Imaging side effects and complications of antineoplastic therapy in liver, pancreas and gastrointestinal tract- a pictorial review
Gina Al-Farra1* ; Dania Cioni2; E Neri2
1Senior consultant in oncoradiology, Dept. of Radiology, University Hospital of Herlev-Gentofte, Denmark.
2Master in Oncologic Imaging, Diagnostic and Interventional Radiology, Department of Translational Research, University of Pisa, Via Roma, 67, 56126 Pisa, Italy
Received Date: 15/12/2021; Published Date: 19/01/2022.
*Corresponding author: Gina Al-Farra, Senior consultant in oncoradiology, Department of Radiology, University Hospital of Herlev-Gentofte, Denmark.
Antineoplastic treatment can affect all organs and types of tissues, with manifestations that may appear acute or after prolonged treatment as a result of stochastic effects. Recognizing the side effects can have a big impact in the treatment itself but also save the patient's life, certain conditions can be life threatening ( for example, pneumonitis, infections, sinusoidal obstructive syndrome, etc.).Types of Cancer Treatment include Surgery, Chemotherapy, Radiation Therapy, Targeted Therapy, Immunotherapy, Stem Cell or Bone Marrow Transplant and Hormone Therapy.
Cancer treatments induce local and systemic changes on normal tissues,all cancer treatment modalities are associated with toxic effects (both short and long term).
During treatment complications can appear to be related to treatment but also cross-complications, often cancer patients have concomitant diseases.
Radiologists are tasked to differentiate expected findings from residual/relapse of tumors and cross complications.
Newer biologic drugs and immunomodulatory agents, as well as more tolerated and effective radiation therapy schemes have reduced treatment toxicity in oncology patients. The treatment are more precisely and personalized. However, although imaging assessment of tumor response is adapting to atypical responses like tumor flare, expected changes and complications of chemo/radiotherapy are still routinely encountered in post-treatment imaging examinations. Radiologists must be aware of old and newer therapeutic options and related side effects or complications to avoid a misinterpretation of imaging findings. Fast and highly performing CT and MRI technologies have opened new frontiers in oncology imaging, allowing tissue characterization, early diagnosis, prognostic evaluation, and accurate response assessment .
The table below lists the most well-known organ-related side effects associated with cancer treatment (surgery it is not included).
Table 1: Complications of Cancer Therapy Categorized by Affected Organ System.
Other complications are related to oncological intervention, from the simple drainage to complex treatments such as TACE, RF and Crio Ablation. It is absolutely essential to ensure that the patient's blood sample is within the permissive limits of intervention to avoid bleeding which is especially difficult to treat. The purpose of this review is to present the most common complications that may occur during antineoplastic treatment, while understanding that oncological imaging is actually a form of clinical radiology, conditioned by knowledge of various forms of treatment in oncology and their effects. The presentation includes explanation found on CT and a few MRI, these are used in the follow-up of cancer patients in our practice.
Cancer therapy induced hepatic toxicity
Chemotherapy-induced liver injury can present as hepatitis, steatosis, sinusoidal obstruction syndrome, and chronic parenchymal damages, molecular targeted therapy-associated liver toxicity ranges from mild liver function test elevation to fulminant life-threatening acute liver failure. Immune checkpoint inhibitors in oncology has given rise to immune-related adverse events, with differing mechanisms of liver toxicity and varied imaging presentation of liver injury. Highdose chemotherapy regimens for haematopoietic stem cell transplantation are associated with sinusoidal obstruction syndrome However, many chemotherapeutic agents and regimens are dosed based on the highest dose tolerated without toxicity.
Drug-induced liver injury (DILI) occurs as results of the main liver metabolic function, direct or secondary. The direct alterating of liver function is result that drugs are carried to the liver through either the systemic or portal circulations following absorption by the gastrointestinal tract. DILI occurs secondary to toxicity to hepatocyte and biliary ducts, alteration of lipid metabolism or damage to the hepatic vascular network.The end result of drug toxicity is injury to the hepatocytes in the form of mild to severe hepatitis and potential evolution to cirrhosis and fibrosis. Indirect toxicity occurs via altered lipid metabolism, which leads to deposition of fat within the liver, resulting in steatosis or steatohepatitis . Druginduced vascular changes leads to liver injury in the form of sinusoid obstructive syndrome (SOS), portal vein thrombosis, and peliosis hepatis .
Drug-induced hepatitis can be categorised histologically into three forms: hepatocellular, cholestatic, or mixed but cannot be distinguished on imaging,can occur a few days after therapy start or weeks/month.
Various chemotherapeutic drugs have been associated with DILI, including asparaginase, intra-arterial 5-fluoro-uracil (FU), cyclophosphamide, 6mercaptopurine, high-dose methotrexate, paclitaxel, docetaxel, and cisplatin . Besides conventional chemotherapeutic agents, MTTs, including vascular endothelial growth factor (VEFG) tyrosine kinase inhibitors (TKI), non-VEGF TKI, epithelial growth factor receptors (EGFR) inhibitors, and immune checkpoint inhibitors have been associated with acute hepatitis . Essentially, chemotherapy drugs that can induce an acute hepatitis can likely cause hepatic necrosis. Mithramycin, an antitumor antibiotic, has been identified to be the most hepatotoxic to induce liver necrosis.
Reactivation of viral hepatitis has also been observed in patients treated with antineoplastic agents. Rituximab, alemtuzumab, and gemcitabine have been associated with reactivation of viral hepatitis B and C with percentages reaching 48% of cases in patients with hepatitis C undergoing treatment with rituximab .Imaging features of acute hepatitis include generalised hepatomegaly, perihepatic and pericholecystic fluid, gallbladder wall thickening (>3 mm), periportal reactive lymphadenopathy, and periportal oedema.On ultrasound, diffusely decreased parenchymal echogenicity with increased portal vein conspicuity (so-called “starry sky” appearance of the liver) has been reported in acute hepatitis but is insensitive.The most common finding is gallbladder wall thickening or oedema of the gallbladder fossa.Computed tomography (CT) or magnetic resonance imaging (MRI) shows diffusely decreased attenuation of the liver or diffuse T2-hyperintensity, with heterogeneous enhancement following contrast medium administration.CT imaging features of hepatitis with severity showed that gallbladder wall thickening >3 mm was associated with severe hepatitis and prolonged cholestasis.Choledochus thickening is seen associated with cholestasis.
Figure 1 : Imatinib induced acute hepatitis.Patient treated for metastatic gastrointestinal stromal tumour (GIST) with imatinib mesylate,presents with fever,abdominal pain.Coronal (a) and axial(b) enhanced CT shows periportal edema and small amount of free fluid. No infection focus was found except decreased attenuation around the portal system and at the hepatic hilum (periportal edema).Grade 3–4 liver toxicity could occur in one out of 40 treated patients with Imatinib for GIST.
Table 2: Hepatotoxicity according to drug agent and radiologic findings.
Steatosis and steatohepatitis
Fatty infiltration of the liver associated with chemotherapy it is known as CASH (chemotherapy-associated steatohepatitis) .CASH has been associated with 5-FU, associated with steatosis, and irinotecan, commonly associated with steatohepatitis. Tamoxifen and anastrozole, two hormonal agents utilised in oestrogen-receptorpositive breast cancer therapy, have been associated with steatosis seen in 14.6% of patients treated with anastrozole and in 41.1% of patients treated with tamoxifen [2, 4]. The imaging distinction among these entities CASH, NAFLD(Nonalkoholisk fedtleversygdom ) and hormone-related fatty liver disease is impossible, and the imaging features of steatosis and steatohepatitis frequently overlap.
Ultrasound demonstrates increased liver echogenicity,focal fat deposition or sparing may simulate a hepatic mass, but can be recognised by characteristic location, geographic shape, and absence of mass effect on vasculature. Moderate or severe fatty liver, defined as >33% of fat infiltration of hepatocytes documented by a liver biopsy, is detected by sonography with a sensitivity of 67–84% and specificity of 77– 100%.On unenhanced CT, observes reduced liver density, with hyperattenuation of vessels relative to the liver tissue, on contrast-enhanced CT, hepatic steatosis in moderate to severe cases can be diagnosed if absolute attenuation is <40 HU, with sensitivity and specificity of 86–87% [6, 7].
Figure 2: Liver steatosis induced by CAPOX, patient with disseminated colorectal cancer. Axial contrastenhanced CT image reveal fatty infiltration of the liver, reduced liver attenuation.Liver-spleen differentia lattenuation (liver minus spleen) cutoffs ranging from less than -20 to less than -43 HU on portal venous phase, depending on injection protocol, in this case HU liver 53 and spleen 104.
