Aki Ohinata, MSPA-C
Department of Gastrointestinal Medical Oncology
The University of Texas MD Anderson Cancer Center
Today, I'd like to talk about colorectal cancer survivorship and the late effects of chemotherapy. My name is Alexandria Phan. I work in the GI Medical Oncology Department here at the University of Texas MD Anderson Cancer Center.
At the conclusion of this lesson, participants will be able to recognize general long-term effects or late effects of chemotherapy agents; recognize long-term or late effects from specific chemo agents used for colorectal cancer; identify management strategies and indications for referral for further management of late effects of chemotherapy.
The classification of therapeutic adverse effects such as chemotherapy is done so by time of onset versus duration of exposure. Time of onset can be immediate, which occur minutes to hours from administration. Delay occurs days to weeks from administration. Late does not occur at the time of treatment or after treatment until later. Long-term effects persist after treatment and these can be years, months, or weeks after treatment.
Adverse effects may be general versus agent specific, irreversible versus reversible.
The challenges in defining risk of late effects of chemotherapy are that published literature often consists of case reports lacking prospective evidence. Inadequate long-term follow-up data exist. Risk factors associated with individual agents or late effects are not well defined and limited. Unique complex of adverse effects, contributing by each anti-neoplastic agent cannot be accurately delineated, since systemic chemotherapy are combination of chemotherapeutic agents.
Some of the most obvious limitations of retrospective evidence include the fact that these evidence have recall biases. They usually consist of loss of follow-up. They are nonstandard follow-up intervals or times. They are usually missing in datas. No comparability of groups and variation in treatment also exist in these retrospective evidence. Additionally, variation in outcome assessment instruments and outcomes assessed by multiple individuals in nonstandard ways exists in retrospective evidence supporting or reporting the late effects of chemotherapy.
The gaps in medical literatures supporting late effects of chemotherapy may be due to many unknowns regarding long-term effects, such as the incidence, the prevalence, the risk factors, causality, and the natural history such as onset, duration, and severity.
General late effects of chemotherapy are --- typically consist of fatigue and malaise, reproduction and sexuality issues such as fertility, anovation --- anovulation, menopausal symptoms, and decreased libido. Cognitive dysfunction commonly referred to che --- referred to as "chemobrain", osteoporosis, and cataracts. Again, these are general effects of chemotherapy and they are --- generally occur late.
For fluoropyrimidine, which is a class of chemotherapy consisting of two agents, 5-fluorouracil and capecitabine also referred to as 5-FU and Xeloda. There are currently no published report on long-term effects for these agents. However, reports of late effects that are in literature include leukoencephalopathy and seconla --- secondary acute or chronic myeloid leukemia. Leukoencephalopathy are similar to early onset dementia. That's the clinical presentation of leukoencephalopathy.
For oxaliplatinum, another chemotherapy agent used in colorectal cancer, published reports of long-term side effects are rare, but may include peripheral runo --- peripheral neuropathy, splenomegaly, hepatotoxicity. Reported late effects include interstitial lung disease, such as pulmonary fibrosis or secondary acute myelogenous leukemia. Based on our experience, electrolyte disturbances can be long-term side effects of oxaliplatinum.
Oxaliplatinum-induced peripheral neuropathy is cumulative, may worsen after drug discontinuation, typically manifests by numbness, tingling, and paresthesia and often times can be permanent and they are less frequently painful.
Hepatotoxicity from oxaliplatinum are well described in literatures. Sinusoidal obstruction may develop during treatment, though it may not be identified until after treatment has been discontinued. Sinusoidal obstruction syndrome may progress to liver fibrosis and cirrhosis. Often times, this condition, sinusoidal obstruction caused by oxaliplatinum can be referred to as similar to liver toxicity from bone marrow transplantation for patients with hema --- blood leukemia or lymphoma malignancy.
The effect of oxaliplatinum on the liver is not correlative to the degree of sinusoido --- sinusoidal dilation and it is not correlated to durations of exposure to oxaliplatinum. This table represents the degree of sinusoidal dilation of --- caused by oxaliplatinum depending on the number of weeks' exposure to oxaliplatinum. As you can see here, that it started out with two to eight weeks of exposure to oxaliplatinum and you can get a grade two to three sinusoidal do --- dilation of 18 percent to 19 percent. But, even with higher or longer duration of exposure, you still have a fairly high, if not similar, grade of dilation in the sinusoidal system in the liver. So, regardless of exposure duration or amount of durations --- amount of oxaliplatinum exposure, the sinusoidal dilation occurring in the liver can happen at similar degrees or severity.
