When to Consider Adjuvant/Neoadjuvant Therapy for Adult Soft-Tissue Sarcoma

In patients with adult soft-tissue sarcoma (ASTS), the use and timing of adjuvant chemotherapy or chemoradiotherapy remains controversial. The appropriate target population is generally accepted as International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) stage III extremity or trunk sarcomas (ie, > 5 cm, grade 3/4, located deep to the superficial fascia, with no evidence of metastases). After definitive local treatment, the 5-year disease-free and overall survival rates in this population are approximately 52% and 56%.[1]

Meta-analysis

In 1997, the Sarcoma Meta-analysis Collaboration (SMAC)[2] reported a meta-analysis of survival outcomes of randomized trials of adjuvant chemotherapy (doxorubicin alone or in combination), for which accrual was completed before December 1992. Data were available on 1,544 patients in 14 trials. The investigators found a trend toward improvement in overall survival (hazard ratio [HR] = 0.89; 95% confidence interval [CI] = 0.76-1.03; P = .12), resulting in an absolute benefit in the chemotherapy arm of 4% at 10 years. Interestingly, significant improvements were seen in both local recurrence-free interval (HR = 0.73; 95% CI = 0.56-0.94; P = .016; absolute benefit of 6%); and distant recurrence-free interval (HR = 0.70; 95% CI = 0.57-0.85; P = .0003; absolute benefit of 10%).

An unplanned subgroup analysis of the cohort of 886 patients with extremity soft-tissue sarcoma revealed a significant improvement in overall survival (HR = 0.80; P = .029), for an absolute benefit of 7%. This meta-analysis had a number of limitations: (1) a possible dilution of the beneficial effects of chemotherapy for extremity ASTS by inclusion of tumors at all locations; (2) a similar dilution of effects of chemotherapy from inclusion of patients with low-grade (5%) or unknown grade (28%) tumors; (3) none of the chemotherapy regimens (except in one small unpublished study) included ifosfamide; (4) long accrual period back to 1973; (5) suboptimal chemotherapy compliance; and (6) variable protocol designs.

Italian Trial

Some of these limitations were addressed by an Italian Cooperative Group study, which included 104 patients with high-grade extremity ASTS ≥ 5 cm in size. Patients were randomized between postoperative high-dose epirubicin (Ellence) and ifosfamide for four cycles, or no chemotherapy. Because of the potential toxicity of the regimen, only patients ≤ 65 years old were included. Four patients did not complete therapy due to toxicity or refusal. Despite the use of granulocyte colony-stimulating factor (G-CSF, Neupogen), grade 4 leukopenia occurred in 35%, and neutropenic fever in 13%.

When the trial was first reported in 2001, the median follow-up was 60 months.[3] At 2 years, disease-free survival was 72% in the chemotherapy arm vs 45% in the control group (P = .04) but was not significantly different at 4 years (50% vs 37%; P = .19). For overall survival, the reverse was true-at 2 years, disease-free survival was 85% vs 72% (P = .10), and at 4 years, 69% vs 50% (P = .04), respectively. However, when the trial was reported at a longer follow-up of 90 months, overall survival was no longer significantly different-57% for chemotherapy recipients vs 42% for control patients.[4] This trial was originally designed to recruit twice the number of patients, but was discontinued halfway through recruitment due to an early-stopping rule based on disease-free survival.

EORTC Studies

The European Organisation for Research and Treatment of Cancer (EORTC) initiated a randomized phase II trial of neoadjuvant chemotherapy[5] with the intention of proceeding to a phase III study if progression during chemotherapy was infrequent and accrual was adequate. Poor accrual led to the study's termination after entry of 150 patients. Approximately 89% (134 patients) were deemed eligible, and had high-risk (> 8 cm, any grade; < 8 cm, grade 2/3; grade 2/3, local recurrence/inadequate first surgery) extremity, head and neck, trunk, and pelvis sarcomas. Patients were given three cycles of preoperative doxorubicin and ifosfamide or no chemotherapy, and then proceeded to surgery with or without postoperative radiotherapy. No postoperative chemotherapy was planned.

