Neoadjuvant Chemotherapy With High-Dose Ifosfamide, High-Dose Methotrexate, Cisplatin, and Doxorubicin for Patients With Localized Osteosarc
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《临床肿瘤学》
the Chemotherapy, Surgery, Pathology, and Basic Research Divisions of the Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna
Oncologic/Orthopaedic Surgery, Centro Traumatologico Ortopedico, Firenze
Department of Pediatric Oncology, Meyer Hospital, Firenze
Department of Medical Oncology, S Maria delle Croci Hospital, Ravenna
Department of Oncology, Gradenigo Hospital
Department of Pediatric Oncology, Ospedale Regina Margherita, Torino, Italy
Department of Medical Oncology, The Norwegian Radium Hospital, Oslo, Norway
Department of Cancer Epidemiology, and Paediatric Oncology, Lund University Hospital, Lund
Department of Orthopaedics, Karolinska Hospital, Stockholm, Sweden
Department of Pathology, Haartman Institute, Helsinki, Finland.
ABSTRACT
PURPOSE: To explore the effect of high-dose ifosfamide in first-line treatment for patients 40 years of age with nonmetastatic osteosarcoma of the extremity.
PATIENTS AND METHODS: From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m2), methotrexate (12 g/m2), cisplatin (120 mg/m2), and doxorubicin (75 mg/m2). Postoperatively, patients received two cycles of doxorubicin (90 mg/m2), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m2). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination.
RESULTS: No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence.
CONCLUSION: The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.
INTRODUCTION
The prognosis for patients with nonmetastatic osteosarcoma of the extremity has been improved dramatically with the introduction of multiagent chemotherapy added to the surgical removal of the tumor.1-4 Attempting to improve the oncologic results in nonmetastatic osteosarcoma of the extremity, cooperation between the Italian Sarcoma Group (ISG) and the Scandinavian Sarcoma Group (SSG) was formed in 1995. It is generally accepted that there are four active drugs against osteosarcoma: methotrexate (MTX),5 cisplatin (CDP),6 doxorubicin (ADM),7 and ifosfamide (IFO).8,9 However, insufficient data comparing the efficacy of different combinations of the four active drugs against osteosarcoma were available at the time of the study project. On the basis of the literature10-14 and experience of the cooperating groups,15-17 it was concluded that the best probability of disease-free survival was expected with the combined use of all the four active drugs. Moreover, promising data on the efficacy of high-dose IFO (HDIFO; 14 to 15 g/m2/cycle) in recurrent osteosarcoma were available.18,19 The nephrotoxicity of HDIFO had been evaluated prospectively in patients (all patients except infants and the elderly) treated for recurrent osteosarcoma.20 Those patients had been treated previously with standard-dose IFO for a cumulative dose of 30 g/m2. At relapse, they received HDIFO (15 g/m2/cycle) for four cycles, for a cumulative dose of 60 g/m2. A pilot study for primary patients was carried out at the Rizzoli Institute (Bologna, Italy) to assess the feasibility of an intensified protocol in which HDIFO (15 g/m2/cycle) for a cumulative dose of 75 g/m2 was added to MTX, CPD, and ADM.21
On the basis of the results of the pilot study, the ISG/SSG I protocol was designed using the combination of the four active drugs with IFO at the high-dose level (15 g/m2) to all patients.
PATIENTS AND METHODS
Eligibility criteria for entry onto the study were diagnosis of primary, central, high-grade osteosarcoma of the extremity; age 40 years; normal hepatic, renal, bone marrow, and cardiac function; and informed consent collected in accordance with the standard procedure in each country. Representative histologic slides and conventional x-rays of the involved bone had to be sent together with the registration form to the Group Secretariat. Exclusion criteria were as follows: evidence of overt metastatic disease at diagnosis, previous treatment for osteosarcoma, medical contraindications to the drugs included in the protocol, or lack of availability for follow-up. Baseline laboratory studies included CBC, serum electrolytes, and glomerular filtration rate estimation; serum alkaline phosphatase and lactate dehydrogenase levels; total bilirubin and aminotransferase levels; and cardiac function including measurement of baseline left ventricular ejection fraction estimated by means of echocardiography or radionuclide ventriculography. The primary tumor was evaluated on plain radiograms, computed tomography (CT), and/or magnetic resonance (MR) scans. Screening for metastases was by bone scintigraphy and CT scanning of the chest. An expert panel of radiologists reviewed the tumor volume at diagnosis. Measurements were based on MR scans, when available, or otherwise by CT scans.
