Abstract
Objective
To determine whether regional hyperthermia (RHT) in addition to chemotherapy improves local tumor control after macroscopically complete resection of abdominal or retroperitoneal high-risk sarcomas.
Background
Within the prospectively randomized EORTC 62961 phase- III trial, RHT and systemic chemotherapy significantly improved local progression-free survival (LPFS) and disease-free survival (DFS) in patients with abdominal and extremity sarcomas. That trial included macroscopically complete and R2 resections.
Methods
A subgroup analysis of the EORTC trial was performed and long-term survival determined. From 341 patients, 149 (median age 52 years, 18–69) were identified with macroscopic complete resection (R0, R1) of abdominal and retroperitoneal soft-tissue sarcomas (median diameter 10 cm, G2 48.3%, G3 51.7%). Seventy-six patients were treated with EIA (etoposide, ifosfamide, doxorubicin) + RHT (≥5 cycles: 69.7%) versus 73 patients receiving EIA alone (≥5 cycles: 52.1%, P = 0.027). LPFS and DFS as well as overall survival were determined.
Results
RHT and systemic chemotherapy significantly improved LPFS (56% vs 45% after 5 years, P = 0.044) and DFS (34% vs 27% after 5 years, P = 0.040). Overall survival was not significantly improved in the RHT group (57% vs 55% after 5 years, P = 0.82). Perioperative morbidity and mortality were not significantly different between groups.
Conclusions
In patients with macroscopically complete tumor resection, RHT in addition to chemotherapy resulted in significantly improved local tumor control and DFS without increasing surgical complications. Within a multimodal therapeutic concept for abdominal and retroperitoneal high-risk sarcomas, RHT is a treatment option beside radical surgery and should be further evaluated in future trials.
Keywords: local progression-free survival, multimodal therapy, retroperitoneal sarcoma, surgical resection
Retroperitoneal and abdominal soft-tissue sarcomas are rare tumors with a reported incidence of 2.7 cases per million.1 For localized abdominal and retroperitoneal tumors, surgical resection with gross negative margins remains the standard of care. As opposed to extremity sarcoma, mortality from tumors located in the retroperitoneum occurs mainly because of local relapse. Local recurrence is responsible for 3 of 4 tumor-related deaths.2 Systematic compartmental resection, that is, removal of the tumor en bloc with a rim of normal tissue, including macroscopically unaffected structures, has been shown to reduce local recurrence rates.3–5 These studies indicate that complete removal of the tumor represents the most important prognostic factor in patients with retroperitoneal soft-tissue sarcoma.
Despite gross complete multivisceral resections, small surgical margins may occur in the retroperitoneum in patients with large soft-tissue sarcoma.3,6 To improve local tumor control, multimodal therapeutic concepts with radiation and systemic perioperative chemotherapy have been developed in addition to radical surgery.7–9 The prospective randomized multicenter trial EORTC (European Organisation for Research and Treatment of Cancer) 62961 indicated that hyperthermia combined with systemic chemotherapy with etoposide, ifosfamide, and doxorubicin (EIA) significantly increased local progression-free survival (LPFS) and disease-free survival (DFS) compared to chemotherapy alone in patients with high-risk sarcoma (diameter > 5 cm, FNCLCC grading 2 or 3).10 This study, however, included a heterogeneous patient collective with retroperitoneal and extremity soft-tissue sarcomas, as well as different resection status (R0/R1 vs R2 resections). Therefore, it remains unknown whether hyperthermia in addition to chemotherapy compensates for insufficient surgery or is also effective in decreasing local recurrence in patients after macroscopically complete resection of sarcomas. Because from a surgical, anatomical, and prognostic perspective, extremity, abdominal, and retroperitoneal sarcoma represent different entities, this manuscript will focus only on abdominal and retroperitoneal sarcoma.11,12 Aim of this study was to evaluate the effect of hyperthermia in the subgroup of patients with R0/R1 resection of retroperitoneal and abdominal sarcoma on local-recurrence, progression-free, and overall long-term survival. Moreover, the effect of the intensified treatment in the regional hyperthermia (RHT) group on perioperative morbidity and mortality was evaluated.
