Abstract
Background
Whether current postoperative surveillance regimes result in improved overall survival (OS) of patients with extremity sarcomas is unknown.
Questions/purposes
We hypothesized that a less intensive followup protocol would not be inferior to the conventional followup protocol in terms of OS. We (1) assessed OS of patients to determine if less intensive followup regimens led to worsened survival and asked (2) whether chest radiograph followup group was inferior to CT scan followup group in detecting pulmonary metastasis; and (3) whether less frequent (6-monthly) followup interval was inferior to more frequent (3-monthly) followup in detecting pulmonary metastasis and local recurrence.
Methods
A prospective randomized single-center noninferiority trial was conducted between January 2006 and June 2010. On the basis of 3-year survival of 60% with intensive, more frequent followup, 500 nonmetastatic patients were randomized to demonstrate noninferiority by a margin (delta) of 10% (hazard ratio [HR], 1.36). The primary end point was OS at 3 years. The secondary objective was to compare disease-free survival (DFS) (time to recurrence) at 3 years. At minimum followup of 30 months (median, 42 months; range, 30–81 months), 178 deaths were documented.
Results
Three-year OS and DFS for all patients was 67% and 52%, respectively. Three-year OS was 67% and 66% in chest radiography and CT groups, respectively (HR, 0.9; upper 90% confidence interval [CI], 1.13). DFS rate was 54% and 49% in chest radiography and CT groups, respectively (HR, 0.82; upper 90% CI, 0.97). Three-year OS was 64% and 69% in 6-monthly and 3-monthly groups, respectively (HR, 1.2; upper 90% CI, 1.47). DFS was 51% and 52% in 6-monthly and 3-monthly groups, respectively (HR, 1.01; upper 90% CI, 1.2). Almost 90% of local recurrences were identified by patients themselves.
Conclusions
Inexpensive imaging detects the vast majority of recurrent disease in patients with sarcoma without deleterious effects on eventual outcomes. Patient education regarding self-examination will detect most instances of local recurrence although this was not directly assessed in this study. Although less frequent visits adequately detected metastasis and local recurrence, this trial could not conclusively demonstrate noninferiority in OS for a 6-monthly interval of followup visits against 3-monthly visits.
Level of Evidence
Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Introduction
Sarcomas (bone and soft tissue) are rare tumors, accounting for < 1% of all adult malignancies. The majority of primary sarcomas occur in the extremities. The ultimate determinant of survival in patients with sarcomas is whether they develop distant metastasis [22]. After treatment of the primary sarcoma, 40% to 50% of the patients will develop either local or distant recurrent disease or both [22]. With improved patient survival, followup surveillance strategies are becoming increasingly important with considerable clinical and fiscal implications. However, the ideal postoperative protocol, particularly the frequency of followup and appropriate screening modalities for these uncommon neoplasms, remains ill defined [8, 10, 18]. Current guidelines are not based on high-quality evidence [10, 18]. Current postoperative surveillance regimes are empirical and vary widely from center to center [8, 9, 18]. Even consensus guidelines lack definite recommendations [20]. Routine postoperative followup in most high-volume centers includes a rather intensive regime both in terms of frequency and the modality of screening for recurrent disease. Whether an increased frequency of followup visits and the use of various expensive imaging modalities for screening and early detection of recurrence actually result in improving overall survival of patients with extremity sarcomas is a question that remains as yet unanswered [8]. The additional radiation exposure to the patient resulting from repeated imaging undertaken for surveillance is also a matter of concern [2]. The financial costs incurred by surveillance are considerable and this includes both the cost to the health service and to the patient in terms of hospital visits and lost working days [9, 19]. This is relevant in both resource-challenged societies where patients often travel long distances to access specialized health care and developed countries that are facing increasing healthcare budgetary constraints. In an increasingly “cost-conscious” healthcare scenario, allocation of limited health funding is best guided by evidence-based recommendations rather than empirical beliefs [18, 19]. A well-designed prospective trial to evaluate the impact of followup strategies on disease outcomes would help develop an evidence-based surveillance schedule [1, 8, 9].
We therefore performed a randomized trial (Trial for Optimal Surveillance in Sarcomas [TOSS]) to test our hypothesis that a less intensive, followup protocol would be noninferior to the conventional followup protocol in terms of overall survival in patients operated on for extremity sarcoma. We (1) assessed the overall survival of patients on these regimens to assess if the less intensive followup regimens led to worsened survival. We also asked (2) whether a chest radiograph followup group was inferior to a CT scan followup group in terms of detecting pulmonary metastasis; and (3) whether a less frequent (6-monthly) followup interval was inferior to a more frequent (3-monthly) followup group in terms of detecting pulmonary metastasis and local recurrence in patients treated surgically for a sarcoma.