After primary chemotherapy and before surgery, CT and/or MR of the tumor and CT of the chest were repeated during postoperative chemotherapy, patients were checked every 2 months with radiograms of the chest and treated limb.
After completion of chemotherapy, patients were followed-up by x-ray of the chest and operated limb every 2 to 3 months for 3 years (every 3 months if the CT scan of the chest was used), at 4-month intervals during the fourth and fifth years, and subsequently every 6 months. Chemotherapy-related follow-up included CBC, serum creatinine, electrolytes, alkaline phosphatase, and LDH measurements. Glomerular filtration rate and echocardiographic measurement of the left ventricular ejection fraction were performed at the end of chemotherapy treatment and every year for the first 3 years of follow-up. An audiogram was required at the end of the treatment.
Chemotherapy consisted of MTX, ADM, CDP, and IFO according to the schedule and doses reported in Table 1. MTX was administered as a 4-hour infusion (12 g/m2) with leucovorin (folinic acid) rescue (8 mg/m2) every 6 hours, beginning 24 hours from the start of the MTX infusion for a total of 11 doses. Hydration with 1.5 L/m2 on day 1 of the infusion, and with 2 L/m2 on the subsequent days was suggested, but dose modification according to local standard was accepted. Adequate alkalinization was required to keep the urinary pH more than 7 starting from the time of the MTX infusion until the serum MTX level was less than 0.2 μmol/L. CDP was delivered during 48 hours as a continuous intravenous infusion at a dose of 120 mg/m2, and was followed by ADM 75 mg/m2 administered as a 24-hour continuous infusion. IFO, in combination with an equimolar dose of mesna, was delivered as a continuous intravenous infusion at a dose of 3 g/m2/d for 5 consecutive days. Postoperative chemotherapy was scheduled 7 days after surgery. All drugs were given as single agents per course. MTX and IFO were administered as in the preoperative treatment, whereas ADM was administered at the dose of 90 mg/m2 in a 24-hour continuous infusion, and CDP dose was kept at the same preoperative level (120 mg/m2) in patients who showed a total or almost total primary chemotherapy-induced necrosis, and it was increased to 150 mg/m2 in the remaining patients. To reduce chemotherapy toxicity, the last three courses of chemotherapy (MTX, CDP, HDIFO) were omitted for patients with total or almost total tumor necrosis induced by primary chemotherapy.
CBC and renal and liver function were checked before each chemotherapy administration. No dose reduction was allowed, and if the absolute granulocyte count was less than 1,000/mL (800 for MTX cycles), and/or the platelet count was less than 100,000/mL (80,000 for MTX cycles), chemotherapy was delayed until recovery. Renal function in the normal range was required to deliver MTX, CDP, and IFO. After each cycle, the blood count was monitored every 2 days starting on day 7 from the beginning of the chemotherapy infusion. Granulocyte colony-stimulating factor support was mandatory after HDIFO, CDP/ADM, and ADM cycles.
The type of surgery was chosen depending on the size and the location of the tumor, neurovascular involvement, and skeletal maturity. For conservative surgery, it was mandatory that preoperative staging assured the possibility of achieving wide surgical margins. In resected patients, the type of reconstruction was chosen according to tumor location and extension, and patient age, lifestyle, and preferences.
After surgery, the surgical margins were assessed according to Enneking22 as radical, wide, marginal, intralesional, or contaminated. The histologic analysis of the tumor map was performed in accordance with a method reported previously by Picci.23 Given that the study design established a shorter chemotherapy treatment for patients with total or almost total tumor necrosis, the histologic response to primary treatment was assessed in terms of persistence of viable tumor cells or absence of viable tumor cells (total necrosis), or evidence of no more than 10 foci containing not more than 30 cells/focus (almost total necrosis). Additional evaluation of histologic tumor response according to other grading systems was not prospectively required. Diagnosis, histologic subtype, and histologic response were reviewed by an expert pathology panel with members from both groups.
Statistics
ISG/SSG I was a nonrandomized prospective study protocol with historical control. On the basis of prior group accrual, the study was expected to enroll 60 patients per year and to continue for 3 years. The event-free survival (EFS) was calculated from the first day of chemotherapy until recurrence (local or distant) or chemotherapy-related death, or until the last follow-up examination. The overall survival (OS) was calculated from the first day of chemotherapy until death or until the last follow-up examination. The survival curves were calculated according to the Kaplan and Meier method and compared using the log-rank test.
