Front line Hodgkin: taking it to the patient

Hodgkin Lymphoma happily has been on the receiving end of many well conducted, randomised phase III clinical trials. Yet in the rather small world of physicians treating advanced Hodgkin lymphoma there is still heated debate on whether to initiate treatment with the fairly potent and relatively well tolerated regimen ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or whether to initiate therapy with the most effective regime we know of for curing the disease albeit with an increased toxicity profile: escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, procarbazine and prednisolone). Opinions tend to fall along geographical boundaries with escalated BEACOPP favoured by Germany and central Europe and ABVD favoured by most of the rest of the world. Since the ECHELON-1 trial, which showed a modest improvement of AVD+Brentuximab vedotin versus ABVD, some of North America has switched to this regimen although it has had little impact on the rest of the world. 

The purpose of this post is to encourage all those who treat Hodgkin lymphoma to involve the patient in the decision as to whether to use ABVD or escalated BEACOPP (or escalated BEACOPDac where the procarbazine is relapsed with dacarbazine) as initial treatment. As physicians we tend to assume we know what's best for the patient yet with the frontline treatment of Hodgkin lymphoma there are genuine options, and the concerns and priorities of the patient are important in determining which regimen is right for the particular patient in front of you. 

What can we say with confidence to patients with advanced stage Hodgkin about to start treatment with one of these two regimens?

ABVD:

• Consistently in trials, 6 courses is associated with a long term PFS (ie. cure rate) of about 75%. Even in the RATHL study which was a response adapted trial, the 5y PFS for all patients was just below 80% and a significant proportion of patients in that study had stage II disease. So 75% still seems about right. 
• In advanced stage disease, patients will receive 6 courses which delivers 300mg/m2 of doxorubicin and in epidemiological studies, this does increase the risk of heart problems (mainly cardiac failure) by about 4 fold.
• In the RATHL study, for the 85% achieving a PET negative scan after 2 cycles, the bleomycin can be safely omitted and the observed pneumonitis rate in these patients is very low indeed
• There is a very low reported rate of second cancers such as AML or MDS but the risk is not zero (I usually quote 1% or less).
• There seems to be a negligible risk on female fertility, although there is still a possibility that it could bring forward the menopause in some patients.
• 6 courses takes 6 months which is very disruptive for especially young patients who maybe at school, university, starting out on their career or raising a family.
• Importantly, the RATHL study did NOT confirm that intensifying to escalated BEACOPP would overcome the negative prognostic significance of a positive interim PET as the PFS in that group was relatively poor. It maybe that group did better than historical patients, but it's very hard to be certain in the absence of a randomisation for those patients in the trial.

Escalated BEACOPP:

• Consistently in trials (such as HD18 and AHL2011), 6-8 courses of escalated BEACOPP is associated with a long term PFS (and therefore cure rate) of 86-90% which is greater than in any ABVD trial in a similar patient population. 6 courses is as effective and less toxic than 8. 
• 2 response adapted trials have shown that in patients achieving an interim negative PET scan, de-escalation is safe; this can be to either 2 more (rather than 4 more) courses of escalated BEACOPP (HD18) or to 4 courses of ABVD (AHL2011). 
• If an HD18 approach is being followed and the patient achieves a negative interim PET scan, their treatment will take just 3 months in total (although it may take longer to recover from than ABVD). 
• 6 courses of escalated BEACOPP delivers 150 mg/m2 (significantly less than ABVD) meaning that the risk of late cardiac effects is likely to be less.
• However, there is a significantly higher rate of febrile neutropenia, neuropathy and requirement for blood products.
• The impact on fertility is also significant. In a female in her 20s, the risk of reduced fertility is around 20%, rising to over 50% in the over 40s. These figures are for 6-8 cycles of the regimen, the effect is less clear when smaller numbers of courses of used, as they are in many patients now with a response adapted approach. 
• There is also an increased risk of 2nd cancers although this remains a small risk (1-3%).
• It is not recommended to give escalated BEACOPP to any patient over the age of 60 and be cautious in patients over 50 or in those with a poor performance status or significant co-morbidities. 