At a median follow-up of 7.3 years, 5-year actuarial outcomes for chemotherapy vs control were 56% vs 52% for disease-free survival (P = .36), and 65% vs 64% (P = .22) for overall survival. One toxic death occurred in the neoadjuvant chemotherapy group, but no difference was seen in postoperative complications. Approximately 12% of patients progressed on neoadjuvant chemotherapy. Isolated local recurrence rates were 12%, with no difference between the arms, but 25% of patients had local recurrence in the setting of distant metastases. Although underpowered to observe significant differences in disease-free or overall survival, this trial[5] was 50% larger than the Italian study.[3,4] Major criticisms of this study were that the dose of ifosfamide (5 g/m²) was low by current standards (whereas the doxorubicin dose was adequate at 75 mg/m²) and the total duration of chemotherapy was short.

Another major randomized trial of adjuvant chemotherapy, EORTC 62931, completed accrual in December 2003 but is not yet ready for analysis. Following surgery, 351 patients with grade 2/3 tumors of all sites were given postoperative doxorubicin/ifosfamide for five cycles or no chemotherapy. Radiotherapy, if needed, was postponed until the completion of chemotherapy. The duration of chemotherapy was longer than in the previous neoadjuvant EORTC study, but the doses of doxorubicin and ifosfamide per course were the same.

Retrospective Studies

Although of more limited value than prospective randomized studies, two retrospective series have provided some interesting hypothesis-generating data. In 2004, Grobmyer et al[6] reported on a combined analysis of outcomes for patients with stage III extremity ASTS seen between 1990 and 2001 in two centers-Memorial Sloan-Kettering Cancer Center (MSKCC) and the Dana-Farber Cancer Institute (DFCI). A majority of patients (n = 282) were treated with surgery alone, but 74 patients received neoadjuvant chemotherapy with doxorubicin and ifosfamide. This latter group differed from the former in a number of ways, including the fact that the patients receiving neoadjuvant chemotherapy were younger (40 vs 62 years), had larger tumors (12 vs 10 cm), and had more synovial sarcomas.

In multivariate analysis, patients who received neoadjuvant chemotherapy had a better disease-specific survival (P = .02), with the main benefit seen in patients with tumors > 10 cm.[6] Thus, disease-specific survival for patients with tumors > 10 cm was better for those who had neoadjuvant chemotherapy, with an HR of 0.62 (95% CI = 0.39-0.98). For those with smaller tumors (5-10 cm), the HR showed a trend in the opposite direction (1.2; 95% CI = 0.64-2.3) but was not significant.

A larger retrospective study, combining data from MSKCC and M.D. Anderson Cancer Center (MDACC) was reported by Cormier et al in 2004.[7] Between 1984 and 1999, 338 patients with stage III extremity ASTS were treated by local therapy only, and 336 similar patients received doxorubicin-based adjuvant chemotherapy pre- or postoperatively. Of note, MDACC contributed 43% of patients, but 66% of this group received adjuvant chemotherapy, whereas MSKCC contributed 57% of patients, but only 38% received adjuvant chemotherapy, reflecting the prevailing practice in these institutions. At a median follow-up of 6.1 years for the combined groups, respective 5-year local and distant relapse-free survivals were 83% and 56%, and disease-specific survival was 61%. Cox regression analyses showed a time-varying effect associated with chemotherapy, such that during the first year the HR for disease-specific survival, favoring the use of chemotherapy, was 0.37 (95% CI = 0.20-0.69; P = .002). Thereafter, the HR was reversed (1.36; 95% CI = 1.02-1.81; P = .04).

Results from the largest series of patients treated with neoadjuvant chemoradiotherapy at a single center-the University of California, Los Angeles (UCLA)-were updated by Eilber et al in 2001.[8] Between 1975 and 1988, patients with nonmetastatic extremity, grade 2/3 ASTS were treated in a series of neoadjuvant protocols. These initially comprised doxorubicin with different doses of concurrent radiotherapy and evolved into a standard radiotherapy protocol of 28 Gy with doxorubicin/cisplatin ± ifosfamide. The total number of patients included in all protocols was 496, and, at 5 and 10 years respectively, local recurrence rates were 11% and 15%, and overall survival rates were 71% and 66%.