METHODS
Trial Design
The EORTC 62961 trial is a multicenter, randomized phase III trial. It has been registered with ClinicalTrials.gov (NCT 00003052) and has been published previously.10 The study protocol was approved by the EORTC, and approval from institutional review boards was obtained at all 9 participating centers.
Patients
Between 1997 and 2006, a total number of 341 patients (age 18–70 years) with abdominal and extremity soft-tissue sarcomas were included. Eligible patients had the following risk factors: Fédération Nationale des Centres de Lutte contre le Cancer (FNCLCC) Grade 2 and 3, tumor diameter more than 5 cm. Patients with evidence of distant disease were excluded. Written and informed consent was obtained for all patients.
Total Patient Cohort
Tumor resection was performed within a multimodal therapeutic approach. Patients were randomly assigned to 2 groups. Patients in group “EIA” (n = 172) received perioperative chemotherapy consisting of etoposide, ifosfamide, and doxorubicin (EIA: etoposide 250 mg/m2 on day 1 and 4, ifosfamide 6 g/m2 on days 1–4, doxorubicin 50 mg/m2 on day 1 every 3 weeks). Patients in group “EIA + RHT” (n = 169) received chemotherapy according to the same protocol plus RHT (tumor temperatures of 42°C for 60 minutes were given on day 1 and day 4 of each EIA cycle). RHT and thermal mapping were done according to the ESHO guidelines for quality and safety assurance.13 The BSD-2000 hyperthermia system (BSD Medical Corporation, Salt Lake City, UT) was used. Blinding was not possible due to the nature of the allocated treatment.
After 4 cycles of induction chemotherapy, tumor response was evaluated according to World Health Organization criteria14 and confirmed blinded and independently by board members of the EORTC Soft Tissue and Bone Sarcoma Group. Patients who developed progressive disease after 4 cycles did not receive further systemic therapy according to the EORTC 62961 trial protocol. Patients with stable disease or a positive tumor response continued to receive chemotherapy cycles 5 to 8.
For radiotherapy, if indicated, a total dose of 50 to 60 Gy was delivered, with daily fractions of 1.8 to 2.0 Gy, administered 4 to 6 weeks after surgery. The recommended doses were adjusted depending on the individual situation and potential radiosensitive tissue within the radiation field.
Subgroup Analysis
To evaluate the effect of RHT particularly in patients with abdominal and retroperitoneal soft-tissue sarcoma, we performed a subgroup analysis of the earlier described EORTC 62961 trial (Fig. 1).10 A total of 192 patients with retroperitoneal and abdominal sarcomas were identified (N = 192, EIA + RHT 96 vs EIA 96). From this cohort, patients (n = 149, 77.6%) with macroscopically complete resections (R0, R1) were selected for the present analysis. Resection status was reviewed by an independent pathologist not involved in the study. Patients with intraoperative tumor rupture during operation were considered as R2 resections.
FIGURE 1.
Profile of the EORTC 62961 trial and process of subgroup selection.
Primary and Secondary Endpoints
Patients’ recurrence status was documented every 3 months during the first year, every 4 months up to 3 years, every 6 months up to 5 years, and yearly thereafter. Thus, median follow-up was increased from 34 months [interquartile range (IQR): 20–67] in the original publication to 99 months (IQR 20–185) in this article (Fig. 2).
FIGURE 2.
Kaplan-Meier estimates of LPFS (A), DFS (B), and OS (C).
LPFS was chosen as the primary endpoint of this study. It was defined as the time between randomization to confirmed local progression, relapse, or death, whichever occurred first and irrespective of any occurrence of distant metastases. For patients without confirmed progression, recurrence, metastasis or death, data were censored at the time of the last valid assessment.
Secondary endpoints were DFS, overall survival (OS), tumor response after induction therapy, and perioperative morbidity and mortality. DFS was outlined as the time between randomization and confirmed local failure, distant metastases, or death due to disease or treatment, whichever occurred first. OS was defined as the time between randomization to death of any cause, with survivors being censored at the time of last follow-up. Perioperative mortality was defined as death occurring within 30 days postoperatively. Perioperative morbidity was monitored prospectively including infections, vascular complications, bleeding, neurological complications, etc.
