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 My name is <PRESIDIO_ANONYMIZED_PERSON>. I'm a senior staff specialist in medical oncology working at Westmead Hospital. Today I'm going to present to you the topic of chemotherapy in bowel cancer. After completing today's talk, you'll be able to understand the rationale of the common chemotherapies used in the treatment of bowel cancer, and you'll understand the mechanism of action, and you should also be able to identify and manage common side effects of these agents and finally to understand how these agents are used clinically i like gardening and also i like using gardening as an illustration of cancer treatment one of the least enjoyable things when I'm doing gardening is to get rid of weeds. When weeds are in small amount, I can hand pick them just like when the cancer is localized to a certain area, we can use surgery or radiotherapy as local treatment. We're also getting more and more different types of local therapies available such as the different ablative therapies quite specifically dealing with limited amount of cancer in the liver or the lungs offered by the interventional radiologists on the other hand especially after On the other hand, especially after you have neglected your garden for a while, these weeds may grow everywhere over your garden, and it's really hard to handpick. So you might choose to just spray the chemicals over the whole garden. So this is basically the principle of different drug therapy in cancer medicine, including obviously including chemotherapies as well as the newer type of therapies such as targeted therapies and immunotherapies. So by using these systemic treatments, it really doesn't matter where the weeds are, it doesn't matter where the wits are it doesn't matter where the cancer cells are so basically these agents can circulate in the in the blood system to reach the cancer cells mode of action of which chemotherapy is not cell cycle specific? 5FU, oxaliplatin, enritican, ralitrexate. The answer is oxaliplatin, and we'll go through that later on. This is a list of the commonly used chemotherapy agents in bowel cancer. Follinic acid and 5-ferrouracil or 5-FU have been used for many years. Oxaliplatin and erythritic are two more toxic agents, followed by some relatively new agents such as ralatrexate, Trifluoridine in combination with Ti-Pyracyl. And I'll go through that one by one later. Let's go through how these agents work. The first two I'm going to talk about are 5-F-U and folinic acid. The first two I'm going to talk about are 5-F-U and folinic acid. Phymitilase synthase is an important enzyme responsible for the production of famidine, which is essential for DNA synthesis. In the presence of 5-F-U, phymitilase synthase is inhibited, and therefore reducing the thymidine production and in turn reducing DNA synthesis. 5-FabU is regarded as a cell cycle dependent chemotherapy where the cell growth is affected when the cell is going through DNA synthesis so especially during the G1 slash S phase folin acid is regarded as a helper to 5fu where it stabilizes the binding of 5fu to famidylase synthase therefore potentiating its cytotoxicity folin acid is required especially when 5-FU is given in the bolus form where usually is given as a short push intravenously either given daily or weekly on the other hand if 5-FU is given through an infusion over a period of hours or if it is given orally, fungal acid is not required to stabilize the binding. there's also an oral form, an inactive form of 5-FU as a tablet, it's called capcitabine. So capcitabine is a prodrug which has to go through three enzymatic activation steps to be converted to active 5-FU. And the last step requires the use of famidine phosphorylase, which is highly expressed in the tumor microenvironment. So the advantages in using capcitabine apart from that being an oral agent which is easy to use because it is mainly activated in the tumor microenvironment, capcitabine can relatively spare the side effects on normal tissues. If you come across a patient with advanced colorectal cancer presented to emergency department with severe diarrhea and skin changes as pictured. Which agent is most likely related to this presentation? 5-FU, oxaliplatin, erythritic acid, or doxorubicin? The answer is 5-FU. Common side effects of 5-FU and folinacid include fatigue, mouth ulcers, diarrhea, and Hanford syndrome. These side effects are usually mild and can be easily managed. However, in some rare circumstances, severe side effects may also occur, such as chronic artery spasm. This tends not just affects patients who have known ischemic heart disease, but also may affect younger people who have known ischemic heart disease history at all. Patients typically complain of having angiolatite chest pain, and in some cases, unfortunately, sudden death may occur. may occur. And in the case described in the previous question, this may occur in patients with severe deficiency in an enzyme called dihydropyrimidine dehydrogenase or DPD in short. DPD is a metabolic enzyme responsible also for the deactivation of 5-FU. And in about 2% of Caucasian where polymorphisms of DPD may be present, as a result DPD activity may be greatly reduced or even absent. So in these patients, potentially they may have severe side effects from the use of 5-FU. And in the case of patients who have known overdose on 5-FU, or in patients with severe side effects which occur within 96 hours of administration, an antidote, uridine triacetate, should be considered. Oxaliplatin is another commonly used agent. It belongs to the platinum group, which is regarded as a non-cell cycle-specific agent. Oxaliplatin forms cross-links across a single strand of DNA resulting in reduction of DNA replication and transcription. It has to be used in combination with 5-FU plus or minus other cytotoxic agents such as urinaltecan. And then we start off different combination, we have come across different acronyms to describe these combinations such as FOLFOX which is an acronym stands for folinic acid 5-FU and oxaliplatin KPOX which is a combination of capsaicin which is the oral form of 5-Fbu plus oxaliplatin or Folfoxiri which is combining Folfox with Enrutekin oxaliplatin is more toxic than 5-Abu and folin acid it causes more fatigue nausea and mild malus depression. Like other platinum agents, oxaliplatin causes peripheral neuropathy. And in the case of oxaliplatin, it causes a special type of sensory neuropathy characterized by having pins and needle sensation or lateral numbness in the fingers and toes. or lateral numbness in the fingers and toes. And in some cases, patients developed laryngeal diasphesia, which can be a fairly unpleasant or scary experience to the patients where they describe unable to breathe, which can mimic a hypersensitivity reaction. And this tends to happen during the administration of oxaliplatin unfortunately this is there's no good treatment for managing the peripheral