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Guideline Summary
Guideline Title
ACR Appropriateness Criteria® follow-up of Hodgkin's lymphoma.
Bibliographic Source(s)
Ng A, Constine LS, Advani R, Das P, Flowers C, Friedberg J, Hodgson DC, Schwartz CL, Wilder RB, Wilson LD, Yunes MJ, Expert Panel on Radiation Oncology-Hodgkin's Lymphoma. ACR Appropriateness Criteria® follow-up of Hodgkin's lymphoma. [online publication]. Reston (VA): American College of Radiology (ACR); 2010. 10 p. [63 references]
Guideline Status

This is the current release of the guideline.

It updates a previous version: Ng AK, Constine LS, Deming RL, Wolkov HB, Hoppe RT, Abrams RA, Mendenhall NP, Morris DE, Yahalom J, Chauvenet A, Hudson MM, Winter JN, Mauch PM, Expert Panel on Radiation Oncology-Hodgkin's Disease Work Group. Follow-up of Hodgkin's Disease. [online publication]. Reston (VA): American College of Radiology (ACR); 2005. 6 p. [43 references]

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Scope

Disease/Condition(s)
  • Hodgkin's lymphoma
  • Complications of Hodgkin's lymphoma and its treatment
Guideline Category
Evaluation
Management
Prevention
Risk Assessment
Clinical Specialty
Oncology
Radiation Oncology
Radiology
Intended Users
Health Plans
Hospitals
Managed Care Organizations
Physicians
Utilization Management
Guideline Objective(s)

To evaluate the appropriateness of radiologic and other procedures for the follow-up of patients after treatment for Hodgkin's lymphoma

Target Population

Patients with Hodgkin's lymphoma who have completed their treatment and response assessment

Interventions and Practices Considered

Evaluation/Management/Prevention

  1. Interim history and physical examination
  2. X-ray, chest
  3. Computed tomography (CT)
    • Chest, abdomen, and pelvis
    • Neck, chest, abdomen, and pelvis
    • Chest
  4. Fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)/CT
    • Whole body
    • Chest, abdomen, and pelvis (if whole body scan is negative at six months)
  5. Mammography
  6. Magnetic resonance imaging (MRI), breast
  7. Exercise tolerance test and echocardiogram
  8. Laboratory tests
    • Complete blood count (CBC)
    • Erythrocyte sedimentation rate (ESR)
    • Chemistry panel (CHEM)
    • Thyroid panel
    • Lipid profile
  9. Patient education and counseling
Major Outcomes Considered
  • Utility of radiologic examination in the follow-up of Hodgkin's lymphoma
  • Cost-effectiveness of radiologic tests

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

Literature Search Procedure

The Medline literature search is based on keywords provided by the topic author. The two general classes of keywords are those related to the condition (e.g., ankle pain, fever) and those that describe the diagnostic or therapeutic intervention of interest (e.g., mammography, MRI).

The search terms and parameters are manipulated to produce the most relevant, current evidence to address the American College of Radiology Appropriateness Criteria (ACR AC) topic being reviewed or developed. Combining the clinical conditions and diagnostic modalities or therapeutic procedures narrows the search to be relevant to the topic. Exploding the term "diagnostic imaging" captures relevant results for diagnostic topics.

The following criteria/limits are used in the searches.

  1. Articles that have abstracts available and are concerned with humans.
  2. Restrict the search to the year prior to the last topic update or in some cases the author of the topic may specify which year range to use in the search. For new topics, the year range is restricted to the last 5 years unless the topic author provides other instructions.
  3. May restrict the search to Adults only or Pediatrics only.
  4. Articles consisting of only summaries or case reports are often excluded from final results.

The search strategy may be revised to improve the output as needed.

Number of Source Documents

The total number of source documents identified as the result of the literature search is not known.

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Strength of Evidence Key

Category 1 - The conclusions of the study are valid and strongly supported by study design, analysis and results.

Category 2 - The conclusions of the study are likely valid, but study design does not permit certainty.

Category 3 - The conclusions of the study may be valid but the evidence supporting the conclusions is inconclusive or equivocal.

Category 4 - The conclusions of the study may not be valid because the evidence may not be reliable given the study design or analysis.

Methods Used to Analyze the Evidence
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

The topic author drafts or revises the narrative text summarizing the evidence found in the literature. American College of Radiology (ACR) staff draft an evidence table based on the analysis of the selected literature. These tables rate the strength of the evidence for all articles included in the narrative text.

The expert panel reviews the narrative text, evidence table, and the supporting literature for each of the topic-variant combinations and assigns an appropriateness rating for each procedure listed in the table. Each individual panel member forms his/her own opinion based on his/her interpretation of the available evidence.

