CHOP: the King of Chemotherapy

The commonest chemotherapy regimen in lymphoma medicine by far is CHOP. This is an odd acronym and takes some explanation. The drugs included are Cyclophosphamide, Doxorubicin (this is the red drug and is otherwise called Hydroxydaunorubicin, hence the 'H'), Vincristine (which comes from the Madagascan Periwinkle hence the vinca plant symbol for Lymphoma Action - otherwise known as Oncovin, giving the 'O') and Prednisolone. 

CHOP exemplifies the principles behind combination chemotherapy. Imagine the days before combination chemotherapy, sitting down in a bar with some colleagues trying to work out which drugs to put together. The following principles are helpful to guide the final result:

- each individual drug should be active in the disease of interest

- the mechanism of action (and therefore of resistance) of each agent should be distinct

- each agent should work at a different part of the cell cycle

- each agent should have distinct (and preferably non-overlapping) dose limiting toxicities enabling the delivery of each drug at near maximal dose

- the pharmacokinetics should not interfere too much with each other

The table below demonstrates how CHOP (combined with rituximab) exemplifies this approach. Under toxicity, 'Myelo' means myelosuppression i.e. low bloods counts (neutropenia etc) and DLT stands for dose-limiting toxicity. You'll note that some of the drugs are cell cycle non-specific which means they act on cancer cells irrespective of whether they are actively cycling or not. Since in any given cancer, usually a minority of cells are actively cycling (high grade lymphoma often being an exception to this rule), including a cycle non-specific drug in a regimen is highly desirable. 

Drug	Action	Cell cycle	Toxicity
Rituximab	Anti-CD20 mAb	Cycle non-specific	No DLT
Cyclophosphamide	Alkylating agent	Cycle non-specific	Myelo (also bladder)
Doxorubicin	Intercalates DNA	S-phase	Myelo (also heart)
Vincristine	Anti-metabolite	M-phase	Neuropathy
Prednisolone	glucocorticoid	G1 phase	Metabolic / neurol

CHOP was initially used for high grade non-Hodgkin Lymphomas. This was in the era before pathologists had immunohistochemistry, so physicians were blind to whether they were treating B-cell or T-cell NHL. With the advent of immunostaining, and then with therapeutic monoclonal antibodies, rituximab was added to the CHOP regimen in high grade B-cell lymphoma (initially diffuse large B-cell lymphoma, the commonest subtype). Results were dramatic with a notable prolongation not just in remission lengths, but also in overall survival. This was first demonstrated by Coiffier et al (who sadly recently passed away) in patients aged 60-80. 

Prof B Coiffer

He performed a randomised study comparing 8 cycles of CHOP with 8 cycles of R-CHOP. Long term follow up of this study is shown graphically below and is taken from Coiffier et al (2010) Blood. The 10 year overall survival rose from 27% to 43% - a massive 16% absolute increase. Since then, adding rituximab to this regimen has cured 1000s of people of their diffuse large B-cell lymphoma. 

Overall survival with 10 years of follow up

CHOP and R-CHOP also have what physicians often describe as an acceptable safety profile. Of course it is really up to the patient to say whether the side effects are 'acceptable' or not. But generally what is meant by this is that it is delivered as an out patient, it is safely given to patients even as they get older (certainly up to 80 years of age) and patients mostly report that the side effects improve with time after finishing. Common side effects include:

- Infusional reactions due to the rituximab (this is quite common but usually only happens with the first dose; subsequent doses are often much less affected.

- Fatigue: a common complaint, often under-estimated by doctors and for which we can do very little. Sometimes this can also be prolonged, interfering with recovery after chemotherapy.

- Hair loss: due largely to the doxorubicin, this is pretty much invariable although it does grow back afterwards (and is frequently different from before - sometimes curly and sometimes even a different colour!)