Compliance with the protocol was evaluated for each patient and it was expressed in terms of relative received dose of each drug (received cumulative dose and protocol-planned cumulative dose [in milligrams per square meter] ratio). Furthermore, for each patient the received dose-intensity was calculated by dividing the average of relative received cumulative doses by the relative chemotherapy duration (ratio between actual duration of the chemotherapy treatment and protocol-planned duration).
RESULTS
The ISG/SSG 1 protocol was activated in March 1997 and closed in September 2000; 182 patients were included in the study period. The clinical characteristics are listed in Table 2. With regard to the histologic subtype, the diagnosis of fibroblastic osteosarcoma was more frequent in Italian patients, whereas in about one fourth of Scandinavian patients other histologic subtypes were listed in the pathology reports, in which the main histologic components observed in each patient's slides (ie, osteoblastic-chondroblastic osteosarcoma, osteoblastic-fibroblastic osteosarcoma, and so on) had been recorded without grouping them according to a specified histologic subtype.
Treatment Compliance
Four patients (2%) died before completion of treatment: three as a result of chemotherapy-related toxicity, and one as a result of acute pulmonary embolism after a pathologic fracture. Two patients (1%) were treated postoperatively according to different chemotherapy protocols (SSG VIII and SSG XIV) due to medical decisions by the treating centers, and early metastases developed in two patients (1%). The case report forms were incomplete for 17 patients (9%).
The treatment compliance of the remaining 157 patients (86%) is listed in Tables 3 and 4. Only 13 patients (8%) completed the treatment without any delay. In terms of protocol-received dose-intensity, the median value was 0.82. Main changes to the protocol were omission of nephrotoxic drugs due to a chemotherapy-related impairment of renal function.
Toxicity
Data on hematologic and nonhematologic toxicities are summarized in Table 5.
Three patients died as a result of chemotherapy-related toxicity: two patients during the preoperative phase and the third during postoperative chemotherapy. All of these patients presented with a similar pattern of toxicity. After HDIFO, a Fanconi-like syndrome developed, with electrolyte alterations and glycosuria in combination with febrile neutropenia, and, despite adequate antibiotic treatment and granulocyte colony-stimulating factor support, all three patients died in a clinical status of sepsis and acute renal failure. In addition to the three occurrences of acute renal failure after IFO, 16 patients (9%) experienced a mild to moderate renal impairment, which caused changes in planned treatment schedule, and no additional administration of nephrotoxic drugs (MTX, CPD, and IFO). None of these patients required dialysis. Renal failure occurred in six patients during preoperative chemotherapy; renal failure occurred in 10 patients postoperatively. Ten patients experienced renal failure after MTX delayed excretion, in three patients renal failure followed the CDP cycle, and in three patients it followed the cycle with HDIFO. Twelve patients (75%) are alive at present: 10 (62.5%) are in continuous complete remission, one is alive with disease, one is in a second complete remission, and four died as a result of disease. Chronic renal failure has developed in four of the patients, but none required dialysis. Acute renal failure developed 4 years after chemotherapy completion in one patient. At the end of the treatment, the tests of renal function were within a normal range, and no causal factors other than previous chemotherapy were identified.
Acute heart failure due to chemotherapy-associated cardiomyopathy developed in one patient, 4 months after completion of chemotherapy. She is currently alive and receiving medication to prevent heart failure.
No occurrences of severe ototoxicity or clinically evident hearing loss were reported during the treatment, but at the audiogram performed at the end of treatment, hearing loss for high frequency without clinical relevance was found in 40% of patients.
During IFO infusion, the reported incidence of microhematuria was negligible. In nine patients, CNS toxicity was reported, but the subsequent IFO was not administered only in one patient. In one patient, convulsive seizures appeared during the first day of infusion of HDIFO. That patient, a 30-year-old man, had suffered from epilepsy in childhood, and he was not taking neurologic therapy since postpuberty. No additional cycles of chemotherapy were given. For the remaining patients, CNS toxicity was mild, with transient confusion, somnolence, and mood alteration.
Fifteen male patients (median age at the start of treatment, 22 years; range 14 to 40 years) who had received chemotherapy after the time of puberty underwent seminal analysis 1 to 3 years after chemotherapy completion. Azoospermia was recorded in all patients. Given that only a group of patients underwent the test, we cannot exclude a selection bias toward patients who experienced difficulties in conceiving a child. Permanent amenorrhea was recorded only in two patients, both 40 years old at the time of the treatment, and menarche occurred in all the patients who received chemotherapy before puberty.