Statistical Analysis
Sample size was not calculated but determined by the definition of subgroups in this retrospective analysis. Proportions were compared by χ2 tests, and continuous outcomes by Mann-Whitney U tests. Time-to-event data were analyzed by the Kaplan-Meier method. Differences in survival were assessed by stratified log-rank test. A level of significance of 0.05 was applied to all tests. We assessed treatment differences in selected subgroups by stratified Cox regression. All analyses were done using statistical software SAS (version 9.2, SAS Institute, Cary, NC).
RESULTS
Patient Characteristics
Median age was 52 years (IQR: 18–69) [53 years, (IQR: 19–69) EIA + RTH vs 49 years, (IQR 18–69) EIA, P = 0.33]. Gender distribution was similar in both study groups (P = 0.35). Median tumor diameter was 12.0 cm (IQR: 5–36 cm) in the EIA + RHT group versus 11.0 cm (IQR: 5–40 cm) in the EIA group (P = 0.41). Histopathological findings did not differ between the study groups (P = 0.87). Baseline characteristics of the patients included are outlined in Table 1.
TABLE 1.
Patient Characteristics and Demographics
| EIA + RHT (n = 76) | EIA (n = 73) | P | |
|---|---|---|---|
| Age, median (range), yr | 53.0 (19.0–69.0) | 49.0 (18.0–69.0) | 0.3261 |
| Sex | 0.3520 | ||
| Male | 39 (51.3%) | 43 (58.9%) | |
| Female | 37 (48.7%) | 30 (41.1%) | |
| Presentation of tumor | 0.5388 | ||
| Primary | 69 (90.8%) | 64 (87.7%) | |
| Recurrent | 7 (9.2%) | 9 (12.3%) | |
| Size of tumor, median (range) | 12.0 (5.0–36.0) | 11.0 (5.0–40.0) | 0.4120 |
| Pathology | 0.8730 | ||
| Liposarcoma | 16 (21.1%) | 13 (17.8%) | |
| Leiomyosarcoma | 18 (23.7%) | 16 (21.9%) | |
| Fibrosarcoma | 7 (9.2%) | 10 (13.7%) | |
| Malignant fibrous histiocytoma | 2 (2.6%) | 1 (1.4%) | |
| Other sarcomas | 33 (43.4%) | 33 (45.2%) | |
| Type of surgery | 0.2017 | ||
| Compartmental resection | 17 (22.4%) | 17 (23.4%) | |
| Wide excision | 55 (72.4%) | 51 (69.9%) | |
| Marginal excision | 4 (5.3%) | 5 (6.8%) | |
| Days after surgery until discharge, median (range) | 14 (6–49) | 12 (4–76) | 0.3521 |
A primary tumor was resected in 133 patients [69 (90.8%) EIA + RHT vs. 64 (87.7%) EIA, P = 0.54]. Locally recurred tumors were treated within the study in 16 cases [7 (9.2%) EIA + RHT vs 9 (12.3%) EIA].
Surgical Treatment
In all patients included, macroscopically complete tumor resection was achieved (R0/R1 resection). As surgical procedure, compartmental resection was performed in 22.8% (17 EIA + RHT vs 17 EIA, ns) (Table 1, P=0.20 for all procedures). Most patients (71.2%) underwent wide excision as surgical treatment (55 EIA + RHT vs 51 EIA, ns). Marginal excision still classified as R1 resection was accomplished in 6% (4 EIA + RHT vs 5 EIA, ns).
Morbidity rate in all patients was 19.5%. RHT did not significantly affect postoperative complication rates (21.0% EIA + RHT vs 17.9% EIA, P=0.62). Specific complications are outlined in Table 2. In addition, median postoperative hospital stay did not differ between the study groups (14 days EIA + RHT vs 12 days EIA). There was no perioperative mortality.
TABLE 2.
