Medscape: Continuing Medical Education Online
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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at www.medscape.org/journal/jnccn; (4) view/print certificate.
Release date: May 2, 2011; Expiration date: May 2, 2012
Learning Objectives
Upon completion of this activity, participants will be able to:
Compare survival data between different forms of lymphoma
Distinguish recommended screening intervals for imaging studies in cases of lymphoma
Analyze the cost-effectiveness of imaging studies in the surveillance of patients with lymphoma
Evaluate the risk for cancer associated with radiation exposure from imaging studies
Large randomized trials of surveillance methods guide follow-up testing in patients with breast cancer. These studies showed no survival benefit and no impact on health-related quality of life with routine intensive reimaging studies.1,2 Data such as these do not exist for most other cancers, including lymphoma. Consequently, guidelines for lymphoma follow-up are based on limited retrospective analyses and opinion.
The widespread use of CT scans to assess response to lymphoma treatment, along with the recognition that a subset of patients with relapsed lymphoma can be cured with autologous stem cell transplant, led to the adoption of CT for monitoring patients for early relapse. The frequency with which CT was used in the posttreatment setting largely mimicked the interval adopted for routine follow-up visits. A panel of Hodgkin lymphoma experts at the Cotswolds Meeting in 1989 recommended follow-up every 3 months for the first 2 years, followed by 4-month intervals during year 3; 6-month intervals during years 4 and 5; then annually thereafter.3 The panel further advised that “the frequency and type of radiological studies should reflect the initial sites of disease.”
[18F]-fluorodeoxyglucose-(FDG) PET/CT has largely supplanted CT for assessing response at the end of treatment for both Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL). Despite the usefulness of FDG-PET for initial staging and evaluations at treatment completion, its role as a surveillance modality has not been borne out in small retrospective studies.4–8 FDG-PET often can differentiate viable tumor from posttreatment fibrosis or necrosis, adding valuable information to that obtained with CT for response assessment.9 Two meta-analyses support the important prognostic value of FDG-PET performed at the completion of therapy for lymphoma.10,11 The most recent lymphoma response criteria incorporate FDG-PET into the definition of response,12 using criteria established by the International Harmonization Project in Lymphoma (IHP) to interpret end-of-therapy FDG-PET as positive or negative.13
Practice patterns are often driven by habit and reflect a disregard of the available data, with many survivors undergoing routine scans years beyond the expected likelihood of detecting recurrence, whereas others have a limited period of routine imaging despite a constant risk of relapse. The incidence and duration of risk of relapse varies significantly according to lymphoma subtype (Figure 1). In DLBCL, the 2-year progression-free survival (PFS) rate is 65% to 70% with more than 80% of relapses occurring within the first 3 years and only 10% after 5 years.14,15 In contrast, the 2-year PFS rate for follicular lymphoma is approximately 80%, with a relatively constant rate of relapse at 8% to 10% per year, which extends at least 5 to 8 years.16,17 Early-stage Hodgkin lymphoma is associated with a 5-year PFS rate of 86% to 92% depending on risk factors with few patients relapsing beyond 5 years.18,19 In advanced-stage Hodgkin lymphoma, 2- and 5-year failure-free survival (FFS) rates are approximately 70% and 65%, respectively, with 80% to 90% of relapses occurring in the first 2 years.20 Nodular lymphocyte-predominant Hodgkin lymphoma is associated with a continuous rate of relapse even beyond 10 years, with 5- and 10-year PFS rates of 74% and 60%, respectively.21 Based on the patterns of relapse, surveillance imaging in DLBCL and Hodgkin lymphoma is unlikely to be beneficial beyond the first 2 years. In contrast, an intensive monitoring approach for early relapses in indolent lymphomas will only capture a fraction of the total number of relapses.
Relapse patterns in lymphoma.
Abbreviations: DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HL, Hodgkin lymphoma.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 5; 10.6004/jnccn.2011.0048
Relapse patterns in lymphoma.
Abbreviations: DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HL, Hodgkin lymphoma.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 5; 10.6004/jnccn.2011.0048
Relapse patterns in lymphoma.
