Imaging Recommendations for Diagnosis, Staging and Management of Treatment-Related Complications in Cancer

Abstract Precision medicine is becoming increasingly common in oncology, with treatments tailored to individual patients and cancer. By integrating these underlying concepts of health care, chemotherapy and radiotherapy can be tailored to improve safety and efficacy. On the other hand, oncology treatment regimens may result in local and systemic changes and complications depending on the type of treatment. For the proper and prompt management of cancer patients, it is essential to interpret this posttreatment imaging correctly. This article aims at guiding treating physicians to be able to distinguish complications from expected posttreatment changes.


Introduction
Precision medicine is becoming increasingly common in oncology, with treatments tailored to individual patients and cancer. 1 By integrating these underlying concepts of health care, chemotherapy and radiotherapy (RT) can be tailored to improve safety and efficacy. 2 On the other hand, oncology treatment regimens may result in local and systemic changes and complications depending on the type of treatment. 3 For the proper and prompt management of cancer patients, it is essential to interpret this posttreatment imaging correctly. This article aims at guiding treating physicians to be able to distinguish complications from expected posttreatment changes.
Acute effects of RT are mainly on organs having rapid cell turnover, such as skin or mucosal surfaces. On the other hand, chronic or late complications of RT, such as fibrosis, perforation, or fistula formation, are a result of microvascular injury or direct parenchymal damage. 4 Risk factors for treatment related complications are: • Local extent and histology of the primary neoplasm.
• Preoperative chemotherapy and/or RT.
• Type of radiation therapy.
• Size of the field of irradiation.
• Concurrent use of chemotherapy.

Epidemiology, Clinical Presentation
Around 650,000 cancer patients receive systemic therapy or RT in the United States each year, while 180,000 receive both. The number of emergency department visits associated with cancer treatment outpaced visits related to overall health care. The most implicated cancers were lung (20.0%), breast (13.2%), and non-Hodgkin lymphoma (9.7%). The most common complications in patients with hematologic malignancies were neutropenia (15.0%), sepsis (11.6%), and anemia (11.5%). In the case of solid tumor malignancies, the most frequent complications are sepsis (7.4%), neutropenia (7.3%), and anemia (6.7%).
Among the other common presentations, dehydration was among the most common complications associated with head and neck, colon, and esophageal cancers. Intestinal obstruction was commonly seen in gynecologic (ovary, uterus, and cervix) and gastrointestinal (GI) (colorectal and anal canal) cancers. GI hemorrhage was most commonly seen in prostate cancer. Congestive cardiac failure was commonly seen in breast cancer and non-Hodgkin lymphoma. Pneumonia was associated with lung cancer and multiple myeloma while acute kidney injury (AKI) was most commonly associated with urinary bladder cancer. 5

Imaging Referral Guidelines
National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO), and American Society of Clinical Oncology (ASCO) clinical guidelines are available for the management of immunotherapy-related toxicities 6 and cancer-related infections. 7 These guidelines have also mentioned the management of treatment-related complications according to symptoms.
No consensus guidelines exist on the frequency and modality of routine posttreatment imaging in the asymptomatic patient. In the case of signs and symptoms or the presence of worrisome features on clinical examinations, imaging protocol may be tailored to answer specific clinical questions.
Most of the literature on imaging of complications of cancer therapy predominantly uses computed tomography (CT) and magnetic resonance imaging (MRI).
American College of Radiology (ACR) provided guidelines for the choice of imaging based on clinical presentation in the form of ACR appropriateness criteria. No specific guidelines are available on imaging of posttreatment complications in cancer.
