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Journal of Clinical Oncology, Vol 24, No 4 (February 1), 2006: pp. 619-625 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.5577 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 From the Roswell Park Cancer Institute, Buffalo, NY; Beth Israel Cancer Center, New York, NY; Radiation Therapy Oncology Group, Philadelphia, PA; Massachusetts General Hospital; Francis H. Burr Proton Therapy Center, Boston, MA; Johns Hopkins Medical Center, Baltimore, MD; University of Michigan Medical Center, Ann Arbor, MI; H. Lee Moffitt Cancer Center, Tampa, FL; Dartmouth Hitchcock Medical Center, Lebanon, NH Address reprint requests to William G. Kraybill, MD, Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263; e-mail: william.kraybill{at}roswellpark.org
PURPOSE: On the basis of a positive reported single-institution pilot study, the Radiation Therapy Oncology Group initiated phase II trial 9514 to evaluate its neoadjuvant regimen in a multi-institutional Intergroup setting.
PATIENTS AND METHODS: Eligibility included a high-grade soft tissue sarcoma RESULTS: Sixty-six patients were enrolled, of whom 64 were analyzed. Seventy-nine percent of patients completed their preoperative CT and 59% completed all planned CT. Three patients (5%) experienced fatal grade 5 toxicities (myelodysplasias, two patients; infection, one patient). Another 53 patients (83%) experienced grade 4 toxicities; 78% experienced grade 4 hematologic toxicity and 19% experienced grade 4 nonhematologic toxicity. Sixty-one patients underwent surgery. Fifty-eight of these were R0 resections, of which five were amputations. There were three R1 resections. The estimated 3-year rate for local-regional failure is 17.6% if amputation is considered a failure and 10.1% if not. Estimated 3-year rates for disease-free, distant–disease-free, and overall survival are 56.6%, 64.5%, and 75.1%, respectively. CONCLUSION: This combined-modality treatment can be delivered successfully in a multi-institutional setting. Efficacy results are consistent with previous single-institution results.
Management approaches for newly diagnosed primary sarcoma include wide local resection combined with preoperative1,2 or postoperative radiotherapy,3,4 or wide local excision alone for small superficial lesions.5,6 These treatments control the local tumor in 80% to 95% of patients, and the majority of patients treated with conservative procedures benefit from good extremity function.7,8 However, patients with high-grade sarcomas (grades 2 or 3 in a three-tier grading system or grades 3 or 4 in a four-tier grading system) larger than 5 cm are at significant risk of distant treatment failure and ultimately death from metastatic disease.9 The risk of developing distant metastases in patients with lesions 5.1 to 10 cm is 34% and increases to 43% for lesions 10.1 to 15 cm and to 58% for lesions 15.1 to 20 cm.8 The role of adjuvant chemotherapy remains controversial because of the absence of convincing level 1 evidence. The 1997 meta-analysis of 14 trials testing doxorubicin-based postoperative chemotherapy found that it significantly reduced local failures and distant metastases, and improved disease-free survival (DFS), but with a trend toward better survival.10,11 The subset of patients with extremity lesions experienced the greatest benefit, with a 7% improvement in survival.10 Since the publication of the meta-analysis, three additional randomized trials using more modern dosing schedules have explored the benefit of doxorubicin- or ifosfamide-based chemotherapy.12-15 These trials failed to demonstrate improvement in survival. The importance of long-term follow-up in assessing the benefit from chemotherapy was shown in a recent report from Memorial Sloan-Kettering Cancer Center and M.D. Anderson Cancer Center.16 Adjuvant doxorubicin-based chemotherapy was administered to 336 patients (50%), whereas 338 patients (50%) were treated with local therapy only. Both groups of patients were well matched for tumor location, histopathologic subtype, and resection margin. With a median follow-up of 6.1 years, the benefit of doxorubicin-based chemotherapy in patients with high-risk extremity soft tissue sarcomas (STSs) was not sustained beyond 1 year. The risk of recurrence in the treated patients beyond 1 year was greater than in patients not receiving chemotherapy, with a hazard ratio of 1.36 (95% CI, 1.02 to 1.81; P = .04).
In another recent article from Memorial Sloan-Kettering Cancer Center and the Dana Faber Cancer Institute, Grobmyer et al17 compared patients with high-grade STS tumors Spiro et al18 instituted a program of aggressive chemotherapy interdigitated with radiotherapy for patients with large, high-grade extremity sarcomas. This was a pilot study of neoadjuvant modified mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy, with split-course radiation therapy followed by resection and postoperative adjuvant MAID chemotherapy. With median follow-up of 13 months, the actuarial 5-year local control, DFS rate, and overall survival (OS) rates for MAID patients were 100%, 84%, and 93%, respectively, compared with retrospectively matched patients treated with radiation and surgery with results of 97%, 45%, and 60%, respectively. On the basis of these data, the Radiation Therapy Oncology Group (RTOG) initiated a phase II trial to evaluate the efficacy and toxicity of a modified MAID regimen in similar patients in a multi-institutional setting.