With regard to hematologic toxicity, all patients experienced grade 4 platelet and leukocyte toxicity. Overall, 52% of the cycles were followed by grade 4 leucopenia and 31% grade 4 thrombocytopenia (MTX excluded). After 21% of the cycles, a neutropenic fever that required hospitalization was reported.
Surgery and Histologic Response
No occurrences of tumor progression during preoperative chemotherapy were recorded. Three patients did not undergo surgery because of adverse events during the preoperative phase. Of the remaining 179 patients, 164 (92%) underwent conservative surgical procedures, 11 (6%) underwent amputation, and four (2%) underwent rotation plasty. The percentage of resection was similar in Italian (93%) and in Scandinavian patients (89%). The quality of the surgical margins was reported in 157 patients, and it was adequate (radical or wide) in 147 patients (94%), whereas in eight patients (5%) the surgical margins were marginal, and in two patients (1%) the margins were intralesional.
Chemotherapy-induced tumor necrosis was total in 17 (10%) patients, and almost total in 13 (7%) patients. Some pathology forms reported also the local pathology evaluation: in 42 patients the histologic response was graded according to Huvos' classification, with one (2%) grade 4 response 24 (57%) grade 3 responses, and 17 (41%) grade 2 responses. In 121 patients, the percentage of tumor necrosis was reported: 45 (37%) reported less than 90% and 76 (63%) reported more than 90%. Nonetheless, according to study requirements, these data were not revised by the panel of pathologists.
Follow-Up
With a median follow-up of 55 months (range, 23 to 78 months), 119 patients (65%) were continuously event free; 59 patients (32%) had local recurrence or distant relapse, three died as a result of chemotherapy-related toxicity, and one died as a result of pulmonary embolism. The 5-year probability of EFS (Fig 1) was 64% (95% CI, 57% to 71%) without any difference between patients treated in the ISG centers (5-year EFS, 65%; 95% CI, 56% to 73%) and SSG centers (5-year EFS, 64%; 95% CI, 51% to 76%). A total of 140 patients were alive, and the 5-year probability of OS was 77% (95% CI, 67% to 81%; Fig 1).
The median time to relapse was 21 months (range, 3 to 54 months); 52 of the patients who experienced relapse (88%) developed lung metastases, combined with local recurrence in two patients and other locations in five patients. In two patients the primary site of distant relapse was the skeleton, whereas five patients first developed local recurrence. Overall, the local recurrence rate was 4% (seven of the 179 patients who underwent surgery with an estimated 5-year risk of local recurrence of 5%).
The probability of 5-year EFS did not differ according to sex, site of the tumor, histologic subtype, or baseline serum level of LDH. The serum level of alkaline phosphatase influenced the EFS, which was significantly (P = .02) better for those patients with normal baseline values (5-year EFS, 75%; 95% CI, 66% to 95%) than that of patients with high baseline values (5-year EFS, 52%; 95% CI, 41% to 64%). The mean tumor volume, calculated in 140 patients, was significantly (P = .002) higher in patients who experienced relapse (274 mL) than in patients who were continuously event free (162 mL). With a cutoff at 100 mL, a significant (P = .04) difference in EFS was observed. The 5-year EFS was 71% (95% CI, 58% to 85%) in patients with tumors smaller than 100 mL and 54% (95% CI, 44% to 65%) in patients with larger tumors.
According to the type of local treatment, patients who underwent amputation had a 5-year EFS of 22% (95% CI, 0% to 48%), which was significantly (P = .005) worse than that observed in patients who underwent resection (67%; 95% CI, 60% to 75%). The tumor volume in these groups of patients was significantly (P =.003) higher in patients who underwent amputation (mean tumor volume, 436 mL) than in patients who underwent resection (mean tumor volume, 189 mL).
Patients with primary chemotherapy-induced total necrosis had a 5-year EFS of 81% (95% CI, 62% to 100%), patients with evidence of no more than 10 foci containing not more than 30 cells/focus (almost total necrosis) had a 5-year EFS of 61.5% (95% CI, 35% to 88%), and those with a higher persistence of viable tumor cells had a 5-year EFS of 64% (95% CI, 55% to 72%; P = .3).
Protocol compliance had no impact on EFS, given that the mean received cumulative dose was similar in patients who were continuously event free (0.92) compared with those who experienced relapse (0.93). A similar analysis was carried out for the mean cumulative dose/relative duration ratio, which was 0.82 ± 0.13 in patients who experienced relapse and 0.8 ± 0.12 in those who were continuously event free.
