis in 5, and neutropenic sepsis in 4). Thirteen patients (19%) died whilst on treatment with PEP-C but it is not clear that these deaths were a direct result of the treatment.

In summary we suggest that PEP-C can be an effective palliative treatment for lymphoma, particularly but not exclusively where the lymphoma is known to be chemosensitive. The regimen has a tolerable side effect profile, and also has the advantage of being cheap. The cost of the 'median' course of treatment with PEP-C in our cohort was a little over £500 (BNF 73, 2017).