Patient Inclusion Criteria Protocol eligibility required the patients to have large (  8 cm), high-grade (grade 2 or 3 in a three-tier grading system) primary or locally recurrent STSs of the extremities or torso, and have  four pulmonary lesions that were all 3 mm in diameter each. Patients who were protocol candidates were to be seen by clinicians in surgery, medical oncology, and radiation oncology departments before signing the consent. Eligibility was based on the clinical judgment of R0 surgical intent on completion of neoadjuvant chemotherapy and radiation therapy. Patients were seen by clinicians in surgery, radiation oncology, medical oncology, and if necessary, plastic surgery departments for operative planning and evaluation. In addition, patients were to be 18 years of age, and have a Karnofsky performance status of 80%, with normal heart function (study of ejection fraction 50% within the last 6 months) and normal laboratory values. All patients were required to sign an institutional review board–approved consent form. Patients with rhabdomyosarcoma, extraosseous Ewing, primitive neuroectodermal tumors, osteosarcoma or chondrosarcoma, Kaposi's sarcoma, angiosarcoma of the scalp/face, or any sarcoma of the head and neck were ineligible.
Treatment Plan: Chemotherapy
Postoperative chemotherapy was instituted between 21 and 35 days following surgery. The modified MAID chemotherapy regimen (Fig 1) was mesna 2,500 mg/m2/d as a continuous intravenous infusion via a peripheral line days 1 to 4, doxorubicin 20 mg/m2/d as a continuous intravenous infusion via a central line days 1 to 3, ifosfamide 2,500 mg/m2/d as a continuous intravenous infusion via a peripheral line days 1 to 3, and dacarbazine 225 mg/m2/d as a continuous intravenous infusion via a central line days 1 to 3. Granulocyte colony-stimulating factor (filgrastim) 5 µg/kg/d was administered as a subcutaneous injection starting on day 5 and continuing daily until WBC count recovered (granulocyte count > 1,500/mm3). Drug doses were attenuated for both hematologic and nonhematologic toxicity according to schedules in the protocol. For hematologic toxicity, the most severe toxicity was used to determine the degree of attenuation.
Treatment Plan: Radiation Therapy
Treatment Plan: Surgery
Pathologic Evaluation
Study End Points After completion of neoadjuvant therapy, clinical response was assessed by CT or MRI using the Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria and pathologic response of the operative specimens according to the percentage of viable tumor.21 The National Cancer Institute Common Toxicity Criteria, version 1.0, were used for chemotherapy toxicity and the RTOG acute and late toxicity criteria were used to describe toxicity secondary to radiotherapy.22
Statistical Analysis and Measurement of Response Amputation for any indication initially was considered a treatment failure because the protocol's aim was to achieve limb preservation. LRF and DFS rates were also calculated without amputation as a treatment failure to allow comparison with other series. Estimates for time to LRF and distant metastases were calculated using the method of cumulative incidence; this accounts for the competing risks of death without local or distant relapse.23 Estimates for OS, DFS, and DDFS rates were calculated using the method of Kaplan-Meier.24 There are an insufficient number of patients at risk to estimate yearly rates beyond 3 years.
Patient Population RTOG 9514 was an Intergroup trial conducted by RTOG and the Eastern Cooperative Oncology Group. Sixty-six patients from 31 institutions were enrolled between February 1997 and February 2000. Two patients were ineligible (one had metastatic disease and one had ineligible histology), leaving 64 analyzable patients. Fifty-nine of these patients underwent central pathology review for histology and tumor grade. Pretreatment characteristics (histology, primary location, and so on) are summarized in Table 1. Fifty-six patients (88%) had tumors of the extremities and eight patients (12%) had tumors of the torso. Only one patient had a localized recurrent primary tumor. The median tumor size as measured by MRI, CT, or clinical findings was 15 cm (range, 8.2 to 55 cm). Eighty percent (n = 51) of tumors were grade 3 tumors (in a three-tier grading system). Median follow-up for all patients is 2.57 years (range, 0.16 to 4.95 years), and for 50 patients still alive at the time of this report, median follow-up is 2.75 years (range, 1.70 to 4.95 years).