Veno-occlusive disease and sinusoidal obstruction syndrome (SOS)
SOS, also known as hepatic veno-occlusive disease, is an injury to the hepatic venous endothelium causing deposition of fibrous material within the venule walls and liver sinusoids leading to histological changes ranging from sinusoidal dilation to occlusion; SOS can progress to regenerative nodular hyperplasia.Preoperative neoadjuvant therapy for colorectal liver metastases (CRLM) is increasing in use and can lead to chemotherapy-induced damage to sinusoidal integrity.SOS is a rare complication of stem cell transplantation and has significant morbidity and mortality [8, 9]. On ultrasound ,which is the imaging modality of choice, which may show hepatomegaly ,portal vein abnormalities (dilatation,pulsatility,hepatofugal portal venous flow,elevated hepatic artery resistive index > 0.8), loss of triphasic hepatic venous flow ,gallbladder wall thickening (> 6-8 mm) ,ascites.On CT may be seen hepatomegaly, nutmeg liver,portal vein dilatation +/- portal thrombosis or perifere vein thrombosis,ascites. MRI with hepatocyte-specific contrast agent show a diffuse hypointense reticular pattern on post-contrast T1 delayed hepatobiliary phase as a highly specific sign for the diagnosis [8, 9].
Figure 3 : Folfirinox-induced sinusoid obstructive syndrome (SOS) in 69-year-old woman diagnosed with locally advanced pancreatic adenocarcinoma ,due to significant vascular involvement underwent FOLFIRINOX neoadjuvant chemotherapy.(a) Axial contrast-enhanced CT image demonstrates progressive changes in liver with heterogeneous hypo attenuation and patchy liver enhancement and perivascullary edema (b). Between scan a and b, and b and c (axial and d-coronal) it is a three-week interval, shows small and ill-defined intrahepatic arteries and decrease of hepatic parenchyma enhancement
Portal vein thrombosis
Portal vein thrombosis in cancer patients can occur as a hypercoagulable state associated with cancer; direct invasion of tumour into the portal vein, particularly common in patients with hepatocellular carcinoma; and as a complication of antineoplastic therapy.However, in adults, a few cases have been reported following chemotherapy treatment of L-asparaginase, autologous stem cell transplantation, and after haematopoetic cell transplantation . There are not enough previous data on vascular events in association with 5fluorouracil alone, drug in use for more than 50 years and raises the possibility of trombotic event is more possible associated with bevacizumab and/or irinotecan treatment in colorectal cancer patients.The proposed mechanism of bevacizumabrelated thrombosis is complex-both hemorrhagic and thrombotic events may be involved. Briefly, bevacizumab by antagonizing VEGF’s functions might decrease the renewal capacity of endothelial cells in response to trauma, leading simultaneously to a tendency to bleeding and thrombosis .
Figure 4 : Chemotherapy-induced pseudocirrhosis. Patient with metastatic breast cancer,not responding to first line chemotherapy developed pseudocirrhosis 5 months after changing the treatment. Axial contrast-enhanced images from (a) baseline CT (change the treatment) and (b) follow-up CT demonstrate
development of multifocal capsular retraction with pseudocirrhosis appearance at end of treatment (EOT).
Chronic liver toxicity
Chronic DILI may manifest as hepatic steatosis, chronic hepatitis, or cirrhosis, usually secondary to intrahepatic cholestasis. Other forms of chronic hepatotoxicity include NRH (Nodular Regenerative Hyperplasia) and peliosis hepatis . "Pseudocirrhosis" is a radiologic term used to describe the serial development of diffuse hepatic nodularity caused by chemotherapy for metastatic disease of the liver,seen in both metastatic breast and colon cancer, but it has also been reported in metastatic pancreatic cancer after gemcitabine and oxaliplatin therapy.In pseudocirrhosis changes in the liver parenchyma mimics liver cirrhosis, tumor tissue is retracted and scarring . Furthermore, pseudocirrhosis may be associated with signs of portal hypertension,ascites, portosystemic collateral veins and splenomegaly. Changes are irreversible.
Postembolization syndrome occurs in ~90% of patients following TACE, manifested by fever, malaise, right upper quadrant pain, nausea, and vomiting. Patients and their caregivers need to be apprised of this prior to TACE and provided with adequate analgesics and antiemetics for symptom control.Leung et al analyzed predictors of severe postembolization syndrome and found that gallbladder embolization and higher doses of chemoembolic agents correlated with prolonged postembolization syndrome [12, 13].
Hepatic abcess and biloma?
The pathophysiology of biloma formation involves ischemic injury to the peribiliary capillary plexus, which is supplied by branches of the hepatic artery. As a result, the integrity of the biliary tree is disrupted with subsequent biloma formation.Bacterial seeding of these bilomas can produce a hepatic abscess. Another mechanism is the development of an abscess within the necrotic center of a devascularized hepatic tumor. In either situation, patients who have chronic colonization of the biliary tree with enteric flora are at significantly higher risk of hepatic abscess formation .
Figure 5 : Biloma as complication after Radiofrecvens Therapy (RF), 35-yearold patient with cholangiocarcinoma and immune induced sclerosing cholangitis, complaints of pain below the right ribs, 2 weeks after treatment of liver metastasis in segment 5., shown on axial enhanced CT scan (a and b).MRI
is performed with specific liver contrast, the content of the accumulation has high T2w and low T1w signal. There is slightly increased signal on diffusionweighted sequences but no restriction in the accumulation (not shown her). It is thus considered most likely that it is a biloma and not an abscess. Low T1w signal speaks against hematoma. The accumulator has an outlet anterolateral along the puncture duct from the RFA procedure.
Figure 6 : Abcess as complication after TACE in liver .67 year old man known with HCC in cirrhotic liver,has received 4.TACE treatment, after one week admitted in hospital with abcess in segment 4/8 ,Klebsiella pneumonia, enterobacter cloacae and streptococcus anginosus in the drain fluid.Axial enhanced CT image reveal well circumscribed slightly peripherally enhancing, centrally hypoattenuating lesion with gas.Treated with drain (not shown on this image).
Hepatic Artery Injury
Tortuous anatomy and congenital anatomic variations in the hepatic arteries may require extensive catheter manipulation to enable access to the target artery. Advancement of a catheter against resistance or without a sufficient length of leading guide wire can produce arterial spasm, dissection, or thrombosis .
Radiation-Induced Liver Disease
Liver Injury from External Beam Radiation:
Radiation induced liver disease (RILD) after conventionally fractionated radiotherapy was first described several decades ago, and it was soon thereafter recognized to have the histopathologic features of sinusoidal of venoocclusive disease (VOD), currently termed sinusoid obstructive syndrome (SOS) .The clinical scenario commonly called “classic” radiation induced liver disease (RILD) occurs typically within 4 months after hepatic radiation therapy. It is characterized by anicteric ascites and hepatomegaly and an isolated elevation in alkaline phosphatase disproportionate to that of other liver enzymes. “Classic” RILD is unlikely to occur after a mean liver dose of approximately 30 Gy in conventional fractionation [15-17].
Pancreas changes under cancer treatment
Chemotherapy-induced pancreatitis is well documented in the literature and is associated with chemotherapeutic agents as L-asparaginase, carboplatin cisplatin, cytarabine, ifosfamide, paclitaxel, tretinoin, and vinorelbine.The onset of pancreatitits range from hours to 1 month after drug administration [18,19]. Nitsche et al[ 80] believe that the overall incidence of drug-induced pancreatitis may be between 0.1% and 2%. Pancreatitis is an uncommon but severe complication of TACE. The incidence of this complication is rare, reported in only 1.7 % of TACE patients, and may occur because of reflux of chemoembolic agents to the pancreas .
For detecting and grading the severity of acute pancreatitis, multi-detector computed tomography (MDCT) is the modality of choice. Chemotherapeutic agents first cause acute interstitial pancreatitis, which may further progress to acute necrotising pancreatitis. On CT, acute interstitial pancreatitis may be characterised by fluid collections, peripancreatic fat stranding, focal areas of decreased attenuation, or diffuse oedema within the pancreas .
Figure 7 : Pancreatitis on Axial enhanced CT Scan, localised edema around the head of pancreas (b) about 1 month after induced antineoplastic therapy with Gemcitabin og Nab-Paclitaxel + Nivolumab. Axial enhanced CT scan (a) at the start of treatment shows tumor in the head of pancreas and clear peripancreatic fat tissue.
Pancreatic atrophy and cysts
Pancreatic atrophy is a possible adverse effect of cancer therapy. In the literature, it has been reported that long-term use of sorafenib is correlated with pancreatic atrophy. Ganten et al. explored the relationship between extended sorafenib therapy and pancreatic atrophy and reported a mean pancreatic volume loss of 25 % in hepatocellular carcinoma patients being treated with long-term sorafenib .
Atrophy is detectable as soon as 3 months after initiation of sorafenib therapy but may not present until as late as 2–3 years following treatment . Pancreatic atrophy can be best detected using CT and is often accompanied by fatty infiltration of the pancreas.Other pancreatic changes that have been observed include fatty replacement of pancreatic tissue over the course of cancer therapy and cystic changes in the pancreas,the evidence of the relationship of these findings to specific agents is lacking in the literature .