Perioperative Morbidity and Mortality
| Complications | EIA + RHT (n = 76) | EIA (n = 73) | P |
|---|---|---|---|
| None | 60 (78.9%) | 60 (82.2%) | 0.617 |
| Morbidity | 16 (21.0%) | 13 (17.9%) | |
| Superficial wound infection | 4 | 2 | |
| Deep infection | 3 | 4 | |
| Bleeding | 6 | 1 | |
| Neurological | 4 | 2 | |
| Skin necrosis | 4 | 3 | |
| Other | 11 | 8 | |
| Mortality | 0 | 0 | 1.000 |
Chemotherapy ± RHT
In the EIA + RHT group, 67 patients (88.2%) received all 4 cycles of induction chemotherapy, whereas in the EIA group, 63 patients (86.3%) received all 4 cycles. As for the total number of chemotherapy cycles, 5 or more systemic cycles were applied in 53 patients (69.7%) in the EIA + RHT versus 38 patients (52.1%) in the EIA group (P = 0.027).
Response to induction therapy was determined according to World Health Organization criteria in 94 patients (EIA + RHT 49 patients vs EIA 45 patients, ns) after 4 cycles of neoadjuvant treatment. Response rates were significantly higher in the EIA + RHT group than in the EIA group (34.7% vs 15.6%, P = 0.034). Early progression occurred in 10 patients (22.2%) treated only with EIA, whereas no patient in the combined treatment group had early progression (P < 0.001). In 55 patients, systemic therapy was applied adjuvantly. Thus, no evidence of disease was present at randomization in those patients.
Radiation Therapy
Radiation therapy was applied in 95 of 149 patients. The distribution was similar in both study groups [50 patients (65.8%) EIA + RHT vs 45 patients (61.6%) EIA, P = 0.54].
LPFS, DFS, and OS
In patients with macroscopically complete tumor resection, RHT resulted in significantly improved LPFS [hazards ratio (HR) = 0.63, 95% CI: 0.40–0.99; P = 0.044]. Three-year LPFS was 63 months (EIA + RHT) versus 49 months (EIA only) (Table 3).
TABLE 3.
Effect of RHT and EIA on LPFS, DFS, and OS
| EIA + RHT (95% CI) | EIA (95% CI) | HR (95% CI) | P* | |
|---|---|---|---|---|
| LPFS | ||||
| Median duration, yr | 8.3 (3.0 to >12.0) | 2.5 (1.7–6.3) | 0.63 (0.40–0.99) | 0.044 |
| 3 yrs (%) | 63 (52–74) | 49 (37–60) | ||
| 5 yrs (%) | 56 (44–68) | 45 (33–57) | ||
| Disease-free survival | ||||
| Median duration, yr | 2.7 (1.7–4.0) | 1.5 (1.1–2.2) | 0.72 (0.49–1.05) | 0.040 |
| 3 yrs (%) | 46 (34–57) | 31 (21–42) | ||
| 5 yrs (%) | 34 (23–45) | 27 (16–37) | ||
| OS | ||||
| No. deaths | 40 | 44 | 0.82 (0.53–1.26) | 0.5932 |
| Median duration, yr | 6.8 (3.8 to >12.0) | 6.2 (2.8–8.2) | ||
| 3 yrs (%) | 65 (54–76) | 61 (50–72) | ||
| 5 yrs (%) | 57 (45–68) | 55 (43–67) |
Log-rank test.
For the combined treatment group versus the EIA only group the relative hazard for DFS was 0.72 (95% CI: 0.49–1.05; P = 0.040 Log-rank test), with a median duration of 2.7 years versus 1.5 years.
Within the follow-up period of 8.2 years, 84 patients died (40 in the combined treatment group vs. 44 in the EIA only group). OS did not differ significantly between the groups (HR = 0.82, 95% CI: 0.53–1.26; P = 0.59).
