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.  

Why More is not always Better

The frontline treatment of Diffuse Large B-cell Lymphoma (DLBCL) is becoming somewhat of a graveyard for randomised phase III clinical trials. The last major breakthrough came when rituximab was added to CHOP chemotherapy (see previous post). Since then, a number of approaches have been taken to try to improve outcomes, but they have by and large failed. 3 broad approaches have been pursued, with some overlap:

1. Intensify treatment (especially for patients with high risk disease)
2. Add something to the R-CHOP backbone
3. Use biological stratification to target a new agent or approach to those likely to respond

1. Intensify treatment

This first approach hasn't yet yielded much meaningful fruit. It's easy to comment in retrospect but perhaps this isn't too surprising. My favourite clinical trial of all time was published by Richard Fisher and colleagues in 1993. This study was performed to evaluate claims from phase II studies that their new intensive regimen appeared better that CHOP. We hear similar claims today of course. The study compared 8 courses of standard CHOP chemotherapy with 3 intensive regimens: ProMACE-CytaBOM, MACOP-B and m-BACOD. The result was that all were equally effective whilst CHOP had fewer side effects, was cheaper and safer. In subsequent letters it was noted that the results for ProMACE-CytaBOM and MACOP-B were about 30% lower that in the previously reported phase II studies, providing ample reason for insisting on randomised phase III data before a more intensive and toxic regimen is introduced as standard of care. 

More recently, Dose Adjusted (DA) EPOCH-R (etoposide, prednisolone, cyclophosphamide, doxorubicin and rituximab) was developed by the National Cancer Institute in the US for the treatment of aggressive non-Hodgkin lymphoma. The regimen is a model of scientific logic. Lymphoma cell lines are killed more effectively when longer drug exposure occurs, rather than short boluses hence a key part of this regimen is a 4 days continuous infusion. The addition of etoposide also increased cell kill in vitro. Perhaps the most important aspect though is that it takes seriously the observation that different patients handle drugs differently and that patients who excrete chemotherapy drugs rapidly may not have enough exposure to the components of a bolus regimen. The doses of subsequent cycles are therefore titrated according to the nadir neutrophil count of the prior cycle, providing a biomarker for drug exposure. Sufficient myelosuppression indicates that sufficient chemotherapy drug levels have been achieved leading to biological activity within the individual at a given dose of cycle. Phase II studies appeared promising. However, Bartlett and colleagues have recently published the Alliance/CALGB 50303 study which was a well performed study compared R-CHOP with DA-EPOCH-R in the front line treatment of DLBCL. There was no difference in the primary endpoint of progression free survival (PFS) and the toxicity of DA-EPOCH-R was clearly greater than for R-CHOP. This underscores the point that any new regimen must be tested in this way and I congratulate the US groups for doing just this. The point has been made that a clinically meaningful benefit maybe seen in high risk patients. This is true, but for a regimen which is more toxic and less convenient for patients and physicians, this needs to demonstrated in a comparative trial powered to answer the question. 

2. Add something to the R-CHOP backbone.

A number of studies have looked at, and are looking at R-CHOP+X. One of the recent, large studies reporting on this approach was the Phoenix trial which randomised non-GCB cases (defined by immunohistochemistry which isn't ideal as only gene expression profiling can really define cell of origin) to receive either 6-8 courses of  R-CHOP or 6-8 courses of R-CHOP+ibrutinib (a BTK inhibitor). No difference was seen in the primary endpoint. On further evaluation of prior defined subgroups, younger patients did seem to benefit whereas older patients seemed to suffer from more side effects of the combination leading to a reduced dose intensity of immunochemotherapy and increased relapse rate. However as the trial was not powered to look at this group alone, the combination will not receive a license. The REMODL-B trial from the UK assessed the addition of bortezomib to R-CHOP in cycles 2-6 in a randomised phase III and again no benefit was found.

On-going trials include the ROBUST study, a randomised phase III trial of R-CHOP versus R-CHOP plus lenalidomide in gene expression profile-defined ABC subtype of DLBCL. The trial was based on the observation of phase II studies which seemed to show that R-CHOP+lenalidomide overcame the worse outcomes seen in the ABC subtype when treated with R-CHOP. Results are awaited. The POLARIX study is also an ongoing randomised phase III trial but this time comparing R-CHOP with R-CHOP + polatuzumab vedotin, the antibody-drug conjugate targeting CD79b. There is much hope that this trial may lead to a positive result, in view of a randomised trial of bendamustine rituximab (BR) vs BR + polatuzumab in relapsed / refractory DLBCL showing a PFS and OS survival advantage. However we need to wait until these trials are recruited and published with appropriate follow up. Watch this space!

3. Use biological stratification to target a new agent or approach to those more likely to respond

The Phoenix trial attempted this by only randomising those with non-GCB subtype by immunohistochemistry. One flaw with this approach is that it's far from proven that ibrutinib is significantly more effective in this subtype. A small trial in relapsed / refractory disease did show an enrichment for responses in non-GCB subtype, but this is a long way off showing that the combination of R-CHOP + ibrutinib is only going to work in the non-GCB subtype in the upfront setting. The UK REMODL-B trial in my view performed a better study. Although they predicted that bortezomib would work better in the ABC subtype, all patients were randomised and interim analyses were performed during the trial to see in the randomisation into the GCB subtype could be stopped. This did not happen and indeed on subgroup analysis the only real signal of possible improved outcome with the combination was in those patients with a so-called 'molecular high grade subtype' which is largely found in GCB cell of origin patients. There is a lot of belief surrounding the power of biomarkers but they need to properly tested to determine their true potential for directing therapy.

Another approach is to identify those patients not responding well to R-CHOP and to switch to an alternative strategy. The PETAL study identified such high risk patients with an interim PET scan after 2 cycles of R-CHOP. For those with a positive PET scan, patients were randomised to continue with R-CHOP or switch to a Burkitt-lymphoma type of intensive regimen. No benefit was found with the more intensive treatment but more toxicity was certainly evident.

To conclude, R-CHOP gives very good results for many patients with DLBCL. However those who do not respond well have biologically difficult disease and it's proven difficult to improve outcomes despite numerous attempts. This does not mean we should give up trying. Not at all - randomised phase III trials of promising agents are necessary to make progress. But let's demand these trials to be performed before recommending changes in the standard of care, especially when the new therapy is more toxic than the old. Let's learn from Fisher et al, NEJM 1993.