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Randomized Clinical Trials in Soft Tissue Sarcoma
Randomized Clinical Tri a l s i n S o f t T i s s u e S a rco m a Steven C. Katz,
MD
a
, Murray F. Brennan,
MD
b,
*
KEYWORDS Soft-tissue sarcoma Surgery Chemotherapy Radiation therapy
Soft tissue sarcomas (STS) are a heterogeneous group of rare but potentially lethal, extraskeletal mesenchymal neoplasms. Although the absolute incidence is unknown, it is estimated that approximately 12,000 cases of STS are reported annually in the United States, with 3,500 STS deaths.1 The rarity of these diseases explains, in large part, why few randomized controlled trials (RCTs) have been conducted since the previous issue of this publication. The current understanding of STS biology and, hence, ability to provide safe, effective therapy is predicated upon seminal trials performed in the 1980s and 1990s. The authors briefly summarize the trials presented in the previous issue and then critically assess the more recent publications that have addressed the management of STS. This review does not include pediatric sarcomas or gastrointestinal stromal tumors, the latter of which are covered in a separate article. SURGERY
The original RCT addressing the surgical management of STS had a profound impact, despite being small. Rosenberg and colleagues2 reported that when compared with amputation, wide excision with external beam radiation therapy was associated with equivalent 5-year disease-free and overall survival. Demonstration of equivalence for limb preservation clearly has had important functional and quality of life implications for patients with extremity STS. This trial illustrated that while local recurrence may be associated with distant metastases and death from disease, the relationship is not necessarily causative. Recent retrospective studies have provided additional guidance for our surgical treatment of STS.3
Disclosure: See last page of article. a Department of Surgery, Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI 02908, USA b Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA * Corresponding author. E-mail address: [email protected] (M.F. Brennan). Surg Oncol Clin N Am 19 (2010) 1–11 doi:10.1016/j.soc.2009.09.006 surgonc.theclinics.com 1055-3207/09/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
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RADIATION THERAPY
The impact of postoperative radiation therapy on STS was largely defined by two RCTs. Pisters and colleagues4 reported that adjuvant brachytherapy decreased local recurrence following resection of extremity STS, with the greatest benefit being conferred to patients with high-grade tumors. Yang and colleagues5 demonstrated the effectiveness of external beam radiation in limiting local recurrence for both high and low-grade extremity STS. A more recent report addressed preoperative external beam radiation therapy. O’Sullivan and colleagues6 reported a multicenter randomized trial that demonstrated that neoadjuvant external beam radiation therapy is associated with a higher rate of complications than postoperative adjuvant therapy.6 A subsequent article from the same authors demonstrated that, despite the higher rate of wound complications, neoadjuvant radiation therapy leads to better functional outcomes.7 A small survival advantage was associated with preoperative radiation therapy, yet there was no difference in either local or distant recurrence.
CHEMOTHERAPY
The level 1 chemotherapy trials summarized in the previous issue indicated some improvements in recurrence-free intervals or response rates, but not survival.8–11 A recent meta-analysis which included 1953 patients from 18 trials indicated significant recurrence-free and survival advantages associated with adjuvant doxorubicinbased regimens (Table 1).12 The small absolute recurrence and survival benefits (3%–10%) presented in the meta-analysis must be tempered against the known toxicities of doxorubicin-based systemic regimens. Furthermore, the vast majority of the individual trials included in the meta-analysis failed to demonstrate a significant survival benefit. In a small RCT that closed after 12 years because of poor accrual, Petrioli and colleagues13 found a statistically significant recurrence-free advantage for epirubicinbased postoperative chemotherapy, but no significant difference with respect to overall survival. A single trial with a small number of patients found no benefit to the addition of intraperitoneal chemotherapy following cytoreduction for peritoneal sarcomatosis.14 Mace and colleagues15 showed that, in a small group of patients receiving ifosfamide for STS, a regimen incorporating oral mesna as opposed to exclusively intravenous (IV) mesna was as effective in providing uroprotection. In a large phase III trial, Lorigan and colleagues16 found that single agent ifosfamide should not replace doxorubicin as the first-line agent for advanced STS. A randomized phase II trial of neoadjuvant doxorubicin with ifosfamide for high-risk STS demonstrated that preoperative therapy afforded no survival or recurrence benefit compared with surgery alone.17
Table 1 Meta-analysis of RCTs of adjuvant chemotherapy for localized resectable soft-tissue sarcoma12 Outcome
OR (95% CI)
p
ARR (95% CI)
Local recurrence
0.73 (0.56–0.94)
0.02
3% (0%–7%)
25
Distant recurrence
0.67 (0.56–0.86)
<0.01
9% (5%–14%)
12
Overall recurrence
0.67 (0.56–0.82)
<0.01
10% (5%–15%)
10
Overall survival
0.77 (0.64–0.93)
0.01
6% (2%–11%)
17
Abbreviations: ARR, absolute risk reduction; OR, odds ratio; NNT, number needed to treat.
