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Nuclear Medicine in the Assessment of Adverse Effects of Cancer Therapy in the Lung, Kidney, and Gastrointestinal Tract

  • Diego Alfonso López Mora
  • Ignasi CarrióEmail author
Living reference work entry

Abstract

Radiotherapy or chemotherapy and new drugs and strategies in oncology can produce damage in normal organs and tissues affecting the quality of life of the patient. Pulmonary toxicity is frequently seen in patients treated with bleomycin or other chemotherapeutic agents. The most common clinical form of bleomycin pulmonary toxicity is the subacute condition, which may progress to lung fibrosis and death, if not recognized and appropriately managed. The diagnosis is usually established by a combination of clinical, radiographic, and pulmonary function test abnormalities. X-ray and high-resolution CT scan findings are used to identify pulmonary fibrosis. 67Ga-citrate scintigraphy has been used to detect and assess the extent of pulmonary toxicity related to bleomycin in patients who otherwise have normal chest radiographs.

Since conventional CT scanning is not able to distinguish fibrosis and active inflammation, [18F]FDG-PET has been suggested as a tool to indicate the resolution of disease activity. Moreover, [18F]FDG-PET could be useful to detect early preclinical pneumonitis induced by bleomycin. As pulmonary permeability can be altered by chemotherapy, 99mTc-DTPA aerosols can be used to assess a reduced epithelial permeability.

Acute radiation lung injury can occur within 1–3 months after radiation therapy of the thorax, whereas lung fibrosis can develop 6–24 months later, leading to progressive impairment of pulmonary function. Clinical manifestations, chest radiographs, and pulmonary function tests may help to establish an early diagnosis. Scintigraphic abnormalities can be demonstrated in the acute phase often before radiologic changes become apparent by 67Ga-citrate scintigraphy. Moreover, 111In-pentetreotide may have a role in the differential diagnosis of patients with complaints after radiotherapy and in the monitoring of the response to corticosteroid therapy. [18F]FDG uptake in the irradiated region can be observed up to about 2 months following therapy. The persistence of activity beyond 8 weeks raises the likelihood of persistence of disease within the irradiated region.

Lung scintigraphy with 99mTc-DTPA aerosol or 99mTc-MAA (macroaggregates of albumin) has been performed to assess radiation-induced ventilation/perfusion changes.

Drugs for the treatment of abdominal malignancies, such as cisplatin and ifosfamide, and abdominal radiation can cause renal damage.

Chemotherapy-induced nephropathy can be identified with quantitative measurement of glomerular filtration rate. 99mTc-DTPA has become the preferred radiopharmaceutical because of availability and cost. 99mTc-DMSA scintigraphy can be used to establish tubular dysfunction induced by nephrotoxic drugs. Nuclear medicine techniques also offer the possibility to follow the clinical evolution of radiation nephropathy. Bone scans using 99mTc-MDP can show increased kidney uptake early after radiation in patients with radiation fields including kidneys. Over the subsequent 6–12 months the uptake decreases to normal or below normal levels, associated with the loss of function. Renography with 99mTc-DTPA can be performed to assess radiation nephropathy. 99mTc-DTPA Captopril renography test has been used to investigate the relation between small vessel injury due to radiation and hypertension.

Nuclear medicine examinations can play a role in the detection of radiation-induced digestive tract damage.

In cancers of the cervix, endometrium, ovary, prostate, bladder, or rectum, radiation therapy is often required. Radiation proctitis is usually self-limiting and resolves within a month after the conclusion of therapy. Damage of the small bowel is seen in 0.5–15% of the patients. Chronic injuries to the small bowel are manifest 6 and 24 months after radiation. Ileal dysfunction is due to bile acid malabsortion, to bacterial overgrowth in the small bowel, or to the combination of both. 75Se-homocholic acid conjugated with taurine (75Se-HCAT) and 14C-glycochol breath test can be used to differentiate between normal functioning ileum (both tests negative) and ileal dysfunction (one or both tests positive). The combination of both tests may allow the differentiation between bile acid malabsorption (75Se-HCAT positive) and bacterial overgrowth (75Se-HCAT negative).