More information about the evidence table development process can be found in the American College of Radiology (ACR) Appropriateness Criteria® Evidence Table Development document (see "Availability of Companion Documents" field).

Methods Used to Formulate the Recommendations
Expert Consensus (Delphi)
Description of Methods Used to Formulate the Recommendations

Modified Delphi Technique

The appropriateness ratings for each of the procedures included in the Appropriateness Criteria topics are determined using a modified Delphi methodology. A series of surveys are conducted to elicit each panelist's expert interpretation of the evidence, based on the available data, regarding the appropriateness of an imaging or therapeutic procedure for a specific clinical scenario. American College of Radiology (ACR) staff distributes surveys to the panelists along with the evidence table and narrative. Each panelist interprets the available evidence and rates each procedure. The surveys are completed by panelists without consulting other panelists. The ratings are a scale between 1 and 9, which is further divided into three categories: 1, 2, or 3 is defined as "usually not appropriate"; 4, 5, or 6 is defined as "may be appropriate"; and 7, 8, or 9 is defined as "usually appropriate." Each panel member assigns one rating for each procedure per survey round. The surveys are collected and the results are tabulated, de-identified and redistributed after each round. A maximum of three rounds are conducted. The modified Delphi technique enables each panelist to express individual interpretations of the evidence and his or her expert opinion without excessive bias from fellow panelists in a simple, standardized and economical process.

Consensus among the panel members must be achieved to determine the final rating for each procedure. Consensus is defined as eighty percent (80%) agreement within a rating category. The final rating is determined by the median of all the ratings once consensus has been reached. Up to three rating rounds are conducted to achieve consensus.

If consensus is not reached, the panel is convened by conference call. The strengths and weaknesses of each imaging procedure that has not reached consensus are discussed and a final rating is proposed. If the panelists on the call agree, the rating is accepted as the panel's consensus. The document is circulated to all the panelists to make the final determination. If consensus cannot be reached on the call or when the document is circulated, "No consensus" appears in the rating column and the reasons for this decision are added to the comment sections.

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis
  • A cost-effectiveness analysis using Markov modeling techniques questioned the cost-effectiveness of annual computed tomography (CT) follow-up and showed that with adjustment for quality of life, annual CT in early-stage patients is associated with a decrease in quality-adjusted life expectancy.
  • A cost-effectiveness analysis based on 50 patients with unconfirmed complete remission (CRu) or partial response (PR) after first-line therapy showed that the performance of positron emission tomography (PET) in these patients saves costs by limiting the number of patients requiring biopsies, although the comparison may be biased since the assumption was that all patients in CRu/PR will undergo a biopsy if PET is not performed.
  • A cost-effectiveness analysis had suggested that annual low-dose chest CT screening may be a cost-effective strategy among survivors who are smokers.
  • Presence of traditional cardiac risk factors further increases the risk of cardiovascular disease after Hodgkin's lymphoma. One analysis suggests that lipid screening every 3 years would be the most cost-effective strategy in this population.
Method of Guideline Validation
Internal Peer Review
Description of Method of Guideline Validation

Criteria developed by the Expert Panels are reviewed by the American College of Radiology (ACR) Committee on Appropriateness Criteria.

Recommendations

Major Recommendations

ACR Appropriateness Criteria®

Clinical Condition: Follow-up of Hodgkin's Lymphoma

Variant 1: 22-year-old male with stage IIA supradiaphragmatic Hodgkin's lymphoma (ESR 8), treated with ABVD x 4 (PET/CT after 2 cycles) followed by involved-field radiotherapy (IFRT), now 1 month post-treatment.

Procedure Rating Comments
History and physical examination every 2-4 months for 2 years, then every 6 months for 3 years, then yearly 9  
X-ray chest every 6 months for 2 years, then yearly for 3 years 6 Unless chest CT performed.
CT chest abdomen and pelvis every 6 months for 2 years, then yearly for 3 years 7 Frequency of relapse diminishes after 2 years.
FDG-PET/CT whole body every 6 months for 2 years, then yearly for 3 years 2  
FDG-PET/CT whole body at 6 months – if negative then CT chest abdomen and pelvis every 6 months for 2 years, then yearly for 3 years 3 Likely low yield given negative PET/CT after 2 cycles of ABVD.
Laboratory Tests

CBC 1-2 times per year

7  

Chemistry panel 1-2 times per year

No Consensus No data to support performing this test in favorable patients.