Treatment Summary Only 59% of patients received all six cycles of neoadjuvant and adjuvant modified MAID chemotherapy. Seventy-nine percent (n = 50) received all three cycles of preoperative chemotherapy and 61% (n = 38) received all three cycles of postoperative chemotherapy. The most frequent reason for patients not receiving chemotherapy was patient refusal secondary to toxicity. Eighty-nine percent (n = 56) received preoperative radiation dose per protocol (within 5%). Sixty-one patients underwent surgery in RTOG 9514 and three patients did not. Of these three patients, two had persistent and progressive primary tumor and were not candidates for R0 resections. The third patient's primary tumor was controlled; however, he had progressive distant disease and refused local resection. Fifty-eight patients had R0 resections (of which five were amputations), and the other three patients had R1 resections.
Treatment Toxicity
Fifty-three patients (84%) experienced grade 4 toxicity; 50 patients (78%) experienced grade 4 hematologic toxicity, and 12 patients (19%) experienced grade 4 nonhematologic toxicity. The 50 patients with grade 4 hematologic toxicity included 47 patients with grade 4 leukopenia, 25 patients with grade 4 thrombocytopenia, and six patients with grade 4 anemia. Of the 12 patients with nonhematologic toxicity, four developed grade 4 cutaneous toxicity. One of these patients developed an infection at the site of the tumor below the knee after aspiration biopsy, the first cycle of chemotherapy, its associated grade 4 leukopenia, and the first course of radiation therapy. This patient was treated with an above-the-knee amputation and antibiotics. Two other patients developed grade 4 skin toxicity after chemotherapy, radiation therapy, and surgery. These toxicities resolved. A fourth patient developed grade 4 skin toxicity and infection. There were two occurrences of grade 4 pulmonary toxicity. A patient with a primary sarcoma of the pectoralis minor muscle and a positive pleural cytology was recorded as grade 4 pulmonary toxicity. His pulmonary problems may have had multiple etiologies. An additional patient received one cycle of MAID and 22 Gy of radiation therapy. He refused all additional therapy, but had a documented pulmonary embolus and associated sepsis 7 months later. Two patients developed grade 4 nausea and vomiting. One patient with a tumor of the left buttock was admitted for intractable rectal pain after the prescribed chemotherapy and 44 Gy of radiation therapy. This resolved with antibiotics and conservative management. One patient developed grade 4 hypocalcemia. A patient with a femoral neck fracture at the site of radiation therapy was designated with grade 4 toxicity. In summary, the most common grade 4 nonhematologic toxicities were cutaneous (n = 4), infectious (n = 4), and respiratory (n = 2). Of 12 patients with grade 4 nonhematologic toxicities, eight also had grade 4 leukopenia. Of 61 patients who underwent surgery, 54 (89%) had no wound complications or had complications categorized as minor, and seven (11%) had complications considered serious or major that either significantly delayed the institution of postoperative chemotherapy (n = 5) or in which serious tissue loss or amputation was threatened (n = 2). There were five amputations in this series, yielding a limb preservation rate of 92.2%. We considered two of them to be treatment related. There were two patients who developed leukopenia-associated sepsis attributed to infection at the biopsy site. In one patient, this occurred after an aspiration biopsy. He developed a progressive infection of the lower leg in association with leukopenia that was treated with an above-the-knee amputation. The second patient underwent an incisional biopsy of a thigh sarcoma. She developed septicemia and lactic acidosis thought to be related to infection at the biopsy site. She underwent a disarticulation, but died as a result of a sepsis. Two other patients had an inadequate clinical response to neoadjuvant treatment. One underwent a disarticulation and the other underwent Van Ness rotation plasty with a bone graft. There was no viable tumor in either specimen. The fifth patient with a high-grade leiomyosarcoma of the axilla completed neoadjuvant chemotherapy and radiation therapy. On exploration of the axilla, the tumor was deemed too close to the neurovascular bundle and he underwent forequarter resection. Pathology showed extensive necrosis with islands of viable tumor.