Abbreviations: DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HL, Hodgkin lymphoma.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 9, 5; 10.6004/jnccn.2011.0048
Retrospective studies show that few relapses are detected with routine scanning and that suspected relapses are frequently not confirmed, resulting in additional unnecessary procedures. Despite the low yield and the low positive predictive value (PPV) associated with routine imaging in lymphoma, many of the current guidelines continue to recommend an intensive surveillance approach. This review summarizes existing guidelines and published data evaluating surveillance scans for lymphoma.
Published Guidelines for NHL
With limited data to support specific imaging recommendations, oncologists turn to expert opinion for guidance.
2011 NCCN Guidelines for DLBCL and Follicular Lymphoma
Probably the most widely followed guidelines in the United States are those provided by NCCN.22 These guidelines recommend:
Repeating all positive studies at end of treatment
Imaging every 3 to 6 months for 5 years, then yearly or as clinically indicated, based on disease site and clinical presentation
2007 European Society of Medical Oncology Guidelines for DLBCL
In contrast to the North American guidelines, the European Society of Medical Oncology (ESMO) specifically advises against routine imaging except to evaluate residual disease.23 These guidelines recommend:
PET scan at end of treatment, if available
Minimal radiologic examinations in patients with DLBCL at 6, 12, and 24 months after end of treatment, when indicated by site of disease
2007 International Working Group Guidelines for Lymphoma
The International Working Group (IWG), a panel of clinicians, radiologists, and pathologists with expertise in the management of non-Hodgkin's lymphoma (NHL), published response criteria for follow-up of malignant lymphoma in 1999 and revised the guidelines in 2007. These guidelines advise that follow-up will vary according to whether treatment was administered in a clinical trial or clinical practice, or whether it was given with curative or palliative intent.24–26 The panel advises against routine imaging given the lack of evidence supporting its role. The 2007 IWG guidelines recommend:
No regular surveillance CT and/or PET procedures
Published Guidelines for Hodgkin Lymphoma
2011 NCCN Guidelines for Hodgkin Lymphoma
NCCN, the American College of Radiology (ACR) Appropriateness Criteria, and ESMO have also published guidelines for follow-up of Hodgkin lymphoma.27–29 NCCN and ACR also include guidelines for imaging studies to detect second malignancies related to prior therapy for Hodgkin lymphoma. These NCCN Guidelines recommend:
Chest imaging (chest radiograph or CT) every 6 to 12 months for the first 2 to 5 years
Abdominal/pelvic CT scans every 6 to 12 months for the first 2 to 3 years (this is a category 2B recommendation, which means that there was lower-level evidence and nonuniform consensus)
Annual chest imaging after 5 years for patients at increased risk for lung cancer (optional for patients who did not receive radiotherapy to the chest, were treated with nonalkylating agents, and have no other risk factors)
Annual breast screening in women to start 8 to 10 years posttherapy or at age 40 years, whichever comes first, if chest or axillary radiation were administered
The American Cancer Society recommends breast MRI for women who received irradiation to the chest between the ages of 10 and 30 years
Surveillance PET scans are not recommended
2010 ACR Appropriateness Criteria Guidelines for Hodgkin Lymphoma
The 2010 ACR Appropriateness Criteria guidelines for Hodgkin lymphoma recommend:
Routine CT imaging in the first 5 years, with more frequent scans in the first 2 years
No routine imaging for recurrences beyond 5 years
Annual mammograms for women irradiated to the chest at a young age (< 35 years)
Consider breast MRI in women irradiated to the chest at a young age (< 35 years)
Consider low-dose chest CT for lung cancer screening in patients with history of mediastinal irradiation, and/or treatment with an alkylating agent, and a smoking history
2007 ESMO Guidelines for Hodgkin Lymphoma
The 2007 ESMO guidelines for Hodgkin lymphoma recommend:
PET scan at end of treatment, if available
No routine CT
A review of the published guidelines highlights the disparate opinions among the various experts, with recommendations ranging from no surveillance scans to obtaining scans every 3 months. Unfortunately, because no prospective data evaluate the risks and benefits of surveillance imaging, the accuracy of the current guidelines is questionable.