Postrelapse Survival
With a median postrelapse survival time of 26.5 months, 21 patients (36%) are alive—13 (22%) without evidence of disease, and eight (14%) with disease. Thirty-eight patients (64%) died as a result of disease, with a median postrelapse survival of 14.6 months.
The 3-year probability of postrelapse survival was 27% (95% CI, 14% to 40%). Additional chemotherapy treatment based on high-dose carboplatin and etoposide with stem-cell support was given in 28 patients according to a second-line chemotherapy protocol.24 In this subset of patients, the 3-year probability of postrelapse survival was 28% (95% CI, 7% to 50%).
DISCUSSION
This study is the first with HDIFO given in the preoperative phase, in combination with MTX, CDP, and ADM for the treatment of patients with nonmetastatic osteosarcoma of the extremity. We report a 5-year EFS of 63% and a 5-year OS of 77%. The oncologic results are in the same range as those reported by collaborators16,17,25 and by other groups,10,13,14 with IFO used at standard dose, and similar cumulative doses of MTX and CDP, but a higher cumulative dose of ADM. In the fourth neoadjuvant study,26 carried out at the Rizzoli Institute, standard-dose IFO was used in the preoperative phase; the 5-year EFS was 56% and the 5-year overall survival was 71%. In the SSG VIII study,25 carried out from 1990 to 1997, standard-dose IFO combined with etoposide was used in the postoperative phase for poor responders, and a 5-year metastases-free survival of 61% and 5-year overall survival of 74% were reported. Because the current study was not randomized, no definitive conclusions can be drawn; nonetheless, the comparison with previous studies suggests no benefit in using HDIFO compared with standard-dose IFO.
The results achieved by this study were inferior compared with the preceding pilot study.21 In the pilot study, a 4-year EFS of 73% and OS of 87% in the 68 patients included in the study were reported. Compared with ISG/SSG I, the only difference was the cumulative dose of ADM. Because of the occurrence of severe cardiomyopathy in one patient in the pilot study, ADM was reduced from 420 to 330 mg/m2 in ISG/SSG I. We cannot exclude that the different outcome might be related to this cumulative dose reduction. The importance of ADM in the treatment of osteosarcoma is well known,27 and most of the protocols for nonmetastatic osteosarcoma used cumulative doses higher than 400 mg/m2.11,12,14,16
Surgical results are an important aspect of this study: 92% of the patients underwent resection, 2% of patients underwent a rotation plasty, and only 6% of patients underwent amputation. The incidence of local recurrence was 4%. The percentage of conservative surgery performed is the highest ever reported in the treatment of osteosarcoma in multicenter studies with two orthopaedic centers in Italy (Istituto Ortopedico Rizzoli, Bologna, and Centro Traumatologico Ortopedico, Firenze) and 12 Scandinavian centers involved in the surgical treatment of the patients. The surgical expertise probably explains the good results obtained, but we cannot exclude that the primary chemotherapy powered by the addition of HDIFO might have facilitated such an extensive use of limb salvage.
The addition of HDIFO to MTX, CDP, and ADM is possible, although related toxicity was remarkable. In fact, in terms of protocol-received dose-intensity, 57% of the patients received 80% or more of the protocol-planned dose-intensity, which is similar to previous protocols using standard-dose IFO.28 The reduction in dose-intensity compared with protocol is due mainly to a prolongation of chemotherapy treatment and not to dose reduction. Even with mandatory use of growth factor support, there was a tendency to longer delay throughout the treatment period due to prolonged hematologic reconstitution.
When compliance with the chemotherapy protocol was evaluated in relation to the oncologic outcome, it was observed that the received dose-intensity did not have an impact on the probability of EFS. Similar findings have been reported in an analysis of the impact of received dose-intensity on outcome in patients with nonmetastatic osteosarcoma treated with a chemotherapy protocol based on cisplatin and ADM.29 Furthermore, the fact that patients who received a reduced cumulative dose of MTX, CDP, and IFO due to renal impairment (which occurred mainly in the postoperative phase) had a prognosis similar to those who received the full drug dose, makes the need of prolonged postoperative use of these drugs in the chemotherapy treatment of osteosarcoma questionable.