NNT
Randomized Clinical Trials in Soft Tissue Sarcoma
SUMMARY
The lessons learned from the trials discussed above have influenced our management of STS in meaningful ways. Limb-sparing surgery offers an equivalent chance of cure and a clear functional advantage when compared with amputation for extremity STS. Adjuvant radiation therapy for extremity STS significantly decreases the chance of local recurrence. Preoperative radiation therapy increases the risk of wound complications but is associated with better functional outcomes than postoperative radiation treatment. The decrease in local recurrence afforded by radiation therapy does not affect survival time because most patients who succumb to extremity STS die from disseminated disease. Local recurrence is an important cause of death in cases of retroperitoneal sarcoma,18 yet the evidence supporting a role for radiation therapy in these cases is lacking. Trials addressing the impact of modern, more targeted delivery of external beam radiation for retroperitoneal sarcoma are warranted. With regard to systemic therapy, the body of evidence does not indicate a compelling longterm survival benefit for any systemic regimen. More sophisticated predictors of response are needed, in addition to the identification of novel targets and agents. Slight modifications of approaches already proven to have marginal or no survival benefit will not lead to meaningful progress. FUTURE DIRECTIONS
The rarity of soft tissue sarcomas makes conducting RCTs for these diseases extraordinarily challenging. Multi-institutional trials are needed to define the role of neoadjuvant chemotherapy and radiation therapy for high-risk soft tissue sarcomas, including those arising in the retroperitoneum. More importantly, our increasingly sophisticated understanding of the biologic differences among soft tissue sarcoma subtypes, along with tumor heterogeneity within subtypes, should be incorporated into treatment strategies. The success of future trials for soft tissue sarcoma chemotherapy may depend, in large part, on our ability to define inclusion criteria to focus on more biologically homogeneous groups of patients. LEVEL I EVIDENCE: RANDOMIZED CLINICAL TRIALS
1. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. O’Sullivan B, Davis AM, Turcotte R, et al. Lancet 2002;359:2235–41.6 Hypothesis: The use of preoperative radiation therapy would be associated with a higher rate of wound complications. # Patients Randomized 190
Study Groups
Stratification
Preoperative (N594) Postoperative (N596)
Tumor size (10cm)
Significance Demonstrated Yes
Change Identified in Trial 18% absolute increase in wound complication rate with neoadjuvant therapy
Published abstract: BACKGROUND: External-beam radiotherapy (delivered either preoperatively or postoperatively) is frequently used in local management of sarcomas in the soft tissue of limbs, but the two approaches differ substantially in their potential toxic effects. We aimed to determine whether the timing of external-beam
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radiotherapy affected the number of wound healing complications in soft-tissue sarcoma in the limbs of adults. METHODS: After stratification by tumor size (%10 cm or >10 cm), we randomly allocated 94 patients to preoperative radiotherapy (50 Gy in 25 fractions) and 96 to postoperative radiotherapy (66 Gy in 33 fractions). The primary endpoint was rate of wound complications within 120 days of surgery. Analyses were per protocol for primary outcomes and by intention to treat for secondary outcomes. FINDINGS: Median follow-up was 3$3 years (range 0$27–5$6). Four patients, all in the preoperative group, did not undergo protocol surgery and were not evaluable for the primary outcome. Of those patients who were eligible and evaluable, wound complications were recorded in 31 (35%) of 88 in the preoperative group and 16 (17%) of 94 in the postoperative group (difference 18% [95% CI 5–30], P 5 0$01). Tumor size and anatomic site were also significant risk factors in multivariate analysis. Overall survival was slightly better in patients who had preoperative radiotherapy than in those who had postoperative treatment (P 5 0$0481). INTERPRETATION: Because preoperative radiotherapy is associated with a greater risk of wound complications than postoperative radiotherapy, the choice of regimen for patients with soft-tissue sarcoma should take into account the timing of surgery and radiotherapy, and the size and anatomic site of the tumor. (Copyright Elsevier 2002.) Editor’s summary and comments: The principal question posed by the authors was adequately addressed. Patients who received radiation therapy before surgery had a clinically and statistically significant increase in the rate of wound complications. Forty-five percent of the patients in the neoadjuvant group who developed a wound complication required reoperation for management. Lower extremity sites and tumors larger than 10cm were associated with a greater risk of wound complications. The two groups did not differ with respect to recurrence- or progression-free survival. A small 3-year overall survival advantage (P 5 .05) was noted in the preoperative group (85%) compared with the postoperative group (72%). The short duration of follow-up and the use of overall survival as an endpoint warrant caution because 19% of the deaths in the postoperative group were not due to disease, compared with only 7% in the preoperative group. The authors also note that the study was not adequately powered to detect this difference in a secondary endpoint such as overall survival. In a follow-up article, patients who received postoperative radiation therapy were found to have significantly worse functional outcomes with respect to fibrosis, joint stiffness, edema, and functional scores.7 2. Adjuvant epirubicin with or without ifosfamide for adult soft-tissue sarcoma. Petrioli R, Coratti A, Correale P, et al. Am J Clin Oncol 2002;25:468–73.13 Hypothesis: The use of epirubicin with or without ifosfamide after local therapy for STS would improve the disease-free interval and overall survival duration. # Patients Randomized 88
Study Groups
Stratification
Significance Demonstrated
Epiriubicin Ifosfamide (N545) Observation (N543)
None
Yes
Change Identified in Trial Absolute DFS benefit at 5 years of 25% (P 5 .01) with a trend toward improved OS (P 5 .06)
Abbreviations: DFS, disease-free survival: OS, overall survival.
Published abstract: BACKGROUND: This randomized study compared the efficacy of epirubicin-based adjuvant chemotherapy on the disease-free interval (DFI) and
Randomized Clinical Trials in Soft Tissue Sarcoma