National Cancer Grid (NCG) of India has formulated guidelines for palliative care of cancer but does not recommend imaging referral. 8 NCG, however, mentions the use of CT scans in cases where corrective measures are feasible and justifiable. 9 Clinical/Diagnostic Workup (Other than Imaging) Complications of systemic anticancer treatment are classspecific (i.e., agent-specific). A sepsis workup should be done if there is fever and/or cytopenia for localized or systemic features of inflammations (like intra-abdominal collection, pyelonephritis, etc.). Hypokalemia or paralytic ileus should be a differential diagnosis of intestinal obstruction. For suspected lung infection, sputum and blood culture sensitivity with Gram stain and/or bronchoalveolar lavage (BAL) is helpful. Opportunistic and atypical infection should be ruled out by organism-specific polymerase chain reaction test from BAL and/or nasopharyngeal swab. Many tyrosine kinase inhibitors cause lung injury which is a diagnosis of exclusion sometimes with a classical clinical presentation with radiological findings. There is no specific diagnostic test other than a rapid response to steroid and drug withdrawal and infrequent reappearance on rechallenge.
For meningeal enhancement, cerebrospinal fluid cytology, cell count, biochemistry, and/or microbiological culture should be performed before labeling as carcinomatous meningitis in a clinical context. For immune checkpoint inhibitor (ICI)-induced systemic complications, organ-specific diagnostic guidelines exist (NCCN, ESMO, and ASCO guidelines) and infection should be ruled out before giving high-dose steroids for immune-related adverse events (irAE). Bloodborne viral infection (i.e., hepatitis B, hepatitis C, human immunodeficiency virus) and Koch's should be ruled out before giving immunosuppressants like infliximab for the treatment of steroid-refractory irAE.

Imaging Guidelines Screening
Currently, there is no evidence to support screening for complications that may develop as a result of treatment of cancers in the general population except for when they present with symptoms.
intravenous contrast is the modality of choice. CT can be useful for quick assessment of raised intracranial tension, calcifications, acute hemorrhage, venous sinus thrombosis, or infarcts.
MRI angiogram with susceptibility-weighted imaging is preferred for evaluation of radiation-induced vascular injuries such as vascular narrowing or stenosis, capillary telangi-ectasia, cavernous malformations, microhemorrhages, and infarcts. CT can be useful for the detection of basal ganglia calcification associated with mineralizing microangiopathy. 11 If patients with glioma are treated with RT and concurrent temozolomide after surgical resection, they become susceptible to radiation-related brain parenchymal damage, resulting in pseudoprogression and radiation necrosis. 12 The imaging modality of choice for radiation-related brain parenchymal injury is MRI with spectroscopy and perfusion. It helps to discriminate viable tumors from radiation necrosis/pseudoprogression. 13 Imaging guidelines are similar for radiation-induced necrosis associated with brain metastases following radiation therapy. 14-16 MRI brain is the modality of choice for evaluation of chemotherapy-related neurotoxicity. 17 However, most drugs produce similar and nonspecific imaging patterns. The diag-nosis can be established by resolution of MRI findings in post-drug cessation follow-up imaging. Few drugs have characteristic imaging findings and require additional MRI sequences to suggest the diagnosis. Areas of symmetrical diffusion restriction in white matter on diffusion-weighted imaging are most sensitive for detection of acute methotrexate toxicity post-intrathecal route of drug administration. 18 L-asparaginase cause venous sinus thrombosis which can be easily picked up on MRI with MR venography. Contrast image (B) shows irregular and nodular enhancement (Swiss-cheese pattern) and relative cerebral blood volume (rCBV) perfusion (C) did not show any increased perfusion. Presence of lipid-lactate peak in the corresponding area on magnetic resonance (MR) spectroscopy (D) represents necrosis. These imaging features are typical for radiation-induced injury. Absence of increased choline:NAA ratios (D) further helps exclude tumor progression. Posterior reversible encephalopathy syndrome (PRES) (E). Bilaterally asymmetrical FLAIR hyperintensity in frontoparietal white matter suggestive of vasogenic edema. Acute arterial infarcts (F and G). FLAIR hyperintense areas (F) in right frontoparietal cortex and right basal ganglia due to cytotoxic edema, showing restriction on the corresponding diffusion-weighted image (G) are suggestive of watershed territory infarcts. Intracerebral hematoma (H). Acute hematoma in left occipital lobe appears hyperdense on noncontrast computed tomography (CT). There is an intraventricular extension of bleed into the left lateral ventricle. Subdural hematoma is noted along right cerebral convexity as well (red arrow in H). Chemotherapeutic agents are common inciting factors for PRES, cerebral hematoma, and arterial infarcts. CT and MRI are the key cross-sectional imaging modalities that play a complementary role to each other in the diagnosis of treatment complications (►Table 3). CT is useful to pick up gas bubbles adjacent to necrosed cartilages that clinch the diagnosis of chondronecrosis. 19 CT is complementary to MRI to assess bony destruction and remodeling and is thus useful to identify the pattern of bony involvement in osteoradionecrosis.