These techniques may also help to document the benefit of innovative therapeutic approaches such as the use of somatostatin analogs (SOM230). In cases of radiotherapy and chemotherapy-associated liver injury, radionuclide studies can be performed using 99mTc-iminodiacetic acid or 99mTc-colloid. In patients receiving radiotherapy, the most common finding is the loss of function of the part of the liver involved in the radiation field, with a reduced uptake in irradiated areas. Recently, acute radiation-induced hepatitis has been reported as a potential cause of false-positive findings of malignancy on [18F]FDG-PET scans. Moreover, esophagitis postradiotherapy can be observed on [18F]FDG-PET scans.

Leucocytes labeled with 111In or with 99mTc-HMPAO or [18F]FDG can be used in patients with suspected radiation enterocolitis.

Keywords

Nuclear medicine Adverse effects Radiation-induced digestive tract damage Radiation-induced renal damage Pulmonary toxicity with radiation Radiation-induced pulmonary toxicity Renal damage in radiation Gastrointestinal tract damage in radiation Liver damage in radiation 

Glossary

[18F]FDG

2-deoxy-2-[18F]fluoro-D-glucose

75Se-HCAT

75Se-Homocholic acid conjugated with taurine

99mTc-DMSA

99mTc-dimercaptosuccinic acid

99mTc-DTPA

99mTc-diethylenetriaminepentaacetic acid

99mTc-HMPAO

99mTc-hexamethylpropyleneamine oxime

99mTc-IDA

99mTc-iminodiacetic acid

99mTc-MAA

99mTc-macroaggregated albumin

99mTc-MDP

99mTc-methylene diphosphonate

AVBD

chemotherapy regimen based on adriamycin, vinblastine, bleomycin and dacarbazine

CT

X-ray computed tomography

DLCO

Diffusing capacity of the lung for carbon monoxide

EDTA

Ethylenediaminetetraacetic acid

GFR

Glomerular Filtration Rate

GI

Gastrointestinal

Gy

Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)

MIP

Maximum Intensity Projection

NSCLC

Non-small cell lung cancer

PET

Positron emission tomography

PET/CT

Positron emission tomography/Computed tomography

ROS

Reactive oxygen species

SPECT

Single-photon emission computed tomography

SPECT/CT

Single-photon emission computed tomography/Computed tomography

This chapter reviews the nuclear medicine findings in detecting organ injury and adverse effects due to cancer or cancer therapy in the lung, kidney, and gastrointestinal tract. The use of radiotherapy or chemotherapy and new drugs and strategies in order to intensify the anti-tumor effect with a curative intent can produce different types of collateral damage in normal organs and tissues affecting the quality of life of the patient. Chemotherapy acts on the parenchymal cells and radiotherapy causes inflammation both in the organ and in the major vasculature (in the direct path of the beam) and affects the microcirculation. In tissues with high proliferation rates, such as the bone marrow and GI tract, stem cells may be depleted and/or injured. Chemo- and radiotherapy can cause acute injury as well as late damage, months to years after treatment. Such damage is usually subclinical.

However, if the organ sustains an additional injury (in some cases even a minor infection), the organ dysfunction may become clinically apparent.

Lungs

Bleomycin is the most common chemotherapeutic agent associated with pulmonary toxicity. However, nitrosureas, erlotinib, cyclophosphamide, mitomycin, busulfan, and methotrexate can also cause such toxicity. At the same time, radiotherapy to lesions of the lung, breast, mediastinum, or esophagus causes initial inflammation, followed by scarring (depending on the dose). Nuclear medicine studies employing 67Ga-citrate and 111In-pentetreotide are able to detect acute and subacute pulmonary toxicity in patients treated either with chemotherapy or radiotherapy. When necessary, pulmonary V/Q scintigraphy can be performed to assess ventilation/perfusion changes in irradiated patients. SPECT/CT ventilation perfusion studies can be particularly helpful, since many of these patients have underlying lung disease. Following multiple courses of platinum-based chemotherapy, hypersensitivity pulmonary reactions can occur in 5–40% of patients, usually after the sixth cycle of treatment, especially when the agents are administered with paclitaxol [1].