Thyroid panel yearly

8 If neck included in RT field.

ESR 1-2 times per year

5  
Patient Education and Counseling

Increased long-term risk of second malignancy and cardiac disease

8  

Regular exercise

9  

Healthy diet

9  

Smoking cessation if current smoker

9  
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 2: 28-year-old female with stage IIBX supradiaphragmatic Hodgkin's lymphoma (ESR 30), treated with ABVD x 6 (residual PET avidity after 2 cycles of ABVD, avidity resolved after 6 cycles of ABVD) followed by IFRT, now 1 month post-treatment.

Procedure Rating Comments
History and physical examination every 2-4 months for 2 years, then every 6 months for 3 years, then yearly 9  
X-ray chest every 6 months for 2 years, then yearly 6 Unless chest CT performed.
CT chest abdomen and pelvis every 6 months for 2 years, then yearly for 3 years 8  
FDG-PET/CT whole body every 6 months for 2 years, then yearly for 3 years 2  
FDG-PET/CT whole body at 6 months – if negative then CT chest abdomen and pelvis every 6 months for 2 years, then yearly for 3 years 5  
Laboratory Tests

CBC 1-2 times per year

8  

Chemistry panel 1-2 times per year

No consensus No data to support performing this test in favorable patients.

Thyroid panel yearly

8 If neck included in RT field

ESR 1-2 times per year

7  
Patient Education and Counseling

Increased long-term risk of second malignancy and cardiac disease

9  

Monthly self-breast examination

9  

Regular exercise

9  

Healthy diet

9  

Smoking cessation if current smoker

9  
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 3: 68-year-old male with stage IA Hodgkin's lymphoma with right cervical involvement (ESR 12), treated with ABVD x 4 (PET/CT after 4 cycles) followed by IFRT, now 1 month post-treatment.

Treatment Rating Comments
History and physical examination every 2-4 months for 2 years, then every 6 months for 3 years, then yearly 9  
X-ray chest every 6 months for 2 years, then yearly 6 Unless chest CT performed.
CT neck chest abdomen and pelvis every 6 months for 2 years, then yearly for 3 years 7  
FDG-PET/CT whole body every 6 months for 2 years, then yearly for 3 years 2  
FDG-PET/CT whole body at 6 months – if negative then CT chest abdomen and pelvis every 6 months for 2 years, then yearly for 3 years 3  
Laboratory Tests

CBC 1-2 times per year

7  

Chemistry panel 1-2 times per year

No Consensus No data to support performing this test in favorable patients.

Thyroid panel yearly

8  

ESR 1-2 times per year

5  
Patient Education and Counseling

Increased long-term risk of second malignancy and cardiac disease

8  

Regular exercise

9  

Healthy diet

9  

Smoking cessation if current smoker

9  
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 4: 32-year-old female with history of stage IIA Hodgkin's lymphoma with left neck and mediastinal involvement, treated with ABVD x 4 followed by IFRT completing treatment 5 years ago.

Treatment Rating Comments
History and physical examination yearly 9 Including thyroid examination and breast examination.
X-ray chest yearly 5 Unless chest CT performed.
CT chest abdomen and pelvis yearly 3  
Screening exercise tolerance test and echocardiogram only if symptomatic 6 Screening intervals depending on mediastinal irradiation, adriamycin dose, other risk factors, and findings at the baseline screening.
Screening exercise tolerance test and echocardiogram beginning 5 years after treatment 5 Screening intervals depending on mediastinal irradiation, adriamycin dose, other risk factors, and findings at the baseline screening.
Screening exercise tolerance test and echocardiogram beginning 10 years after treatment 6 Screening intervals depending on mediastinal irradiation, adriamycin dose, other risk factors, and findings at the baseline screening.
Mammography yearly beginning 8-10 years after treatment 8  
Mammography and MRI breast yearly beginning 8-10 years after treatment 7  
CT chest yearly beginning 5 years after treatment 2 For lung cancer screening.
CT chest yearly beginning 5 years after treatment only if smoker or smoking history No consensus Lack of data.
Laboratory Tests

CBC yearly

No consensus Lack of data.

Chemistry panel yearly

No consensus No data to support performing this test in favorable patients.

Thyroid panel yearly

8  

Lipid profile every 1-3 years

8  
Patient Education and Counseling

Increased long-term risk of second malignancy and cardiac disease

9  

Monthly self-breast examination

7  

Regular exercise

9  

Healthy diet

9  

Smoking cessation if current smoker

9  
Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Summary of Literature Review

Routine follow-up evaluation of patients after treatment for Hodgkin's lymphoma serves several functions. Detection of relapse is the most important in the first 5 years after treatment. Beyond 5 years, the focus is on monitoring for late effects of therapy.