Contrast-enhanced CT/conventional angiography are required for the diagnosis of vascular complications such as pseudoaneurysms, vascular thrombosis, and carotid blowouts.
MRI is useful in select cases of treated oral cavity, nasopharyngeal, skull base, and sinonasal tumors. In the presence of brachial plexopathy, high-resolution T2-weighted images and short tau inversion recovery images are helpful for diagnosis.
Additional MRI perfusion, diffusion, and spectroscopy sequences are needed to differentiate other causes from radiation-induced brain necrosis affecting the temporal lobes after radiation therapy to nasopharyngeal cancers. 20 Thorax Lungs (►Table 4) Medication-induced pulmonary injury is usually suspected owing to the temporal association of symptoms with the initiation of medication. 4,21 Patient presentations range from asymptomatic individuals to severely symptomatic patients with dyspnea, cough, wheezing, and fever.
The United States National Cancer Institute Common Terminology Criteria for Adverse Events provides a classification system for stratifying the severity of "pneumonitis." This nomenclature ranges from asymptomatic (grade 1, radiologic abnormalities only) to fatal (grade 5). 22 In grade 1 (usually asymptomatic patients) a baseline chest radiograph suffices.
For other grades (2)(3)(4)(5), appearance of any new respiratory symptoms requires prompt investigation. All patients presenting with pulmonary symptoms should be assessed by 23 high-resolution CT scan (without intravenous contrast material) using multiplanar reformation and volumetric expiratory acquisition. 24 Symptoms of radiation-induced lung injury (RILI) include cough, low-grade fever, and dyspnea. These symptoms typically develop between 4 and 12 weeks following treatment.
The severity of radiation pneumonitis is graded based on the clinical presentation. The grading system (scale of 1 to 5) commonly used is the Radiation Therapy Oncology Group system: CT thorax is the modality of choice and depicts the radiation changes before it is evident at radiography. Acute RILI changes are usually detected with CT scan by 4 weeks after the completion of RT. 25 Cardiac (►Table 5) Certain cancer treatments can damage the heart and the cardiovascular system and cause congestive heart failure, ischemia, hypertension, hypotension, and arrhythmias. 26 Currently, posttreatment cardiac evaluation is most often performed with echocardiography which is the first line of imaging. 27 Previous history of cancer and cancer therapy are associated with increased coronary artery calcium scores. These patients often undergo chest CT scan for oncologic surveillance. It is important to note the presence and degree of coronary artery calcifications during these routine scans. Coronary CT is the imaging of choice for coronary artery disease characterization. 28 Late sequelae of high-dose chest RT can cause constrictive pericarditis and valve stenosis.
CT scan or MRI can be used for evaluation of these entities. Cardiac MRI is the noninvasive gold standard for morphofunctional myocardial characterization, thereby improving the detection of cardiotoxicity over conventional functional assessment. Nevertheless, the routine use of cardiac MRI is not currently recommended. 27,29   Liver injury symptoms include fatigue, right upper quadrant pain, nausea, vomiting, jaundice, abdominal swelling, and skin rashes. The different mechanisms of action of chemotherapy and RT may result in a broad spectrum of pathological and radiological hepatic injuries. These include acute or chronic hepatitis, steatosis, fibrosis, pseudocirrhosis, sinusoidal changes, and nodular hyperplasia. Ultrasonography (USG) is performed initially to rule out metastases, hemorrhage, and obstructive causes of jaundice. It may also detect ascites and gallbladder wall thickening (bystander effect). Either CT or MRI can be used for further characterization of liver involvement. MRI is more accurate in diagnosing steatosis/steatohepatitis, sinusoidal obstruction syndrome, and focal nodular hyperplasia-like nodules. [30][31][32] For treatment-related oral mucosal and gingival ulceration, chemotherapy-and RT-induced nausea and vomiting (unless alternative causes are suspected, such as brain metastases or bowel obstruction), and uncomplicated mild diarrhea no imaging is needed.