neuropathy associated with oxaliplatin and the recovery of the neuropathy can be prolonged which may last neuropathy can be prolonged which may last for months or even years after cessation of the drug and in some cases this neuropathy may be permanent the urinotecan has been used in the advanced setting where the cancer has metastasized to other organs. it can be used as a single agent or in combination with other agents mentioned above. it inhibits topoisomerase 1. topoisomerase 1 is an enzyme which is mainly responsible for the uncoiling mainly responsible for the uncoiling of the DNA strands. What it does is it forms a nick on one of the DNA strands so that to allow uncoiling for DNA synthesis to occur. So therefore, inrotican is also regarded as a cell cycle-specific agent, which works as the G1-S phase. What should we do when we are dosing inrutecan in patients with known Gilbert syndrome? Should the dose be reduced, or should we just use the same standard dosages? On the other hand, should we increase the dose, or should we not use this drug at all? Irritating can still be used in the presence of Gilbert syndrome, but we have to substantially reduce the dose. Enrutecan causes similar degree of fatigue, nausea, and milder suppression to oxaliplatin, but it causes more hair loss and diarrhea, but it doesn't cause peripheral neuropathy. Atropine is quite often used to prevent or reduce the development of chronologic syndrome, which occasionally may occur during the administration of inrutecan, characterized by acute diarrhea, increased sweatiness, and increased saliva production. We need to be very careful when we want to use inrutecan in patients with known Gilbert syndrome. Basically, Gilbert syndrome is a fairly common syndrome, and it's usually a fairly harmless syndrome where patients have polymorphisms in affecting the UGT1A1 enzyme, which is responsible for the conjugation of bilirubin. Inreticaine has to go through the same enzyme for inactivation from its active form SN38 to the inactive form. so as a result of the reduced function of UGT1A1, SN38, which is the active metabolite, is greatly accumulated in the body, causing severe side effects. so in the case of patients with Gilbert syndrome, we usually start with 50% of the usual dosage of inritican in order to avoid severe side effects. There are two other less commonly used agents in the treatment of bowel cancer. The first one is Raltetrexate, which is an intravenous agent sharing similar mechanism of actions to 5-FU through inhibiting fibroblastin phase. However, it does not get metabolized through DPD and therefore it can be a useful alternative in patients who are known to have DPD deficiency. It also does not cause any chronic artery spasm. Another is an oral agent which is a combination of two different drugs. It is quite often used as the last line of therapy especially given its favorable toxicity profile mainly mild malus suppression. Triferidin is also similar to 5-FU. It inhibits thymidylase synthase, whereas typeracil inhibits thymidine phosphorylase, which is responsible for the inactivation of triferidin. There are several strategies which are important in the prevention or reduction of side effects. Patient education is very important and patients are made fully aware of the potential side effects of chemotherapy before starting and they also have been educated on what to do when they have severe side effects. Patients are encouraged to have adequate nutrition and hydration, especially good hydration will ensure appropriate elimination of certain chemotherapy drugs. Regular exercises have been shown to reduce treatment-related fatigue and short-term memory loss. We can also consider doing pret treatment dpd testing but currently this test is not covered by medicare costing around 200 dollars to do patients also should do regular mouth washes with salts or bicarbonate-based mouthwashes to reduce the risk of mouth ulcers. They also encourage to apply skin moisturizers especially in the hands and feet region. We have several very good antiemetics which can be used as pre-medication very good anti-emetics which can be used as pre-medication to prevent nausea and vomiting as well as especially during the pandemic we will consider more the use of white cell booster to reduce the risk of infection I presented to you different chemotherapy agents using in bowel cancer. And before the end of the talk, I would like to present to you three different clinical settings where we commonly use these agents. The first one is in the so-called neoadjuvant setting, where chemotherapies are used before the definitive treatment such as surgery. We quite often consider using a combination of 5-FU-based therapy, especially oral capsaicin treatment with radiotherapy for up to six weeks in the treatment of locally advanced rectal cancer. And usually the definition is rectal cancers involving the regional lymph glands or penetrating through three out of four at least layers of the bowel wall more recently there are some studies demonstrating benefit in the so-called total neoadjuvant therapy where not only do we give so-called total neoadjuvant therapy where not only do we give radio sensitizing chemotherapy treatment together radiotherapy we actually give the full dose systemic chemotherapy as well before surgery whereas in the more conventional setting we offer adjuvant chemotherapy following curative resection. Mainly we use it in patients with stage three cancers where the cancer cells have spread to the regional lymph glands. And in this situation we use treatment somewhere between three to six months and I understand you have a separate talk to discuss on adjuvant chemotherapy treatment. And finally, in some patients, unfortunately when they present with cancer, they actually may have the cancer already metastasized to other organs, or the cancers may recur following previous curative treatment. In this case, we may not be able to cure the patients from the cancer and the treatment is regarded as palliative, aiming to prolong survival. However, in some special circumstances where the patients may have resectable disease, where the patients may have resectable disease, especially if we're able to shrink the tumors enough for the surgeons to remove them, then the purpose of chemotherapy is to convert, hopefully to convert unresectable cancer to resectable cancers. cancer to resectable cancers. In my opinion, chemotherapies will remain as very important treatment for bowel cancers even in the presence of targeted therapies and immunotherapies. We have discussed the mechanism of action of some of the commonly used agents and their side effects. We also touched on how to manage some of the more common side effects and also how to prevent the development of these side effects. And finally, we have roughly discussed the different clinical settings where we can use these agents. Thank you very much. where we can use these agents. Thank you very much.