overall survival of patients with high-risk soft-tissue sarcomas. METHODS: After curative surgery, 43 of the 88 enrolled patients were assigned to surgery with or without radiotherapy and 45 to surgery plus chemotherapy (26 epirubicin, 19 epirubicin and ifosfamide) with or without radiotherapy. The trial closed prematurely because of poor patient accrual. FINDINGS: There was a statistically significant difference in the 5-year disease-free survival of the patients receiving adjuvant chemotherapy with or without radiotherapy (69%) and that of those treated with surgery with or without radiotherapy (44%) (P 5 .01). The 5-year survival of the patients treated with adjuvant chemotherapy with or without radiotherapy was 72% as against 47% of those treated with surgery with or without radiotherapy (P 5 .06). The power of the study was 0.65 for both the DFI and overall survival. INTERPRETATION: The results of the study suggest a possible advantage of epirubicin-based adjuvant chemotherapy in patients with soft-tissue sarcoma at high risk of relapse. (Copyright 2002 Lippincott Williams & Wilkins. Reprinted with permission.) Editor’s summary and comments: Although the results of this study indicate a disease-free benefit to epirubicin-based systemic therapy after resection of STS with or without radiation therapy, several important limitations warrant discussion. The authors appropriately exercise caution in interpreting their data by stating that their findings only suggest a benefit to the systemic regimen. Over the course of 12 years, the trial accrued only 88 patients. The small sample size and potential variability in diagnostic and treatment modalities over such a prolonged period are problematic. While 72% of the group that received adjuvant systemic therapy survived for 5 years compared with 47% of the control arm, the result was not significant (P 5 .06). A significant (P 5 .01) overall survival advantage was found when comparing only those patients who received epirubicin plus ifosfamide (84%) to controls (57%). The groups were imbalanced with respect to histologic subtypes and potentially sensitivity to cytotoxic agents. The difference (25%) for disease-free survival was significant (P 5 .01), but the authors found no difference when analyzing local or distant recurrence separately. The findings with respect to a benefit for combination chemotherapy are encouraging, but do not sit well in the context of results from previous, larger RCTs. 3. Randomized trial of cytoreduction followed by intraperitoneal chemotherapy versus cytoreduction alone in patients with peritoneal sarcomatosis. choux C, et al. Eur J Surg Onc 2005;31:917–23.14 Bonvalot S, Cavalcanti A, Le Pe Hypothesis: The use of intraperitoneal chemotherapy would be associated with a decrease in locoregional recurrence and increase in survival after optimal cytoreduction for peritoneal carcinomatosis. # Patients Randomized 38
Study Groups
Stratification
Significance Demonstrated
Change Identified in Trial
IP chemotherapy (n519) No chemotherapy (n519)
None
No
No differences in recurrence-free or overall survival
Published abstract: BACKGROUND: To decrease loco-regional relapse after complete resection of peritoneal sarcomatosis (PS), the role of intraperitoneal chemotherapy (IPEC) was prospectively evaluated. METHODS: Patients (pts) with completely resected PS were randomized between adjunction of IPEC or not. IPEC consisted of doxorubicin, 0.1 mg/kg and cisplatin, 15 mg/m2 per day for 5 consecutive days. FINDINGS: Thirty-eight consecutive pts have been randomized, 19 in each
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group. Ratio of retroperitoneal (RPS) and visceral (VS) sarcomatosis were 9/10 and 6/ 13 in IPEC- and IPEC1 groups, respectively. Histoprognostic grade, Sugarbaker’s score and mean number of resected organs were similar in both groups. There were no toxic deaths and morbidity was similar in both groups (four pts in each group). The median follow-up is 60 months. The median local relapse-free, metastatic relapse-free survival and overall survival were identical in both groups (12.5, 18 and 29 months, respectively), with no difference between RPS and VERSUS sarcomatosis. INTERPRETATION: Administration of IPEC after a macroscopically complete surgery did not allow increasing greatly the outcome of pts. Complete surgery remains the cornerstone of the treatment of patients with sarcomatosis with best results for lowgrade sarcomatosis. (Copyright Elsevier 2005.) Editor’s summary and comments: Based upon the variable success of intraperitoneal chemotherapy (IPEC) with or without hyperthermia for carcinomatosis, the authors attempted to define the role of IPEC following optimal cytoreduction of sarcomatosis. The identical median overall survival time of 29 months in both groups leaves little room for rationalizing the use of IPEC after surgical treatment of sarcomatosis. However, this trial included a very small number of patients and the breakdown of histologic subtypes is not provided. Larger trials with the inclusion of hyperthermia warrant consideration given the high likelihood of locoregional relapse in patients with sarcomatosis. 4. Crossover randomized comparison of intravenous versus intravenous/oral mesna in soft tissue sarcoma treated with high-dose ifosfamide. Mace JR, Keohan ML, Bernardy H, et al. Clin Can Res 2003;9:5829–34.15 Hypothesis: The use of oral plus IV mesna in patients receiving ifosfamide for STS would be equivalent to IV mesna. # Patients Randomized 17
Study Groups
Stratification
Significance Demonstrated
Change Identified in Trial
Crossover comparison
None
No
No difference in the rate of hemorrhagic cystitis with either mesna formulation
Published abstract: BACKGROUND: We conducted our study to determine the pharmacokinetics (PK) and clinical efficacy of oral mesna in patients receiving ifosfamide for soft tissue sarcoma. METHODS: Seventeen patients were enrolled in a randomized prospective Phase I/II study. Seventeen patients were exposed to study medication. Ifosfamide was given at a dose of 2 g/m2/day for 5 days on a 21-day cycle. Before the first cycle, all patients were randomized onto a crossover design and received either the approved i.v. or i.v./oral mesna regimen, with crossover for the second cycle of chemotherapy. The i.v. mesna regimen consisted of dosings (20% ifosfamide dose) at 0, 4, and 8 h. The i.v./oral arm consisted of an i.v. mesna dosing (20% ifosfamide dose) at 0 h, followed by oral tablet dosing (40% ifosfamide dose) at 2 and 6 h. In-patient clinical monitoring and phlebotomy and urine sampling for mesna, dimesna, and ifosfamide PK were performed on all chemotherapy days. FINDINGS: Thirteen patients were evaluable for PK and 17 for efficacy and toxicity. No significant differences were detected in the plasma PK of the concomitantly infused ifosfamide. Rates of hemorrhagic cystitis were similar across mesna schedules. Four of 10 evaluable patients demonstrated objective response.
Randomized Clinical Trials in Soft Tissue Sarcoma
INTERPRETATION: On the basis of our study, an i.v./oral mesna regimen is at least as uroprotective as the approved i.v. regimen. The i.v./oral regimen will improve patient tolerance and convenience, allow for a reduction in elective hospitalizations for ifosfamide chemotherapy, reduce the potential morbidity associated with inpatient administration of chemotherapy, and likely result in decreased costs of care. (Copyright 2003 by the American Association for Cancer Research. Reprinted with permission.) Editor’s summary and comments: This small study suggested that substituting a portion of the IV mesna regimen for tablets in STS patients receiving ifosfamide yields an equivalent approach. In turn, patients may require less inpatient care for systemic therapy administration. 5. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma group study. Lorigan P, Verweij J, Papai Z, et al. J Clin Onc 2007;25:3144–50.16 Hypothesis: Single-agent ifosfamide would be associated with equivalent progression-free survival compared with doxorubicin for the treatment of advanced STS.