In many centres that use escalated BEACOPP, they are replacing the procarbazine with dacarbazine. This is based largely on paediatric data that showed that switching COPP (cyclophosphamide, vincristine, procarbazine and prednisolone) to COPDac did not have any impact on survival rates, and significantly improved fertility in surviving patients. Although it might be predicted that the same would happen with changing escalated BEACOPP to escalated BEACOPDac, caution needs to be exercised here as there is no data suggesting equivalent outcomes or improved fertility. As there are still big doses of cyclophosphamide, reduced fertility may still be an issue. 

Discussing with the Patient

In medicine, it is important not to assume we know what the patient needs. The front line treatment of advanced cHL is an excellent example. If we have a 20 year old woman in front of us, we may think that ABVD offers the best balance of efficacy and tolerability (including fertility preservation). However, by recommending ABVD we are suggesting a regimen which is associated with at least an absolute 10% increased risk of relapse according to the trials. In some patients I have spoken with, their absolute priority is to cure the disease and the risk on subsequent fertility, or short term toxicity, is of little importance to them. Although relapsed Hodgkin lymphoma can be cured in a reasonably high number of patients, the fear of relapse for some patients is very real and should not be underestimated. In this case I would suggest that to give ABVD is not in the best interests of that individual patient. In an interesting study by Brocklemann et al,  patients (some before, some during and some after treatment) were asked to rank the importance of factors they deem as important when associated with a particular chemotherapy regimen for Hodgkin lymphoma. Cure rate was, not surprisingly, ranked highest. Other factors are important too and I have also looked after other patients with advanced cHL who have opted for ABVD as an initial approach, in order to maximise time as an out patient and to preserve fertility. This is a reasonable approach in these patients and in my view escalated BEACOPP would not seem the correct initial treatment for these patients. 

Discussion with the patient to this level of detail does take time. And in some cases patients simply want to be told what the doctor feels is in their best interest, and they will then comply. This of course is their right. But especially for young patients, where the choice of chemotherapy regimen impacts on more than simply cure rate, it is our duty to spend the time explaining the options and supporting their decisions. 

Identifying those at highest risk

In order to inform the decision between an ABVD based approach, or an escalated BEACOPP based approach, it would be ideal to accurately be able to estimate what the chance of cure with each approach would be at the time of diagnosis, for the individual patient in front of you. Unfortunately though, all we have available currently is the international prognostic scoring (IPSS) otherwise known as the Hasenclever index. This score integrates a number of clinical and laboratory parameters. However it can be difficult to apply. For example, it is quite common for the albumin of a patient to be 39 g/l one day, and 41 g/l 2 days later (probably due to laboratory variation). In the IPSS, one mark is given for an albumin of < 40 g/l. Would this patient score a mark here or not? Furthermore, the IPSS does not seem to prognosticate amongst advanced cHL patients treated initially with escalated BEACOPP. And although there was a prognostic significance seen statistically in the RATHL study, the differences were not great. We are therefore poor at identifying patients at high risk of treatment failure. The Vancouver group did report on a 23 gene signature which appeared promising in identifying those patients likely to relapse with ABVD based treatments, but this was not validated when tested on other patient series. The assessment of metabolic tumour tumour volume by FDG-PET scanning may help prognosticate, but requires further study. 

Our approach in Oxford

Due to the slightly lower overall survival for patients with IPPS 3+ treated on the RATHL study, and the absence of an impact of IPSS seen in escalated BEACOPP treated patients, we tend to recommend an ABVD (RATHL) approach for those with IPSS 0-2 and an escalated BEACOPP approach (HD18) for those with IPSS 3+. However as stated above, this is always in discussion with the patient and we have certainly had patients with a rather borderline IPSS of 3 opt for both escalated BEACOPP and ABVD. The escalated BEACOPP patient wanted treatment finished as quickly as possible so he could return to his studies whereas the ABVD patient placed a high value on preservation of her fertility. We have developed some patient-friendly material to use in clinics to help illustrate some of the points here. Clinical nurse specialists play a vital role in helping patients understand the material, to consolidate their understanding and to apply it to the patient's life circumstances. 

To conclude, randomised trials have provided very useful data for treating patients with advanced Hodgkin lymphoma. However, one size definitely does not fit all and it is important that our practises have the flexibility to offer ABVD or escalated BEACOPP based regimens, that we take time in our consultations to discuss these approaches in ways the patient understands and to not assume we as physicians know what is best.