In multivariate analysis, patients showing < 95% necrosis after chemoradiotherapy had an increased hazard of local recurrence (2.51; P = .56) and death (1.86; P = .06).[8] Those with high-grade, locally recurrent, or large tumors also did significantly worse. The percentage of patients who achieved a > 95% pathologic necrosis increased to 48% with the addition of ifosfamide, as compared with 13% for patients in all the other protocols combined (309 patients had assessable tumor for pathologic necrosis).

The same group combined their data with MSKCC[9] to retrospectively evaluate the effects of different types of chemotherapy on specific histologic subtypes of ASTS. For synovial sarcoma, between 1990 and 2002, 101 patients were seen at the two centers, 68 of whom received ifosfamide-based chemotherapy and 33, no chemotherapy. The median follow-up was 58 months; 4-year distant recurrence survival rates for ifosfamide chemotherapy vs none were 74% vs 46% (P = .02), and disease-specific survival rates were 88% vs 67% (P = .01). In multivariate analysis, ifosfamide-based chemotherapy and smaller size were significantly associated with improved disease-specific survival. As there were limited data on the use of doxorubicin without ifosfamide for that time period, this was not investigated.

Similar analyses were performed for liposarcoma, evaluating both doxorubicin- and ifosfamide-based therapies.[9] Between 1975 and 1990, 83 patients received doxorubicin-based chemotherapy and 46, no chemotherapy. Five-year disease-specific survival rates for doxorubicin-based chemotherapy vs none were 64% vs 56% (P = .28). Multivariate analysis confirmed that the use of doxorubicin-based chemotherapy did not improve disease-specific survival. In contrast, between 1990 and 2003, 126 patients with liposarcoma were seen, of whom 63 received ifosfamide-based chemotherapy and 63, no chemotherapy. Five-year distant recurrence-free survival rates for patients receiving ifosfamide-based chemotherapy vs none were 81% vs 63% (P = .02), and disease-specific survival rates were 92% vs 65% (P = .03). These intriguing findings suggest that ifosfamide-based chemotherapy may be particularly effective against synovial sarcomas and liposarcomas. Prospective studies are clearly needed.

Neoadjuvant Radiochemotherapy Trials

For large aggressive ASTS, the integration of radiotherapy and chemotherapy in the preoperative setting has many attractions, as it ensures that both treatments are delivered as soon as possible. A group in Boston[10] reported results of a pilot study in 48 patients with high-grade extremity ASTS greater than 8 cm in size. All patients received three cycles of preoperative MAID chemotherapy (mesna, doxorubicin [Adriamycin], ifosfamide, and dacarbazine) integrated with radiotherapy, 44 Gy (given as two 22-Gy courses), followed by surgery. The protocol was completed with a further three cycles of postoperative MAID and a further 16 Gy of radiotherapy for those with positive margins.

Results were compared with those of a selected control group of 48 patients, matched for age, tumor size/grade, and era (1988-1997). Five-year actuarial outcomes were significantly better for the chemoradiotherapy group in terms of distant metastasis-free survival (75% vs 44%; P = .0016), disease-free survival (70% vs 42%; P = .0002), and overall survival (87% vs 58%; P = .0003).[10] However, complications were significant, with febrile neutropenia occurring in 25% of cases (despite G-CSF administration), moist desquamation of the wound area in 29%, and significant wound healing problems also in 29%. Fracture of bone occurred in 4%, and there was one case of myelodysplasia at 38 months. No data were presented on late fibrosis or limb function.

