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Cutting Back on Computed Tomography Scan Frequency in Curative Oncology: Get the Picture

Erasmus University Medical Center Rotterdam and Rotterdam Cancer Institute, Rotterdam, the Netherlands

Developed in the 1980s, the strategy of surveillance in patients with clinical stage I nonseminoma was built on the assumption that cisplatin-based chemotherapy, if administered at the time of recurrence, would result in survival identical to definitive primary treatment, including primary retroperitoneal lymph node dissection.¹ Studies conducted in the 1980s and 1990s involved a total of more than 2,000 clinical stage I nonseminoma patients. These studies identified the importance of lymphovascular invasion as the main independent prognostic factor for recurrence that discriminates between low risk (15% to 20% relapse, absence of lymphovascular invasion) and high risk (40% to 50% relapse, vascular invasion present). The published data on surveillance have shown that virtually all patients who relapse have low-volume, good-prognosis disease (by International Germ Cell Collaborative Group criteria) at the time of detection.¹ It is rare for a patient to progress to intermediate-/poor-risk disease undetected, unless there have been compliance issues with follow-up examinations. Ninety-five percent of patients who relapse will do so within 2 years, and 99% within 3 to 4 years. The retroperitoneum is usually, but not always, the only site of recurrence. Relapse is frequently first detected by serum tumor marker increase. However, some recurrences are detected only by chest x-rays or computed tomography (CT) scan. Therefore, all follow-up examinations must be performed during surveillance.

Because most recurrences occur within the first 2 years after orchidectomy, the monitoring schedule in surveillance studies originally required monthly clinical and biochemical examinations in the first year, every-other-month examinations in the second year, quarterly in the third year, every 4 months in the fourth year, semiannually in the fifth year, and yearly thereafter. In most studies, chest x-rays were required at the same intervals, and abdominal CT scans were scheduled quarterly in the first year, every 4 months in the second year, and every 6 to 12 months in the years thereafter. Recent reports have assessed the cumulative cancer risk from numerous x-rays or screening CT scans in patients with a high chance of a normal life expectancy.^2,3 However, the number of CT scans required in the monitoring schedule during the initial years of surveillance is still limited, and the benefits of early detection of a potentially lethal disease seem to outweigh those risks.

Another argument for reducing the number of CT scans is the increasing cost of health care and the need for reallocation of health care resources. In the last 20 years, in all European countries, total health care expenditures have grown faster than the gross national product. Governments try to bring down the costs by introducing hospital budget constraints. In the Netherlands, where optimal health care has been provided to its citizens by tradition, in 2005, the Dutch government introduced a case-mix system for reimbursement based on "diagnosis treatment combinations," in which prices are negotiated between health insurers and hospitals.⁴ It is believed by economists that this system will reduce costs by generating competition between hospitals to offer care at the best available rate. In the resulting battle, one may eventually consider to cut back on CT scans, even in the setting of curative oncology.

In this complex area of managing increasing health care costs, the need for optimal allocation of resources—plus the benefit of reducing cumulative radiation exposure—the Medical Research Council in the United Kingdom assessed the optimal number of CT scans during the first 2 years of surveillance in patients with clinical stage I nonseminomatous testis cancer. In this issue of the Journal of Clinical Oncology, the study, led by Rustin et al,⁵ is reported. Patients opting for surveillance were randomly assigned to chest plus abdominal CT scans at either 3 and 12 months or at 3, 6, 9, 12, and 24 months, with all other investigations identical in the two arms. The study was designed to rule out an increase in the proportion of patients relapsing with intermediate- or poor-prognosis disease of more than 3% (with 90% power and 5% significance level, one-sided). Four hundred patients were required. Three of every five patients were allocated to the two-scan schedule to facilitate entry of patients from sites for whom two CT scans had already become standard. A total of 414 patients were randomly assigned from 32 centers. Of these, 90% had no lymphovascular invasion in the primary tumors and were deemed as having low risk of recurrence. With a median follow-up of 40 months, 37 relapses (15%) had occurred in the two-scan arm and 33 (20%) in the five-scan arm. No patients had poor-prognosis disease at relapse, but two of those relapsing in the two-scan arm had intermediate-prognosis disease, compared with one in the five-scan arm. The upper bound of the computed CI was 1.6%, which led the authors to conclude that CT scans at 3 and 12 months after orchidectomy is a reasonable option in surveillance for clinical stage I nonseminoma at low risk for recurrence.