# Patients Randomized 326
Study Groups
Stratification
Significance Demonstrated
Change Identified in Trial
Doxorubicin (N5110) Ifosfamide 3g/m2 (N5109) Ifosfamide 9g/m2 (N5107)
None
No
None
Published abstract: BACKGROUND: Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin. METHODS: This randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m2 every 21 days, ifosfamide 9 g/m2 over 3 days continuous infusion, or ifosfamide 3 g/m2 per day in 3 hours over 3 days. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, and toxicity. FINDINGS: The study included 326 patients. Grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in the ifosfamide arms. Progression-free survival, overall survival, and response rates were not significantly different between the three arms. An independent data monitoring committee reviewed the interim data and recommended early closure of the trial for futility (ie, no significant difference would be shown). INTERPRETATION: Single-agent doxorubicin remains the treatment of choice for patients with advanced soft tissue sarcoma. (Copyright 2007 American Society of Clinical Oncology. Reprinted with permission.) Editor’s summary and comments: This RCT conducted by the European Organization for the Research and Treatment of Cancer (EORTC) and Soft-tissue and Bone Sarcoma Group (STBSG) established that ifosfamide alone should not be considered
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as a first-line therapy for patients with advanced STS. An important message from this well-conducted trial is that novel therapeutic approaches are sorely needed. 6. A randomized phase ii study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Gortzak E, Azzarelli A, Buesa J, et al. Eur J Cancer 2001;37:1096–103.17 Hypothesis: Neoadjuvant chemotherapy for high-risk STS is safe and feasible. # Patients Randomized 150
Study Groups
Stratification
Local treatment only (N 5 75) Preoperative chemotherapy (N575)
<8cm, high grade >8cm, low grade >8cm, high grade Incomplete resection Local recurrence
Significance Demonstrated
Change Identified in Trial
No
Similar 5-year survival rates in both arms
Published abstract: BACKGROUND: The aim of this study was to examine the strategy, feasibility and outcome of neo-adjuvant chemotherapy, with doxorubicin and ifosfamide, in adult patients with ‘high-risk’ soft-tissue sarcomas. METHODS: Patients with ‘high-risk’ soft-tissue sarcomas, defined as tumors R8 cm of any grade, or grade II/III tumors <8 cm, or grade II/III locally recurrent tumors, or grade II/III tumors with inadequate surgery performed in the previous 6 weeks and therefore requiring further surgery, were randomized between either surgery alone or three cycles of 3-weekly doxorubicin 50 mg/m2 intravenous (i.v.) bolus and ifosfamide 5 g/m2 (24 h infusion) before surgery. The type of surgery had to be planned at randomization. Tumors were to be amenable to surgery by amputation, compartmental resection, wide or marginal excision. If chemotherapy was given, surgery had to be performed within 21 days after the last chemotherapy. Patients received postoperative radiotherapy in cases of marginal surgery, microscopically incomplete resection and no further possibility for surgery, and in cases of surgery because of local recurrence. FINDINGS: 150 patients were entered into the study and 134 were eligible, 67 in each arm. The most frequent side-effects of chemotherapy were alopecia, nausea and vomiting (95%), and leukocytopenia (32%). One patient died of neutropenic fever after the first cycle of chemotherapy. Chemotherapy did not interfere with planned surgery and did not affect postoperative wound healing. Limb-salvage was achieved in 88%, amputation was necessary in 12% (all according to the plan at randomization). The trial was closed after completion of phase II, since accrual was too slow to justify expanding the study into the scheduled phase III study. At a median follow-up of 7.3 years, the 5 year disease free survival is estimated at 52% for the no chemotherapy and 56% for the chemotherapy arm (standard error: 7%) (P 5 .3548). The 5 year overall survival for both arms is 64 and 65%, respectively (standard error 7%) (P 5 .2204). INTERPRETATION: Neo-adjuvant-chemotherapy with doxorubicin and ifosfamide at these doses and with this schedule was feasible and did not compromise subsequent treatment, surgery with or without radiotherapy. Although not powered to draw definitive conclusions on benefit, but with an at least 7 year median follow-up, the results render it less likely that major survival benefits will be achieved with this type of chemotherapy. (Copyright Elsevier 2001.) Editor’s summary and comments: Although not designed or powered to determine definitively whether neoadjuvant chemotherapy confers a survival benefit, the 5-year
Randomized Clinical Trials in Soft Tissue Sarcoma
survival rates of both arms were nearly identical. The neoadjuvant regimen was reasonably well tolerated in that not a single patient failed to receive definitive local therapy. However, 18% of patients did progress while receiving neoadjuvant treatment. Whether this is a group of patients who would have been better served by immediate resection or who had extremely aggressive disease biology is a matter for conjecture. The response rate of only 28% to combined doxorubicin and ifosfamide therapy once again points to the need for more targeted and effective systemic agents. 7. Randomized phase ii study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of Sarcoma Alliance for Research Through Collaboration Study 002. Maki RG, Wathen JK, Patel SR, et al. J Clin Onc 2007;19:2755–63.19 Hypothesis: Gemcitabine in combination with docetaxel is superior to gemcitabine alone for recurrent or progressive STS.
# Patients Randomized 122
Study Groups
Stratification
Significance Demonstrated
Gemcitabine (N575) Gemcitabine 1 docetaxel (N575)
Bayesian adaptive randomization
Yes (0.999 posterior probability)
Change Identified in Trial Median overall survival of 17.9 months in the dual-drug regimen compared with 11.5 months
Published abstract: BACKGROUND: Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. METHODS: In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. FINDINGS: One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. INTERPRETATION: Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy. (Copyright 2007 American Society of Clinical Oncology. Reprinted with permission.)
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Editor’s summary and comments: The response rates were 8% and 17% to the gemcitabine and gemcitabine-docetaxel regimens, respectively. Although the dualdrug arm had a significantly longer survival time, the group did contain a higher proportion of patients with leiomyosarcoma, which were more sensitive to the regimen. DISCLOSURE
Authors have nothing to disclose. REFERENCES
1. Cancer facts and figures. In: American Cancer Society. Available at: http://www. cancer.org. 2006. Accessed April 26, 2009. 2. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305. 3. Singer S, Antonescu CR, Riedel E, et al. Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma. Ann Surg 2003;238:358. 4. Pisters PW, Harrison LB, Leung DH, et al. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859. 5. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197. 6. O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002;359:2235. 7. Davis AM, O’Sullivan B, Turcotte R, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 2005;75:48. 8. Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 1993;11:1276. 9. Bramwell V, Rouesse J, Steward W, et al. Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma–reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1994;12:1137. 10. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol 2001;19:1238. 11. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995; 13:1537. 12. Pervaiz N, Colterjohn N, Farrokhyar F, et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 2008;113:573.
Randomized Clinical Trials in Soft Tissue Sarcoma
13. Petrioli R, Coratti A, Correale P, et al. Adjuvant epirubicin with or without Ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol 2002;25:468. 14. Bonvalot S, Cavalcanti A, Le Pechoux C, et al. Randomized trial of cytoreduction followed by intraperitoneal chemotherapy versus cytoreduction alone in patients with peritoneal sarcomatosis. Eur J Surg Oncol 2005;31:917. 15. Mace JR, Keohan ML, Bernardy H, et al. Crossover randomized comparison of intravenous versus intravenous/oral mesna in soft tissue sarcoma treated with high-dose ifosfamide. Clin Cancer Res 2003;9:5829. 16. Lorigan P, Verweij J, Papai Z, et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 2007;25: 3144. 17. Gortzak E, Azzarelli A, Buesa J, et al. A randomized phase II study on neoadjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer 2001;37:1096–103. 18. Canter RJ, Qin LX, Ferrone CR, et al. Why do patients with low-grade soft tissue sarcoma die? Ann Surg Oncol 2008;15:3550. 19. Maki RG, Wathen KJ, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002. J Clin Onc 2007;19:2755–63.