Detection of Relapse

Hodgkin's lymphoma remains the main cause of patient death during the first 10 to 15 years of follow-up. Routine follow-up studies are used to detect relapsed disease so that salvage therapy can be instituted in a timely manner.

The majority of relapses occur within the first 5 years of treatment. As part of follow-up to detect recurrences in addition to interim history (Hx) and physical examination (PE), radiographic tests that have been advocated include chest x-ray (CXR), computed tomography (CT), and functional imaging, including position emission tomography (PET). Blood work commonly performed includes complete blood count (CBC), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), serum copper, and chemistry panel (CHEM).

Interim Hx appears to be the most valuable follow-up tool in detecting relapse of Hodgkin's lymphoma. In their review of early-stage Hodgkin's lymphoma patients treated at Stanford, a group of researchers found that 55% (59 of 107) of the detected relapses were discovered on the basis of the Hx, with the most commonly reported symptom being a new lump, followed by constitutional symptoms (fever, night sweats, weight loss) and pain. In a series from Christie Hospital in Manchester, England, a study found that 81% (30 of 37) of relapses were diagnosed in patients who reported symptoms, with the most common symptoms being a new lump, followed by cough, night sweats, and weight loss. One study from Canada found that 45% (10 of 22) of relapses stemmed from patient concerns and 18% (4 of 22) from physician concerns. PE also plays an important role. In the Stanford series, 14% (15 of 107) of the relapses were detected by PE. In the Manchester series, 5% (2 of 37) of relapses were detected by PE. CXR is also useful in detecting recurrence of Hodgkin's lymphoma. In the Stanford series, 23% (24 of 107) of relapses were detected by CXR. In the Manchester series, 5% (2 of 37) of relapses were detected by CXR. In the series from Canada, 18% (4 of 22) of relapses were detected by CXR.

Limited data are available on the role of routine blood work in detecting relapses. In the Stanford series, only one relapse was detected by an elevated ESR. CBC, CHEM, and serum copper did not detect any relapse. In the series from Canada, abnormal laboratory findings picked up the same number of relapses as CT scans (2 of 22, 9%) though at a lower cost.

CT scan is routinely included in the follow-up of Hodgkin's lymphoma patients. In contrast, a more recent study from University of Pennsylvania that included 40 patients with relapsed lymphoma (23 were Hodgkin's lymphoma), 22 (55%) relapses were detected with surveillance imaging and 18 (45%) were detected by clinical findings. Whether early radiographic detection of asymptomatic relapses has an impact on survival, however, is unknown. A study from Memorial Sloan-Kettering Cancer Center identified 94 patients with relapsed Hodgkin's lymphoma and determined that in 36 patients (38%) the relapses were detected by asymptomatic surveillance scans, and in 58 patients (62%) the relapses were diagnosed based on clinical symptoms or findings. The prognostic risk group distribution at relapse was comparable between the two groups. Furthermore, at a median follow-up of 7.4 years, there were no significant differences in 5-year failure-free survival (58.4% vs 59.3%, P=0.9) and overall survival (62.4% vs 73.3%, P=0.6) between patients with asymptomatic relapses detected by surveillance scans and those with clinically evident relapses. A cost-effectiveness analysis using Markov modeling techniques questioned the cost-effectiveness of annual CT follow-up and showed that with adjustment for quality of life, annual CT in early-stage patients is associated with a decrease in quality-adjusted life expectancy.

Functional imaging studies, in particular PET, are increasingly performed as part of follow-up. Most of the initial studies focused on the effectiveness of post-therapy functional imaging in predicting relapses, showing that PET has a higher specificity than CT in predicting relapses. The superior specificity of PET compared with conventional imaging methods in these studies reflects the ability of PET to detect active disease in abnormal residual masses on CT post-treatment. These results suggest that PET may be a useful test for baseline evaluation after first-line therapy and can help identify patients with active residual disease in whom further therapy may be needed. A cost-effectiveness analysis based on 50 patients with unconfirmed complete remission (CRu) or partial response (PR) after first-line therapy showed that the performance of PET in these patients saves costs by limiting the number of patients requiring biopsies, although the comparison may be biased since the assumption was that all patients in CRu/PR will undergo a biopsy if PET is not performed.