Chemotherapy-Associated Pulmonary Toxicity

Chemotherapy-associated pulmonary toxicity is frequently seen in patients treated with bleomycin. The incidence rate of pulmonary toxicity in patients with Hodgkin’s disease treated with standard AVBD chemotherapy varies between 18% and 28% [2, 3]. The risk factors associated with bleomycin-induced pneumonitis include the cumulative dose administered, the age of the patient, and impaired renal function. The incidence and severity of bleomycin toxicity is clearly increased by previous or concomitant thoracic radiotherapy. In these patients, the risk of lethal outcome is ~4% [3, 4]. The total administered dose is clearly a risk factor, with sporadic toxicity occurring at total doses of 100–450 U and increasing incidence beyond that range. The central event in the development of bleomycin-induced pneumonitis is endothelial damage. Bleomycin causes release of cytokines and reactive oxygen species (ROS), leading to cell damage, followed by recruitment of inflammatory cells into the lung parenchyma, and subsequently of fibroblasts leading to fibrosis [4, 5]. Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix components in the alveolar space, which hampers the normal transfer of oxygen. Pathophysiological enzymes, glycoprotein moieties, and matrix degrading lysosomal hydrolases are key markers and play a crucial role in the progression of fibrosis. One important pathogenic process associated with pulmonary fibrosis is injury to basement membranes by matrix metalloproteinases that are produced mainly by macrophages [6, 7].

The clinical and radiological findings in chemotherapy-associated pulmonary toxicity are nonspecific and may be difficult to detect, as they are often similar to other pulmonary syndromes [4]. Therefore, the diagnosis of chemotherapy-associated pulmonary toxicity is challenging; early detection is important to reduce lung injury and prevent pulmonary fibrosis [3, 4, 5]. Pulmonary toxicity may be short-term or permanent. The lung injury that resolves (returns to normal) after time or after the cause is removed is called acute/subacute pulmonary toxicity and the lung injury that is permanent is called chronic or late pulmonary toxicity.

The most common clinical presentation of Bleomycin-induced pneumonitis is the subacute pneumonitis, which tends to progress with time leading to lung fibrosis and death if not properly diagnosed and treated. The diagnosis of bleomycin-induced pneumonitis can be suspected with the appearance of the clinical manifestations (progressive dyspnea and nonproductive cough), the appearance of pulmonary function tests abnormalities with restrictive patterns (diminished total lung, vital capacities, and DLCO), and the appearance of common findings in chest X-ray (bilateral, lower pulmonary lobes, sometimes followed by diffuse interstitial and alveolar infiltrates) and high-resolution CT scan (diffuse areas of ground-glass opacity, interlobular septal thickening, fibrosis, or consolidation) [4, 8, 9]

Scintigraphy with 67Ga-citrate has been used to detect and assess the extent of pulmonary toxicity related to bleomycin. 67Ga has an atomic structure and biological behavior similar to iron (ferric ion) with the property to bind to any proteins that bind iron. 67Ga circulates in plasma bound to transferrin protein. The complex 67Ga-transferrin is transported to the inflammatory site due to the local increased blood flow and vascular permeability. In the inflammation site, neutrophils release large amounts of lactoferrin, which binds to 67Ga. Also siderophores, compounds secreted by microorganisms such as bacteria can also bind to 67Ga. Therefore, 67Ga localization at the inflammation/infection site is secondary to its ferric ion-like properties [10] and allows localization, delineation of extent, and assessment of the degree of activity of the inflammatory disease [11]. 67Ga scintigraphies in drug-induced pneumonitis show a bilateral diffuse lung uptake, in patients undergoing chemotherapy (including bleomycin) with normal chest X-rays (Fig. 1) [12].
Fig. 1

Patient with Hodgkin’s lymphoma treated with bleomycin. Diffuse bilateral uptake of 67Ga reflects pulmonary toxicity

Positron Emission Tomography with 2-deoxy-2-[18F] fluoro-d-glucose ([18F]FDG PET/CT) is a widely used molecular imaging technique in the assessment of treatment response in oncological patients [9, 13, 14, 15, 16]. Chemotherapy-associated pulmonary toxicity is a potential cause of false-positive results in [18F]FDG PET/CT of patients undergoing chemotherapy [9, 14], in particular when bleomycin is used (standard AVBD treatment for Hodgkin’s disease) [4, 8, 9]. Based on the physiopathology of the inflammatory processes, a number of studies have demonstrated that a higher activation of macrophages, neutrocytes, or lymphocytes is correlated with a higher accumulation of [18F]FDG [17, 18, 19, 20, 21]. Therefore, the degree of [18F]FDG uptake in drug-induced pneumonitis may reflect the metabolic activity and supports its use to assess disease activity [17].

