Nuclear Medicine in the Assessment of Adverse Effects of Cancer Therapy in the Lung, Kidney, and Gastrointestinal Tract
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.
KeywordsNuclear 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
75Se-Homocholic acid conjugated with taurine
chemotherapy regimen based on adriamycin, vinblastine, bleomycin and dacarbazine
X-ray computed tomography
Diffusing capacity of the lung for carbon monoxide
Glomerular Filtration Rate
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)
Maximum Intensity Projection
Non-small cell lung cancer
Positron emission tomography
Positron emission tomography/Computed tomography
Reactive oxygen species
Single-photon emission computed tomography
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.
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 .
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 . 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]
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 .
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].
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 . 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].
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 . 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 . 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 .
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 . 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 , even before chemotherapy-associated nephrotoxicity is observed by other laboratory measurements [45, 46, 47].
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 , and it is characterized by progressive cell depletion, collagen fibrosis, and obliterative vascular injury . 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 . 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 . 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 . 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) . Recent studies have proposed the use of somatostatin analogs (SOM230) to treat diarrhea and to ameliorate intestinal injury after localized irradiation in mice . 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.
The liver is also affected by radio- and chemotherapy treatments. Biopsies show nonspecific fibrosis and rarely cirrhosis, with hepatocellular necrosis and bile stasis . 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 . 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 .
Other Tracers in Injuries on the Digestive Tract
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 .
- 1.Makrilia N, Syrigou E, Kaklamanos I, Manolopoulos L, Saif MW. Hypersensitivity reactions associated with platinum antineoplastic agents: a systematic review. Met Based Drugs. 2010; 2010:pii: 207084.Google Scholar
- 7.Okuma T, Terasaki Y, Kaikita K, Kobayashi H, Kuziel WA, Kawasuji M, Takeya M. C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage in filtration and production of macrophage-derived matrix metalloproteinases. J Pathol. 2004;204:594–604.CrossRefPubMedGoogle Scholar
- 10.Ziessman HA, O’Malley JP, Thrall JH. Infection and inflammation. In: Nuclear medicine, the requisites, 3. Philadelphia: Elsevier-Mosby; 2006. p. 386–7.Google Scholar
- 23.von Rohr L, Klaeser B, Joerger M, Kluckert T, Cerny T, Gillessen S. Increased pulmonary FDG uptake in bleomycin associated pneumonitis. Onkologie. 2007;30:320–3.Google Scholar
- 26.Ziessman HA, O’Malley JP, Thrall JH. Ventilation perfusion scintigraphy. In: Nuclear medicine, the requisites. 3rd ed. Philadelphia: Elsevier-Mosby; 2006. p. 513.Google Scholar
- 27.Graham MM. Scintigraphy. In: James RJ, Stephen GS, Richard KA, editors. Comprehensive respiratory medicine. London: Harcourt-Mosby; 2001.Google Scholar
- 42.Valdés Olmos RA. Chemotherapy-induced tubular injury and 99mTc-DMSA. In: Valdés Olmos RA, editor. The role of nuclear medicine in the detection of organ injury and adverse effects of cancer therapy. Thesis, University van Amsterdam; 1994. p. 37.Google Scholar
- 45.Anninga JK, De Kraker J, Hoefnagel CA, Vaoute PA. Ifosfamide induced nephrotoxicity evaluated by 99mTc-DMSA renal scintigraphy. Med Pediatr Oncol. 1990;18:406.Google Scholar
- 50.Verheij M, Dewit LGH, Valdés Olmos RA, Hoefnagel CA, Arisz L. Captopril Tc-99m-DTPA renography in patients with radiation induced renovascular hypertension. In: Schmidt HAE, Hofer R, editors. Nuclear medicine in research and practice. New York: Schattauer Stuttgart; 1992. p. 545–8.Google Scholar
- 51.Valdés Olmos RA. Radiation nephropathy. In: Valdés Olmos RA, editor. The role of nuclear medicine in the detection of organ injury and adverse effects of cancer therapy. Thesis, University van Amsterdam; 1994. p. 40.Google Scholar
- 54.Galland RB, Spencer J. The natural history of clinically established radiation enteritis. In: Galland RB, Spencer J, editors. Radiation enteritis. London: Edward Arnold; 1990. p. 136–46.Google Scholar
- 56.Fu Q, Berbée M, Boerma M, Wang J, Schmid HA, Hauer-Jensen M. The somatostatin analog SOM230 (pasireotide) ameliorates injury of the intestinal mucosa and increases survival after total-body irradiation by inhibiting exocrine pancreatic secretion. Radiat Res. 2009;171:698–707.CrossRefPubMedPubMedCentralGoogle Scholar
- 58.Valdés Olmos RA. Other tracers in injuries of the digestive tract. In: Valdés Olmos RA, editor. The role of nuclear medicine in the detection of organ injury and adverse effects of cancer therapy. Thesis, University van Amsterdam; 1994. p. 36–7.Google Scholar
- 65.Levi S, Hodgson HJ. The medical management of radiation enteritis. In: Galland RB, Spencer J, editors. Radiation enteritis. London: Edward Arnold; 1990. p. 176–98.Google Scholar