Acute acalculous cholecystitis, biliary inflammation , biliary sclerosis and biliary stasis
Gallbladder inflammation related to cancer therapy has a growing evidence in literature associate to use of targeted therapeutic agents with acute acalculous cholecystitis, particularly everolimus and sunitinib . Tirumani et al. examined the use of molecular-targeted therapies (sunitinib, bevacizumab, everolimus, and sorafenib) and associated gallbladder complications and found acute cholecystitis in 66 % of patients with variable onset between 2 weeks and 5 months . These patients ultimately required dose reduction, temporary discontinuation of the therapy, or permanent discontinuation of the therapy with 50 % requiring either cholecystectomy or cholecystotomy . Biliary excretion of certain oncologic agents may cause changes in the biliary epithelium leading to biliary enhancement on imaging. Common chemotherapeutic agents that are excreted through the bile include L-asparaginase, doxorubicin, epirubicin, and paclitaxel . Excretion of these therapeutic agents may have adverse effects on the epithelium causing irritation, thickening, and inflammation, which can be visualised as enhancement on CT and MR imaging. Chemotherapy-induced biliary sclerosis (CIBS) is a well-known toxicity associated with hepatic arterial infusion pump chemotherapy (HAIPC) with floxuridine . Chemotherapeutic agents can cause CIBS through adverse toxicity on the biliary system or ischaemic changes to the pericholangitic venous plexus, leading to stricture of the biliary ducts . Biliary stasis has been noted after initiation of tamoxifen and doxorubicin, bile cannot be excreted from the liver into the duodenum and causes subsequent formation of biliary sludge and biliary dilatation .
Complications of oncological therapy in the gastrointestinal system
Chemotherapy and targeted therapy complications
Chemotherapy-induced gastrointestinal (GI) complications may occur at any stage during cancer treatment. Its exact incidence is currently unknown. Targeting highlymitotic cells, chemotherapeutic agents may prove cytotoxic to a variety of rapidlydividing, though non-neoplastic tissues. Such tissues are present in the GI tract, potentially resulting in mucosal inflammation, ulceration, and perforation. This direct cytotoxicity may be further compounded by the predisposition to infection, a result of chemotherapy-induced immune-suppression and failure to mount a leucocytosis in response. The majority of chemotherapeutic agents induce mucositis, nausea, vomiting, and diarrhoea as a result, most often mild, self-limiting occurrences that may be empirically-managed.Most common cause of diarrhea is dysbacteriosis,chemotherapy and other drugs has effects on intestinal microbial flora. Nonetheless, the risk of more severe adverse-effects such as typhlitis, enterocolitis, infective colitis, perforation, GI haemorrhage, ischaemic colitis, and obstruction is very real and may require aggressive management and resuscitation . Cross-sectional imaging in the form of CT is the most rapid, widely-available technique for such investigation, if possible enhanced.The clinical presentation and radiological manifestations of chemotherapeutic complications are considerable in consensus.The radiologically findings are for sure important and may potentially improve treatment decision,whether or not the patient needs surgery or just medication.
Gastritis, duodenitis and gastric and duodenal ulceration can be seen in patients receiving hepatic arterial infusion chemotherapy of fluorodeoxyuridine. This has been described in the literature and is thought to be related to malpositioning of the catheter tip in the gastroduodenal artery rather than the hepatic artery .
PIPAC (Pressurized IntraPeritoneal Aerosol Chemotherapy) is a new treatment option in patients with peritoneal carcinomatosis. With PIPAC, chemotherapy is administered directly at the target organ (peritoneum), leading to a high tissue concentration of chemotherapy, without systemic uptake and thereby minimizing side effects. Transient abdominal pain might be explained by the chemical peritonitis induced by PIPAC with oxaliplatin. Some of the patients experienced reversible urinary retention, properly due to pain and the chemical peritonitis induced by PIPAC, sporadic nonspecific pains in the upper abdomen. Classical sideeffects of systemic chemotherapy such as mucositis, nausea/ vomiting, diarrhea, paresthesia, cutaneous symptoms and alopecia were not reported by the patients.
Neutropenic enterocolitis is one of the few oncological emergencies. The diagnostic criteria include neutropenia (neutrophil count less than 1 cell/μl); temperature greater than 38.3 °C and evidence for colitis (diffuse abdominal pain and distension, watery diarrhoea, vomiting, GI haemorrhage). This entity is most likely to occur 5–14 days after commencement of chemotherapy, during the leucocytic nadir. Pathological features of affected bowel include mucosal and transmural oedema, haemorrhage, ulceration, necrosis, and perforation. Neutropenic enterocolitis and typhlitis are the most common GI side effects of chemotherapy and are encountered in association with a number of regimes including paclitaxol, taxotere, platinum-based regimes, and cytosine arabinoside [34, 35]. The term “typhlitis” refers to neutropenic enterocolitis of the caecum, with the caecum and ascending colon to variable degrees involved. Typhlitis was originally described in children with acute leukaemia undergoing chemotherapy and is most often encountered in association with leukaemia or lymphoma. More recently typhlitis has been reported in patients with solid tumours, such as non-small cell lung, ovarian, and peritoneal cancer . This condition has also been described in immunosuppressed patients without cancer, such as kidney transplant patients, and those with cyclical neutropenia, aplastic anaemia, and acquired immunodeficiency syndrome (AIDS) . CT findings on cross-sectional enhanced imaging shows the bowel wall diffusely thickened or edematous, mucosal hyperemia and mucosal ulceration. Pericolonic fat stranding and submucosal bleeding is also seen. Transmural bowel wall involvement with necrosis, pneumatosis and less commonly perforation can also be seen later on. Prompt diagnosis with conservative treatment using antibiotics is used in patients when early diagnosis is made
Figure 10 : Neutropenic necrotizing colitis in 35 years hematologic patient treated with stem cell transplant 10 days earlier. Non enhanced CT , axial (a, b) and coronal pictures (c)demonstrates wall thickening of the entire colon, fat stranding, small amount free fluid and submucosal diffuse bleeding.
Pseudomembranous colitis is seen often related to antibiotic or chemotherapeutic administration as results of replacement of “normal” gut flora and colonization by C. difficile. C difficile produces both a cytotoxin and enterotoxin, resulting in colonic inflammation, diarrhea, and characteristic pseudomembranous exudates. Clinical findings may be absent or range from mild self-limiting diarrhea to fulminant colitis requiring colectomy. CT manifestations of pseudomembranous colitis include mural thickening (up to 3 cm), low-attenuation mural thickening corresponding to mucosal and submucosal edema, the “accordion sign” (interdigitating of orally-administered contrast between the edematous low attenuation haustral folds, giving the appearance of alternating bands of high and low attenuation), the “target sign” (“double halo sign”; intense mucosal enhancement occurring due to mucosal hyperemia and juxtaposed to low attenuation mural edema), mural enhancement, colonic dilatation, pericolonic stranding, thickening of fascial planes, and ascites. The degree of wall thickening is generally greater than in other inflammatory or infectious forms of colitis (often >10 mm) and is classically diffuse in distribution. Distribution may vary considerably, leading to diagnostic uncertainty, involvement ranging from focal segmental rectal thickening to pan colonic abnormality .In one – third of cases there are normal found on CT [37-40].
Enteritis-Chemotherapy-related diarrhea (CRD) is most commonly described with fluoropyrimidines (particularly fluorouracil [FU] and capecitabine) and irinotecan. Diarrhea is the dose-limiting and major toxicity of regimens containing a fluoropyrimidine with irinotecan. However, in addition to conventional cytotoxic drugs, many molecularly targeted agents (including tyrosine kinase inhibitors [TKIs] and monoclonal antibodies) are also associated with CRD. Direct ischemic mucosal damage is reported in patients treated with agents targeting the vascular endothelial growth factor (VEGF), while an immune-mediated colitis is responsible for diarrhea with immune checkpoint inhibitors [41, 42]. The typical appearance of enteritis on CT images illustrates submucosal edema and hyperemia of the mucosa and serosa.
Figure 12 : Irinotecan induced enterocolitis. Patient with metastatic colon cancer, had been undergoing treatment with Irinotecan for approximately 8 moth. Patient complained of abdominal pain during the course of therapy, with newonset diarrhea. Axial (a) and coronal (b) contrast-enhanced CT image through the abdomen reveals bowel wall thickening.
Ulceration, perforation og GI hemorrhage-oncological GI perforation may occur in one of a number of scenarios: spontaneous tumor rupture (particularly primary GI tumors, infiltrating tumors, or infiltrating adenopathy), neoplastic ulceration, tumor necrosis occurring secondary to therapy, drug-induced perforations, and inflammatory conditions. GI lymphomas, in particular, are associated with perforation or bleeding related to regression of the primary tumor during appropriate chemoradiotherapeutic therapy [43, 44]. Other medications commonly coadministered with antiplatelet therapy such as nonsteroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants, and corticosteroids are also known to increase the risk of ulceration and GI bleeding. Concomitant use of these medications and antiplatelet therapy might increase the risk of UGIB .