DISCUSSION
The most common site of first recurrence after surgery for retroperitoneal sarcoma is local relapse.2,15 Local recurrence rates of more than 80% have been reported despite complete surgical resection of high-risk soft-tissue sarcomas,16 underlining the need for novel multimodal therapeutic strategies. In this respect, our previously published randomized phase III trial showed that RHT enhances the efficacy of chemotherapy (EIA) in the treatment of high-risk soft-tissue sarcoma.10 Patients treated with RHT and EIA had increased LPFS and DFS compared to patients treated with EIA alone. This study, however, included patients with different tumor locations and resection status. Thus, it remained unknown whether RHT in addition to systemic chemotherapy improves LPFS in a homogeneous patient collective with macroscopically complete resection of abdominal or retroperitoneal soft-tissue sarcoma. Because macroscopically incomplete resections are an independent predictor of unfavorable outcome,6,16,17 RHT may have improved LPFS due to the inclusion of surgically inadequate resections.10
The present subgroup analysis focuses on patients with R0/R1 resection status, excluding macroscopically incomplete resections. Our results indicate that addition of RHT to systemic perioperative chemotherapy improved local tumor control and DFS as compared to chemotherapy alone also in patients with macroscopically complete resections. Three-year LPFS was 63 months with RHT as opposed to 49 months in the chemotherapy-only group. There was no effect of RHT on OS. When interpreting these results, it has to be considered that the study represents a subgroup analysis of a prospectively randomized multicenter trial. The lack of statistically significant effects of RHT on OS may be due to the small sample size, which has not been calculated for this subgroup in the initial study design. Moreover, patients who developed progressive disease after 4 cycles of EIA were allowed to receive RHT with cycles 5 to 8 which may have influenced OS.
The tumor response rate after 4 cycles of systemic therapy with EIA + RHT was more than twice as high (34.7% vs 15.6%, P = 0.0034) when compared to chemotherapy alone. This reflects the effectiveness of the combined treatment approach for local tumor control.10,18,19 In particular, no patient in the EIA + RHT group showed early progression, whereas 10 patients (22.2%) in the chemotherapy-only group had early progression (P < 0.001). As a consequence of reduced early progression, more patients continued to receive systemic therapy cycles 5 to 8 in the EIA + RHT arm.
In the EIA + RHT group, liposarcoma as a histological subtype was slightly more frequent and there were a few more primary tumors (vs recurrent tumors) and wide excisions (vs local tumor resections), although none of these differences was statistically significant. On the contrary, tumors in patients treated only with EIA were smaller by 1 cm. In summary, factors favoring a positive outcome were equally distributed between groups and it seems unlikely that these small differences in patient characteristics are responsible for the observed benefit of RHT on LPFS and DFS. The significantly increased response rate in RHT-treated patients seems to be of greater importance.
Complete surgical tumor resection is the standard of care in retroperitoneal soft tissue sarcomas. Recently, a more aggressive surgical approach with en bloc resection of the tumor together with a rim of normal tissue including uninvolved organs has been introduced in an attempt to further minimize the risk of microscopically positive margins and local relapse. Five-year local recurrence rates of less than 25% have been reported after systematic compartmental resections compared to 44% in the RHT group of this study.3–5 In those studies, however, more than one third of patients had well-differentiated sarcomas, whereas patients with G1 tumors were specifically excluded in our study protocol. High tumor grade (G2/G3) has been shown to negatively influence DFS and OS more than any other tumor-associated risk factor (size, histological subtype, location).20 Given that well-differentiated sarcomas are associated with significantly lower recurrence rates and better long-term survival,4,17,20 the unequal distribution of tumor grading precludes a comparison of local and distant recurrence-free survival rates.
In this study, less than 25% of patients were treated with compartmental resection, which was established as a standard procedure after EORTC 62961 started recruiting patients. Because of the small number of patients, further studies are required to evaluate whether RHT in addition to systemic chemotherapy improves the promising results of systematic compartmental resection. Furthermore, extensive multivisceral resections are not feasible in some patients due to accompanying diseases or tumor location. Although previous data presented by Perez et al17 suggest that these patients benefit even from incomplete tumor resections, RHT may improve local tumor control also after R2 resection of retroperitoneal soft tissue sarcoma.