The acute toxicity was considerable, and was characterized mainly by hematologic and renal toxicity. With the exclusion of the patient who died as a result of pulmonary embolism, the incidence of treatment-related death was 1.6%. All deaths occurred after administration of HDIFO, and all patients developed a combined pattern of neutropenic fever and Fanconi-like syndrome. However, the percentage of toxic deaths was equal and even lower than in previous studies by ISG and SSG or other groups with similar oncologic results.14,16,17
The incidence of ototoxicity was negligible in contrast to what has been reported with short infusion delivery of cisplatin,14 confirming the relation between ototoxicity and the duration of administration of cisplatin.30
Chemotherapy against osteosarcoma harbors a risk of long-term toxicity. The addition of IFO to a three-drug combination of MTX, ADM, and CDP is likely to induce azoospermia in males, especially at the high-dose level. All male patients examined who had received chemotherapy after the time of puberty were diagnosed with azoospermia. Similar figures have been reported previously in long-term follow-up studies of Italian patients receiving standard-dose IFO.31 The incidence of chronic renal failure in survivors is 3.6% (five of 140) at a median follow-up of 55 months. Continuous follow-up of these patients will be important to assess the frequency and seriousness of chronic renal failure, and results should be compared with patients receiving chemotherapy without IFO or standard-dose IFO.
The total dose of ADM in the protocol (330 mg/m2) was considered to harbor a low risk of cardiomyopathy,32 and only one patient developed cardiac malfunction requiring medical treatment. Acute cardiac toxicity related to HDIFO has been reported recently,18 and a combined effect of doxorubicin and HDIFO cannot be excluded. It is important to note that the incidence of cardiotoxicity in this study is low (one in 181), and that the strategy of reducing the total dose of ADM did not negatively affect the oncologic results, which were similar to those achieved in protocols based on a higher total dose of ADM, leading to higher incidence of cardiotoxicity.14,31 This could suggest that the increased cumulative dose of IFO might compensate for the reduction of the cumulative dose of ADM.
The ISG/SSG I study showed that the use of HDIFO first-line chemotherapy added to MTX, CDP, and ADM is feasible, even with considerable acute toxicity in a multicentric setting, and that more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery with a risk of local failure lower than 5%. Compared with studies in which four drug regimens with standard-dose IFO have been used, the rate of major toxicity was not increased, but the oncologic results were not improved. Continuous follow-up of the patients will be important for assessment of long-term toxicity.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Oncologic/Orthopaedic Surgery, Centro Traumatologico Ortopedico, Firenze
Department of Pediatric Oncology, Meyer Hospital, Firenze
Department of Medical Oncology, S Maria delle Croci Hospital, Ravenna
Department of Oncology, Gradenigo Hospital
Department of Pediatric Oncology, Ospedale Regina Margherita, Torino, Italy
Department of Medical Oncology, The Norwegian Radium Hospital, Oslo, Norway
Department of Cancer Epidemiology, and Paediatric Oncology, Lund University Hospital, Lund
Department of Orthopaedics, Karolinska Hospital, Stockholm, Sweden
Department of Pathology, Haartman Institute, Helsinki, Finland.
ABSTRACT
PURPOSE: To explore the effect of high-dose ifosfamide in first-line treatment for patients 40 years of age with nonmetastatic osteosarcoma of the extremity.
PATIENTS AND METHODS: From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m2), methotrexate (12 g/m2), cisplatin (120 mg/m2), and doxorubicin (75 mg/m2). Postoperatively, patients received two cycles of doxorubicin (90 mg/m2), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m2). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination.
RESULTS: No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence.
CONCLUSION: The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.
INTRODUCTION
The prognosis for patients with nonmetastatic osteosarcoma of the extremity has been improved dramatically with the introduction of multiagent chemotherapy added to the surgical removal of the tumor.1-4 Attempting to improve the oncologic results in nonmetastatic osteosarcoma of the extremity, cooperation between the Italian Sarcoma Group (ISG) and the Scandinavian Sarcoma Group (SSG) was formed in 1995. It is generally accepted that there are four active drugs against osteosarcoma: methotrexate (MTX),5 cisplatin (CDP),6 doxorubicin (ADM),7 and ifosfamide (IFO).8,9 However, insufficient data comparing the efficacy of different combinations of the four active drugs against osteosarcoma were available at the time of the study project. On the basis of the literature10-14 and experience of the cooperating groups,15-17 it was concluded that the best probability of disease-free survival was expected with the combined use of all the four active drugs. Moreover, promising data on the efficacy of high-dose IFO (HDIFO; 14 to 15 g/m2/cycle) in recurrent osteosarcoma were available.18,19 The nephrotoxicity of HDIFO had been evaluated prospectively in patients (all patients except infants and the elderly) treated for recurrent osteosarcoma.20 Those patients had been treated previously with standard-dose IFO for a cumulative dose of 30 g/m2. At relapse, they received HDIFO (15 g/m2/cycle) for four cycles, for a cumulative dose of 60 g/m2. A pilot study for primary patients was carried out at the Rizzoli Institute (Bologna, Italy) to assess the feasibility of an intensified protocol in which HDIFO (15 g/m2/cycle) for a cumulative dose of 75 g/m2 was added to MTX, CPD, and ADM.21
On the basis of the results of the pilot study, the ISG/SSG I protocol was designed using the combination of the four active drugs with IFO at the high-dose level (15 g/m2) to all patients.