Clinical Trial Guidelines
Many community and academic oncologists follow an aggressive surveillance approach, closely patterning the follow-up evaluation requirements outlined in clinical trials. Although the follow-up requirements for many of the clinical trials are similar, with more intense monitoring in the first 2 years, even within the currently accruing Intergroup studies, the follow-up frequency and duration of required scans varies. Uniform reassessment guidelines are essential in clinical trials to ensure comparability of study end points. In standard practice, however, this issue is irrelevant, whereas an understanding of whether routine imaging changes outcome is paramount.
Retrospective Reviews of Surveillance Imaging
Surveillance CT scans offer the prospect of detecting early, asymptomatic relapses, which by virtue of having less tumor burden should be associated with a lower secondary international prognostic index (IPI) score and therefore an improved survival.30 Small retrospective reviews shed light on the practice patterns of clinicians and the yield of routine imaging in the follow-up setting. However, studies evaluating the impact of follow-up CT and PET/CT on survival are lacking. In the pre-CT era, Torrey et al.31 reported that the method of relapse detection in early-stage Hodgkin lymphoma did not have a significant impact on survival. The 10-year actuarial survival rate after salvage therapy was 65% overall, with no significant difference between relapses detected radiographically (chest radiography, kidney-ureter-bladder radiography) and those detected through history or physical examination. As described later, most modern reviews continue to show that the majority of lymphoma relapses are identified through signs or symptoms, regardless of the imaging schedule.
Surveillance CT in DLBCL
In DLBCL, routine CT surveillance imaging is of limited value in detecting asymptomatic relapses, with 80% to 89% of relapses diagnosed by the presence of new signs or symptoms.32–35 Because 25% to 35% of patients experience relapse in new sites only, a targeted screening approach is impractical.32,33 In a retrospective review of 108 patients with relapsed DLBCL treated at Memorial Sloan-Kettering Cancer Center, Liedtke et al.35 reported that patients were 4 times more likely to have low-risk secondary age-adjusted IPI scores if relapse was diagnosed through routine imaging. Patients whose relapse was diagnosed with routine imaging were also 4 times as likely to have chemosensitive disease. A trend was seen toward improved 5-year overall survival in patients with relapse found through routine imaging, but the difference was not statistically significant (54% vs. 43%; P = .13). The mode and precise interval of routine imaging were not described. The authors commented that their observations may be partly the result of lead time or length time bias, with the explanation that faster growing tumors are less likely to be detected with surveillance imaging and inherently have a worse prognosis. This is the only published study to address the outcome of patients detected through surveillance versus symptoms.
Surveillance PET/CT in DLBCL
In a retrospective analysis of surveillance PET/CT in 75 patients with DLBCL, 40 had PET/CT performed because of symptoms, and from these, PET/CT was positive in 23 (53%) and relapse confirmed in 20 (50%).36 Of the 35 asymptomatic patients, 4 had positive PET/CT results and relapse was confirmed in 3. The authors advise against routine use of PET/CT in the follow-up setting and instead advocate a risk-adapted approach, targeting surveillance imaging to patients at highest risk for relapse, including those with advanced age and signs of relapse. These recommendations assume, however, that early detection of relapse will improve survival, which is currently unproven.
Surveillance CT in Indolent Lymphomas
The indolent lymphomas are unique because relapses after modern chemoimmunotherapy, with or without maintenance rituximab, occur at a relatively constant rate for many years after treatment. Therefore, the early intensive screening approaches adopted in Hodgkin lymphoma and DLBCL are less appropriate in these diseases. In addition, a subset of patients with active indolent lymphoma are followed expectantly and the frequency of radiographic reevaluation is undefined. Oh et al.37 retrospectively evaluated the yield of abdominal/pelvic CT in 257 patients with stages I through III follicular lymphoma who experienced a complete response after treatment. The typical follow-up schedule included scans every 3 to 6 months for the first 5 years and yearly thereafter. At a median follow-up of 101 months, 78 (30%) patients relapsed, with most detected through history and physical examination (71%; n = 55) and only 11 (14%) detected solely with CT. The probability of relapse detection was 7% (29/259) through routine abdominal CT and 8% (19/242) through pelvic CT.