Limited data are available for addressing the utility of PET as part of routine follow-up imaging. In the revised response criteria for malignant lymphoma published in 2007, it was stated that there were insufficient data at that time to recommend PET as routine follow-up in lymphoma patients. More recent studies evaluated the use of surveillance PET after an initial negative post-treatment PET, and yielded somewhat conflicting results. One study prospectively followed 421 patients (160 with Hodgkin's lymphoma) who had a negative post-treatment baseline PET. Patients underwent PET scans every 6 months for the first 2 years, and then annually after 2 years. In the 160 Hodgkin's lymphoma patients, 51 relapses were detected at a mean follow-up of 41 months (41 based on positive PET, 11 inconclusive on PET). Fourteen (27%) of the relapses were missed by CT, and 16 (31%) were missed by clinical signs or symptoms. The findings led the authors to conclude that PET is a valid tool for follow-up of these patients. Of note, in this study, the detected relapses were mostly in the 35 patients with unfavorable disease, defined as having positive PET findings after 2 cycles of chemotherapy. Twenty-six (74%) of these patients relapsed (12, 12 and 2 relapses picked up at the 6, 12 and 18 months scans, respectively), suggesting that PET follow-up may be of greater value in these high-risk patients. In another study in 94 Hodgkin's lymphoma patients with negative PET findings after therapy, 155 regular follow-up PET scans were carried out in 67 patients, the timing of which was based on the physician's decision. There were 18 cases of positive PET findings, six with confirmed malignancies (five Hodgkin's lymphoma relapses and one lung cancer). The finding that regular follow-up PET scans correctly identified tumor in only 6 (3.9%) of the 155 PET studies led the authors to conclude that regular follow-up with PET scans in PET-negative patients at the end of therapy is not indicated. However, in patients with clinical findings suspicious for relapse, PET scan may be of value.

In a study from the Dana-Farber Cancer Institute on 45 Hodgkin's lymphoma patients with a negative PET scan after therapy, patients were followed with CT or PET/CT at regular intervals. The surveillance imaging detected four asymptomatic relapses, all of which had CT or corresponding CT abnormalities. In addition, 14 (31%) patients had false-positive findings leading to additional scans or biopsies. It was therefore concluded that PET had no clinical utility in the surveillance of patients with Hodgkin's lymphoma in remission.

Investigators from Stanford University reported on their experience with surveillance PET/CT in 113 Hodgkin's lymphoma patients after a complete response to primary therapy. A total of 326 surveillance PET/CT scans were performed within the first 5 years after treatment. Among the 30 positive scans, 14 were true positives, yielding a positive predictive value of only 47% and an overall recurrence detection rate with PET/CT of 4%. Moreover, 86% of the relapses occurred in the first year. Although 75% of the PET/CT-detected relapses were in asymptomatic patients, the impact of early detection of asymptomatic relapse on salvage outcome is not clear. These data therefore also do not support the routine use of PET/CT surveillance, especially beyond the first year.

Detection of Second Malignancies

Numerous studies have demonstrated that patients who survive Hodgkin's lymphoma are at increased risk for second neoplasms. Solid tumors comprise the majority of cases of second malignancies, with the most common ones being breast cancer and lung cancer.

Breast cancers after Hodgkin's lymphoma typically occur after a long latency of 10 to 15 years. They are associated with young age at irradiation, and premature menopause has a protective effect. A significant radiation dose-response relationship has been demonstrated, and recent studies also showed a significant relationship between breast cancer risk and radiation field size.

Mammography has been shown to be an effective tool for screening even among these young women. In one study, 81% of 37 women with breast cancer after Hodgkin's lymphoma had mammographic abnormalities of a mass and/or microcalcifications. Another study prospectively evaluated the utility of mammography in 90 female survivors of Hodgkin's lymphoma. During the study period, 10 women developed 12 breast cancers, all of which were evident on mammogram. The high frequency of mammographically detected abnormalities supports the value of mammographic screening in these patients. In a study on breast cancer after Hodgkin's lymphoma, the authors found that the proportion of patients with early-stage breast cancer was higher in cases that were diagnosed after 1990, which may be due to the more frequent use of mammography screening in the more recent era.

A study from Princess Margaret Hospital performed annual breast cancer surveillance, mostly with mammography, in 100 female survivors of Hodgkin's lymphoma. With 855 person-years of follow-up, 12 cases of breast cancer were diagnosed; seven presented with palpable mass (four with negative mammogram in the preceding 6-12 months, one had indeterminate mammogram findings, two had deferred screening) and five were detected by mammogram, four of which were ductal carcinoma in situ detected by calcifications. It was noted that 52% of screened women had moderate to extremely dense breast tissue and that these women were more likely to receive adjuvant breast magnetic resonance imaging (MRI).

Similarly in a Stanford study 99 mammograms of female Hodgkin's lymphoma survivors were secondarily reviewed, and 60% were noted to have high-density breast tissue, which was also associated with a higher frequency of recall for further imaging.