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a
, Murray F. Brennan,
MD
b,
*
KEYWORDS Soft-tissue sarcoma Surgery Chemotherapy Radiation therapy
Soft tissue sarcomas (STS) are a heterogeneous group of rare but potentially lethal, extraskeletal mesenchymal neoplasms. Although the absolute incidence is unknown, it is estimated that approximately 12,000 cases of STS are reported annually in the United States, with 3,500 STS deaths.1 The rarity of these diseases explains, in large part, why few randomized controlled trials (RCTs) have been conducted since the previous issue of this publication. The current understanding of STS biology and, hence, ability to provide safe, effective therapy is predicated upon seminal trials performed in the 1980s and 1990s. The authors briefly summarize the trials presented in the previous issue and then critically assess the more recent publications that have addressed the management of STS. This review does not include pediatric sarcomas or gastrointestinal stromal tumors, the latter of which are covered in a separate article. SURGERY
The original RCT addressing the surgical management of STS had a profound impact, despite being small. Rosenberg and colleagues2 reported that when compared with amputation, wide excision with external beam radiation therapy was associated with equivalent 5-year disease-free and overall survival. Demonstration of equivalence for limb preservation clearly has had important functional and quality of life implications for patients with extremity STS. This trial illustrated that while local recurrence may be associated with distant metastases and death from disease, the relationship is not necessarily causative. Recent retrospective studies have provided additional guidance for our surgical treatment of STS.3
Disclosure: See last page of article. a Department of Surgery, Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI 02908, USA b Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA * Corresponding author. E-mail address: [email protected] (M.F. Brennan). Surg Oncol Clin N Am 19 (2010) 1–11 doi:10.1016/j.soc.2009.09.006 surgonc.theclinics.com 1055-3207/09/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
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RADIATION THERAPY
The impact of postoperative radiation therapy on STS was largely defined by two RCTs. Pisters and colleagues4 reported that adjuvant brachytherapy decreased local recurrence following resection of extremity STS, with the greatest benefit being conferred to patients with high-grade tumors. Yang and colleagues5 demonstrated the effectiveness of external beam radiation in limiting local recurrence for both high and low-grade extremity STS. A more recent report addressed preoperative external beam radiation therapy. O’Sullivan and colleagues6 reported a multicenter randomized trial that demonstrated that neoadjuvant external beam radiation therapy is associated with a higher rate of complications than postoperative adjuvant therapy.6 A subsequent article from the same authors demonstrated that, despite the higher rate of wound complications, neoadjuvant radiation therapy leads to better functional outcomes.7 A small survival advantage was associated with preoperative radiation therapy, yet there was no difference in either local or distant recurrence.
CHEMOTHERAPY
The level 1 chemotherapy trials summarized in the previous issue indicated some improvements in recurrence-free intervals or response rates, but not survival.8–11 A recent meta-analysis which included 1953 patients from 18 trials indicated significant recurrence-free and survival advantages associated with adjuvant doxorubicinbased regimens (Table 1).12 The small absolute recurrence and survival benefits (3%–10%) presented in the meta-analysis must be tempered against the known toxicities of doxorubicin-based systemic regimens. Furthermore, the vast majority of the individual trials included in the meta-analysis failed to demonstrate a significant survival benefit. In a small RCT that closed after 12 years because of poor accrual, Petrioli and colleagues13 found a statistically significant recurrence-free advantage for epirubicinbased postoperative chemotherapy, but no significant difference with respect to overall survival. A single trial with a small number of patients found no benefit to the addition of intraperitoneal chemotherapy following cytoreduction for peritoneal sarcomatosis.14 Mace and colleagues15 showed that, in a small group of patients receiving ifosfamide for STS, a regimen incorporating oral mesna as opposed to exclusively intravenous (IV) mesna was as effective in providing uroprotection. In a large phase III trial, Lorigan and colleagues16 found that single agent ifosfamide should not replace doxorubicin as the first-line agent for advanced STS. A randomized phase II trial of neoadjuvant doxorubicin with ifosfamide for high-risk STS demonstrated that preoperative therapy afforded no survival or recurrence benefit compared with surgery alone.17
Table 1 Meta-analysis of RCTs of adjuvant chemotherapy for localized resectable soft-tissue sarcoma12 Outcome
OR (95% CI)
p
ARR (95% CI)
Local recurrence
0.73 (0.56–0.94)
0.02
3% (0%–7%)
25
Distant recurrence
0.67 (0.56–0.86)
<0.01
9% (5%–14%)
12
Overall recurrence
0.67 (0.56–0.82)
<0.01
10% (5%–15%)
10
Overall survival
0.77 (0.64–0.93)
0.01
6% (2%–11%)
17
Abbreviations: ARR, absolute risk reduction; OR, odds ratio; NNT, number needed to treat.