Surveillance CT in HL
Similar to DLBCL, retrospective studies show that most patients with Hodgkin lymphoma present with signs or symptoms at relapse, with approximately 65% to 80% of relapses identified by patient symptoms or physical examination findings.38–40 Surveillance imaging infrequently identifies relapse in asymptomatic patients with Hodgkin lymphoma.31,38–41 In a retrospective review of 107 patients with Hodgkin lymphoma, relapse was suspected in 109 instances as a result of patient concerns (42%), physician concerns (26%), radiologic findings (28%), and laboratory abnormalities (4%).38 Of the 22 confirmed relapses, 14 (64%) were identified clinically, 6 (27%) radiologically (2 CT, 4 chest radiograph), and 2 (9%) through laboratory testing. The unconfirmed suspected radiographic relapses stemmed from routine CT in 12, routine chest radiograph in 7, routine gallium scan in 5, and ultrasound in 1. Of 211 routine CT scans performed, only 2 relapses (< 1%) were detected.
A Canadian population-based study of follow-up care among 2071 Hodgkin lymphoma survivors showed that the proportion of patients who had an annual CT remained relatively constant over the first 5 years of follow-up.41 Routine scanning continued in a substantial number of patients beyond 5 years, with 44% undergoing at least 1 CT at 6 to 9 years, and 33% at 10 to 15 years after Hodgkin lymphoma diagnosis. Of the 5353 CT scans performed during years 2 through 5, only 125 (2.3%) patients underwent chemotherapy within 6 months of a CT scan, suggesting a low yield of relapses detected with routine CT.
Surveillance PET/CT in Hodgkin Lymphoma
Several retrospective studies have evaluated the potential role of surveillance FDG-PET/CT in patients with Hodgkin lymphoma.7,8,42–44 In the largest series conducted by investigators at Dana-Farber Cancer Institute (DFCI), 192 patients with a history of Hodgkin lymphoma were retrospectively evaluated to assess the use of surveillance PET/CT and CT scans for detecting recurrent disease or secondary malignancy.42 Of 800 primary surveillance PET/CT (n = 474) and CT (n = 321) scans performed, 62 (7.8%) were positive; 37 of the PET/CT (7.8%) and 10 of the CT (3.1%) scans were false-positive (P = .009); 5 CT scans were excluded for various reasons. PET/CT was not superior to CT in detecting recurrent Hodgkin lymphoma or secondary malignancy, with a PPV of 22.9% versus 28.6%, respectively (P = .73). On univariate analysis, involvement of a previous disease site and the presence of a radiologic abnormality within 12 months improved the PPV. Determining whether routine detection impacted outcome was not possible because of the small number of events.
In another series from Stanford evaluating PET/CT in 113 patients with a history of Hodgkin lymphoma, 326 PET/CT scans were performed and 30 (9.2%) patients had one or more positive scans.7 Only 14 of the 30 patients with positive scans experienced relapse (PPV of 47%), with 86% of these occurring within the first year. Salvage with chemotherapy and autologous stem cell transplantation was successful in all patients.
In a retrospective analysis of 134 patients with Hodgkin lymphoma in confirmed or unconfirmed complete remission who received one or more follow-up PET/CT scans after front-line therapy, Petrausch et al.44 reported a PPV of 98%. Similar to other studies, 76% of the relapses were detected in symptomatic patients. Notably, 25% of patients underwent CT alone at the end of treatment, raising the concern that some of the relapses detected on PET/CT during follow-up may have been present at completion of therapy. In multivariate analysis, the only significant risk factor for relapse in asymptomatic patients was the presence of a residual mass. The retrospective nature of this report and the lack of any description of predetermined guidelines for ordering a PET/CT precludes use of this data to guide recommendations about surveillance PET/CT in Hodgkin lymphoma. The very high PPV of PET/CT may simply reflect physician bias in choosing which patients to scan during follow-up.