Adverse effects of irinotecan: irinotecan is another chemotherapeutic agent in use in colorectal cancer. The side effects include fatty liver or steatohepatitis, and it can risk to progression to cirrhosis and liver failure. There are reported late effects of irinotecan which are secondary acute myelogenous leukemia.
Fatty liver or steatohepatitis from chemotherapy can come from agents that are used commonly in colorectal cancer, including 5-fluorouracil, oxaliplatinum, and irinotecan. On this table listing these three agents and the frequency of steatohepatitis, listing irinotecan to be the most frequently associated with fatty liver or steatohepatitis.
This slide represents an example of chemotherapy-related hepatic injury. For example, this is a baseline CT scan of a patient showing a cross-sectional anatomy --- or cross-sectional CT image of the liver, the gallbladder, the spleen. After six months of chemotherapy with FOLFOX or oxaliplatinum, Ire --- oxaliplatinum, 5-fluorouracil and leucovorin, the patient's CT scan has changed. As you can see here, the liver --- I mean the spleen is enlarged compared to this baseline spleen. Another obvious chemotherapy-related hepatic injury is shown here with fluoro --- four FOLFIRI, which consists of irinotecan, 5-FU, or flor --- 5-fluorouracil and leucovorin. After two months of therapy, patients develop steatohepatitis or fatty liver, as demonstrated in this scan with these different discoloration or blood vasculatures in the liver. This is a normal liver. This is a liver that is considered fatty liver.
Moving on to agents that are considered targeted anti-neoplastic agents, anti-VEGF, or anti-vascular endothelial growth factor, such as bevacizumab, have been used in colorectal cancer to improve survival. Their long-term effects may include proteinuria, hypertension. And the duration of these effects have not been reported because these agents are relatively new.
EGFR Inhibitors, or endothelial growth re --- [epithelial] growth factor receptor inhibitors, such as cetuximab or panitumumab, have long --- no long-term effects that has been reported. Perhaps, it is because these agents are even newer than anti-VEGF therapy. In our experience, hypomagnesemia may persist for duration that is unknown. It may initiate at the time of administration of these agents and persist long-term, which may be months or years after the complucion --- completion of these agents.
Recognition of chemotherapy effect is important. It is essential to be aware of the risk of long-term hepatic effects following irinotecan and oxaliplatinum. Currently, no studies are available to specifically guide management of long-term effects or long-term hepatic toxicity. Prompt attention to laboratory results that may indicate the development of myeloid dysplastic syndrome or chronic leukemia are necessary because these conditions may be early representation of secondary development of leukemia.
There is no guideline available to address long-term and late effects related to colorectal cancer treatment. Strategy that has been used in our practice include use of anti-seizure medications such as gabapentin commonly known as Neurontin or Lyrica for painful neuropathy has been done --- has been used successfully in our experience, lifestyle intervention, which may be helpful in improving chronic fatigue, monitoring hypertension for improved follow-up therapy with reduction or discontinuation of anti-hypertensive agents as indicated.
Indication of referrals is important to know. But, patients who has sexual dysfunction or infertility should be referred to cancer of excellence or cancer center that is capable of addressing these condition. Other indication for referral include painful neuropathy that are unresponsive to medical management or progressive hepatic dysfunction. Lastly, chronic complaint interfering with quality of life or function that does not respond to routine management should be another indication for referral.
In summary, it is important to remember that patients treated with chemotherapy for colorectal cancer may experience persistent long-term effects such as hypertension, peripheral neuropathy and fatigue. Hepatotoxicity may develop during or following treatment with chemotherapy. Management of many long-term effects may be provided by the primary care provider with consideration for referral for serious sequelae or those that interfere with quality of life. I'd like to conclude today's discussion with a encouragement for participant to give us feedback on any aspect of our educational material. Thank you for your attention.
Late Effects of Chemotherapy video
©2012 The University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd, Houston, TX 77030
1-800-392-1611 (USA) / 1-713-792-6161