Ileus and obstruction
Paralytic ileus is associated with infections or disorders of autonomic neuropathy caused by chemotherapy drugs, such as vincristine and vinblastine or opioid, which depress bowel peristalsis. Paralytic ileus has been recognised as a potential side effect of capecitabine with an estimated incidence of 4% to 6% . The pathophysiology of capecitabine-induced paralytic ileus is not well understood. Information regarding fluoropyrimidines and their effect on the enteric motor system is scant. It can be speculated that 5FU metabolites may play a role in causing paralytic ileus because of the association between 5FU metabolites and peripheral neuropathy . Ileus is seen as focal or diffusely dilated bowel without evidence of an obstructing mass (f.eg. carcinosis ) .Bowel obstruction seen on CT shows dilated loops of bowel proximal to the obstruction, with distinct transition point, a normal caliber or collapsed bowel distally. As above, small bowel obstruction has been associated with vincristine and bevacizumab . If bowel vessels are involved, they can give rise to critical ischemic events, which lead to necrosis and perforation. Thrombotic and thromboembolism events pathogenesis is induced by drug-related endothelial damage, with consequent basement membrane exposure and abnormal coagulation cascade activation .
Mesenteric infarction and pneumatosis
Mesenteric infarction leads indirect to bowel damage and it is related to thromboembolic events, arteriel thrombosis is less frequent and intestinal ischemia is a rare complication in cancer patients treated with chemotherapy . Thrombotic and thromboembolism events pathogenesis is induced by drug-related endothelial damage, with consequent basement membrane exposure and abnormal coagulation cascade activation [49, 51]. Platinum-based chemotherapy regimens are responsible for higher thromboembolism risk, but not other vascular events; this risk is superimposable between cisplatin and carboplatin . Molecular target agents can increase thrombotic risk: thalidomide, an immunomodulatory and antiangiogenetic drug commonly used in multiple myeloma therapy, has shown thromboembolic events raise, anti-VEGFR and anti-VEGF targeted agents as bevacizumab, sorafenib and sunitinib are responsible to arterial thrombotic events increase, because of their role in endothelial integrity regulation probably. Thromboembolisms and vasculitis caused by immune checkpoint regulators such as anti-PDL1 seem to be rare events [53, 54, 55]. CT is the gold standard to diagnose pathological bowel features in the emergency setting because it allows detection of vascular anatomy and secondary signs of mesenteric ischemia, with high sensitivity and specificity (82–96% and 94%, respectively [56, 57].
Figure 13 : CAPOX(capecitabine-oxaliplatin combination)induced panniculitis/infarction .Patient with duodenal cancer, Whipple operation before 2 years ago, in treatment with CAPOX, complains on painfull right lumbar zone. CT axial demonstrate Whipple operation, (a) and diffuse localized infiltration of
mesenterium in right side (b).
Pneumatosis intestinalis (PI) is defined as bowel wall gas that presents as submucosal or subserosal cysts,ranging from benign conditions to fulminant diseases. PI is a radiological finding and not a diagnosis. It is usually diagnosed by plain abdominal radiography or CT scanning, but it could also be documented by MRI and ultrasonography. The presence of mesenteric stranding, bowel wall thickening and dilatation, ascites and confinement of the intramural gas to the small bowel. PI confined to the right colon is more frequently benign, whereas the presence of pneumoperitoneum is nearly always associated with every case of PI . A variety of conditions and treatments can lead to this complication, including chemotherapy. PI is an uncommon complication of chemotherapy, but it should be considered in any cancer patient who presents with vague gastrointestinal or obstructive symptoms. Chemotherapeutic agents reported to induce PI are cyclophosphamide, cytarabine, docetaxel, irinotecan, cisplatin, fluorouracil, and bleomycin.
Gastrointestinal toxicity of radiation therapy .
Risk Factors for predisposing to Radiation Injury
Treatment-related risk factors
Higher radiation doses
Higher volume of irradiated small bowel
Extended- or opposed-field radiation techniques
Postoperative chemo radiotherapy
Concurrent administration of chemotherapy
Patient-related risk factors
Inflammatory bowel disease (Crohn disease, UC)
Connective tissue disorders (SLE, scleroderma, polymyositis, dermatomyositis, excluding RA)
Heavy smoking (at least one pack per day)
Abnormally low BMI (< 18.5)
Previous abdominal or pelvic surgery
Genetic predisposition (AT heterozygotes)
(AT = ataxia-telangiectasia; BMI = body mass index; RA = rheumatoid arthritis; SLE= systemic lupus erythematosus; UC = ulcerative colitis.)
Gastrointestinal toxicity can occur following irradiation of thoracic, abdominal, or pelvic malignancies, gastrointestinal structures are often located within the radiation therapy (RT) field. These toxicities can limit the maximum tolerated dose of RT and chemotherapy and thus may limit the efficacy of treatment. Acute toxicities refer to those with onset during or shortly after the course of treatment. Late toxicities are those occurring after three months after completion of RT. These often reflect the spectrum of radiation tissue changes that can be lasting and irreversible . The incidence and severity of RT side effects depend upon the site, volume of tissue exposed, and treatment schedule, including total dose, dose per fraction, and type of radiation. Other risk factors for radiation induced GI toxicity include the use of concomitant chemotherapy.
Symptoms of acute radiation esophagitis include dysphagia, odynophagia, and substernal discomfort. Patients with late toxicity often present with dysphagia secondary to stricture or altered motility caused by fibrosis/muscular damage or nerve injury or odynophagia due to chronic ulceration [9, 60]. In patients with acute radiation esophagitis, double-contrast esophagograms may reveal a variable segment of esophageal narrowing with multiple discrete ulcers or a distinctive granular appearance of the mucosa within a known radiation portal. The majority of patients with esophagitis had abnormalities on CT, including a thickened esophageal wall (≥5 mm) in 55% and a target sign in 17%. Although barium studies and endoscopy are more sensitive modalities for detecting this condition, the CT finding of a relatively long segment of circumferential esophageal wall thickening, with or without a target sign, should suggest the diagnosis of esophagitis in the proper clinical setting .
Acute radiation gastritis can cause nausea and vomiting within 24 hours after the start of treatment. Symptoms generally resolve within one to two weeks following completion of RT. Manifestations of late radiation gastritis include abdominal pain due to nonulcer dyspepsia, gastric ulcers, and antral stenosis [59, 62]. Radiation gastritis usually occurs 2-9 moth after the initial radiotherapy. The dose at which 5% of patients develop complications at 5 years, when the entire stomach is irradiated, is estimated to be 50 Gy. Small doses of radiation (up to 15 Gy) cause reversible mucosal damage, whereas higher doses cause irreversible damage with atrophy and ischemic-related ulceration [63, 64]. CT may demonstrate nonspecific gastric wall thickening along with stranding in the perigastric fat, especially in acute fase , radiation gastritis it is better demonstrate with barium studies .Ulcers are typical seen in acute fase and cannot be differentiated from benign ulcer disease.
The small intestine is very radiosensitive, it is relatively mobile and radiationinduced changes are therefore less common than might otherwise be expected. Symptoms of acute radiation enteritis include diarrhea, abdominal pain, nausea and vomiting, anorexia, and malaise. Radiation-induced diarrhea often appears during the third week of treatment and typically disappears two to six weeks after the completion of RT. Late effects include malabsorption and diarrhea. Patients may have bloating, excessive gas, and borborygmi due to small intestinal bacterial overgrowth. Other symptoms include bleeding or abdominal pain due to ulceration, and fever secondary to abscess formation. Patients with severe disease may develop intermittent, partial, or complete small bowel obstruction due to strictures [59, 65, 66]. In acute and subacute radiation enteritis, barium studies of the small intestine often show nodular filling defects or thumb printing. Changes similar to those of intestinal ischemia may result from arteriolar obliteration. The most frequent manifestation of chronic radiation enteropathy is submucosal thickening of the bowel wall. Focal areas of narrowing and long-segment strictures may develops. In some cases, bowel obstruction occurs as a result of the strictures or of adhe- sions. Fistulas may also develop [59, 65, 66, 67].
The incidence of radiation proctitis is not clear due to the lack of consensus on its definition and reporting methodologies. There is a general agreement that the incidence is likely related to the dose of radiation, area of exposure, method of delivery, and the use of cytoprotective agents. The doses generally delivered to the pelvis vary from 45 to 50 Gy for adjuvant or neoadjuvant treatment for prostate or anorectal malignancies; up to 90 Gy is considered the definitive therapy for gynecological malignancies . It is generally agreed that treatments <45 Gy cause very few side effects. Doses between 45 and 70 Gy, which is the dosage range for most treatments, cause more complications, but the complications tend to be of lesser intensity .Doses above 70 Gy cause significant and long standing injury to the surrounding area.