Breast MRI has been shown to have a higher sensitivity than mammography in genetically predisposed women. The American Cancer Society recommends annual breast MRI as an adjunct to mammogram screening in women who had received therapeutic radiation to the chest at age 30 or younger. Similarly, in the American College of Radiology (ACR) practice guideline for MRI of the breast, one of the indications for MRI screening included a history of mantle irradiation for Hodgkin's lymphoma. However, these recommendations are expert consensus-based rather than direct evidence-based.

Lung cancer is another well-documented second malignancy after Hodgkin's lymphoma. In addition to radiation therapy, prior chemotherapy exposure (alkylating agents in particular) significantly increases the lung cancer risk in a dose-dependent manner. Several studies showed that tobacco use further adds to the risk of lung cancer after Hodgkin's lymphoma. In a case-control study, survivors of Hodgkin's lymphoma who did not have more than 5 Gy of radiation exposure and had never been exposed to alkylating agents had a seven-fold greater risk of lung cancer than survivors who had been treated with radiation therapy and alkylating agents. However, among those with the treatment exposures as well as tobacco exposure, there was a 49-fold increased risk, suggesting a multiplicative interaction between the alkylating agents and/or radiation with tobacco use. Unlike breast cancer, the prognosis of lung cancer after Hodgkin's lymphoma is poor, with a median survival of only about 1 year. Given the significantly increased risk of lung cancer after Hodgkin's lymphoma, especially among smokers, and the associated poor prognosis, there may be a potential role for screening and early detection of lung cancer in high-risk survivors. A cost-effectiveness analysis had suggested that annual low-dose chest CT screening may be a cost-effective strategy among survivors who are smokers.

Detection of Nonmalignant Late Effects of Treatment

A number of studies have shown that patients who have been cured of the Hodgkin's lymphoma are at significantly increased risk of death from cardiac disease compared with the normal population.

A wide spectrum of radiation-induced cardiovascular disease has been identified in asymptomatic survivors of Hodgkin's lymphoma, including pericardial disease, coronary artery disease, cardiomyopathy, valvular disease, arrhythmia, and autonomic dysfunction.

The major contributor to the excess risk of cardiac mortality after Hodgkin's lymphoma is coronary artery disease, accounting for two-thirds of all cases of fatal cardiac events in survivors of Hodgkin's lymphoma. The main risk factor is mediastinal irradiation, and a dose-response relationship has been shown. Presence of other traditional cardiac risk factors further increases the risk of cardiovascular disease after Hodgkin's lymphoma. There may be a role for screening for and treatment of modifiable cardiac risk factors. An analysis by a group of authors suggests that lipid screening every 3 years would be the most cost-effective strategy in this population.

The Stanford group prospectively evaluated the role of cardiac screening in asymptomatic Hodgkin's lymphoma survivors with Hx of mediastinal irradiation. A total of 294 patients at a median of 15 years post-treatment were included. In the first publication of the study, the prevalence of valvular abnormalities was found to increase significantly with increasing follow-up time, most of which were rarely picked up by auscultation. Based on the findings, it was estimated that the number of echocardiography screenings needed to identify a candidate for endocarditis prophylaxis decreased dramatically with time following irradiation: 13 for patients at 2 to 10 years, 4 for those at 11 to 20 years, and 1.6 for those more than 20 years, suggesting that echocardiography screening may be beneficial, particularly in those who received their radiation treatment >10 years earlier. However, the optimal screening interval is unclear, and likely needs to be individualized based on treatment-related and host-related cardiac risk factors.

The same group subsequently reported on the high prevalence of diastolic dysfunction based on the screening, with increased incidence for those who are older, for those who have hypertension, diabetes, or wall motion abnormalities, and for those with a longer latency period from radiation treatment to screening. For patients who had completed radiation therapy 11 to 20 years earlier and >20 years earlier, 15% and 23%, respectively, had mild to moderate diastolic dysfunction. Furthermore, the presence of diastolic dysfunction was significantly associated with increased risk of deaths or events due to coronary artery disease. In the most recent report from the same group 14% were found to have perfusion defects, impaired wall motion, or both on stress testing. Based on the results, 40 patients (14%) underwent coronary angiography. The angiography showed >50%, <50%, and no stenosis in 55%, 22.5%, and 22.5% of patients, respectively. As a result of the screening, seven of these asymptomatic patients (2.4%) underwent bypass graft surgery. In addition, 23 patients (8%) subsequently developed coronary events during a median of 6.5 years of follow-up, including 10 cases of acute myocardial infarctions. Of note, the median dose to the mediastinum among patients included in this Stanford screening study was 44 Gy (range, 35-54.6 Gy), which are doses that are considerably higher than those used in current practice.