Response Of 64 patients, 58 (91%) underwent R0 resections, of which five were amputations; three patients had R1 resections. Three patients did not have resections: two because of disease progression and one because of patient refusal. All three died as a result of their disease. Of three patients with positive microscopic margins (R1 resections), two achieved a complete response after adjuvant therapy. One had a local-regional recurrence and the other did not have a recurrence. One patient with a positive margin who did not achieve a complete response had progressive disease and died as a result of the disease. At the time of analysis, 50 patients were alive, of whom 38 had no evidence of disease. The median follow-up for surviving patients is 2.75 years (range, 1.70 to 4.95 years). Fourteen of 64 patients (22%) have died. The causes of death were tumor progression (n = 11) and treatment toxicity (n = 3). Figure 2 and Table 3 show estimated rates and plots, respectively, for time-to-failure end points. The estimated 3-year LRF and DFS rates using amputation as a failure were 17.6% (95% CI, 8.0% to 27.2%) and 56.6% (95% CI, 43.2% to 68.0%), respectively. With amputation not considered a failure, there were five fewer LRFs and the 3-year LRF rate decreased to 10.1% (95% CI, 2.3% to 17.8%). With DFS, there were only two fewer failures and the estimated 3-year DFS increased to 59.7% (95% CI, 46.2% to 70.8%). The estimated 3-year rates for time to distant metastases, DDFS, and OS were 28.4% (95% CI, 17.2% to 39.6%), 64.5% (95% CI, 51.0% to 75.1%), and 75.1% (95% CI, 60.2% to 85.1%), respectively.
RTOG 9514 was opened in 1997 to assess a promising regimen that had been piloted at the Massachusetts General Hospital (MGH) by Spiro et al18 and first reported in 1996. Updated results from this trial have been reported by DeLaney.19 This is a single-institution trial of 48 patients that accrued during 10 years (range of follow-up, 10 to 124 months), whereas more than 30 institutions enrolled patients onto RTOG 9514. The median follow-up on RTOG 9514 is 33 months with a narrower range (range of follow-up, 20 to 59). Although the tumor sizes were similar (median, 14.2 cm; range, 8 to 35 cm for MGH; median, 15 cm; range, 8.2 to 55 cm for RTOG), 80% of RTOG patients had high-grade tumors (grade 3 in a three-tier grading system) compared with 48% (grade 3 in a three-tier grading system) on the MGH study.19 The chemotherapy regimen MAID was modified in RTOG 9514 by increasing the daily dose of ifosfamide from 2,000 to 2,500 mg/m2 and decreasing the dacarbazine dose from 250 to 225 mg/m2. Only 59% of patients were able to complete all six cycles of the modified MAID regimen compared with 83.3% on the MGH study. The rate of grade 4 leukopenia was twice as high in the RTOG trial (73.4% v 35.4%) and there were three treatment-related deaths. Two were secondary to the development of myelodysplasias. One such outcome was reported on the MGH pilot study.19 Myelodysplasias are a recognized complication of high-dose chemotherapy, more frequently seen in breast cancer and lymphoma patients.25-27 In the MGH study, response rates based on the RECIST criteria were 11% partial, 77% stable, and 12% progressive; these rates on RTOG 9514 were 22% partial, 64% stable, and 14% progressive. The median and the mean necrosis on the MGH pilot study were 95% and 85%, respectively. In RTOG 9514, 27% had no viable tumor, 37% had less than 25% viable tumor, 25% had 25% to 50% viable tumor, 4% had 51% to 75% viable tumor, and 6% had more than 75% viable tumor. In the MGH study, the 5-year estimated rates for local failure, DDFS, DFS, and OS were 8%, 75%, 70%, and 87%, respectively.19 In RTOG 9514, there was only sufficient follow-up to estimate 3-year rates, and they were poorer at 17.6%, 64.5%, 56.6%, and 75.1%, respectively. If amputation was not classified as a failure per se, the 3-year estimated local failure and DFS rates become 10.1% and 59.7%, respectively. Although R0 surgical intent was required for protocol eligibility, three patients were treated with amputation because they were judged not to be candidates for limb salvage procedures at the time of surgery; three patients did not have resection, two because of primary tumor progression and one because of patient refusal; and three patients had positive margins (R1 resections). The patient who refused resection did so because of systemic disease and subsequently died as a result of his disease. Of the three patients with R1 resections, two achieved complete response with adjuvant therapy, one of whom died as a result of disease and the other has had long-term DFS. One patient who did not achieve a complete response developed progressive disease and died as a result of disease. Although the protocol was planned for candidates for R0 resections, the requirement that patients have large, deep, high-grade sarcomas, and with the limitations of preoperative assessment, it was expected that some patients would experience local treatment failure and be borderline candidates for R0 resections. It is noteworthy that in two of the three amputations for advanced disease, no viable tumor was found in the specimen. In both the MGH trial and RTOG 9514, preoperative split-course radiation therapy was used in combination with neoadjuvant and adjuvant MAID chemotherapy. Forty-four Gy would be considered subtherapeutic in the absence of chemotherapy. The local control rate in the MGH trial and pathologic response rates in both experiences suggests