CT may demonstrate acute radiation injury findings such as bowel wall edema and enhancement of the mucosa with contrast . Chronic changes of radiation injury to the pelvis structures include thickening and increased density of the perirectal fat, fascia, and rectal wall and fibrosis between the sacrum and rectum. Edema and enhancement of the mucosa are no longer present in the chronic phase of injury. MRI may demonstrate increased signal uptake indicative of inflammatory changes as well as a characteristic pattern of varying edema .However, both CT and MRI can fail to differentiate between postradiation changes and recurrent malignancy
Figure 14 : Radiation induced proctitis and colitis as side effect after analcancer treatment with RT.Chronic radiation-induced enteropathy in a 63-year-old woman, 2 years after ended treatment, axial contrastenhanced CT scan (a) and MRI (b) shows diffuse thick walls to the rectosigmoid colon, no haustrae and fibrosis in bowl wall.
The anal canal is typically spared from significant radiation exposure but it may be affected if radiation therapy (RT) is used to treat anal, low rectal, or gynecologic cancers. Acute anal toxicity is relatively common, and its incidence is increased with concurrent chemotherapy or large RT fraction size .It presents as a perianal skin reaction that ranges from minimal skin changes to moist desquamation and erythema. Late complications of RT can appear months to years after completion of therapy and include anorectal ulceration, anal strictures or stenosis, and anorectal fistulas. Patients with late anal radiation toxicity usually present with anal pain and anal incontinence [67, 68].
CT findings includes increased density but blurred appearance of the subcutaneous fat , with common cords, mesh intervals, thickened mesenteric vessels, blurred edges, swollen pelvic wall muscles and blurred muscle borders. MRI is most sensitive to show fibrosis and narrowing, fat changes and necrosis.
Figure 15 : Radiation induced proctitis as side effect after analcancer treatment with RT.Aksial MRI, T1w (a) before treatment shows almost circumferencial anal tumour.One year after ended RT, control MRI scan, T1w axial (b) and coronal (c) shows fibrosis in anal canal and infiltration of the fat tissue, fat infiltration of pelvis bone
Figure 3 : Folfirinox-induced sinusoid obstructive syndrome (SOS) in 69-year-old woman diagnosed with locally advanced pancreatic adenocarcinoma ,due to significant vascular involvement underwent FOLFIRINOX neoadjuvant chemotherapy.(a) Axial contrast-enhanced CT image demonstrates progressive changes in liver with heterogeneous hypo attenuation and patchy liver enhancement and perivascullary edema (b). Between scan a and b, and b and c (axial and d-coronal) it is a three-week interval, shows small and ill-defined intrahepatic arteries and decrease of hepatic parenchyma enhancement
The broad spectrum of cancer treatment and technological improvements, including CT-guided and MRI-guided planning, IMRT, particle therapy combined with better diagnostic imaging provides the opportunity for decrease the risk of acute and late toxicity .The complications related to treatment can only be clinical without radiological findings but for the most part there is the possibility of radiological support to confirm unexpected events during the treatment. Awareness of cancer therapy-induced toxicities is important for all oncologists but to recognize the complication which can be life threatening, do the oncologic imaging an important part of the patient's disease course and treatment.
- Jean M Torrisi, LawrenceH,Marc J Gollub, Michelle S Ginsberg, George J Bosl, Hedvig Hricak, CT findings of Chemotherapy induced toxicity: What radiologist need to know about the clinical and radiological manifestation of chemotherapy toxicity,Radiology. 2011; 258:1.
- Xia WANG and Yong LIN, Tumor necrosis factor and cancer, buddies or foes?,Acta Pharmacol Sin. 2008; 29(11):1275-1288. [DOI: 10.1111/j.1745-7254.2008.00889.x]. https://www.cancerresearchuk.org/about-cancer/cancer-in general/treatment/immunotherapy/types/checkpoint-inhibitors
- WB Coley, “II. Contribution to the knowledge of sarcoma,” Annals of Surgery. 1891; 14(3):199-220.
- Yuka Igarashi, Tetsuro Sasada, "Cancer Vaccines: Toward the Next Breakthrough in Cancer Immunotherapy", Journal of Immunology Research. 2020; 13:5825401. [https://doi.org/10.1155/2020/5825401]
- DL Porter, BL Levine, M Kalos, A Bagg, and CH June, “Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia,” New England Journal of Medicine. 2011; 365(8):725-733.
- US Food and Drug Administration FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma, 2017, https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm581216.htm.
- M Martinez and EK Moon, “CAR T cells for solid tumors: new strategies for finding, infiltrating, and surviving in the tumor microenvironment,” Frontiers in Immunology. 2019; 10:128.
- Nicholas Mark, Basak Coruh, Chemotherapy-Related Drug-Induced Lung Injury,https://www.pulmonologyadvisor.com/home/decision-support-in-medicine/pulmonary- medicine/chemotherapy-related-drug-induced-lung-injury/
- Lateef O, Shakoor N, Balk RA, Methotrexate pulmonary toxicity.Expert Opin Drug Saf. 2005; 4(4):723-30.
- Brolin B Poole, PharmD, Leslie A Hamilton, Megan M Brockman, Debbie C Byrd, et al. Interstitial Pneumonitis from Treatment with Gemcitabine, Hosp Pharm. 2014; 49(9):847-850. [DOI: 10.1310/hpj4909-847].
- Milda Rudzianskiene, Rasa Griniute, Elona Juozaityte, Arturas Inciura, Viktoras Rudzianskas, and Greta Emilia Kiavialaitis, Corticosteroid-Responsive Pulmonary Toxicity Associated with Fludarabine Monophosphate: A Case Report, Turk J Haematol. 2012; 29(4):392-396. [DOI: 10.5505/tjh.2012.50490].
- Sandeep Garg, Manisha S Garg, Neil Basmaji, Multiple pulmonary nodules: an unusual presentation of fludarabine pulmonary toxicity: case report and review of literature,Am J Hematol. 2002; 70(3):241-5. [DOI: 10.1002/ajh.10144].
- Kazuhiko Nakagawa, Kindai University, Shoji Kudoh, Fukujuji Hospital Yuichiro Ohe, Postmarketing Surveillance Study of Erlotinib in Japanese Patients With Non–Small-Cell Lung Cancer (NSCLC) Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2012; 7(8):1296-303 [DOI:10.1097/JTO.0b013e3182598abb]
- Kudoh S, Kato H, Nishiwaki Y, Fukuoka M, Nakata K, Ichinose Y et al. Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case–control study. Am J Respir Crit Care Med. 2008; 177:1348-1357. https://doi.org/10.1164/rccm.200710-1501OC
- Taroh Satoh, Akihiko Gemma, Shoji Kudoh, Fumikazu Sakai, Kensei Yamaguchi, Toshiaki Watanabe, et al. Incidence and Clinical Features of Drug-induced Lung Injury in Patients with Advanced Colorectal Cancer Receiving Cetuximab: Results of a Prospective Multicenter Registry, Jpn J Clin Oncol. 2014; 44(11):1032-1039. [DOI: 10.1093/jjco/hyu128]
- Herbert H, Loong Winnie Yeo, Imatinib-induced interstitial lung disease and sunitinib-associated intra-tumour haemorrhage, Hong Kong Med J. 2008; 14:495-8.
- Barber Ganti AK. Pulmonary toxicities from targeted therapies: a review. Target Oncology. 2011; 6:235-243.
- Bruce Sabath, Hasan A Muhammad, Amulya Balagani, David Ost, CenterSecondary spontaneous pneumothorax in patients with sarcoma treated with Pazopanib, a case control study Springer, October 2018; 18(1). [DOI:10.1186/s12885-018-4858-8]
- Van Vollenhoven RF, Fleischmann RM, Furst DE, Lacey S, Lehane PB. Longterm safety of rituximab: final report of the rheumatoid arthritis global clinical trial program over 11 years. J Rheumatol. 2015; 42(10):1761-1766.
- Akinori Sugaya, Shingo Ishiguro, Shoichi Mitsuhashi, Masahiro Abe, Ikuta Hashimoto, Takayuki Kaburagi, et al. Interstitial lung disease associated with trastuzumab monotherapy: A report of 3 cases. 2016. [DOI: 10.3892/mco.2016.1113]
- Abulkhair O, El Melouk W. Delayed paclitaxel- trastuzumab-induced interstitial pneumonitis in breast cancer. Case Rep Oncol. 2011; 4:186–191. [DOI: 10.1159/000326063].
- Kuip E, Muller E. Fatal pneumonitis after treatment with docetaxel and trastuzumab. Neth J Med. 2009; 67:237-239.
- Mason KA, Hunter NR, Milas M, Abbruzzese JL, Milas L. Docetaxel enhances tumor radioresponse in vivo. Clin Cancer Res 1997; 3:2431-2438.
- K A Semb, S Aamdal, P Oian, Capillary protein leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment, [PMID: 9779722 DOI: 10.1200/JCO.1922.214.171.12426]
- Karin A Semb, Steinar Aamdal, Pål Oian, Capillary protein leak syndrome appears to explain fluid retention in cancer patients who receive docetaxel treatment.JournalJournal of Clinical Oncology. 1998; 16:10.