In acute drug-induced pneumonitis, the process starts with pulmonary infiltration of neutrophils, followed by morphological changes seen on high-resolution CT scan. Thus, in early stages of pulmonary toxicity, high-resolution CT scans may be unable to detect such abnormal morphological changes. In this case, [18F]FDG PET/CT may be a more sensitive tool to detect early drug-induced pneumonitis, even before the onset of pulmonary symptoms and the appearance of parenchymal changes in chest X-ray and/or CT scan. Such early detection may be useful for accurate treatment to reverse the lung injury and prevent pulmonary fibrosis [22] (Fig. 2). Along this line, [18F]FDG PET/CT in drug-induced pneumonitis may be used to monitor the effects of corticosteroid treatment. Von Rohr et al. [23] reported that PET scan and CT scan findings resolve after immunosuppressive therapy. Also Butchler et al [24] reported that the PET scan performed within 2 months of onset of bleomycin-induced pneumonitis demonstrated diffuse pulmonary [18F]FDG uptake which resolved after corticosteroid treatment with persistence of morphological (parenchymal) changes in conventional CT scan. These data suggests that [18F]FDG PET/CT may be used to distinguish between residual changes and active inflammation and that [18F]FDG PET/CT may provide a tool to indicate the resolution of disease activity, even in the presence of residual pulmonary scarring [24]. Along the same line, Connerotte et al [25] have shown that PET abnormalities can resolve after cessation of bleomycin as the only intervention, suggesting that [18F]FDG PET/CT could be useful to detect early preclinical bleomycin-induced pneumonitis at a stage that is fully reversible upon cessation of bleomycin. Therefore, [18F]FDG PET/CT may be used in the detection of bleomycin-induced pneumonitis before clinical symptoms and possibly before significant lung function or conventional radiology alterations take place.
Fig. 2

Chemotherapy-associated pulmonary toxicity in a 53-year-old woman who received erlotinib/bevacizumab for metastatic non-small cell lung cancer (NSCLC). (a) After the third chemotherapy cycle, the MIP PET image demonstrates a diffuse [18F]FDG uptake in both lungs (red arrows) and a focal [18F]FDG uptake that corresponds to the NSCLC (green arrow). (b) Axial PET and (c) fused PET/CT images show hypermetabolic diffuse ground-glass infiltrates in both lungs. In the context of recent chemotherapy, these findings were consistent with chemotherapy-induced pneumonitis. The anatomical pathology of the transbronquial biopsy of the left inferior pulmonary lobe demonstrated acute inflammatory changes. (d) MIP PET, (e) axial PET and (f) fused PET/CT images performed 3 weeks after bevacizumab stop, reduce erlotinib dose, and steroid administration showed resolution of the hypermetabolic diffuse ground-glass lung infiltrates

Pulmonary Permeability During Chemotherapy

In chemotherapy-induced lung injury, pulmonary permeability is altered because of alveolar epithelial disruption with fluid and protein leakage into the alveolar spaces and focal necrosis of type I pneumocytes and fibrosis. Permeability can be assessed using 99mTc-DTPA aerosols. The inhalated aerosol is deposited in the alveoli, permitting the acquisition of scintigraphic images that show different patterns of ventilation. In the noninflammed lung there is minimal permeability of the DTPA from the air space to the vasculature, hence minimal activity in the systemic circulation. The inflammed lung has greater permeability, allowing passage of the tracer from the air space to the vasculature. The clearance time decreases as epithelial permeability [26, 27] increases. In untreated patients, permeability was reduced, possibly because of tumor infiltration, while it was increased in treated patients, suggesting early injury [28, 29].