PATIENTS AND METHODS
Eligibility criteria for entry onto the study were diagnosis of primary, central, high-grade osteosarcoma of the extremity; age 40 years; normal hepatic, renal, bone marrow, and cardiac function; and informed consent collected in accordance with the standard procedure in each country. Representative histologic slides and conventional x-rays of the involved bone had to be sent together with the registration form to the Group Secretariat. Exclusion criteria were as follows: evidence of overt metastatic disease at diagnosis, previous treatment for osteosarcoma, medical contraindications to the drugs included in the protocol, or lack of availability for follow-up. Baseline laboratory studies included CBC, serum electrolytes, and glomerular filtration rate estimation; serum alkaline phosphatase and lactate dehydrogenase levels; total bilirubin and aminotransferase levels; and cardiac function including measurement of baseline left ventricular ejection fraction estimated by means of echocardiography or radionuclide ventriculography. The primary tumor was evaluated on plain radiograms, computed tomography (CT), and/or magnetic resonance (MR) scans. Screening for metastases was by bone scintigraphy and CT scanning of the chest. An expert panel of radiologists reviewed the tumor volume at diagnosis. Measurements were based on MR scans, when available, or otherwise by CT scans.
After primary chemotherapy and before surgery, CT and/or MR of the tumor and CT of the chest were repeated during postoperative chemotherapy, patients were checked every 2 months with radiograms of the chest and treated limb.
After completion of chemotherapy, patients were followed-up by x-ray of the chest and operated limb every 2 to 3 months for 3 years (every 3 months if the CT scan of the chest was used), at 4-month intervals during the fourth and fifth years, and subsequently every 6 months. Chemotherapy-related follow-up included CBC, serum creatinine, electrolytes, alkaline phosphatase, and LDH measurements. Glomerular filtration rate and echocardiographic measurement of the left ventricular ejection fraction were performed at the end of chemotherapy treatment and every year for the first 3 years of follow-up. An audiogram was required at the end of the treatment.
Chemotherapy consisted of MTX, ADM, CDP, and IFO according to the schedule and doses reported in Table 1. MTX was administered as a 4-hour infusion (12 g/m2) with leucovorin (folinic acid) rescue (8 mg/m2) every 6 hours, beginning 24 hours from the start of the MTX infusion for a total of 11 doses. Hydration with 1.5 L/m2 on day 1 of the infusion, and with 2 L/m2 on the subsequent days was suggested, but dose modification according to local standard was accepted. Adequate alkalinization was required to keep the urinary pH more than 7 starting from the time of the MTX infusion until the serum MTX level was less than 0.2 μmol/L. CDP was delivered during 48 hours as a continuous intravenous infusion at a dose of 120 mg/m2, and was followed by ADM 75 mg/m2 administered as a 24-hour continuous infusion. IFO, in combination with an equimolar dose of mesna, was delivered as a continuous intravenous infusion at a dose of 3 g/m2/d for 5 consecutive days. Postoperative chemotherapy was scheduled 7 days after surgery. All drugs were given as single agents per course. MTX and IFO were administered as in the preoperative treatment, whereas ADM was administered at the dose of 90 mg/m2 in a 24-hour continuous infusion, and CDP dose was kept at the same preoperative level (120 mg/m2) in patients who showed a total or almost total primary chemotherapy-induced necrosis, and it was increased to 150 mg/m2 in the remaining patients. To reduce chemotherapy toxicity, the last three courses of chemotherapy (MTX, CDP, HDIFO) were omitted for patients with total or almost total tumor necrosis induced by primary chemotherapy.