Patients and Methods
The study was designed as a prospective randomized noninferiority trial and was conducted at a single tertiary cancer center with a high volume of sarcoma surgery between January 2006 and June 2010. The trial was approved by the institutional review board and all patients provided written informed consent. The study was conducted in accordance with the guiding principles of the Declaration of Helsinki. The trial was registered with Clinical Trials.gov (NCT 00384735). This study was funded by an intramural hospital grant facilitated by the Terry Fox Foundation.
Patients
All patients with histologically proven extremity sarcoma presenting to our hospital were considered for the trial. Patients fulfilling the inclusion criteria and giving voluntary consent after appropriate counseling were enrolled in the study. Eligible participants were all patients (up to 65 years of age) operated on for primary or recurrent extremity sarcomas (both limb salvage and amputations) who were without metastases at presentation. Patients who expressed uncertainty on counseling as to whether they would be able to followup at the requisite intervals either as a result of financial or logistic reasons were excluded from the trial. A total of approximately 1200 nonmetastatic extremity sarcomas operated during this period were eligible for the trial of which 500 were recruited. The inability of the patient to offer an assurance that they would regularly followup (as necessitated by the randomization) was one of the major reasons for not recruiting all eligible patients because we felt that too large a number of such patients would compromise the quality of data. Neoadjuvant and adjuvant radiotherapy and chemotherapy were offered to patients according to the existing hospital protocol.
Trial Design
We randomized patients in a two-by-two factorial design (based on the nature of investigations: intensive using CT scan of the thorax versus less intensive using only chest radiography and frequency of followup: 3- versus 6-monthly visits) using computer-generated random permuted blocks. Patients were thus randomized into one of four groups: CT × 3-monthly visits, CT × 6-monthly visits, chest radiography × 3-monthly visits, and chest radiography × 6-monthly visits.
Stratification was done for (1) origin (bone versus soft tissue); (2) presentation (primary versus recurrent); (3) tumor size (cutoff 8 cm for bone and 10 cm for soft tissue sarcomas); (4) histopathological tumor grade (high versus low grade); and (5) adjuvant chemotherapy (for soft tissue sarcomas).
Central telephonic randomization was done by staff at the Clinical Research Secretariat (trials unit) of the institution, thereby ensuring allocation concealment. Investigators, patients, and outcome assessors were not blinded to the study group assignments.
All patients had a detailed clinical examination on every followup. In the CT followup group, imaging included a chest radiograph and appropriate local imaging at every followup. A CT scan of the chest was done 6-monthly. The CT followup group was further divided based on frequency of followup visits: CT × 3-monthly visits in which patients were scheduled for followup 3-monthly for the first 2 years and 6-monthly for the next 3 years and CT × 6-monthly visits in which patients were scheduled for followup 6-monthly for all 5 years. In the chest radiograph followup group, imaging included only a chest radiograph and appropriate local imaging at every followup. The chest radiography group was similarly divided into chest radiograph × 3-monthly visits and chest radiograph × 6-monthly visits based on frequency of followup visits.
Patients were counseled to followup regardless of their group allocation if they had clinical symptoms suggestive of disease relapse. If recurrence was suspected on clinical evaluation or imaging, patients were investigated further and treated appropriately. Data regarding disease relapse (local or distant) were identified and classified as symptomatic presentation/clinically diagnosed/diagnosed on imaging. Subsequent followup visits were scheduled according to their original randomization.
Evaluation and Outcomes and Statistical Analysis
The primary objective was to show noninferiority in 3-year overall survival of the less intensive (chest radiography-based) followup group to the intensive (CT scan-based) followup group and that of the less frequent (6-monthly) to the more frequent (3-monthly) followup group in the two-by-two comparisons. On the basis of a 3-year survival rate of 60% with intensive, more frequent followup, 500 patients were necessary to demonstrate noninferiority by a margin (delta) of 10% with a power of 80% and a one-sided alpha of 0.1 for both comparisons; this corresponds to a hazard ratio of 1.36. The noninferiority margin of 10% was chosen as an acceptable margin based on mutual consensus by the investigators. The primary end point for both comparisons (imaging modality and frequency of visits) of 3-year overall survival was defined as the time from randomization to death as a result of any cause (to determine overall survival, patients were censored at 36 months).