- Sebastien Dejust, David Morland, Claire Bruna-Muraille, Jean Christophe Eymard, Gabriel Yazbek, Aude-Marie Savoye, et al. Everolimus-induced pulmonary toxicity, Findings on 18F-FDG PET/CT imaging,Medicine (Baltimore). 2018; 97(40):e12518. [DOI: 10.1097/MD.0000000000012518].
- Rowena N Schwartz, Lori Stover RN, Janice P Dutcher, Managing Toxicities of High-Dose Interleukin-2, Oncology. 2002; 16(11):13.
- Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis.,JAMA Oncol. 2016; 2(12):1607.
- James P Jinnur, Praveen K Yi, Eunhee S, Ryu Jay H, Midthun David E, Davis John. Acute Bilateral Pulmonary Opacities Associated With Use of Tocilizumab, Journal of Clinical Rheumatology: October 2015; 21(7):382-385.
- Evangelos Briasoulis, Nicholas Pavlidis, Noncardiogenic Pulmonary Edema: An Unusual and Serious Complication of Anticancer Therapy Department of Medical Oncology, University of Ioannina, Ioannina, Greece.
- Tenholder MF, Hooper RG: Pulmonary infiltrates in leukemia. Chest 1980; 78:468-473.
- Carolina A Souza, Nestor L Müller, Takeshi Johkoh and Masanori Akira, Drug-Induced Eosinophilic Pneumonia: High-Resolution CT Findings in 14 Patients, https://www.ajronline.org/doi/full/10.2214/AJR.04.1847
- D Montani, LC Price, P Dorfmuller, L Achouh, X Jaïs, A Yaïci, et al. Pulmonary veno-occlusive disease,European Respiratory Journal. 2009; 33:189-200. [DOI: 10.1183/09031936.00090608]
- Perlin E, Bang KM, Shah A, et al: The impact of pulmonary infections on the survival of lung cancer patients. Cancer. 1990; 66:593-596.
- Greene JN. Catheter-related complications of cancer therapy. Infect Dis Clin North Am. 1996; 10:255295.
- Susan K Seo, Infectious Complications of Lung Cancer, Oncology, ONCOLOGY. 19(2).
- Robbins RA, Linder J, Stahl MG, et al: Diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Am J Med. 1989; 87:511-518.
- Jules-Elysee K, Stover DE, Yahalom J, et al: Pulmonary complications in lymphoma patients treated with high-dose therapy autologous bone marrow transplantation. Am Rev Respir Dis. 1992; 146:485-491.
- Kwa S, Lebesque JV, Theuws JC, Marks LB, Munley MT, Bentel G, et al. Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys. 1998; 42:1-9.
- Pierce S, Recht A, Lingos TI, Abner A, Vicini F, Silver B, et al. Long-term radiation complications following conservative surgery (CS) and radiation therapy (RT) in patients with early stage breast cancer. Int. J Radiat Oncol Biol Phys. 1992; 23:915-23.
- Rothwell R, Kelly SA, Joslin CF. Radiation pneumonitis in patients treated for breast cancer. Radiother Oncol. 1985; 4:9-14.
- Lingos T, Recht A, Vicini F, Abner A, Silver B, Harris JR. Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys. 1991; 21:355-60.
- Hui-Ming Chang, Rohit Moudgil, Tiziano Scarabelli, Tochi M, Okwuosa, Edward T.H. Yeh, MDa, Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management—Part 1 and 2 ,J Am Coll Cardiol. 2017; 70(20):2536-2551. [DOI: 10.1016/j.jacc.2017.09.1096]
- Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC. Cardiotoxicity of cancer therapy. J Clin Oncol. 2005 Oct 20; 23(30):7685-96.
- Yeh ET, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management.Circulation. 2004 Jun 29; 109(25):3122-31.
- Lauk S, Kiszel Z, Buschmann J, Trott KR. Radiation-induced heart disease in rats. Int J Radiat Oncol Biol Phys. 1985; 11:801-808. [DOI: 10.1016/0360-3016(85)90314-1].
- McGale P, Darby SC, Hall P, Adolfsson J, Bengtsson NO, Bennet AM, et al. Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Radiother Oncol. 2011; 100:167-175. [DOI: 10.1016/j.radonc.2011.06.016].
- Joe-Elie Salem, Ali Manouchehri, Melissa Moey, Bénédicte Lebrun-Vignes, Lisa Bastarache, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study RSS, Lancet Oncology, The. 2018; 19(12):1579-1589.
- Francesca Elice, Francesco Rodeghiero, Anna Falanga, Frederick R Rickles, Thrombosis associated with angiogenesis inhibitors, Best practice & research.Clinical haematology. 2009; 22(1):115-28. [DOI:10.1016/j.beha.2009.01.001]
- Edwards RL, Klaus M, Matthews E, et al. Heparin abolishes the chemotherapy-induced increases in plasma fibrino-peptide A levels. Am J Med. 1990; 89:25-8.
- Dasanu CA. Gemcitabine: vascular toxicity and prothrombotic potential. Expert Opin Drug Saf. 2008; 7(6):703-716.
- Bendix N, Glodny B, Bernathova M, Bodner G. Sonography and CT of vasculitis during gemcitabine therapy. AJR Am J Roentgenol. 2005; 184(3):S14-S15.
- Shahab N, Haider S, Doll DC. Vascular toxicity of antineoplastic agents. Semin Oncol. 2006; 33(1):121-138.
- Grenader T, Shavit L, Ospovat I, Gutfeld O, Peretz T. Aortic occlusion in patients treated with Cisplatin-based chemotherapy. Mt Sinai J Med. 2006; 73(5):810-812.
- Weijl NI, Rutten MF, Zwinderman AH et al. Thromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the literature. J Clin Oncology. 2000; 18(10):2169-2178.
- Feldman DR, Bosl GJ, Sheinfeld J, Motzer RJ. Medical treatment of advanced testicular cancer. JAMA. 2008; 299(6):672-684.
- Stewart FA, Hoving S, Russell NS. Vascular damage as an underlying mechanism of cardiac and cerebral toxicity in irradiated cancer patients. Radiat Res. 2010; 174(6):865-9. [PMID: 21128810 DOI: 10.1667/RR1862.1][Epub 2010 Aug 30].
- Neal L Weintraub, W Keith Jones, and David Manka, Understanding Radiation-Induced Vascular Disease,J Am Coll Cardiol. Mar 23, 2010; 55(12). [DOI: 10.1016/j.jacc.2009.11.053].
- Candice Johnstone, Shayna E Rich, Bleeding in cancer patients and its treatment: a review, Ann Palliat Med. 2018; 7(2):265-273. [DOI: 10.21037/apm.2017.11.01]. [Epub 2017 Dec 18].
- F Alessandrino, SH Tirumani, KM Krajewski, AB Shinagare, JP Jagannathan, et al. Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors ,Publication: Clinical Radiology. 2017; 72(7):521-533. [DOI: 10.1016/j.crad.2017.04.003].
- Lee WM, Drug-induced hepatotoxicity. N Engl J Med. 2003; 349:474-485.
- King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncologist. 2001; 6:162-176.
- Parag Mahale, Dimitrios P Kontoyiannis, Roy F Chemaly, Ying Jiang, Jessica P Hwang, Marta Davila and Harrys A. Torres, Acute exacerbation and reactivation of chronic hepatitis C virus infection in cancer patients, Journal of Hepatology. 2012; 57(6):11771185.
- Tchelepi H, Ralls PW, Radin R, et al. Sonography of diffuse liver disease. J Ultrasound Med. 2002; 21:1023-1032.
- Jacobs JE, Birnbaum BA, Shapiro MA, et al.: Diagnostic criteria for fatty infiltration of the liver on contrast-enhanced helical CT. AJR Am J Rogentgenol. 1998; 171:659-664.
- Maor Y, Malnick S. Liver injury induced by anti-cancer chemotherapy and radiation therapy. Int J Hepatol. 2013: 815105.
- Jeong WK, Choi SY, Kim J, Pseudocirrhosis as a complication after chemotherapy for hepatic metastasis from breast cancer. Clin Mol Hepatol. 2013 Jun; 19(2):190-4.
- Keraliya AR, Rosenthal MH, Krajewski KM, et al. Imaging of fluid in cancer patients treated with systemic therapy: chemotherapy, molecular targeted therapy, and haematopoietic stem cell transplantation. AJR Am J Rogentgenol. 2015; 205:709-719.
- Matteo Donadon, Jean-Nicolas Vauthey, Evelyne M Loyer, Chusilp Charnsangavej, and Eddie K Abdalla, Portal thrombosis and steatosis after preoperativechemotherapy with FOLFIRIbevacizumab for colorectal liver metastases,World J Gastroenterol. 2006 Oct 28; 12(40):6556-8. [DOI: 10.3748/wjg.v12.i40.6556].