For patients presenting with moderate or severe diarrhea, abdominopelvic CT scan with intravenous contrast needs to be done if complications such as enteritis, toxic megacolon, or abscess are suspected. 6 CT enterography may be performed in subacute or chronic situations.
Patients with suspected bowel obstruction (which may be due to complications of therapy such as stricture, adhesions, enteritis, and colitis) should undergo a supine abdominal radiograph as the initial investigation. Abdominopelvic CT scan with intravenous contrast would be needed to further localize and demonstrate the cause of obstruction. Subacute cases may be investigated with oral contrast fluoroscopy, small bowel follow-through or enema studies, CT, or MR enterography.
Patients with dysphagia, retrosternal pain, and odynophagia, that is, suspected esophagitis, endoscopy would be needed. Fluoroscopic examination (contrast swallow studies) may be done in subacute presentation. For suspected esophageal stricture, fibrosis, or fistula, fluoroscopy examination and/or CT scan with oral and intravenous contrast would be needed.
If a patient presents with upper abdominal pain, epigastric tenderness, and vomiting, radiation-induced gastritis or gastric/duodenal ulceration would be a possible cause, for which endoscopy would be diagnostic and no imaging would be required.   In case these symptoms are associated with raised serum amylase and lipase, acute pancreatitis is suspected, and an abdominopelvic CT scan with intravenous contrast is indicated. If the scan is normal, magnetic resonance cholangiopancreatography may be considered.
Neutropenic patients presenting with acute abdominal pain, fever, vomiting, and diarrhea, would be suspected to have infective or noninfective colitis/enterocolitis. USG would be recommended as an initial investigation and abdominopelvic CT scan with intravenous contrast would be indicated.
For patients with suspected urinary tract infection presenting with fever, burning micturition, hematuria, and/or pyuria, USG would be the initial imaging. Patients on cytotoxic che-motherapy (such as cyclophosphamide) or RT presenting with hematuria, hemorrhagic cystitis can be due to the therapy or viral infections. Cystoscopy and urinary tract imaging is indicated in refractory and severe cases. If renal function allows, CT urogram is done, otherwise, MR urogram and renal USG may be performed. 33 Patients with rising urea and creatinine would be suspected to have AKI or chronic kidney disease in appropriate setting. Usually, USG is performed. MRI may be done to evaluate the kidney and other organs.
If female patients on pelvic radiation therapy present with lower abdominal pain and distension, cervical stenosis with hematometra or pyometra is a possibility. USG would be the initial investigation of choice. MRI of the pelvis would , and maintained mural stratification. The patient was found to be severely neutropenic, and these imaging findings along with the clinical presentation, suggested neutropenic enterocolitis/typhlitis. (D) A 6-year-old boy suffering from acute lymphoblastic leukemia, on treatment regimen containing L-asparaginase, presented to the ED with acute abdominal pain and vomiting. He was found to be hypotensive and serum amylase and lipase were raised. Axial CT scan of the abdomen with IV contrast shows nonenhancing areas within the pancreatic parenchyma indicating necrosis (yellow arrowheads), and collection in peripancreatic region containing foci of fat (yellow asterisk). The features suggest acute necrotizing pancreatitis with peripancreatic fat necrosis. (E) A 47-year-old lady receiving radiation therapy for carcinoma of the cervix uteri, underwent response assessment magnetic resonance imaging (MRI) after 20 fractions along with cisplatin. Axial T2-weighted MR image shows submucosal edema as hyperintense signals (white block arrow) deep to the hypointense mucosal layer (black arrow), and maintained mural stratification, involving pelvic small bowel loops, indicating radiation-induced enteritis. The tumor with posttreatment changes is seen involving the cervix (M). (F) A 32-year-old man with rectal adenocarcinoma, underwent a response assessment MRI after neoadjuvant chemoradiotherapy. He complained of mild lower urinary tract symptoms. Axial T2-weighted MR image shows edematous wall of urinary bladder (UB), with hyperintense signals involving the submucosa and muscularis (yellow block arrow), and surrounding edematous pelvic fat (F). The features suggested radiationinduced cystitis.