The secondary objective was to compare disease-free survival (time to recurrence) at 3 years between the groups. For the comparison between the chest radiography-based followup group to the CT scan-based followup group, disease-free survival was defined as the time from random assignment to the first date of documented pulmonary metastasis. For the comparison between the less frequent (6-monthly) to the more frequent (3-monthly) followup groups, disease-free survival was defined as the time from random assignment to the first date of documented recurrence of disease at local or distant sites.
The study was reviewed annually for quality of trial conduct and data management by the institutional data monitoring and safety committee. No formal interim analysis was performed.
All analyses were performed on a per-protocol population (patients were considered as being compliant to the designated protocol if the difference in number of scheduled imaging studies did not vary beyond 30% in the initial 3 years). Analysis was also performed on an intention-to-treat population. Data were graphically depicted using Kaplan-Meier curves. Hazard ratios (HRs) and their one-sided 90% confidence intervals were estimated by Cox proportional hazards regression using SPSS Version 20.0 (SPSS, Chicago, IL, USA).
Followup
Five hundred patients were accrued on the trial (Fig. 1). There were 376 males and 124 females. The median age was 20 years (range, 3–65 years). The study groups were well balanced in terms of their baseline characteristics (Table 1).
Fig. 1.
Trial profile detailing the numbers in the various groups. CXR = chest radiography; ITT = intention to treat; LFU = lost to followup.
Table 1.
Baseline characteristics of patients in the trial
| Groups (N = 500) | CT scan × 3-monthly visit (n = 126) |
CT scan × 6-monthly visit (n = 123) |
CXR × 3-monthly visit (n = 126) |
CXR × 6-monthly visit (n = 125) |
|---|---|---|---|---|
| Bone (359) | 90 | 87 | 93 | 89 |
| STS (141) | 36 | 36 | 33 | 36 |
| Age (years), median/range | 20/(3–64) | 21/(5–66) | 18/(3–61) | 21/(5–63) |
| Male | 79% | 78% | 77% | 67% |
| Female | 21% | 22% | 23% | 33% |
| Bone—primary/recurrent | 88/2 | 86/1 | 91/2 | 88/1 |
| Bone—< 8 cm (52) | 12 | 12 | 15 | 13 |
| Bone—> 8 cm (307) | 78 | 75 | 78 | 76 |
| Bone—high grade (352) | 89 | 86 | 90 | 87 |
| Bone—low grade (7) | 1 | 1 | 3 | 2 |
| STS—primary/recurrent | 21/15 | 20/16 | 17/16 | 21/15 |
| STS—< 10 cm (82) | 22 | 22 | 18 | 20 |
| STS—> 10 cm (59) | 14 | 14 | 15 | 16 |
| STS—high grade (125) | 30 | 33 | 29 | 33 |
| STS—low grade (16) | 6 | 3 | 4 | 3 |
| STS—had chemotherapy: yes/no | 13/23 | 14/22 | 13/20 | 12/24 |
CXR = chest radiograph; STS = soft tissue sarcoma.
Five patients were excluded from the analysis because of incorrect eligibility criteria (Fig. 1). The remaining 495 patients were analyzed as per their random assignment based on their intensity of investigations and frequency of visits.
The followup was completed up to December 31, 2012, for this analysis. At the time of analysis, followup details were available for a total of 461 patients.
At a median followup of 42 months, 178 deaths were documented.
Results
The 3-year overall survival and the disease-free survival for all patients was 67% and 52%, respectively.
Chest radiograph as an imaging modality did not lead to worsened survival and was not inferior to CT scan in terms of detecting pulmonary metastasis. A total of 226 patients had pulmonary metastasis (180 had only pulmonary metastasis, and 46 had combined [local recurrence + pulmonary metastasis] recurrence). The 3-year overall survival rate was 67% and 66% in chest radiography and CT groups, respectively (HR, 0.9; upper 90% confidence interval [CI], 1.13) (Fig. 2A). The disease-free survival was 54% and 49% in chest radiography and CT groups, respectively (HR, 0.82; upper 90% CI, 0.97). Analysis performed on an intention-to-treat population also showed similar results.
Fig. 2A–B.
(A) The graph shows the Kaplan-Meier overall survival curve in the CXR as opposed to the CT (dotted line) group. (B) The graph shows the Kaplan-Meier overall survival curve in the 6-monthly as opposed to the 3-monthly (dotted line) group.
