My Colleague today brought to my attention a couple of websites that have many helpful resources for revising. They cover Physics particularly well and some radiobiology. The links are:


1. http://radonc.wikidot.com
2. http://ozradonc.wikidot.com


These have both been created by Leinna and Alexis, radiation oncologists in Australia. Many Thanks.

DRUG-DRUG INTERACTIONS

I think the following will be useful to learn:

• Cisplatin can lead to renal damage which can therefore reduce the renal clearance of methotrexate
• If cisplatin is given before topotecan, exposue to topotecan increases, due to reduced renal clearance of topotecan

• Allopurinol reduces the metabolic inactivation of 6-mercaptopurine and increases its toxicity.
• Penicillins, Probenacid and sulfonamides and NSAIDs reduce the renal clearance of Methotrexate. Compete for the tubular secretion pathway

• If Carboplatin/Cisplatin are administered simultaneously with paclitaxel there is less myelosuppression compared to when platinum preceeds paclitaxel.
• There is increased neurotoxicity when cisplatin ans paclitaxel are administered together. This interaction is worse when paclitaxel infusion has along duration.

• Methotrexate can be displaced from Albumin by 1.sulphonamides 2.tetracycline 3.chloramphenicol 4.phenytoin 5.NSAIDs. This will increase the plasma concentration, causing more side effects such as mucositis and myelosuppression

RANDOM PHARM FACTS

• MESNA binds acrolein (metabolite of ifosamide) that is irritant to urothelium
• Dexrasone iv is used with anthracycline extravasation
• Epirubicin and Doxorubicin are a red solution and can cause urine and sweat to appear pink after treatment.
• Methotrexate is yellow
• Mitomycin C is a light blue solution
• You can give vincristine, bleomycin and gemcitabine on day 8 as they have less myeloosuprresive effects on the pre-cursor cells.
• Gemcitabine and Fludarabine have synergy with cisplatin by inhibiting the repair of cisplatin adducts (by NER)
• 5-FU as a BOLUS affects RNA metabolism
• 5-FU as an INFUSION affects DNA metabolism

More to come soon.

 I never realised people from so many countries are all gearing up for the FRCR. In the last few months this page has been going, people from every continent have been visiting. I am so excited and can't wait to do more to help you in any way I can. Twesi was telling me how difficult it is knowing where to start with revision. I also found the FRCR very frustrating, with little available to help me through. That is why I set this up. I will do my best to be helpful. 

Recently I have been on-call and generally  busy at work as an oncology registrar, so not added much. In the next few weeks I will be adding alot more to the blog as I have some time off work. Keep in touch. Good Luck. Stephen

Irinotecan is a popular question and I think it is well worth learning as much as you can about it. It has an interesting pharmacology, so lots can be asked about it.

THANK YOU Everyone

Hi. Just a thank you to everyone who has taken a look at the blog so far. Really good to see people all over the world are taking a look.  I have not been putting too much on this last month. as I have been busy at work and having fun sailing. I hope these notes on Drug development and trials helps. I remember this being asked about quite a bit. What's great is it is very easy to understand -so easy marks there.

Hope your studying is going well. Remember is now 3 months to go!

DRUG DEVELOPMENT 2

• Phase 1 : Human Pharmacology, (Dose finding)
• Phase 2 : Therapeutic Exploratory (? anti-tumour activity)
• Phase 3: Therapeutic action Confirmed and compared to standard
• Phase 4 : Post launch

For classical Cytotoxics

1. Dose escalation Phase 1 to determine Dose Limiting Toxicity (DLT) & Max Tolerated Dose (MTD)
2. No-randomised Phase 2 to determine efficacy
3. Phase 3 - for comparative effficacy

DLT -for example

• neutrophil count <0.5 for 5 days associated with fever or infection
• Platelet count <10 or bleeding
• Other Grade 3 toxicity