Radiation Pneumonitis

In radiation therapy of the thorax, radiation pneumonitis can appear 2–8 months after treatment. Radiation lung injury occurs in proportion to the amount of lung that is exposed to doses of >20 Gy. Symptoms vary from none, when radiation is delivered to a small region of the lung, to systemic signs and symptoms of fever, dyspnea, cough, and respiratory distress syndrome, when radiation is delivered to >20% of the total lung volume. Following lung radiation there are two phases of cytokine expression: one occurring hours to days or weeks after radiation, typically returning to normal after ~2 weeks and a second phase at 6–8 weeks, leading to pulmonary parenchymal and vascular damage [30], which may progress for 6–24 months following radiation exposure. Within 1–3 months of exposure, acute radiation lung injury can occur, manifested by dyspnea, cough, and hypoxia. Six to twenty-four months after radiation lung fibrosis can occur, leading to progressive impairment of pulmonary function. Early detection of radiation pneumonitis enables adequate treatment with a reasonable chance to prevent or limit late sequelae [31]. Clinical manifestations, chest radiographs, and pulmonary function tests may help establish an early diagnosis, but scintigraphic abnormalities can be demonstrated in the acute phase often before radiologic changes become apparent. 67Ga-citrate scintigraphy is also a sensitive method for the early detection of radiation pneumonitis [32], although the delineation of lung injury may be hampered due to the normal 67Ga uptake in sternum and thoracic spine. Pentetreotide, a synthetic somatostatin analog with strong affinity for the somatostatin receptor subtypes 2 and 5, can be labeled with 111In. Somatostatin has been shown to modulate fibroblast activation and to have antifibrotic properties also [33], although the exact mechanisms of such antifibrotic action of octreotide still remains unclear. 111In-pentetreotide may have a role in the differential diagnosis of patients with complaints after radiotherapy and in the monitoring of the response to corticosteroid therapy [31]. Some false-positive studies have been reported with increased pulmonary uptake in patients with neuroendocrine tumors which eventually was due to pulmonary fibrosis (Fig. 3) [34, 35]. [18F]FDG-PET has also been recently proposed to detect radiation pneumonitis [36] and may be used as a predictor for acute radiation pneumonitis [37] (Fig. 4).
Fig. 3

Patient with a neuroendocrine tumor studied 10 months after radiotherapy. (a) CT. (b) Pulmonary fibrosis in the right paramediastinum shows 111In-pentetreotide uptake on the SPECT image. (c) Decreased radiollabeled octreotide uptake 9 months later (Ref. [33], with permission)

Fig. 4

Post radiotherapy pneumonitis in areas of the radiotherapy treatment field (left and central panels), with resolution on the [18F]FDG PET/CT scan 2 months later (right panel)

There may be significant [18F]FDG uptake in the irradiated region up to about 2 months following therapy. Persistence of significant focal activity beyond 8 weeks raises the likelihood of persistence of disease within the irradiated region.

Ventilation/Perfusion Changes Induced by Thoracic Irradiation

Radiation-induced lung damage may lead to decreased lung perfusion, lung ventilation, and diffusion of gases in the irradiated region. A decrease in pulmonary blood flow in the irradiated areas has been reported in breast cancer patients receiving radiotherapy [38]. Lung scintigraphy with 99mTc-DTPA aerosol or 99mTc-MAA (macroaggregates of albumin) has been performed to assess abnormal ventilation/ perfusion patterns. A reduction in both ventilation and perfusion was observed 3 months after radiotherapy. Other radiotracers used in different studies include 133Xe, 81mKr gas, or 131I-MAA with reduced perfusion in the irradiated areas as the common finding [38, 39, 40].

Kidneys

Chemotherapy drugs (cisplatin and ifosfamide) can cause renal damage , while abdominal radiation in the treatment of abdominal malignancies can lead to renal nephropathy. Several radionuclide techniques have been proposed to evaluate the effect of these treatments on the kidneys.

Chemotherapy-Induced Tubular Injury

The use of nephrotoxic chemotherapeutic agents can lead to both acute and chronic toxicity, including life-threatening progressive deterioration of kidney function. Cisplatin, a frequently used chemotherapeutic agent, may cause renal toxicity in about one third of patients, usually manifest as a decrease in glomerular filtration rate (GFR). The process is initiated by proximal tubular damage followed by alterations in the GFR and in the effective plasma renal flow [41]. The decrease in GFR is closely related to the dose. Cisplatin can be given in four cycles of 20 mg/m2 for 5 days without kidney damage, but a treatment dose of 40 mg/m2 daily for 5 days results in the reduction of GFR and tubular function [42]. The strategies to prevent cisplatin nephrotoxicity are based on early detection and reduction of toxic effects using diuretics (mannitol and furosemide) or on the use of other platinum derivatives such as carboplatin and iroplatin which have less kidney toxicity. On the other hand, ifosfamide can induce Fanconi’s syndrome, a disorder of the proximal tubule of the kidney, with increasing risk at doses exceeding 50 mg/m2 [43].