NNT
Randomized Clinical Trials in Soft Tissue Sarcoma
SUMMARY
The lessons learned from the trials discussed above have influenced our management of STS in meaningful ways. Limb-sparing surgery offers an equivalent chance of cure and a clear functional advantage when compared with amputation for extremity STS. Adjuvant radiation therapy for extremity STS significantly decreases the chance of local recurrence. Preoperative radiation therapy increases the risk of wound complications but is associated with better functional outcomes than postoperative radiation treatment. The decrease in local recurrence afforded by radiation therapy does not affect survival time because most patients who succumb to extremity STS die from disseminated disease. Local recurrence is an important cause of death in cases of retroperitoneal sarcoma,18 yet the evidence supporting a role for radiation therapy in these cases is lacking. Trials addressing the impact of modern, more targeted delivery of external beam radiation for retroperitoneal sarcoma are warranted. With regard to systemic therapy, the body of evidence does not indicate a compelling longterm survival benefit for any systemic regimen. More sophisticated predictors of response are needed, in addition to the identification of novel targets and agents. Slight modifications of approaches already proven to have marginal or no survival benefit will not lead to meaningful progress. FUTURE DIRECTIONS
The rarity of soft tissue sarcomas makes conducting RCTs for these diseases extraordinarily challenging. Multi-institutional trials are needed to define the role of neoadjuvant chemotherapy and radiation therapy for high-risk soft tissue sarcomas, including those arising in the retroperitoneum. More importantly, our increasingly sophisticated understanding of the biologic differences among soft tissue sarcoma subtypes, along with tumor heterogeneity within subtypes, should be incorporated into treatment strategies. The success of future trials for soft tissue sarcoma chemotherapy may depend, in large part, on our ability to define inclusion criteria to focus on more biologically homogeneous groups of patients. LEVEL I EVIDENCE: RANDOMIZED CLINICAL TRIALS
1. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. O’Sullivan B, Davis AM, Turcotte R, et al. Lancet 2002;359:2235–41.6 Hypothesis: The use of preoperative radiation therapy would be associated with a higher rate of wound complications. # Patients Randomized 190
Study Groups
Stratification
Preoperative (N594) Postoperative (N596)
Tumor size (10cm)
Significance Demonstrated Yes
Change Identified in Trial 18% absolute increase in wound complication rate with neoadjuvant therapy
Published abstract: BACKGROUND: External-beam radiotherapy (delivered either preoperatively or postoperatively) is frequently used in local management of sarcomas in the soft tissue of limbs, but the two approaches differ substantially in their potential toxic effects. We aimed to determine whether the timing of external-beam
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radiotherapy affected the number of wound healing complications in soft-tissue sarcoma in the limbs of adults. METHODS: After stratification by tumor size (%10 cm or >10 cm), we randomly allocated 94 patients to preoperative radiotherapy (50 Gy in 25 fractions) and 96 to postoperative radiotherapy (66 Gy in 33 fractions). The primary endpoint was rate of wound complications within 120 days of surgery. Analyses were per protocol for primary outcomes and by intention to treat for secondary outcomes. FINDINGS: Median follow-up was 3$3 years (range 0$27–5$6). Four patients, all in the preoperative group, did not undergo protocol surgery and were not evaluable for the primary outcome. Of those patients who were eligible and evaluable, wound complications were recorded in 31 (35%) of 88 in the preoperative group and 16 (17%) of 94 in the postoperative group (difference 18% [95% CI 5–30], P 5 0$01). Tumor size and anatomic site were also significant risk factors in multivariate analysis. Overall survival was slightly better in patients who had preoperative radiotherapy than in those who had postoperative treatment (P 5 0$0481). INTERPRETATION: Because preoperative radiotherapy is associated with a greater risk of wound complications than postoperative radiotherapy, the choice of regimen for patients with soft-tissue sarcoma should take into account the timing of surgery and radiotherapy, and the size and anatomic site of the tumor. (Copyright Elsevier 2002.) Editor’s summary and comments: The principal question posed by the authors was adequately addressed. Patients who received radiation therapy before surgery had a clinically and statistically significant increase in the rate of wound complications. Forty-five percent of the patients in the neoadjuvant group who developed a wound complication required reoperation for management. Lower extremity sites and tumors larger than 10cm were associated with a greater risk of wound complications. The two groups did not differ with respect to recurrence- or progression-free survival. A small 3-year overall survival advantage (P 5 .05) was noted in the preoperative group (85%) compared with the postoperative group (72%). The short duration of follow-up and the use of overall survival as an endpoint warrant caution because 19% of the deaths in the postoperative group were not due to disease, compared with only 7% in the preoperative group. The authors also note that the study was not adequately powered to detect this difference in a secondary endpoint such as overall survival. In a follow-up article, patients who received postoperative radiation therapy were found to have significantly worse functional outcomes with respect to fibrosis, joint stiffness, edema, and functional scores.7 2. Adjuvant epirubicin with or without ifosfamide for adult soft-tissue sarcoma. Petrioli R, Coratti A, Correale P, et al. Am J Clin Oncol 2002;25:468–73.13 Hypothesis: The use of epirubicin with or without ifosfamide after local therapy for STS would improve the disease-free interval and overall survival duration. # Patients Randomized 88
Study Groups
Stratification
Significance Demonstrated
Epiriubicin Ifosfamide (N545) Observation (N543)
None
Yes
Change Identified in Trial Absolute DFS benefit at 5 years of 25% (P 5 .01) with a trend toward improved OS (P 5 .06)
Abbreviations: DFS, disease-free survival: OS, overall survival.
Published abstract: BACKGROUND: This randomized study compared the efficacy of epirubicin-based adjuvant chemotherapy on the disease-free interval (DFI) and
Randomized Clinical Trials in Soft Tissue Sarcoma