MTD

• Dose at which < or = 33% patients experience an unacceptable toxicity

Characteristics of a Phase 1 trial

• Usually in patients with an advanced malignancy, refractory to standard therapies
• Patients usually otherwise well
• Start with a very cautious dose as determined from pre-clinical studies.
• Starting dose (mg/M2) 1/10th of the LD10 (dose at which 10% of rodents die)
• 1/3rd of minimal toxic dose in large animal studies
• Minimise number of patients treated with sub-therapeutic doses. Escalate dose quickly if toxicity absent. Escalate slowly if toxicity present.
• Example: Treat 3 pts with safe starting dose (as described above), increase dose if no toxicity. If toxicity in 1 patient add 3 more. Stop escalation when more than 33% pts have an unacceptable toxicity.
• Modified Fibomaci Scheme: Start at 1/10th of LD10, then increase by 100% then 67%, then 50%, then 40%, then 33% thereafter (100--67--50--40--33). If the LD10 is accurate, should be 5-6 dose incriments.
• PURPOSE: Estimate the recommended dose for later trials, study drug metabolism, elimination and side effects
• LIMITATIONS: Chronic/cumulative toxicities not well assessed, uncommon toxicities missed, dose for Phase 2 may be conservative as Phase 1 patients often heavily pre-treated.

PHASE 1 ETHICS

- Pt benefit is not the primary goal, but the trial dose need to have a therapeutic intent

- Low probability of response expected - approx 5%

DRUG DEVELOPMENT

DRUG DEVELOPMENT

Overall View

1.      Identify Molecular Target

-        Involved in cancer growth/development

-        Promise ‘Lead’

2.      Find/Screen/Design a product to interact with target (inhibitor/activator)

3.      Optimisation and Formulation

4.      Pre-clinical studies

-        ‘proof of principle’

-        Animal models for proof of concept and safety data 

5.      Clinical Studies  Phase 1 à 4

e.g. Imatinib (Gleevec)

-        Identify Target: Chromosome Transolcation t(9,22), BCR-ABL fusion protein

-        Lead Compound was found to have Kinase Inhibition, from screening of high throughput screening

-        Optimisation to enhance bioavailability and target specificity

-        Pre-clinical testing demonstrated proof of principle

-        Phase I  to III trials

Screening for Useful Compounds

•       High Throughput –millions of compounds (libraries) exposed to cell cultures and levels of apoptosis measured
•      Cominatorial Chemistry- synthetic molecules created
•            Natural products
•      ‘In-silico’ approach – virtual computer screening, selecting compounds binding based on knowledge of target structure

Product Information sheets for Pharmacology

I found for pharmacology it was useful to read the product information literature from the drug companies. They are normally comprehensive and give a lot of detail on the pharmacology, especially interactions and side effects.

I recommend doing this for the drugs the FRCR seem to commonly ask about.

The links are as follows:

• Capecitabine (Xeloda®) link
• Herceptin® link
• ADRIAMYCIN® (Doxorubicin)link
• Epirubicin (Pharmorubicin®) link
• Docetaxel (Taxotere®) link
• Paclitaxell  (Taxol®)
• Irinotecan (Campto®)link

Practice questions

I used the 2010 ASTRO RADIATION/CANCER BIOLOGY PRACTICE EXAMINATION AND
STUDY GUIDE, which is free to download of the ASTRO website. Has hundreds of BoF type questions. It is really helpful and I think it would be unwise not to use this. I must have read through this all twice and some parts for a third time. Currently their web site seems to be having maintenance and you can't access it. Keep on checking. I will post the link as soon as it is available again.

RAPHEX questions & Answer booklets are good for Physics. Again these are BoF too. I got hold of these from my local Physics department who had a whole lot of these from previous years. They don't seem to have a website like ASTRO. Amazon seem to know of its existence, but don't have any in stock at the moment. I think your best bet is trying your local library and Physics department. I will do a bit more investigating to see how individuals can get hold of these

Best books to use

Finding the best books can be difficult. The Royal College suggest core texts and additional reading. My own problem was I really disliked some of their core texts. There are some books that are just not user friendly. My advice is to read the core texts as much as possible, but only if you can stay awake. I think some of the exam questions are taken directly out of the books they recommend and this is why it is important to have read them.