Although we could not conclude noninferiority between the 6- and 3-month followup regimens using the end point of overall survival, a 6-monthly followup regime was not inferior to a 3-monthly followup regime in terms of detecting metastasis and local recurrence. A total of 17 patients had only local recurrence, 180 had only pulmonary metastasis, and 46 had combined (local recurrence + pulmonary metastasis) recurrence. The 3-year overall survival was 64% and 69% in the 6-monthly and 3-monthly groups, respectively (HR, 1.2; upper 90% CI, 1.47) (Fig. 2B). The disease-free survival rate was 51% and 52% in the 6-monthly and 3-monthly groups, respectively (HR, 1.01; upper 90% CI, 1.2). Analysis performed on an intention-to-treat population also showed similar results. The details of how the disease relapses were identified are shown (Table 2). Fifty-six of 63 local recurrences were identified by the patients themselves, who were symptomatic.
Table 2.
Identification of disease relapse
| Groups | Local relapse only (n = 17) | |||
|---|---|---|---|---|
| Total | Symptomatic | Clinical | Imaging | |
| CT scan (3 monthly + 6 monthly) | 8 | 8 | – | – |
| CXR (3 monthly + 6 monthly) | 9 | 7 | 1 | 1 |
| 3 monthly (CT scan + CXR) | 7 | 7 | – | – |
| 6 monthly (CT scan + CXR) | 10 | 8 | 1 | 1 |
| Pulmonary metastasis only (n = 180) | ||||
|---|---|---|---|---|
| CT scan (3 monthly + 6 monthly) | 92 | 27 | – | 64 |
| CXR (3 monthly + 6 monthly) | 88 | 44 | 1 | 41 |
| 3 monthly (CT scan + CXR) | 89 | 36 | – | 51 |
| 6 monthly (CT scan + CXR) | 91 | 35 | 1 | 54 |
| Local relapse (LR) + pulmonary metastasis (PM) (n = 46) | ||||
|---|---|---|---|---|
| CT scan (3 monthly + 6 monthly) | 23 | LR = 20 | – | LR = 3 |
| PM = 4 | PM = 1 | PM = 18 | ||
| CXR (3 monthly + 6 monthly) | 23 | LR = 21 | LR = 1 | LR = 1 |
| PM = 4 | PM = 1 | PM = 18 | ||
| 3 monthly (CT scan + CXR) | 25 | LR = 23 | LR = 1 | LR = 1 |
| PM = 6 | PM = 1 | PM = 18 | ||
| 6 monthly (CT scan + CXR) | 21 | LR = 18 | – | LR = 3 |
| PM = 2 | PM = 1 | PM = 18 | ||
CXR = chest radiography.
Discussion
The detection of a recurrence of the index lesion is the foundation of surveillance. Whether an increased frequency of followup visits and the use of various expensive imaging modalities for surveillance actually results in improving overall survival of patients with extremity sarcomas is debatable [8]. The expense and effort involved in surveillance is quite considerable. Hence, it is appropriate that just like treatment protocols, surveillance regimes too are based on credible evidence rather than traditional beliefs [9, 19].
To the best of our knowledge, this trial (TOSS) is the first prospective randomized trial that has sought the impact of a surveillance regime on overall survival and disease-free survival in terms of intensity of imaging investigations and frequency of visits. At a median followup of 42 months, our trial was able to demonstrate that chest radiography as an imaging modality did not lead to worsened survival and was not inferior to CT scan in terms of detecting pulmonary metastasis. It also showed that a 6-monthly follow up regime was not inferior to a 3-monthly followup regime in terms of detecting metastasis and local recurrence but we could not conclude noninferiority between the 6- and 3-month followup regimens using the end point of overall survival.
Our study does have its limitations. Low-grade sarcomas have little metastatic potential [13] and tumor-related mortality; hence, retrospective studies suggest that surveillance is likely to have a positive impact only in high-risk cases [4]. TOSS included all sarcomas without risk assessment. This is not a major drawback of the study because 95% of patients in TOSS had high-grade bone and soft tissue sarcomas with 76% of these being larger than 8 cm (bone) and 10 cm (soft tissue), thereby constituting a high-risk group with a greater propensity for disease relapse. Second, we used a relatively large noninferiority margin and a large alpha (a difference of 10% between the groups was the margin of noninferiority with a one-sided alpha of 10%). These were decided after a discussion between the investigators to maintain a pragmatic sample size so as to allow accrual to be accomplished within a reasonable timeframe [16].