overall survival of patients with high-risk soft-tissue sarcomas. METHODS: After curative surgery, 43 of the 88 enrolled patients were assigned to surgery with or without radiotherapy and 45 to surgery plus chemotherapy (26 epirubicin, 19 epirubicin and ifosfamide) with or without radiotherapy. The trial closed prematurely because of poor patient accrual. FINDINGS: There was a statistically significant difference in the 5-year disease-free survival of the patients receiving adjuvant chemotherapy with or without radiotherapy (69%) and that of those treated with surgery with or without radiotherapy (44%) (P 5 .01). The 5-year survival of the patients treated with adjuvant chemotherapy with or without radiotherapy was 72% as against 47% of those treated with surgery with or without radiotherapy (P 5 .06). The power of the study was 0.65 for both the DFI and overall survival. INTERPRETATION: The results of the study suggest a possible advantage of epirubicin-based adjuvant chemotherapy in patients with soft-tissue sarcoma at high risk of relapse. (Copyright 2002 Lippincott Williams & Wilkins. Reprinted with permission.) Editor’s summary and comments: Although the results of this study indicate a disease-free benefit to epirubicin-based systemic therapy after resection of STS with or without radiation therapy, several important limitations warrant discussion. The authors appropriately exercise caution in interpreting their data by stating that their findings only suggest a benefit to the systemic regimen. Over the course of 12 years, the trial accrued only 88 patients. The small sample size and potential variability in diagnostic and treatment modalities over such a prolonged period are problematic. While 72% of the group that received adjuvant systemic therapy survived for 5 years compared with 47% of the control arm, the result was not significant (P 5 .06). A significant (P 5 .01) overall survival advantage was found when comparing only those patients who received epirubicin plus ifosfamide (84%) to controls (57%). The groups were imbalanced with respect to histologic subtypes and potentially sensitivity to cytotoxic agents. The difference (25%) for disease-free survival was significant (P 5 .01), but the authors found no difference when analyzing local or distant recurrence separately. The findings with respect to a benefit for combination chemotherapy are encouraging, but do not sit well in the context of results from previous, larger RCTs. 3. Randomized trial of cytoreduction followed by intraperitoneal chemotherapy versus cytoreduction alone in patients with peritoneal sarcomatosis. choux C, et al. Eur J Surg Onc 2005;31:917–23.14 Bonvalot S, Cavalcanti A, Le Pe Hypothesis: The use of intraperitoneal chemotherapy would be associated with a decrease in locoregional recurrence and increase in survival after optimal cytoreduction for peritoneal carcinomatosis. # Patients Randomized 38
Study Groups
Stratification
Significance Demonstrated
Change Identified in Trial
IP chemotherapy (n519) No chemotherapy (n519)
None
No
No differences in recurrence-free or overall survival
Published abstract: BACKGROUND: To decrease loco-regional relapse after complete resection of peritoneal sarcomatosis (PS), the role of intraperitoneal chemotherapy (IPEC) was prospectively evaluated. METHODS: Patients (pts) with completely resected PS were randomized between adjunction of IPEC or not. IPEC consisted of doxorubicin, 0.1 mg/kg and cisplatin, 15 mg/m2 per day for 5 consecutive days. FINDINGS: Thirty-eight consecutive pts have been randomized, 19 in each
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group. Ratio of retroperitoneal (RPS) and visceral (VS) sarcomatosis were 9/10 and 6/ 13 in IPEC- and IPEC1 groups, respectively. Histoprognostic grade, Sugarbaker’s score and mean number of resected organs were similar in both groups. There were no toxic deaths and morbidity was similar in both groups (four pts in each group). The median follow-up is 60 months. The median local relapse-free, metastatic relapse-free survival and overall survival were identical in both groups (12.5, 18 and 29 months, respectively), with no difference between RPS and VERSUS sarcomatosis. INTERPRETATION: Administration of IPEC after a macroscopically complete surgery did not allow increasing greatly the outcome of pts. Complete surgery remains the cornerstone of the treatment of patients with sarcomatosis with best results for lowgrade sarcomatosis. (Copyright Elsevier 2005.) Editor’s summary and comments: Based upon the variable success of intraperitoneal chemotherapy (IPEC) with or without hyperthermia for carcinomatosis, the authors attempted to define the role of IPEC following optimal cytoreduction of sarcomatosis. The identical median overall survival time of 29 months in both groups leaves little room for rationalizing the use of IPEC after surgical treatment of sarcomatosis. However, this trial included a very small number of patients and the breakdown of histologic subtypes is not provided. Larger trials with the inclusion of hyperthermia warrant consideration given the high likelihood of locoregional relapse in patients with sarcomatosis. 4. Crossover randomized comparison of intravenous versus intravenous/oral mesna in soft tissue sarcoma treated with high-dose ifosfamide. Mace JR, Keohan ML, Bernardy H, et al. Clin Can Res 2003;9:5829–34.15 Hypothesis: The use of oral plus IV mesna in patients receiving ifosfamide for STS would be equivalent to IV mesna. # Patients Randomized 17
Study Groups
Stratification
Significance Demonstrated
Change Identified in Trial
Crossover comparison
None
No
No difference in the rate of hemorrhagic cystitis with either mesna formulation
Published abstract: BACKGROUND: We conducted our study to determine the pharmacokinetics (PK) and clinical efficacy of oral mesna in patients receiving ifosfamide for soft tissue sarcoma. METHODS: Seventeen patients were enrolled in a randomized prospective Phase I/II study. Seventeen patients were exposed to study medication. Ifosfamide was given at a dose of 2 g/m2/day for 5 days on a 21-day cycle. Before the first cycle, all patients were randomized onto a crossover design and received either the approved i.v. or i.v./oral mesna regimen, with crossover for the second cycle of chemotherapy. The i.v. mesna regimen consisted of dosings (20% ifosfamide dose) at 0, 4, and 8 h. The i.v./oral arm consisted of an i.v. mesna dosing (20% ifosfamide dose) at 0 h, followed by oral tablet dosing (40% ifosfamide dose) at 2 and 6 h. In-patient clinical monitoring and phlebotomy and urine sampling for mesna, dimesna, and ifosfamide PK were performed on all chemotherapy days. FINDINGS: Thirteen patients were evaluable for PK and 17 for efficacy and toxicity. No significant differences were detected in the plasma PK of the concomitantly infused ifosfamide. Rates of hemorrhagic cystitis were similar across mesna schedules. Four of 10 evaluable patients demonstrated objective response.
Randomized Clinical Trials in Soft Tissue Sarcoma
INTERPRETATION: On the basis of our study, an i.v./oral mesna regimen is at least as uroprotective as the approved i.v. regimen. The i.v./oral regimen will improve patient tolerance and convenience, allow for a reduction in elective hospitalizations for ifosfamide chemotherapy, reduce the potential morbidity associated with inpatient administration of chemotherapy, and likely result in decreased costs of care. (Copyright 2003 by the American Association for Cancer Research. Reprinted with permission.) Editor’s summary and comments: This small study suggested that substituting a portion of the IV mesna regimen for tablets in STS patients receiving ifosfamide yields an equivalent approach. In turn, patients may require less inpatient care for systemic therapy administration. 5. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma group study. Lorigan P, Verweij J, Papai Z, et al. J Clin Onc 2007;25:3144–50.16 Hypothesis: Single-agent ifosfamide would be associated with equivalent progression-free survival compared with doxorubicin for the treatment of advanced STS.