The following were my own favourites and on reflection seemed to help me with the exams the most. These were all used in conjunction with lecture notes and web resources

For Radiobiology and Cell Biology

• Radiobiology for the Radiobiologist, Hall & Giaccia. I found these really helpful and is pitched at the right level for the exam. Covers cell biology, but not enough to use this alone.
• The Basic Science of Oncology, Tannock. This is a great text. To be honest I did not read all of it. Some parts seemed a bit too in depth.
• Molecular Biology of Cancer, L Pecorino. This is not on the RCR list, but it should be! Great book that is very user friendly, but be warned do not use on its own.
• ASTRO questions and answers. Link to web site for 2010 and 2011 is currently not working, but you can still get 2009 guide free off ASTRO web site at the moment. This study guide has hundreds of questions and detailed answers. I think these questions are very similar to FRCR exam and I think a few were more or less identical. 

Pharmacology

• Cancer Clinical Pharmacology, Schellens.  My first impressions of this book were not great as it looks quite dense and the lay-out is not brilliant. But please read this book. I don't think I could have passed Pharmacology without it. There is so little out there to help prepare for pharmacology you can't afford not to have read this. I found lots of really useful 'gems' in here - little pockets of facts hidden in the text that came in useful for the exam. 
• I looked at some of the others, but I did not find them that helpful. 
• Go on to one of the great pharm courses to supplement any reading.

Statistics

• It has to be Medical Statistics at a Glance by Petrie & Sabine. How can an 'at a glance' book ever be enough for the FRCR exam I hear you ask, but in my experience it is. A classic book that is pretty much loved by everyone. This has to be your core text and supplemented a little with the other texts.

Physics

• Honestly I did not use many Physics texts as the Physics lecture notes from The Christie course are so good. 
• I used a little from The Physics of Radiation Therapy by Khan. It costs alot of money to buy, so if you have good lecture notes, probably not justified.

Broad overview of Subjects

I always think it is really important to get a sense of what the examiners want from you. This is especially important when you are 'drowning' in information and you need to prioritise your revision for the FRCR. And remember the exam is there to enable you to be a good safe oncology trainee. So most questions have some relevance to clinical practice. Here is a copy of what they say on the RCR web-site (link above)

1. Cancer Biology and Radiobiology: the processes of cancer cell transformation and tumour development and how these processes may be demonstrated and the response to ionising radiation of cells both individually and grouped as tissues
2. Clinical Pharmacology: the structure, action, use and evaluation of drugs used in the treatment of a patient with cancer.
3. Medical Statistics: with special reference to clinical trials and assessment of results, and the epidemiology of cancer
4. Physics: the application of physical principles and methods in clinical radiotherapy, physical basis of the therapeutic uses of radioactive isotopes, radiation hazards and protection

The examiners include clinical oncologists, biologists, clinical pharmacologists, medical statisticians, medical physicists and radiobiologists.

Pharmacology - cell cycle action of CHEMO agents

TOP TIPS for Passing FRCR Oncology

Firstly I wish you luck in your exam. The FRCR is no easy endeavour. After medical school exams, the MRCP, starting a new training post the last thing you want to think about is more exams! But it must be done and it can be - if I can do it you can too.

So what have I learnt? And what can I advise?

1. Start revising early,  but not too early. I suggest getting started 6 moths before hand, but gettting serious 2 months before i.e. having no social life for 2 months.

2. Read the core texts on the FRCR reading list. Don't be tempted to solely rely on books not on the list, that are flasher and more interesting. The questions are sometimes taken directly out of the core texts.

3. Attend courses in all of the 4 modules as early as possible. I attended cancer pharmacology, cellular biology, physics and medical statistics at The Christie Hospital http://www.christie.nhs.uk/pro/education/events/. The Systemic Chemotherapy course in Sheffield was excellent http://onc-education.group.shef.ac.uk/. There is another Chemotherapy course in Leicester, but I did not attend this myself. http://www.le.ac.uk/cm/RPScourse.html. Take a look at the RCR website for a general overview of courses in UK http://www.rcr.ac.uk/externalmeetings.aspx?PageID=114.

4. Gather as many practice questions as possible. This as you may have realised is quite difficult as there are no dedicated FRCR question books out there for the part 1. The RCR publish a few questions which you are sent when you apply. There are a few books out there, but all for similar US exams. I will give details of these soon.

5. Enjoy what you are learning. If you have chosen oncology it is likely you will find it interesting and it does make the day job make more sense.

This might sound obvious, but remember the application deadline. Don't miss it!