- Neuropathy: due to the vincristine. Symptoms are usually mild with numbness and tingling in the finger and toes. If it gets worse (starting to interfere with function) then the dose should be reduced. Usually it does recover although not always completely and it can take up to 2 years to get the most recovery. Beware giving vincristine to someone with foot drop as this could be an indication of an underlying hereditary neuropathy which maybe dramatically unmasked when this drug is administered!

- Heart damage: due to the doxorubicin. This is less common but is probably underestimated. 6 courses gives a cumulative dose of doxorubicin of 300mg/m2 which probably increases the risk of heart failure over the years by several fold. 

- Infection risk: the 2nd of the 3 weeks in a cycle is usually characterised by neutropenia. Neutropenic fever (which is medical emergency) happens in about 15-20% of patients on R-CHOP and usually necessitates hospital admission. This frequency can be reduced by the use of G-CSF injections and prophylactic antibiotics.

- Nausea: thankfully we have excellent anti-sickness drugs now so debilitating nausea is uncommon.

- Taste change: this is common although the mechanism isn't clear. Patients often describe a metallic taste and they can go off foods which they previously enjoyed such as curry or coffee. It usually does reverse at the end of treatment but it can take some time.

- Mood changes and raised blood sugars due to the prednisolone. It is important to tell diabetics to monitor their blood sugars more closely and they may need to alter their anti-diabetic medication when on R-CHOP. 

There are numerous other side effects reported, but these are the main ones and the ones I discuss with patients. I also explain that there is a small risk of dying on chemotherapy, but R-CHOP is generally considered a safe chemotherapy and the risk is 1% or less for most people. Certain groups do have a higher risk though, such as the elderly, and those who have had a previous organ transplant. The cause of death is often infection and it's often when people haven't told us they are unwell with a fever, so contacting the medical team for advice quickly is important when on chemotherapy. 

R-CHOP is generally given once every 3 weeks. Before the introduction of rituximab, the German High Grade Lymphoma study group found that administering CHOP every 14 days was a little more effective. In oder to deliver this schedule, they had to routinely give all patients GCSF injections and also additional preventative antibiotics (against an infection called PCP). Once rituximab was introduced it was controversial whether there was any benefit with the 14 day administration. This issue was largely settled by a UK study comparing R-CHOP given every 21 days with every 14 days. The study was led by Professor Cunningham of the Royal Marsden in London and showed equivalent outcomes. This is illustrated by the graph below taken from Cunningham et al (2013) Lancet. 

R-CHOP-21 therefore has remained standard of care. Many attempts to better R-CHOP have been made and have largely failed - but I will blog about that in a subsequent post. 

For now, R-CHOP in my view is the King of Chemo, exemplifying the principles of combination chemotherapy, resulting in excellent outcomes for the majority of patients with high grade B-cell non-Hodgkin lymphomas and all with side effects which, although sometimes severe, are generally tolerable. Of course R-CHOP isn't right for everybody but it remains the gold standard regimen world wide for most with the commonest forms of lymphoma.  As I say to my trainees - if someone asks you how to treat someone with lymphoma, you'll not usually be too far wrong saying R-CHOP-21. 

Where Chemo Comes from

Chemotherapy gets a bad press. It undoubtedly has sometimes severe side effects yet it has saved 100s of thousands of lives from premature cancer deaths. The history of chemotherapy is very interesting. What I'm going to present here is a commonly told tale and I think mostly true, but I really can't vouch for all the historical details.

World War I was full of horrors, perhaps none more horrific than the use of chemical weapons. When World War II broke out, the allies were fearful of its renewed use so they stockpiled a store of mustard gas to use as retaliation. The SS John Harvey had a secret store of mustard gas and was stationed in Bari harbour, Italy when it was subject to an air-raid. Many hundreds of people died due to exposure of released mustard gas. Post-mortem examination of the bodies showed profound lymphoid and myeloid hypoplasia leading physicians to hypothesise it may have therapeutic use in cancer. Two pharmacologists, Goodman and Gilman (picture below), modified the chemical structure of mustard gas to make the more stable nitrogen mustard. Trials on humans with lymphoid malignancies (yes - lymphoma blazed the trial!) showed it could induce temporary responses.