One of the main strengths of TOSS in determining the ultimate impact of surveillance is the use of overall survival as an end point rather than detection rate as has been the norm in other studies [5, 12]. CT scanning of the chest is known to be more sensitive than chest radiography in detecting lung lesions, but its specificity in detecting metastatic lesions is lower. The role of CT scanning in the surveillance of metastatic disease is therefore not clear. Cho et al. [3] performed a retrospective study on 176 patients operated on for a high-grade soft tissue sarcoma and followed up with CT or chest radiography for pulmonary metastasis monitoring after surgery. Although they suggested that serial monitoring with chest CT could give rise to early detection of pulmonary metastases, the 5-year survival estimates of the two groups were similar. Whooley et al. [21] do not recommend CT scanning of the chest as a surveillance technique because of the high accuracy of chest radiography in detection of pulmonary metastases. Korholz et al. [12] too demonstrated the efficacy of chest radiography in diagnosing metastasis in which 13 of 16 patients were detected by routine chest radiographs. The findings of Whooley and Korholz appear justified based on the results of our trial, which demonstrates the adequacy of chest radiography in detecting pulmonary metastasis with no deleterious impact on overall survival as also concluded by Cho.
Instituting effective treatment of relapse depends on the ability to pick up disease recurrence early and this forms the basis of frequent surveillance visits. In TOSS, almost 90% of local relapses were identified by the patients who presented to the clinic with symptomatic complaints, whereas 39% of pulmonary metastasis was initially detected based on patients’ symptoms. Similar results have also been reported by others [5, 8, 11]. In Korholz et al.’s [12] series of relapsed patients with osteosarcoma, five of six local recurrences were detected by clinical symptoms. In Whooley et al.’s [21, 22] series, all but one of 29 local recurrences was detected before imaging and 37% of their distant recurrences were symptomatic at presentation. A retrospective analysis of 29 cases of relapsed sarcomas by Postovsky et al. [17] concluded that regular imaging studies did not facilitate earlier recognition of relapse and regular followup with imaging studies did not influence overall survival. They suggested that surveillance may not be a critical determinant of survival because there is an absence of effective second-line therapy in relapsed sarcomas and survival may be determined more by the inherent tumor biology of the disease. A retrospective analysis on a cohort of 80 relapsing patients after primary treatment for an extremity soft tissue sarcoma by Chou et al. [4] showed no difference in time to detection and the median size of both pulmonary metastasis and local recurrences detected based on the frequency of followup visits. Although they did suggest that more frequent followup was associated with improved survival after treatment for relapse in patients with high-risk features, they failed to define objective followup intervals and patients in their study had varying followup intervals based on physicians’ preferences. Our study too showed that frequency of followup did not impact detection of relapse, but we could not conclude noninferiority between the 6- and 3-month followup regimens using the end point of overall survival.
Although we have not addressed the cost differentials among the various groups, a surveillance regime that recommends less frequent visits with inexpensive imaging has obvious fiscal benefits [22]. There is reasonable evidence in the literature from other solid tumor types (such as breast cancer, colorectal cancer, endometrial cancer, and melanoma) that challenges the use of multiple followup imaging tests in terms of efficacy, cost-effectiveness, and survival benefit [6, 7, 14, 15]. It appears from our study that the same may hold true for extremity bone and soft tissue sarcomas. We believe that based on our observations, inexpensive chest imaging and patient education regarding local self-examination of the operated area will detect the majority of recurrences without deleterious effects on eventual outcomes. Although less frequent visits adequately detected metastasis and local recurrence, we could not conclusively demonstrate noninferiority in overall survival for a 6-monthly interval of followup visits against 3-monthly in the initial 2 years. This might have been a function of a small sample size; longer followup in larger populations may confirm this finding. Key opinion leaders have stressed the need for clinical trials to prospectively evaluate imaging modalities used in followup and to identify an optimal surveillance strategy, one balancing gains in survival, quality of life, costs, and societal willingness to expend resources as well [9]. This study showing that less costly followup regimens are not inferior to more expensive testing and followup is an important step in that direction.
Acknowledgments
We thank Dr C. S. Pramesh for his assistance in analysis and interpretation of the data and review of the manuscript. We also thank all consultants, fellows, and trial coordinators of the Bone & Soft Tissue–Disease Management Group for their assistance during the conduct of the trial.
Footnotes
This study was funded by an intramural hospital grant facilitated by the Terry Fox Foundation.
All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request.
Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained.
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