- Leung DA, Goin JE, Sickles C, Raskay BJ, Soulen MC. Determinants of postembolization syndrome after hepatic chemoembolization. J Vasc Interv Radiol. 2001; 12:321-326.
- Timothy WI Clark, Complications of Hepatic Chemoembolization, Complications in Interventional Radiology, Semin Intervent Radiol. 2006 Jun; 23(2):119-125.
- Yoon DY, Park JH, Chung JW, Han JK, Han MC. Iatrogenic dissection of the celiac artery and its branches during transcatheter arterial embolization for hepatocellular carcinoma: outcome in 40 patients. Cardiovasc Intervent Radiol. 1995; 18:16-19.
- C Guha and BD Kavanagh, Hepatic radiation toxicity: avoidance and amelioration, Seminars in Radiation Oncology. 2011; 21(4):256-263.
- GB Reed and AJ Cox, The human liver after radiation injury. A form of veno-occlusive disease, American Journal of Pathology. 1966; 48(4):597-611.
- Y Maor and S Malnick, Liver Injury Induced by Anticancer Chemotherapy and Radiation Therapy ,nt J Hepatol. 2013: 815105. [DOI: 10.1155/2013/815105].
- Morgan C, Tillett T, Braybrooke J, Ajithkumar T. Management of uncommon chemotherapy-induced emergencies. Lancet Oncol. 2011; 12:806-814.
- Singh V, Devata S, Cheng YC. Carboplatin and docetaxel-induced acute pancreatitis: brief report. Int J Clin Oncol. 2010; 15(6):642-644.
- Nitsche CJ, Jamieson N, Lerch MM, Mayerle JV, Drug induced pancreatitis,Best Pract Res Clin Gastroenterol. 2010 Apr; 24(2):143-55.
- Bae SI, Yeon JE, Lee JM, Kim JH, Lee HJ, Lee SJ et al. A case of necrotizing pancreatitis subsequent to transcatheter arterial chemoembolization in a patient with hepatocellular carcinoma. Clin Mol Hepatol. 2012; 18(3):321-325.
- Danny Ngo, Jemianne Bautista Jia, Christopher S Green, Anjalie T Gulati & Chandana Lall Cancer therapy related complications in the liver, pancreas, and biliary system: an imaging perspective, Insights into Imaging. 2015; 6:665–677.
- Ganten MK, Schuessler M, Bruckner T, Ganten TM, Koschny R. Pancreatic atrophy in hepatocellular carcinoma patients receiving long-term treatment with sorafenib. Oncology. 2015.
- Hescot S, Vignaux O, Goldwasser F. Pancreatic atrophy-a new late toxic effect of sorafenib. N Engl J Med. 2013; 369:1475-1476.
- Cetin B, Coskun U, Yildiz R, Buyukberber S, Baykara M, Benekli M. Acute cholecystitis in a patient with metastatic renal cell carcinoma treated with everolimus: a case report. J Oncol Pharm Pract. 2010; 17(3):274-278.
- Tirumani SH, Krajewski KM, Shinagare AB, Jagannathan JP, Ramaiya NK. Gallbladder complications associated with molecular targeted therapies:clinical and imaging features. Clin Imaging. 2014; 38:50-55.
- Superfin D, Iannuci AA, Davies AM. Oncologic drugs in patients with organ dysfunction: a summary. Oncologist. 2007; 12:1070-1083.
- Hohn D, Melnick J, Stagg R, Altman D, Friedman M, Ignoffo R et al. Biliary sclerosis in 76 patients receiving hepatic arterial infusions of floxuridine. J Clin Oncol. 1985; 3(1):98-102.
- Padda MS, Sanchez M, Akhtar AJ, Boyer JL. Drug induced cholestasis. Hepatology. 2011; 53:1377-1387.
- Jemianne Bautista Jia, Chandana Lall, Temel Tirkes, Rajesh Gulati, Ramit Chemotherapy-related complications in the kidneys and collecting system: an imaging perspective, Insights Imaging. 2015 Aug; 6(4):479-487.
- Ravelli A, Tonolini M, Bianco R, Chronic radiation cystitis: MDCT-urography and MRI findings, Section:Uroradiology & genital male imaging, [DOI: 10.1594/EURORAD/CASE.9228], ISSN: 1563-4086.
- CG Cronin, M O'Connor, DG Lohan, M Keane, C Roche, JF Bruzzi and JM Murphy, Imaging of the gastrointestinal complications of systemic chemotherapy, Clinical Radiology. 2009; 64(7):724-733.
- Hall DA, Clouse ME, Gramm HF. Gastroduodenal ulceration after hepatic arterial infusion chemotherapy. AJR. 1981; 136:1216-18.
- Furonaka M, Miyazaki M, Nakajima M, et al. Neutropenic enterocolitis in lung cancer: a report of two cases and a review of the literature. Intern Med. 2005; 44:467-470.
- Vlasveld LT, Zwaan FE, Fibbe WE, et al. Neutropenic enterocolitis following treatment with cytosine arabinoside-containing regimens for hematological malignancies: a potentiating role for amsacrine. Ann Hematol. 1991; 62:129-134.
- Davila ML. Neutropenic enterocolitis. Curr Opin Gastroenterol. 2006; 22:44-47.
- Kirkpatrick ID, Greenberg HM. Gastrointestinal complications in the neutropenic patient: characterization and differentiation with abdominal CT. Radiology. 2003; 226:668-674.
- Kirkpatrick IDC, Greenberg HM. Evaluating the CT diagnosis of Clostridium difficile colitis: should CT guide therapy?. AJR Am J Roentgenol. 2001; 176:635-639.
- Boland GW, Lee MJ, Cats AM, et al. Radiology. 1994; 191:103-106.
- Philpotts LE, Heiken JP, Westcott MA, et al. Colitis: use of CT findings in differential diagnosis. Radiology. 1994; 190:445-449.
- Smitha S Krishnamurthi, Suneel Kamath, Enterotoxicity of chemotherapeutic agents, UpToDate, https://somepomed.org/articulos/contents/mobipreview.htm?40/20/41281
- Di Fiore F, Van Cutsem E, Acute and long-term gastrointestinal consequences of chemotherapy.Best Pract Res Clin Gastroenterol. 2009; 23(1):113.
- Talamonti MS, Dawes LG, Joehl RJ, et al.: Gastrointestinal lymphoma. A case for primary surgical resection. Arch Surg. 1990; 125:972-977.
- Meyers PA, Potter V, Wollner N, et al. Bowel perforation during initial treatment for childhood non-Hodgkin's lymphoma. Cancer. 1985; 56:259-261.
- Nielsen GL, Sorensen HT, Mellemkjoer L, et al. Risk of hospitalization resulting from upper gastrointestinal bleeding among patients taking corticosteroids: a register-based cohort study. Am J Med. 2001; 111:541-545.
- Laudadio L, Biondi E, D’Ostilio N, Cesta A, Di Giandomenico F, Forciniti S, Nuzzo A: Paralytic ileus associated with capecitabine. Tumori. 2008; 94:742-745.
- Walko CM, Lindley C: Capecitabine: a review. Clin Ther. 2005; 27:23-44.
- Hurwitz H, Fehrenbacher L., Novotny W., et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: pp. 2335-2342.
- Elice F, Rod-eghiero F, Falanga A, Rickles FR. Thrombosis associated with angiogenesis inhibitors. Best Pract Res Clin Haematol. 2009; 22(1):115-128.
- Alfonso Reginelli, Angelo Sangiovanni, Giovanna Vacca, Maria Paola Belfiore, Maria Pignatiello, et al. Chemotherapy-induced bowel ischemia: diagnostic imaging overview, Abdominal Radiology, 2021.
- Calabro L, Di Giacomo AM, et al. Primary hepatic epithelioid hemangioendothelioma progressively responsive to interferon-alpha: is there room for novel anti-angiogenetic treatments? Journal of Experimental and Clinical Cancer Research March 2007.
- Gupta A, Long JB, Chen J, Gross CP, Feldman DR, Steingart RM. Risk of Vascular Toxicity with Platinum Based Chemotherapy in Elderly Patients with Bladder Cancer. J Urol. 2016 Jan; 195(1):33-40.
- Bennett CL, Angelotta C, Yarnold PR, et al. Thalidomide and lenalidomide-associated thromboembolism among patients with cancer. JAMA. 2006; 296(21):2558-2560.
- Grassi R, Rambaldi PF, Di Grezia G, et al. Inflammatory bowel disease: Value in diagnosis and management of MDCT-enteroclysis and 99mTc-HMPAO labeled leukocyte scintigraphy. Abdom Radiol. 2011; 36(4):372-381.
- Eskens FA, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer. 2006; 42(18):3127-3139.
- Reginelli A, Iacobellis F, Berritto D, Gagliardi G, Di Grezia G, Rossi M, et al. Mesenteric ischemia: the importance of differential diagnosis for the surgeon BMC Surgery 2013.