Chemotherapy-induced nephropathy can be identified with quantitative measurement of GFR. Although the gold standard for this measurement utilized intravenous injection of 51Cr-labeled EDTA, 99mTc-DTPA has become the preferred radiopharmaceutical because of availability and cost. Typically, three blood samples are obtained over 2–3 h and tracer clearance is calculated. Methods proposed to evaluate tubular function include the determination of the fractional excretion of electrolytes, the renal threshold for phosphate, aminoaciduria follow-up, and determination of low-molecular-weight proteins (beta-2 microglobulin). Results of such methods should be interpreted with caution before assuming proximal tubular damage because they are affected by excessive secretion of hormones, dependence on plasma concentration of proteins, and urine-plasma measurement. 99mTc-DMSA scintigraphy can be used to establish tubular dysfunction [44]. It binds to proximal tubular cells. Diseases affecting the proximal tubules, such as tubular acidosis, Fanconi’s syndrome, or tubular dysfunction due to nephrotoxic drugs, inhibit 99mTc-DMSA uptake. In patients treated with ifosfamide, a significant correlation has been found between 99mTc-DMSA uptake and cumulative doses of ifosfamide (p < 0.01). Anninga et al. found that 99mTc-DMSA scintigraphy is more consistent than urine levels of beta-2 microglobulin in detecting ifosfamide-induced tubular dysfunction and concluded that the test is also able to detect subclinical injury. Other studies show that ifosfamide-induced tubular injury can be detected with 99mTc-DMSA scintigraphy [45], even before chemotherapy-associated nephrotoxicity is observed by other laboratory measurements [45, 46, 47].

Radiation Nephropathy

Radiation therapy can cause damage to the endothelial cells of the glomeruli, the parenchymal vessels, or the renal tubules leading to the radiation nephropathy [48]. Lesion progress is typically slow but resulting in complete atrophy of the irradiated renal tissue with a total loss of function. Nuclear medicine techniques offer the possibility to follow the clinical evolution of radiation nephropathy. Bone scans, using 99mTc-MDP, show abnormal uptake in the kidney of patients with radiation fields including kidneys, as for vertebral or rib malignancies. Early after radiation (over about 6–9 months) 99mTc-MDP uptake is increased. Over the succeeding 6–12 months the uptake decreases to normal or below normal levels, associated with the gradual loss of renal parenchymal function [49]. Renography with 99mTc-DTPA can be performed to assess radiation nephropathy. 99mTc-DTPA is cleared through glomerular filtration providing information about glomerular function. Simultaneous 99mTc-DTPA scans to study glomerular function and 99mTc-DMSA imaging to study tubular function show a decline in renal function at about 6 months after irradiation. Scintigraphic studies with 99mTc-DTPA and 99mTc-DMSA have been found to be more sensitive than biochemical tests to assess radiation injury. Renal toxicity has been demonstrated during treatment at radiation doses over 18 Gy. In these patients, radionuclide studies performed at regular intervals are useful for appropriate assessment of renal toxicity [49]. Some studies have described a relation between small vessel injury due to radiation and hypertension. Using 99mTc-DTPA renography with and without Captopril in patients with hypertension, it has been shown that small-vessel injury appears in hypertensive patients due to increased release of renin [50]. Other studies with 99mTc-DMSA in unilateral kidney irradiated patients have evaluated the function of each kidney. After a follow-up of 5 years, results showed that the increase of volume in the contralateral kidney was less accentuated than the increase in uptake. This suggests that the mechanism to compensate the radiation nephropathy of the contralateral kidney would be hyperfunction rather than hypertrophy [51]. These findings underline the need to perform follow-up function studies in unilateral kidney disease (Fig. 5).
Fig. 5

99mTc-DMSA scintigraphy in a patient who received radiotherapy involving the left kidney. Right kidney remains normal

Digestive Tract

Nausea, vomiting, diarrhea, and enteritis often occur due to radiotherapy and chemotherapy. Nuclear medicine examinations can play a role in the detection of radiation-indu ced late injury on the small bowel.