In a prospective cardiac screening study, the incidence of asymptomatic cardiac disease in 48 survivors of childhood Hodgkin's lymphoma was reported. The median age of the study population at the time of initial therapy was 16.5 years, and the median dose received was 40 Gy. The median follow-up time was 14.3 years. On echocardiogram, 42% were found to have significant valve defects, 75% had conduction defects, and 22% had echocardiographic changes suggestive of restrictive cardiomyopathy. Aortic regurgitation was found to be associated with a decreased physical component score (PCS) on the SF-36 test (r = –.371, P=.011). A decreased peak myocardial oxygen uptake during exercise (VO2max), a predictor of mortality in heart failure, was associated with increased fatigue (r = –.35, P=.02), increased shortness of breath (r = –.35, P=.02) and decreased PCS (r = .554, P=.00017). These findings suggest that late effects of treatment can contribute to the increased fatigue level seen in long-term Hodgkin's lymphoma survivors. In addition, in survivors with symptoms of fatigue, evaluation for underlying cardiac disease should be considered.

Noncoronary artherosclerotic disease has also been identified in long-term Hodgkin's lymphoma survivors. In a childhood cancer survivor study, compared to siblings, the relative risk of stroke in Hodgkin's lymphoma survivors treated with mantle irradiation was 5.6. However, the absolute excess risk was only 109.8 per 100,000 person-years (or one case per 100 patients followed for 10 years). It was estimated that at least 982 carotid duplex screening ultrasound examinations need to be performed to prevent a stroke, and it is concluded that there was no role for such screening. One study found a significant dose-response relationship for noncoronary artherosclerotic disease in Hodgkin's lymphoma survivors. The median doses to the low neck in patients with or without subclavian stenosis were 44 Gy and 36 Gy (P=0.002), respectively. Smoking and diabetes were also found to be associated with an increased risk of noncoronary artherosclerotic disease. In a cohort study, Hodgkin's lymphoma survivors at a median of 17.5 years out from treatment had a 2.2-fold increase in risk of stroke and a 3.1-fold increase in risk of transient ischemic attack compared to the normal population. However, similar to the National Cancer Institute's Childhood Cancer Survivor Study, the absolute excess risk was also low, at 9-12 per 10,000 person-years (0.9-1.2 cases per 100 patients followed for 10 years). Because of its rarity, it was also concluded that screening for carotid disease in this population is not indicated.

Irradiation to the upper mediastinum and low neck can result in thyroid abnormalities. An analysis of patients treated for Hodgkin's lymphoma at Stanford demonstrated that the 20-year actuarial risk of thyroid abnormality was 50%, with 90% of the cases being hypothyroidism. Fifty-seven percent of patients with primary hypothyroidism had subclinical disease detected by an elevated serum thyroid-stimulating hormone (TSH) level with a normal FT4 level. The greatest risk of hypothyroidism occurred during the first 5 years after treatment, but new cases continued to emerge beyond 20 years after Hodgkin's lymphoma. In a study among pediatric Hodgkin's lymphoma survivors, risk factors for the development of hypothyroidism included increasing radiation dose, older age at diagnosis, and female gender.

Acute radiation pneumonitis occurs in 3% to 10% of patients after mediastinal irradiation. Lung fibrosis as a late effect can result in chronic shortness of breath and contribute to fatigue symptoms in long-term survivors. In the era of combined-modality therapy, the combination of bleomycin-based chemotherapy with mediastinal irradiation can further potentiate lung toxicity. In a study that prospectively measured the pulmonary function of Hodgkin's lymphoma patients during and after bleomycin-based chemotherapy with or without mediastinal radiotherapy, persistently reduced percentage of predicted carbon monoxide diffusing capacity (%DLCO) at 1 year was significantly associated with radiation dose and a smoking history.

Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), the currently most widely accepted systemic therapy for Hodgkin's lymphoma, does not appear to affect gonadal function. However, the newer, more aggressive regimen — bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) for patients with unfavorable or advanced-stage disease — is associated with a significant risk of continued amenorrhea in women and azoospermia in men. In addition, for patients with infradiaphragmatic Hodgkin’s lymphoma, who comprise 5% to 10% of all early-stage patients, radiation treatment to the pelvis may affect patients' reproductive function. Four to 6 Gy of fractionated radiation therapy to the testes will result in permanent azoospermia in most men. After 8 to 10 Gy of fractionated radiation therapy to the ovaries, most women will develop ovarian failure.

Other late effects of Hodgkin's lymphoma treatment include immunosuppression, fatigue, psychological distress, and social maladaptation. Awareness of the potential consequences of treatment is necessary for physicians conducting patient follow-up to detect problems at the earliest possible time.