demonstrate the cause better. Patients presenting with urinary incontinence, urine, or stool discharge through vagina would be suspected to have fistulas, and fluoroscopic examination with relevant contrast is the initial investigation. CT scan of the pelvis with intravenous contrast (delayed phase images) or with rectal contrast will delineate the communication better. MRI of the pelvis or MR fisulogram may demonstrate some fistulous communications better. In patients who present with difficulty in micturition following radiation therapy, urethral strictures are suspected and retrograde cystourethrography/voiding cystourethrography are required imaging modalities for diagnosis.

Bones and Soft Tissues (►Table 7)
The imaging recommendations are given in ►Table 7. [34][35][36] Follow-Up and Surveillance Women who were exposed to thoracic irradiation as an adolescent should undergo routine follow-up screening (with adjunctive breast MRI) sooner than usually recommended. Mammographic screening is recommended annually by the Society of Breast Imaging, ACR, and NCCN beginning 8 to 10 years after the radiation exposure. 37,38 For patients undergoing combined chemotherapy and radiation therapy, imaging monitoring of left ventricular ejection function has been recommended at 2-year intervals. 39 Echocardiography is typically used. In patients who are found to have decreased systolic function, the next step should be cardiac MRI. 40 There exists no other substantial role for surveillance to detect treatment-related complications.

Principles of Management
Most of the grade 1or grade 2 systemic anticancer drug-related and RT toxicity is manageable with supportive care without altering the recommended dose and frequency. For any grade 3 or grade 4 toxicity every effort should be made to find out any identifiable underlying factor(s) contributing to such toxicity (like uncontrolled comorbidity, poor nutritional status, etc.). Any correctable cause should be addressed accordingly. Majority of the time dose reduction is recommended in case of grade 3/4 toxicity. Prophylactic hematopoietic growth factor should be used liberally whenever indicated to reduce the incidence of febrile neutropenia. Permanent interruption is required in majority of grade 4 and few grade 3 toxicities. Patient counseling, home remedies, early identification, and treatment of toxicities are very important and effective strategy to maintain treatment compliance. For ICI-induced irAE, well-recommended and well-studied organ-specific guidelines exist (ASCO and ESMO guidelines). No dose reduction is recommended or permitted for any ICI-related irAE. Initial antibiotics cover and ruling out underlying or associated infection is recommended for any immunosuppressive therapy to treat irAE. Imaging is required to differentiate treatment complications from infection and tumor recurrence.

Summary of Recommendations
• There are no consensus guidelines regarding the frequency and modality of routine posttreatment imaging in an asymptomatic patient. • In the case of equivocal signs and symptoms or presence of worrisome features on clinical examinations and other laboratory tests, imaging protocol may be tailored to answer specific clinical questions. • Most imaging guidelines advocate the use of MRI and CT scan in complementary roles. BMD measurement/DEXA every 2 years or more frequently depending upon age and risk factors 5 BMD measurement/DEXA and risk monitoring every 1-to 2-year interval 6 Baseline DEXA followed by DEXA scan at 1 year to assess risk and response 7 Abbreviations: ADT, androgen deprivation therapy; BMD, bone mineral density; CT, computed tomography; DEXA, dual energy X-ray absorptiometry; IV, intravenous; MRI, magnetic resonance imaging.