The results were felt sufficiently encouraging to further test the regimen in a multicenter Radiation Therapy Oncology Group (RTOG) trial (RTOG 9514). This prospective single-arm study[11] included 64 patients with high-grade extremity/body wall ASTS ≥ 8 cm, who received identical chemoradiotherapy to that given in the Boston study. When results were reported in 2006, 3-year actuarial outcomes were already significantly worse than the 5-year outcomes reported by the Boston group. Thus, for the RTOG and Boston studies, respectively, distant disease-free survival rates were 64.5% vs 75%; disease-free survival rates were 57% vs 70%; and overall survival rates were 75% vs 87%. Fatal chemotherapy-related toxicity occurred in three patients (5%), and grade 4 toxicities were seen in 83% of patients (hematologic in 78% and nonhematologic in 19%). Only 59% of patients were able to complete six cycles of MAID. These results do not support the widespread implementation of such a protocol.[12]

Conclusions

To summarize, the potential benefits of adjuvant/neoadjuvant therapy are (1) delay in local/distant recurrence, (2) possible improvement of overall survival, (3) the potential to increase operability for large tumors and proportion of limb salvage operations, and (4) possible histology-specific effects of different types of chemotherapy. The potential risks of such therapy include (1) local progression during chemotherapy, (2) short-term toxicities, which may be chemotherapy related or associated with poor wound healing, and (3) long-term toxicities, such as cardiac or renal effects of chemotherapy and local chemoradiotherapy effects, such as fibrosis and fractures. Of note, in most studies of aggressive combination chemotherapy patients more than 65 years of age have been excluded, which can amount to 20%-30% of patients with ASTS. Many of the risks are enhanced by integration of chemotherapy and radiotherapy.

Based on the above review, I would draw the following conclusions. First, adjuvant/neoadjuvant therapy may be considered for patients with stage III ASTS. The greatest evidence for benefit is in patients with extremity or trunk tumors. Second, integration of chemotherapy and radiotherapy delivers both treatments in an optimal timeframe, but causes more toxicity. Third, chemo(radio)therapy mainly improves local control and delays metastasis, whereas improvements in overall survival are marginal and disappear over time. Fourth, such treatment should be used with caution in patients who are older than 65 years or who have comorbidities. Fifth, chemotherapy should include both an anthracycline and ifosfamide, but data on possible histology-specific effects of ifosfamide are hypothesis-generating. Sixth, the timing of therapy (neoadjuvant/adjuvant) may not be critical, but should be part of a multidisciplinary plan. Finally, results of the EORTC 62931 may shed some further light on these controversies.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

This article is part of a series based on the proceedings of a special symposium of the Intergroup Coalition Against Sarcomas, "Progress in Translational and Clinical Research for Sarcomas of Adults," which was held October 8, 2006, in Seattle. The series is guest edited by Margaret von Mehren, MD, Director of Sarcoma Oncology at Fox Chase Cancer Center, Philadelphia.

References:

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2. Sarcoma Meta-analysis Collaboration: Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: Meta-analysis of individual data. Lancet 350:1647-1654, 1997.

3. 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 19:1238-1247, 2001.

4. Frustaci S, De Paoli A, Bidoli E, et al: Ifosfamide in the adjuvant therapy of soft tissue sarcomas. Oncology 65:80-84, 2003.

5. Gortzak E, Azzarelli A, Buesa J, et al: A randomized phase II study on neo-adjuvant chemotherapy for 'high-risk' adult soft-tissue sarcoma. Eur J Cancer 37:1096-1103, 2001.

6. Grobmyer SR, Maki RG, Demetri GD, et al: Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol 15:1667-1672, 2004.

7. Cormier JN, Huang X, Xing Y, et al: Cohort analysis of patients with localized, high-risk, extremity soft tissue sarcoma treated at two cancer centers: Chemotherapy-associated outcomes. J Clin Oncol 22:4567-4574, 2004.

8. Eilber FC, Rosen G, Eckardt J, et al: Treatment-induced pathologic necrosis: A predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas. J Clin Oncol 19:3203-3209, 2001.

9. Eilber FC, Tap W, Nelson SD, et al: Advances in chemotherapy for patients with extremity soft tissue sarcoma. Orthop Clin North Am 37:15-22, 2006.

10. DeLaney TF, Spiro IJ, Suit HD, et al: Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 56:1117-1127, 2003.

11. Kraybill WG, Harris J, Spiro IJ, et al: Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. J Clin Oncol 24:619-625, 2006.

12. Pisters PWT: Preoperative chemotherapy and split-course radiation therapy for patients with localized soft-tissue sarcomas: Home run, base hit, or strike out? J Clin Oncol 24:549-551, 2006.