Radiation Damage of the Small Bowel

In cancers of the cervix, endometrium, ovary, prostate, bladder, or rectum, radiation therapy is often required. In the course of radiation therapy, rectal toxicity of grade 1–2 (Radiation Therapy Oncology Group definition = grade 1 = minor symptoms requiring no treatment; grade 2 = symptoms that respond to simple management) occurs in ~70% of patients. The occurrence of radiation proctitis is related to the volume of the rectum exposed to doses >60 Gy. Radiation proctitis is usually self-limiting and resolves within a month after the conclusion of therapy. Damage of the small bowel is seen in 0.5–15% of the patients [52], and it is characterized by progressive cell depletion, collagen fibrosis, and obliterative vascular injury [53]. Small bowel radiation results in epithelial stem cell injury as an early effect and in evolving vascular injury and collagen fibrosis as late effects. Chronic injuries to the small bowel are manifest 6 and 24 months after radiation [54]. Factors predisposing to late small bowel complications include the total radiation dose, the dose per fraction, the volume of small bowel irradiated, previous surgery, age, diabetes, and chemotherapy combined with radiation therapy [53]. Ileal dysfunction is very frequent in patients with radiation damage of the small intestine, and it is due to bile acid malabsortion, to bacterial overgrowth in the small bowel, or to the combination of both. Endoscopy cannot detect radiation injury of the small bowel. Valdés Olmos et al. used 75Se-homocholic acid conjugated with taurine (75Se-HCAT) and [14C] glycochol breath test to differentiate between normal functioning ileum (both tests negative) and ileal dysfunction (one or both tests positive) in a group of patients who received radiotherapy treatment. Unfortunately, a positive 14C breath test alone cannot differentiate between bile acid malabsorption and bile acid loss due to bacterial overgrowth [51]. However, the combination of both tests may allow the differentiation of those with bile acid malabsorption (75Se-HCAT positive) from those with bacterial overgrowth (75Se-HCAT negative) [55]. Recent studies have proposed the use of somatostatin analogs (SOM230) to treat diarrhea and to ameliorate intestinal injury after localized irradiation in mice [56]. The results show that SOM230 increases survival, preserves mucosal surface area, and reduces bacterial translocation in a dose dependent manner and with a mechanism that likely involves reduction of intraluminal pancreatic enzymes. Nuclear medicine techniques may help to document the benefit of such innovative approaches that can provide effective countermeasures against radiation injury of the digestive tract.

Liver Damage

The liver is also affected by radio- and chemotherapy treatments. Biopsies show nonspecific fibrosis and rarely cirrhosis, with hepatocellular necrosis and bile stasis [57]. In these cases of radiotherapy- and chemotherapy-associated liver injury, radionuclide studies can be performed using 99mTc-IDA scintigraphy or 99mTc-colloid. 99mTc-IDA has the same behavior as bilirubin. After entering the hepatocyte, it is transported into the bile canaliculi and from bile ducts to small intestine. Gallbladder filling is typically seen. In patients receiving radiotherapy, the most common finding is the loss of function of the part of the liver involved in the radiation field, with a reduced uptake in irradiated areas. A gallbladder filling defect can also be detected in gallbladder carcinomas after radiation therapy [58]. Recently, acute radiation-induced hepatitis has been reported as a potential cause of false-positive findings of malignancy on [18F]FDG-PET scans. [18F]FDG-PET performed 26 days after chemoradiotherapy in an esophageal cancer shows a wedge-shaped hypermetabolic area in which the degree of [18F]FDG uptake is correlated with the prescribed radiation dose. Follow-up [18F]FDG-PET 4 months later showed no abnormal uptake in the liver consistent with acute radiation-induced hepatitis, indicating that PET images must be carefully compared with the distribution of prescribed radiation dose [59].

Other Tracers in Injuries on the Digestive Tract

Finally, irradiation-induced odynophagia and esophageal ulcerations can be visualized by 99mTc-sucralfate, a tracer that accumulates on esophageal lesions and has shown a very good correlation with endoscopy [60]. Esophagitis postradiotherapy can be observed on [18F]FDG-PET scans (Fig. 6) [36]. Esophagitis postradiotherapy occurs usually, by week 3 or 4 in patients undergoing radiotherapy, treated for thoracic nodal disease and non–small cell lung cancer [61]. Some risk factors are associated with the severity and incidence of esophagitis postradiotherapy such as the age of the patient, tumor type, tumor burden, concurrent chemotherapy, body mass index, and dosimetric predictors (mean esophageal dose, maximal esophageal dose, and percentage of esophagus volume that receives more than 20Gy of radiation) [62, 63, 64].
Fig. 6

Diffuse [18F]FDG uptake along the esophagus with a characteristic pattern of post-radiotherapy esophagitis

In addition, radiopharmaceuticals commonly employed to assess inflammation, such as leucocytes labeled with 111In or with 99mTc-HMPAO or [18F]FDG, can be used in patients with suspected radiation enterocolitis in order to localize areas of increased inflammatory activity in small bowel and colon [65].

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Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  1. 1.Department of Nuclear Medicine, Hospital Sant PauAutonomous University of BarcelonaBarcelonaSpain

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