So proof of principle was demonstrated. Shortly afterwards, the pathologist Sydney Farber (of Dana-Farber fame - picture below) reasoned that as the bone marrow in folic acid deficient patients had similarities to the bone marrow of children with acute leukaemia, treating leukaemia with folic acid may have therapeutic benefit. Sadly he was wrong and in fact the exact opposite was observed! Thankfully though Farber had also heard of the recent development of folate antagonists and correctly reasoned that if folic acid made things worse, anti-folates might make things better. Initially aminopterin was used but later methotrexate. Impressive responses were seen in children with ALL and later on in other cancers such as choriocarcinoma.

In a different medical field, experience in infectious diseases suggested that cures for TB could be achieved using combinations of antibiotics to avoid resistance. So it was reasoned that combinations of chemotherapy may achieve similar effects with cancer. Combination chemotherapy was born. Some of the first combination chemotherapy regimens shown to cure cancer, were developed in the lymphomas such as MOPP (in Hodgkin Lymphoma) and later CHOP (in high grade non-Hodgkin lymphoma).

So in a very real sense we have chemical weapons to thank for the development of chemotherapy - a wonderful unintended consequence of a tremendous evil.

Lymphoma - an introduction

This is my first post as a blogger!

Why a lymphoma blog? Lymphoma is a disease which in my view is endlessly fascinating. Some people don't like to use the term 'fascinating' when it comes to a disease as clearly for those affected, it is a source of worry, stress and illness. I don't want to minimise this at all. However, if you are affected by a disease then it is much better to have a specialist who is interested by the disease rather than someone who is bored by it! I hope these blogs will inform, educate and interest people in all the many and various subtype of lymphoma. I hope it will be accessible to patients but also of interest trainees and more senior clinicians. 

Lymphoma in simple terms is a cancer of the adaptive immune system. In particular, the cells of adaptive immune response - lymphocytes - have become cancerous and grow and divide in a poorly controlled way.  Lymphocytes (and we have 2 main types - B lymphocytes and T lymphocytes) coordinate and effect the immune response to many different micro-organisms. B lymphocytes are involved in the production of antibodies and are vital for fighting various bacteria and viruses. Certain types of B-cells (memory B cells) also enable the adaptive immune system to have a memory so it can respond faster second time around. T-lymphocytes can be thought of as the conductors of the immune orchestra, coordinating the immune response. Certain subtypes however kill infected cells whilst other subtypes actually damp down immune responses. 

The majority of lymphomas we see in the UK, Europe and the US are B-cell lymphomas with T-cell lymphomas making up < 10% of cases. This is because during their life-time B-cells have to transit a structure within lymph nodes called the germinal centre. Here, 2 forms of physiological DNA damage occur. Class switch recombination involves a double strand DNA break and results in a change in the subclass of antibody. Somatic hypermutation involves single base-pair mutations in an attempt to refine the specificity of the antibody being produced. In order for this to happen quickly in response to micro-organisms, mechanisms to identify damaged DNA (such as p53 expression) are repressed. This makes the germinal centre a dangerous place for B-cells as if these genetic changes go wrong they are not recognised. If they affect genes that can induce cancer (oncogenes) then normal healthy lymphocytes can turn into lymphoma cells. 

There are 2 broad categories of lymphoma: Hodgkin and non-Hodgkin lymphoma. Thomas Hodgkin was a pathologist at Guys hospital in London in the 19th century and described the first cases of what became known as Hodgkin Lymphoma (although some of his original cases turned out to have TB instead!). I won't go into the details of the different types in this blog but suffice to say Hodgkin lymphoma predominantly affects young people whereas non-Hodgkin lymphoma increases in incidence as you get older. There are high and low grade versions of non-Hodgkin lymphoma. 

I hope you enjoy these posts and find them interesting. I'm not sure yet what shape they'll take and I would very much appreciate feedback or suggestions for future topics.