Several critical comments may question the correctness of this conclusion. The investigators used a noninferiority statistical design to test the hypothesis that surveillance by two CT scans was not inferior to surveillance by five CT scans, on the basis of a comparison between the numbers of intermediate-/poor-risk relapses at the time of detection. The transition between good and intermediate-/poor-risk nonseminoma, though, is directed merely by serum marker concentrations (intermediate prognosis), or the presence of nonpulmonary visceral metastasis (poor prognosis).⁶ It is thus very unlikely that this end point can be used as the primary measure to guide us in determining whether intervals between CT scans can be increased. The size of retroperitoneal nodal disease at the time of detection, which would better reflect the impact of postponing reassessment CT scans, was used only as a secondary end point. Although the mean size of nodal disease is reported in the article, it is difficult to interpret the data because most recurrences were detected at the 3-month evaluation point, which was identical between the two arms. It is doubtful that a noninferiority conclusion can be made on the basis on the few patients relapsing in each arm beyond 3 months. Moreover, patients with retroperitoneal nodal disease that grows and remains undetected for several months, which can occur especially in marker-negative tumors, may be at greater risk of a need for postchemotherapy surgery to resect residual disease, which could have been avoided by earlier detection. Postchemotherapy surgery that would be required in just one or two more patients in the study arm would completely nullify any cost savings by the reduced CT scan frequency. It will be extremely difficult to design a trial with a sufficient number of events to determine whether prolonged intervals between repeat CT scans can still be considered optimal surveillance.

Of concern is the apparent lack in the protocol of how to respond to CT findings of small retroperitoneal lymph nodes of uncertain significance. To date, nodal metastatic landing zones in the retroperitoneal area are well defined, and informed clinicians who observe a 5- to 8-mm lymph node in the ipsilateral landing zone recognize that more vigilance may be necessary, as size 5 mm or greater alone suggests disease involvement.^7-9 Such findings will require a repeat CT scan at 6 to 8 weeks rather than at 3 months, and will certainly not permit even greater intervals. Meticulous examination of abdominal CT scans diminishes the risk of missing small, but detectable, retroperitoneal disease, and should be considered the standard of care in surveillance in 2007, irrespective of whether patients are considered at high or low risk for recurrence.

Most guidelines recommend abdominal CT scans for evaluation of the retroperitoneal area during surveillance, and the thorax is examined by chest x-rays. Virtually all pulmonary metastases can by seen on a plain chest x-ray, and the risk of mediastinal nodal disease in the absence of any retroperitoneal lymph nodes is extremely low.^10-13 The radiation exposure of a full-chest plus abdominal CT scan, as was used in the study by Rustin et al, is at least twice that of an abdominal CT. The radiation exposure of a full-chest plus abdominopelvic CT scan, which was also allowed in the study, is at least thrice that of an upper abdominal CT that is confined to the anatomic area of the retroperitoneal landing zone and stops at the level of the aortic bifurcation.^14-18 Hence, at least two or three abdominal CT scans evaluating the area of importance can be performed for one CT chest/abdomen that was studied here for the benefit of reduced radiation exposure. In addition to limiting radiation exposure by confining to the area of anatomic importance, with the advent of increasingly sensitive ultrasound devices, national surveillance guidelines in Europe are acknowledging the use of abdominal ultrasound examinations as an alternative diagnostic modality beyond the second year of surveillance.¹⁹

With the current findings, where do we go from here? In a low risk for recurrence, initial serum tumor marker–positive patient, with a staging CT scan without any suspicion of nodal disease in the ipsilateral retroperitoneal landing zone, one may consider not to do a repeat CT scan within the next 6 or 9 months, as suggested by the authors. Alternatively, one may also omit reassessment chest and pelvic CT scans and keep to the recommended intervals by confining the CT scan to the upper abdomen. In an initially marker-negative patient, and in all cases at high risk of recurrence opting for surveillance, it will be very difficult to confront a patient with a retroperitoneal mass at 12 months, representing potentially lethal disease that could potentially have been detected 6 months earlier. Therefore, the safest option remains keeping to the strict surveillance protocols, with reassessment investigations at regular intervals, as have evolved during the last two decades.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author indicated no potential conflicts of interest.

REFERENCES

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