This study included only high-risk G2/G3 retroperitoneal sarcomas. The rather favorable prognosis of G1 tumors does not justify the use of chemotherapy because of the associated risks of toxicity. Whether radiotherapy improves local tumor control in patients with differentiated sarcomas after radical surgery is being addressed in the ongoing EORTC trial (NCT01344018). We propose the use of EIA and RHT for patients with G2/G3 retroperitoneal sarcomas as part of a differentiated approach tailored to the risk of an individual patient.
The importance of RHT in addition to chemotherapy is emphasized by a recently published study by Woll et al.21 This prospective randomized trial failed to demonstrate reduced LPFS for patients receiving adjuvant chemotherapy (doxorubicin, ifosfamide) after macroscopically complete resection of high-risk soft-tissue sarcomas.21 To what extent the difference in the chemotherapy protocol and the inclusion of mainly extremity sarcomas contributes to the negative results in that study remains to be determined. In this respect, a retrospective analysis revealed significantly improved DFS in 262 patients with grade 3 sarcoma treated with adjuvant chemotherapy.22
Perioperative radiotherapy was applied in 65.8% of patients in the EIA + RHT group and in 61.6% of EIA only patients (P = 0.54). In a retrospective cohort study based on the SEER (Surveillance, Epidemiology, and End Results) database involving 1901 patients with retroperitoneal sarcoma, perioperative radiotherapy increased LPFS compared to surgery alone.23 Systematic perioperative radiotherapy has been shown to be feasible in patients with retroperitoneal sarcomas.24 Thus, increasing the number of patients receiving radiotherapy within our multimodal treatment concept may improve local tumor control. The benefit of radiotherapy is currently being evaluated in an ongoing EORTC phase III trial (NCT01344018).
Intensifying chemotherapy via RHT did not increase perioperative complication rates. In this respect, comparable morbidity rates between 18% and 26% have recently been reported after resection of retroperitoneal sarcomas without neoadjuvant therapy.4,25,26 In addition, this study documented all complications including neurological and cardiovascular morbidity whereas most surgical studies reporting lower morbidity rates focused on major complications requiring surgical reintervention.27 Most importantly, this trial prospectively recorded all complications whereas previous studies were retrospective and might, therefore, by the nature of their design, have missed some of the complications. Finally, the higher number of completed systemic therapy cycles in the RHT group demonstrates that this novel concept is well-tolerated during systemic therapy and perioperatively. These findings emphasize that improved local tumor control in the RHT group was not achieved at the expense of unacceptable treatment-associated morbidity and mortality.
Contributing centers represented high-volume institutions treating more than 30 soft-tissue sarcomas per year. In particular, high-risk soft tissue sarcomas seem to profit from treatment at high-volume centers.3,4,28 This effect of center size has to be considered when interpreting the results of the present trial for the general patient population. Also, the fact that this subgroup analysis was not initially planned may be a source of statistical bias and reflects a limitation of this article.
The previously published EORTC 62961 trial failed to demonstrate improved OS for the whole patient group.10 Extending the observation time and focusing on a more homogenous subgroup in the present analysis did not eliminate the discrepancy between significantly improved LPFS/DFS and statistically unaffected OS. Furthermore, 70% of patients completed more than 4 cycles of systemic therapy. Whether increasing the number of patients completing the entire study protocol or individualizing the use of RHT based on pretherapeutically identified predictive factors will result in improved OS remains to be determined. To date, such predictive factors have not yet been defined.
CONCLUSION
In summary, addition of RHT to chemotherapy resulted in significantly improved LPFS and DFS after macroscopically complete resection of abdominal and retroperitoneal sarcomas. Intensification of the local effects of perioperative chemotherapy via RHT did not significantly increase surgical complication rates. Whether more aggressive surgical strategies with systematic compartmental resections will further improve local tumor control for patients treated with RHT and chemotherapy remains to be elucidated in future studies.
Acknowledgments
This study was supported by Deutsche Krebshilfe (M99/94/Wi II, 70-I702-Wi II), Helmholtz Association (VHVI-140), EORTC 62961, ESHO RHT-95, and NIH P01 CA42745.
Footnotes
Disclosure: The authors declare no conflicts of interest.
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