# Patients Randomized 326
Study Groups
Stratification
Significance Demonstrated
Change Identified in Trial
Doxorubicin (N5110) Ifosfamide 3g/m2 (N5109) Ifosfamide 9g/m2 (N5107)
None
No
None
Published abstract: BACKGROUND: Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin. METHODS: This randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m2 every 21 days, ifosfamide 9 g/m2 over 3 days continuous infusion, or ifosfamide 3 g/m2 per day in 3 hours over 3 days. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, and toxicity. FINDINGS: The study included 326 patients. Grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in the ifosfamide arms. Progression-free survival, overall survival, and response rates were not significantly different between the three arms. An independent data monitoring committee reviewed the interim data and recommended early closure of the trial for futility (ie, no significant difference would be shown). INTERPRETATION: Single-agent doxorubicin remains the treatment of choice for patients with advanced soft tissue sarcoma. (Copyright 2007 American Society of Clinical Oncology. Reprinted with permission.) Editor’s summary and comments: This RCT conducted by the European Organization for the Research and Treatment of Cancer (EORTC) and Soft-tissue and Bone Sarcoma Group (STBSG) established that ifosfamide alone should not be considered
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as a first-line therapy for patients with advanced STS. An important message from this well-conducted trial is that novel therapeutic approaches are sorely needed. 6. A randomized phase ii study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Gortzak E, Azzarelli A, Buesa J, et al. Eur J Cancer 2001;37:1096–103.17 Hypothesis: Neoadjuvant chemotherapy for high-risk STS is safe and feasible. # Patients Randomized 150
Study Groups
Stratification
Local treatment only (N 5 75) Preoperative chemotherapy (N575)
<8cm, high grade >8cm, low grade >8cm, high grade Incomplete resection Local recurrence
Significance Demonstrated
Change Identified in Trial
No
Similar 5-year survival rates in both arms
Published abstract: BACKGROUND: The aim of this study was to examine the strategy, feasibility and outcome of neo-adjuvant chemotherapy, with doxorubicin and ifosfamide, in adult patients with ‘high-risk’ soft-tissue sarcomas. METHODS: Patients with ‘high-risk’ soft-tissue sarcomas, defined as tumors R8 cm of any grade, or grade II/III tumors <8 cm, or grade II/III locally recurrent tumors, or grade II/III tumors with inadequate surgery performed in the previous 6 weeks and therefore requiring further surgery, were randomized between either surgery alone or three cycles of 3-weekly doxorubicin 50 mg/m2 intravenous (i.v.) bolus and ifosfamide 5 g/m2 (24 h infusion) before surgery. The type of surgery had to be planned at randomization. Tumors were to be amenable to surgery by amputation, compartmental resection, wide or marginal excision. If chemotherapy was given, surgery had to be performed within 21 days after the last chemotherapy. Patients received postoperative radiotherapy in cases of marginal surgery, microscopically incomplete resection and no further possibility for surgery, and in cases of surgery because of local recurrence. FINDINGS: 150 patients were entered into the study and 134 were eligible, 67 in each arm. The most frequent side-effects of chemotherapy were alopecia, nausea and vomiting (95%), and leukocytopenia (32%). One patient died of neutropenic fever after the first cycle of chemotherapy. Chemotherapy did not interfere with planned surgery and did not affect postoperative wound healing. Limb-salvage was achieved in 88%, amputation was necessary in 12% (all according to the plan at randomization). The trial was closed after completion of phase II, since accrual was too slow to justify expanding the study into the scheduled phase III study. At a median follow-up of 7.3 years, the 5 year disease free survival is estimated at 52% for the no chemotherapy and 56% for the chemotherapy arm (standard error: 7%) (P 5 .3548). The 5 year overall survival for both arms is 64 and 65%, respectively (standard error 7%) (P 5 .2204). INTERPRETATION: Neo-adjuvant-chemotherapy with doxorubicin and ifosfamide at these doses and with this schedule was feasible and did not compromise subsequent treatment, surgery with or without radiotherapy. Although not powered to draw definitive conclusions on benefit, but with an at least 7 year median follow-up, the results render it less likely that major survival benefits will be achieved with this type of chemotherapy. (Copyright Elsevier 2001.) Editor’s summary and comments: Although not designed or powered to determine definitively whether neoadjuvant chemotherapy confers a survival benefit, the 5-year
Randomized Clinical Trials in Soft Tissue Sarcoma
survival rates of both arms were nearly identical. The neoadjuvant regimen was reasonably well tolerated in that not a single patient failed to receive definitive local therapy. However, 18% of patients did progress while receiving neoadjuvant treatment. Whether this is a group of patients who would have been better served by immediate resection or who had extremely aggressive disease biology is a matter for conjecture. The response rate of only 28% to combined doxorubicin and ifosfamide therapy once again points to the need for more targeted and effective systemic agents. 7. Randomized phase ii study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of Sarcoma Alliance for Research Through Collaboration Study 002. Maki RG, Wathen JK, Patel SR, et al. J Clin Onc 2007;19:2755–63.19 Hypothesis: Gemcitabine in combination with docetaxel is superior to gemcitabine alone for recurrent or progressive STS.
# Patients Randomized 122
Study Groups
Stratification
Significance Demonstrated
Gemcitabine (N575) Gemcitabine 1 docetaxel (N575)
Bayesian adaptive randomization
Yes (0.999 posterior probability)
Change Identified in Trial Median overall survival of 17.9 months in the dual-drug regimen compared with 11.5 months
Published abstract: BACKGROUND: Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. METHODS: In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. FINDINGS: One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. INTERPRETATION: Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy. (Copyright 2007 American Society of Clinical Oncology. Reprinted with permission.)
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Editor’s summary and comments: The response rates were 8% and 17% to the gemcitabine and gemcitabine-docetaxel regimens, respectively. Although the dualdrug arm had a significantly longer survival time, the group did contain a higher proportion of patients with leiomyosarcoma, which were more sensitive to the regimen. DISCLOSURE
Authors have nothing to disclose. REFERENCES
1. Cancer facts and figures. In: American Cancer Society. Available at: http://www. cancer.org. 2006. Accessed April 26, 2009. 2. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305. 3. Singer S, Antonescu CR, Riedel E, et al. Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma. Ann Surg 2003;238:358. 4. Pisters PW, Harrison LB, Leung DH, et al. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859. 5. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197. 6. O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002;359:2235. 7. Davis AM, O’Sullivan B, Turcotte R, et al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 2005;75:48. 8. Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 1993;11:1276. 9. Bramwell V, Rouesse J, Steward W, et al. Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma–reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1994;12:1137. 10. Frustaci S, Gherlinzoni F, De Paoli A, et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. J Clin Oncol 2001;19:1238. 11. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995; 13:1537. 12. Pervaiz N, Colterjohn N, Farrokhyar F, et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 2008;113:573.
Randomized Clinical Trials in Soft Tissue Sarcoma
13. Petrioli R, Coratti A, Correale P, et al. Adjuvant epirubicin with or without Ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol 2002;25:468. 14. Bonvalot S, Cavalcanti A, Le Pechoux C, et al. Randomized trial of cytoreduction followed by intraperitoneal chemotherapy versus cytoreduction alone in patients with peritoneal sarcomatosis. Eur J Surg Oncol 2005;31:917. 15. Mace JR, Keohan ML, Bernardy H, et al. Crossover randomized comparison of intravenous versus intravenous/oral mesna in soft tissue sarcoma treated with high-dose ifosfamide. Clin Cancer Res 2003;9:5829. 16. Lorigan P, Verweij J, Papai Z, et al. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 2007;25: 3144. 17. Gortzak E, Azzarelli A, Buesa J, et al. A randomized phase II study on neoadjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer 2001;37:1096–103. 18. Canter RJ, Qin LX, Ferrone CR, et al. Why do patients with low-grade soft tissue sarcoma die? Ann Surg Oncol 2008;15:3550. 19. Maki RG, Wathen KJ, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002. J Clin Onc 2007;19:2755–63.
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