- Mazzei MA, Guerrini S, Cioffi Squitieri N, Genovese EA, Mazzei FG, Volterrani L. Diagnosis of acute mesenteric ischemia/infarction in the era of multislice CT, Recenti Prog Med. 2012 Nov; 103(11):435-7.
- Claudia Sassi, Milena Pasquali, Giancarlo Facchini, Alberto Bazzocchi, and Giuseppe Battista, Pneumatosis intestinalis in oncologic patients: when should the radiologist not be afraid?, BJR Case Rep. 2017; 3(1): 20160017. [DOI: 10.1259/bjrcr.20160017].
- Brian G Czito, Jeffrey J Meyer, Christopher G Willett, Overview of gastrointestinal toxicity of radiation therapy, UpToDate, https://www.uptodate.com/contents/overview-ofgastrointestinal-toxicity-of-radiation-therapy
- Cosset JM, Henry-Amar M, Burgers JM, et al. Late radiation injuries of the gastrointestinal tract in the H2 and H5 EORTC Hodgkin's disease trials: emphasis on the role of exploratory laparotomy and fractionation. Radiother Oncol 1988; 13:61.
- Henriksson R, Bergström P, Franzén L, et al. Aspects on reducing gastrointestinal adverse effects associated with radiotherapy. Acta Oncol. 1999; 38:159.
- Gene Y Berkovich, Marc S Levine and Wallace T Miller, CT Findings in Patients with Esophagitis, American Journal of Roentgenology. 2000; 175:1431-1434. [DOI: 10.2214/ajr.175.5.1751431].
- Sell A, Jensen TS. Acute gastric ulcers induced by radiation. Acta Radiol Ther Phys Biol. 1966; 4:289.
- Akiva J Marcus, David Greenwald, What is the pathophysiology of radiation gastritis? Medscape radiology, Updated: Jun 07, 2019.
- Goldstein HM. Small bowel and colon. In:Libshitz HI, ed. Diagnostic roentgenology of radiotherapy change. Baltimore, Md: Williams& Wilkins, 1979; 85-100.
- Mendelson RM, Nolan DJ. The radiological features of chronic radiation enteritis. Clin Radiol 1985; 36:141-148.
- Rachel E Beard and Deborah Nagle, Acute and chronic radiation injury to the lower gastrointestinal tract, Gastrointestinal tract and abdomen, Scientific American Surgery, 04/15116.
- Beard CJ, Propert KJ, Rieker PP, Clark JA, Kaplan I, et al. Complications after treatment with external-beam irradiation in early-stage prostate cancer patients: a prospective multiinstitutional outcomes study. J Clin Oncol. 1997 Jan; 15(1):223-9.
- Reuss-Borst M, Hartmann U, Scheede C, Weiß J, Prevalence of osteoporosis among cancer patients in Germany: prospective data from an oncological rehabilitation clinic. Osteoporos Int. 2012 Apr; 23(4):1437-44.
- Theriault RL, Pathophysiology and implications of cancer treatment-induced bone loss, Oncology (Williston Park). 2004 May; 18(3):11-5.
- Chandra A, Park SS, Pignolo RJ. Potential role of senescence in radiation-induced damage of the aged skeleton. Bone. 2019; 120:423-31. [DOI: 10.1016/j.bone.2018.12.006]
- Jereczek-Fossa BA, Orecchia R. Radiotherapy-induced mandibular bone complications. Cancer Treat Rev. 2002 Feb; 28(1):65-74.
- Maryam Ebadi and Vera C Mazurak ,Evidence and Mechanisms of Fat Depletion in Cancer, Nutrients 2014; 6:5280-5297. [DOI: 10.3390/nu6115280]
- Giuseppe Buragina, Alberto Magenta Biasina, Gianpaolo Carrafiello, Clinical and radiological features of mesenteric panniculitis, Acta Biomed. 2019; 90(4): 411-422. [DOI: 10.23750/abm.v90i4.7696].
- Deborah A Frassica, Gopal K Bajaj, Theodore N Tsangaris, Treatment of Complications After Breast-Conservation Therapy,Oncology, Oncology. 2000; 17(8).
- Wazer DE, Lowther D, Boyle T, et al. Clinically evident fat necrosis in women treatedwith highdose-rate brachytherapy alonefor early-stage breast cancer. Int J Radiat OncolBiol Phys. 2001; 50:107111.
- Perera F, Engel J, Holliday R, et al:Local resection and brachytherapy confined tothe lumpectomy site for early breast cancer: Apilot study. J Surg Oncol. 1997; 65:263-267.
- CA Perez, LW Brady: Principles and Practice of Radiation Oncology. 2004: 5.
- YM Kirova, L Gambotti, Y De Rycke , et al. Risk of second malignancies after adjuvant radiotherapy for breast cancer: A large-scale, single-institution review Int J Radiat Oncol Biol Phys. 2007; 68:359-363.
- J Huang, WJ Mackillop: Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma Cancer. 2001; 92:172-180.
- RA Kleinerman, MA Tucker, RE Tarone, et al: Risk of new cancers after radiotherapy in longterm survivors of retinoblastoma: An extended follow-up J Clin Oncol. 2005; 23:2272-2279.
- Frédéric Illouz, Claire Briet, Lucie Cloix, Yannick Le Corre, Nathalie Baize, Thierry Urban, et al. Endocrine toxicity of immune checkpoint inhibitors: essential crosstalk between endocrinologists and oncologists.
- Albarel F, Gaudy C, Castinetti F, Carré T, I Morange, Conte-Devolx B, et al. Longterm follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur. J. Endocrinol. 2015; 172:195-204.
- Judith Gebauer, Claire Higham, Thorsten Langer, Christian Denzer, Georg Brabant, Long-Term Endocrine and Metabolic Consequences of Cancer Treatment: A Systematic Review, Endocrine Reviews. 2019; 40(3):711-767, https://doi.org/10.1210/er.2018-00092
- Alexandra Fairchild, Sree Harsha Tirumani, Michael H Rosenthal, Stephanie A Howard, Katherine M Krajewski, Hormonal Therapy in Oncology: A Primer for the Radiologist, AJR. June 2015; 204(6). https://www.ajronline.org/doi/abs/10.2214/AJR.14.13604?journalCode=ajr
- Carole S Scherling, Andra Smith, Opening up the Window into “Chemobrain”: A Neuroimaging Review, Journal ListSensors (Basel). 2013; 13(3). PMC: 3658739.
- Abraham J, Haut MW, Moran MT., Filburn S, Lemiuex S, & Kuwabara H. Adjuvant chemotherapy for breast cancer: effects on cerebral white matter seen in diffusion tensor imaging. Clinical Breast Cancer. 2008; 8:88-91.
- Agata Juszczak , Avinash Gupta, Niki Karavitaki, Mark R Middleton, Ashley B Grossman, Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review,Eur J Endocrinol. 2012 Jul; 167(1):1-5. [DOI: 10.1530/EJE-12-0167] [Epub 2012 Apr 10].
- Moeber Mahzari, Dora Liu, Amel Arnaout, and Heather Lochnan,Immune Checkpoint Inhibitor Therapy Associated Hypophysitis,Clin Med Insights Endocrinol Diabetes. 2015; 8:21-28.
- KJ Carpenter, RD Murtagh, H Lilienfeld, J Weber and FR Murtagh, Ipilimumab-Induced Hypophysitis: MR Imaging Findings, American Journal of Neuroradiology October 2009, 30(9):1751-1753.
- Ahmadi J, Meyers GS, Segall HD, et al. Lymphocytic adenohypophysitis: contrast-enhanced MR imaging in five cases. Radiology. 1995; 195:30-34.
- Sato N, Sze G, Endo K. Hypophysitis: endocrinologic and dynamic MR findings. AJNR Am J Neuroradiol. 1998; 19:439-44.
- Sato N, Ishizaka H, Yagi H, et al. Posterior lobe of the pituitary in diabetes insipidus: dynamic MR imaging. Radiology. 1993; 186:357-60.
- Casmir Turnquist, Brent T Harris, Curtis C Harris, Radiation-induced brain injury: current concepts and therapeutic strategies targeting neuroinflammation, Neuro-Oncology Advances. 2020; 2(1):057.
- Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD. Radiationinduced brain injury: a review. Front Oncol. 2012; 2:73.
- Ritu Shah, Surjith Vattoth, Rojymon Jacob, Fathima Fijula Palot Manzil, Janis P O’Malley, Peyman Borghei, et al. Radiation Necrosis in the Brain: Imaging Features and Differentiation from Tumor Recurrence, RadioGraphics. 2012; 32(5):© RSNA.
- Tormod A M Egeland, Jon-Vidar Gaustad, Kanthi Galappathi, Einar K Rofstad, Magnetic resonance imaging of tumor necrosis, Acta Oncol. 2011 Apr; 50(3):427-34. [DOI: 10.3109/0284186X.2010.526633] [Epub 2010 Oct 18]