Abbreviations

  • ABVD, adriamycin, bleomycin, vinblastine, and dacarbazine
  • CBC, complete blood count
  • CT, computed tomography
  • ESR, erythrocyte sedimentation rate
  • FDG-PET, fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography
  • IFRT, involved-field radiotherapy
  • MRI, magnetic resonance imaging
  • PET, positron emission tomography
  • RT, radiation therapy
Clinical Algorithm(s)

Algorithms were not developed from criteria guidelines.

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The recommendations are based on analysis of the current literature and expert panel consensus.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Selection of appropriate radiologic imaging procedures for follow-up of patients with Hodgkin's lymphoma

Potential Harms

False-positive findings of diagnostic tests lead to additional scans and biopsies.

Qualifying Statements

Qualifying Statements

The American College of Radiology (ACR) Committee on Appropriateness Criteria and its expert panels have developed criteria for determining appropriate imaging examinations for diagnosis and treatment of specified medical condition(s). These criteria are intended to guide radiologists, radiation oncologists, and referring physicians in making decisions regarding radiologic imaging and treatment. Generally, the complexity and severity of a patient's clinical condition should dictate the selection of appropriate imaging procedures or treatments. Only those examinations generally used for evaluation of the patient's condition are ranked. Other imaging studies necessary to evaluate other co-existent diseases or other medical consequences of this condition are not considered in this document. The availability of equipment or personnel may influence the selection of appropriate imaging procedures or treatments. Imaging techniques classified as investigational by the U.S. Food and Drug Administration (FDA) have not been considered in developing these criteria; however, study of new equipment and applications should be encouraged. The ultimate decision regarding the appropriateness of any specific radiologic examination or treatment must be made by the referring physician and radiologist in light of all the circumstances presented in an individual examination.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Living with Illness
Staying Healthy
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Ng A, Constine LS, Advani R, Das P, Flowers C, Friedberg J, Hodgson DC, Schwartz CL, Wilder RB, Wilson LD, Yunes MJ, Expert Panel on Radiation Oncology-Hodgkin's Lymphoma. ACR Appropriateness Criteria® follow-up of Hodgkin's lymphoma. [online publication]. Reston (VA): American College of Radiology (ACR); 2010. 10 p. [63 references]
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
1999 (revised 2010)
Guideline Developer(s)
American College of Radiology - Medical Specialty Society
Source(s) of Funding

The American College of Radiology (ACR) provided the funding and the resources for these ACR Appropriateness Criteria®.

Guideline Committee

Committee on Appropriateness Criteria, Expert Panel on Radiation Oncology--Hodgkin's Lymphoma

Composition of Group That Authored the Guideline

Panel Members: Andrea Ng, MD (Principal Author; Panel Chair); Louis S. Constine, MD (Panel Vice-Chair); Ranjana Advani, MD; Prajnan Das, MD, MPH; Christopher Flowers, MD, MS; Jonathan Friedberg, MD; David C. Hodgson, MD; Cindy L. Schwartz, MD; Richard B. Wilder, MD; Lynn D. Wilson, MD, MPH; Michael J. Yunes MD

Financial Disclosures/Conflicts of Interest

Not stated

Guideline Status

This is the current release of the guideline.

It updates a previous version: Ng AK, Constine LS, Deming RL, Wolkov HB, Hoppe RT, Abrams RA, Mendenhall NP, Morris DE, Yahalom J, Chauvenet A, Hudson MM, Winter JN, Mauch PM, Expert Panel on Radiation Oncology-Hodgkin's Disease Work Group. Follow-up of Hodgkin's Disease. [online publication]. Reston (VA): American College of Radiology (ACR); 2005. 6 p. [43 references]

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site External Web Site Policy.

Print copies: Available from the American College of Radiology, 1891 Preston White Drive, Reston, VA 20191. Telephone: (703) 648-8900.

Availability of Companion Documents

The following are available:

  • ACR Appropriateness Criteria®. Overview. Reston (VA): American College of Radiology; 2 p. Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site External Web Site Policy.
  • ACR Appropriateness Criteria®. Literature search process. Reston (VA): American College of Radiology; 1 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site External Web Site Policy.
  • ACR Appropriateness Criteria®. Evidence table development. Reston (VA): American College of Radiology; 4 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site External Web Site Policy.
Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI on December 15, 2005. The updated information was verified by the guideline developer on January 19, 2006. This NGC summary was updated by ECRI Institute on December 23, 2010.

Copyright Statement

Instructions for downloading, use, and reproduction of the American College of Radiology (ACR) Appropriateness Criteria® may be found on the ACR Web site External Web Site Policy.

Disclaimer

NGC Disclaimer

The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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