Prospective Evaluation of Surveillance PET
In the only prospective study of surveillance imaging, investigators from the University of Bologna evaluated posttreatment FDG-PET in 421 patients with lymphoma, including 160 with Hodgkin lymphoma, 183 with aggressive Hodgkin lymphoma, and 78 with indolent follicular NHL.8 Serial FDG-PET scans were obtained every 6 months for 2 years and then annually thereafter. The incidence of relapse decreased significantly between 12 and 18 months for Hodgkin lymphoma and between 18 and 24 months for aggressive NHL, in contrast to a relatively constant rate of relapse at 4 years for indolent NHL (Table 1). Overall, 1789 PET scans were obtained during the 4-year period and 118 (6.6%) relapses were detected with routine imaging. The false-positive rates for patients with an inconclusive PET and either a suspicious CT scan or a negative CT scan were 33% and 42%, respectively, and were similar for patients with Hodgkin lymphoma, aggressive NHL, and indolent NHL. False-positive test findings were relatively stable over all time points. In summary, the low yield of PET in detecting relapse and the high false-positive rate preclude its widespread application as a surveillance tool.
Incidence of Lymphoma Relapses Detected with Routine Surveillance FDG-PET
Cost-Effectiveness Studies in Hodgkin Lymphoma
Cost-effectiveness analyses performed largely at Harvard University and DFCI argue against the role of surveillance imaging in lymphoma.38,42,45,46 In the retrospective analysis by Lee et al.,42 474 PET/CTs and 321 CTs were performed among 192 patients with Hodgkin lymphoma experiencing complete remission during a median follow-up of 31 months (range, 6–66 months) at Massachusetts General Hospital and DFCI collectively, which accounted for 15 (1.9%) detected events. For the entire population at both hospitals, the estimated primary surveillance expenditure was more than$110,000 to detect one event. The cost of detecting one event using PET/CT was$48,757 among DFCI patients.
A cost analysis performed by Dryver et al.38 determined that although routine CT scans only detected 2 of 22 confirmed Hodgkin lymphoma relapses, the scans accounted for 29% of the total follow-up costs. Most costs were incurred during routine follow-up, as opposed to the costs associated with suspected relapses (84% vs. 16%). Additionally, the high false-positive rate (25/31; 81%) associated with routine CT scans led to needless additional tests and costs to confirm relapse.
Because of a lack of prospective, randomized data evaluating the efficacy of follow-up imaging in lymphoma, investigators from Harvard and DFCI developed a decision analytic model to calculate life expectancy and lifetime costs associated with 3 different follow-up strategies in patients with either early-stage or advanced-stage Hodgkin lymphoma, including annual CT for 10 years, annual CT for 5 years, or follow-up with non-CT modalities only.45 Routine CT imaging for 5 years was associated with costs per life-year gained of $149,000 to $291,500 in the United States for advanced-stage and early-stage Hodgkin lymphoma, respectively. The model was sensitive to a decrease in quality of life associated with a false-positive CT result. With adjustments for quality of life, quality-adjusted life expectancy was decreased for patients with early-stage disease with annual CT for 5 years. For patients with advanced-stage disease, annual CT for 5 years was associated with a very small quality-adjusted survival gain over non-CT follow-up, with an incremental cost-effectiveness ratio of $9,042,300/quality-adjusted life year (QALY).
Screening Studies for Second Cancers
Few studies have evaluated the impact of screening for second malignancies after treatment for lymphoma.
Cost-Effectiveness Study for Screening for Lung Cancer
In contrast to the cost-effectiveness studies on routine screening for Hodgkin lymphoma recurrence, annual screening for lung cancer in Hodgkin lymphoma survivors may provide a survival benefit, which would compare favorably with that of other cancer screening recommendations. A decision analytic model developed by Das et al.46 compared annual low-dose CT lung cancer screening starting 5 years after diagnosis versus no screening in a hypothetical cohort of young patients with early-stage Hodgkin lymphoma. Annual CT screening increased survival by 0.64 years for smokers, with an incremental cost-effectiveness ratio of$34,100/QALY. A recent press release of results from the National Lung Screening Trial (NLST), a multicenter randomized study comparing low-dose spiral chest CT with chest radiograph, reported a remarkable 20% reduction in mortality based on 3 yearly CT scans.47,48 The study was directed at high-risk individuals, defined as current and former heavy smokers between 55 and 74 years of age. How applicable these results will be for a younger population, and moreover for individuals with lymphoma treated with radiotherapy, is unclear. The NLST included cost-effectiveness analyses, and publication of these results is much anticipated.