strongly that this was an appropriate radiation dose. We are not aware of any studies addressing and comparing the efficacy of split-course radiation therapy with chemotherapy versus uninterrupted radiation followed by sequential chemotherapy. The differences in toxicity and end results between the MGH study and RTOG 9514 represent important findings. The MGH study group consists of 48 patients treated at a single institution with an especially active sarcoma program during 10 years.19 RTOG 9514 is an Intergroup phase II trial with 64 patients from 30 different institutions enrolled during 4 years. All registered RTOG patients were included in the analysis. The increased toxicity and difficulty in completing the planned chemotherapy almost certainly is related to the 25% increase in daily ifosfamide dose in the modified MAID regimen. Finally, the effect of 80% of patients on this protocol having high-grade disease (grade 3 in a three-tier grading system) versus 48% (grade 3 in a three-tier grading system) in the pilot study, with the remainder having middle-grade disease (grade 2 in a three-tier grading system) probably accounts for the worse outcome.28 In summary, the toxicity with the regimen as used in this protocol was significant. Five patients required amputation; two amputations were related to the treatment. In both of these patients, one may hypothesize that modestly contaminated biopsy sites developed significant infections in a leukopenic environment. The remaining three amputations were performed because the clinical assessment was that the primary tumor had not responded sufficiently to allow for a limb salvage procedure. In two of these patients there was no viable tumor in the specimen. In the third patient there were islands of viable tumor. The limb preservation rate was 92.2%. Two patients in the MGH pilot study underwent salvage amputation for recurrence and one patient underwent salvage amputation for a wound complication, resulting in a limb preservation rate of 94%.19 There were three deaths: two secondary to AML and one secondary to leukopenia-associated sepsis. In addition, 83% of patients had grade 4 toxicity.
As evidenced by the percentage of patients with no viable tumor or less than 25% viable tumor in the specimen, and the partial response rate in this study, this regimen does have activity in soft tissue sarcomas. It is difficult to compare the results from this trial with surgical series and adjuvant trials after definitive local therapy. For example, the three patients who never underwent surgery were included in all outcome analyses in RTOG 9514 and their survivals were rather short (0.4, 0.5, and 1.6 years). The interpretation of any study has to consider whether it was performed in a single institution or a multicenter cooperative cancer group. A single institution may have a patient referral pattern that leads to differences in important prognostic tumor factors. Using the extensive prospective database at Memorial Sloan-Kettering Cancer Center, Stojadinovic et al29 reported that the time-dependent variable, disease-free interval, was prognostic for disease-specific survival. For a subset of 270 patients with extremity and torso high-grade STSs In conclusion, RTOG 9514 showed that an aggressive neoadjuvant regimen can be delivered in a cancer cooperative group and can generate efficacy outcomes consistent with the institutional pilot study. Therefore, the substantial toxicity of the treatment precludes its use unmodified outside clinical trials. The future of this regimen is likely to be a modified version that includes therapies with noncompeting toxicities, such as targeted therapies, and with reduced doses of cytoxic drugs. Alterations in radiotherapy practice since this trial was designed would likely reduce some of the toxicity associated with this regimen. Nevertheless, when future clinical trials are planned, the severity of toxicity associated with neoadjuvant and adjuvant chemotherapy regimens using doxorubicin and ifosfamide must be considered carefully.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank all clinical investigators for enrolling patients onto this trial. In addition, we acknowledge the dedication and hard work of the statisticians, clinical research associates, and administrative staff who have contributed to the success of this trial. In particular, we thank Thomas F. Pajak, PhD, in statistics, and Mary Gramkowski and Linda Messett in data management for their valuable contributions.
 Deceased. Supported by Grants No. U10 CA21661, U10 CA37422, and U10 CA32115 awarded by the National Cancer Institute.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Krishnan A, Smita B, Slovak ML, et al: Predictors of therapy-related leukemia and myelodysplasias following autologous transplantation for lymphoma: An assessment of risk factors. Blood 95: 1488-1593, 2000 27. Chaplain G, Milan C, Sgro C, et al: Increased risk of acute leukemia after adjuvant chemotherapy for breast cancer: A population-based study. J Clin Oncol 18: 2836-2842, 2000 28. Myhre JO, Kaae S, Madsen EH, et al: Histopathological grading in soft-tissue tumours: Relation to survival in 261 surgically treated patients. Acta Pathol Microbiol Immunol Scand 91: 145-150, 1983 29. Stojadinovic A, Leung DHY, Allen P, et al: Primary adult soft tissue sarcoma: Time-dependent influence of prognostic variables. J Clin Oncol 20: 4344-4352, 2002 Submitted May 9, 2005; accepted September 12, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