Breast Cancer Screening
Young women (age < 25 years) with Hodgkin lymphoma treated with chest radiation are at increased risk for developing breast cancer, with an estimated cumulative absolute risk of 1.4%, 16%, and 29% by age 35, 45, and 55 years, respectively.49 Guidelines recommend annual mammography or breast MRI starting 8 to 10 years after mediastinal radiation in women treated between 10 and 30 years of age.27 In a recently published Canadian study evaluating follow-up care in Hodgkin lymphoma survivors, 526 women were eligible for Hodgkin lymphoma–specific breast cancer screening and only 22% had evidence of receiving the recommended early-onset screening.41 Women who were followed up only by a primary care physician were significantly less likely to undergo Hodgkin lymphoma–specific breast cancer screening (odds ratio, 0.14), highlighting the importance of patient and physician education.
Radiation Risks
The risks related to radiation exposure with routine follow-up imaging are often ignored. Unlike health care workers exposed to radiation who are restricted to 100 millisieverts (mSv) every 5 years, with a maximum of 50 mSv allowed in any given year, patients do not have monitoring requirements or exposure guidelines.50–52 A recent New England Journal of Medicine article highlighted the magnitude of the problem, with estimates of moderate (> 3–20 mSv), high (> 20–50 mSv), and very high (> 50 mSv) annual effective doses of radiation incurring in 194, 19, and 2 nonelderly adults, respectively, per 1000 enrollees per year among 950,000 adults accessing 5 health care markets in the United States.53 The average effective dose for CT of the neck, chest, abdomen, and pelvis is 24 mSv, whereas that of an FDG-PET is 14.1 mSv.54,55 Lee et al.42 retrospectively evaluated the radiation exposure in 192 patients with Hodgkin lymphoma in first remission. The average radiation exposure was 39.65 mSv per PET/contrast-enhanced CT scan and 33.64 mSv per CT scan. Patients were exposed to approximately 146.6 mSv during the follow-up period.
A growing body of literature suggests that radiation exposure, similar to that encountered with CT, may increase the risk of malignancy, with 0.4% to 2% of all cancers in the United States estimated to be attributable to CT scans.56,57 Shenoy et al.58 compared the estimated lifetime cancer incidence attributable to radiation exposure from full-body CT for staging and surveillance of Hodgkin lymphoma and NHL with the cumulative probability of lymphoma death during surveillance. Not surprisingly, the lifetime cancer incidence associated with radiation exposure was much higher in younger patients compared with older patients, but markedly less than the cumulative probability of death from lymphoma within 5 years. Young women had the highest risk of radiation-related lifetime cancer mortality risk. Longitudinal studies are needed to better ascertain the risks associated with radiation exposure in patients with lymphoma undergoing surveillance imaging.
Important Considerations
Approaches to follow-up should reflect the unique relapse patterns observed in the various lymphoma subtypes.
Existing guidelines should clearly state that no prospective trials are available to guide recommendations for routine imaging in asymptomatic individuals and that retrospective studies show that most relapses are symptomatic, even in patients undergoing active surveillance.
Proceeding with surveillance imaging must be balanced with the incurred cost expenditures and the increased risks associated with radiation exposure.
Although PET/CT is superior to CT imaging for assessing response at the end of treatment, the role of PET/CT for long-term follow-up is not supported by the modest available retrospective and prospective data.
Large randomized controlled studies are needed to determine if routine surveillance scans result in improved outcomes for patients with lymphoma.
Conclusions
Available data do not convincingly show a therapeutic advantage for routine imaging in patients with lymphoma. Surveillance CT and PET/CT yield a low rate of detection of recurrence, and suspected relapses are frequently not confirmed, leading to needless downstream testing and patient anxiety because of false-positive results. When considering cost-effectiveness and increased risk secondary to radiation exposure, current imaging guidelines must be questioned. The small number of events detected from the mostly retrospective series precludes an overall assessment of whether early detection of relapse may impact outcome. Analyzing large databases may address these concerns. Ultimately, randomized studies are needed to answer questions regarding the role of routine imaging in lymphoma. A national surveillance study comparing routine imaging versus routine care without imaging, similar to those conducted in breast cancer, is justified and would be an excellent expenditure of resources.
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