CBC and renal and liver function were checked before each chemotherapy administration. No dose reduction was allowed, and if the absolute granulocyte count was less than 1,000/mL (800 for MTX cycles), and/or the platelet count was less than 100,000/mL (80,000 for MTX cycles), chemotherapy was delayed until recovery. Renal function in the normal range was required to deliver MTX, CDP, and IFO. After each cycle, the blood count was monitored every 2 days starting on day 7 from the beginning of the chemotherapy infusion. Granulocyte colony-stimulating factor support was mandatory after HDIFO, CDP/ADM, and ADM cycles.
The type of surgery was chosen depending on the size and the location of the tumor, neurovascular involvement, and skeletal maturity. For conservative surgery, it was mandatory that preoperative staging assured the possibility of achieving wide surgical margins. In resected patients, the type of reconstruction was chosen according to tumor location and extension, and patient age, lifestyle, and preferences.
After surgery, the surgical margins were assessed according to Enneking22 as radical, wide, marginal, intralesional, or contaminated. The histologic analysis of the tumor map was performed in accordance with a method reported previously by Picci.23 Given that the study design established a shorter chemotherapy treatment for patients with total or almost total tumor necrosis, the histologic response to primary treatment was assessed in terms of persistence of viable tumor cells or absence of viable tumor cells (total necrosis), or evidence of no more than 10 foci containing not more than 30 cells/focus (almost total necrosis). Additional evaluation of histologic tumor response according to other grading systems was not prospectively required. Diagnosis, histologic subtype, and histologic response were reviewed by an expert pathology panel with members from both groups.
Statistics
ISG/SSG I was a nonrandomized prospective study protocol with historical control. On the basis of prior group accrual, the study was expected to enroll 60 patients per year and to continue for 3 years. The event-free survival (EFS) was calculated from the first day of chemotherapy until recurrence (local or distant) or chemotherapy-related death, or until the last follow-up examination. The overall survival (OS) was calculated from the first day of chemotherapy until death or until the last follow-up examination. The survival curves were calculated according to the Kaplan and Meier method and compared using the log-rank test.
Compliance with the protocol was evaluated for each patient and it was expressed in terms of relative received dose of each drug (received cumulative dose and protocol-planned cumulative dose [in milligrams per square meter] ratio). Furthermore, for each patient the received dose-intensity was calculated by dividing the average of relative received cumulative doses by the relative chemotherapy duration (ratio between actual duration of the chemotherapy treatment and protocol-planned duration).
RESULTS
The ISG/SSG 1 protocol was activated in March 1997 and closed in September 2000; 182 patients were included in the study period. The clinical characteristics are listed in Table 2. With regard to the histologic subtype, the diagnosis of fibroblastic osteosarcoma was more frequent in Italian patients, whereas in about one fourth of Scandinavian patients other histologic subtypes were listed in the pathology reports, in which the main histologic components observed in each patient's slides (ie, osteoblastic-chondroblastic osteosarcoma, osteoblastic-fibroblastic osteosarcoma, and so on) had been recorded without grouping them according to a specified histologic subtype.
Treatment Compliance
Four patients (2%) died before completion of treatment: three as a result of chemotherapy-related toxicity, and one as a result of acute pulmonary embolism after a pathologic fracture. Two patients (1%) were treated postoperatively according to different chemotherapy protocols (SSG VIII and SSG XIV) due to medical decisions by the treating centers, and early metastases developed in two patients (1%). The case report forms were incomplete for 17 patients (9%).
The treatment compliance of the remaining 157 patients (86%) is listed in Tables 3 and 4. Only 13 patients (8%) completed the treatment without any delay. In terms of protocol-received dose-intensity, the median value was 0.82. Main changes to the protocol were omission of nephrotoxic drugs due to a chemotherapy-related impairment of renal function.
Toxicity
Data on hematologic and nonhematologic toxicities are summarized in Table 5.
Three patients died as a result of chemotherapy-related toxicity: two patients during the preoperative phase and the third during postoperative chemotherapy. All of these patients presented with a similar pattern of toxicity. After HDIFO, a Fanconi-like syndrome developed, with electrolyte alterations and glycosuria in combination with febrile neutropenia, and, despite adequate antibiotic treatment and granulocyte colony-stimulating factor support, all three patients died in a clinical status of sepsis and acute renal failure. In addition to the three occurrences of acute renal failure after IFO, 16 patients (9%) experienced a mild to moderate renal impairment, which caused changes in planned treatment schedule, and no additional administration of nephrotoxic drugs (MTX, CPD, and IFO). None of these patients required dialysis. Renal failure occurred in six patients during preoperative chemotherapy; renal failure occurred in 10 patients postoperatively. Ten patients experienced renal failure after MTX delayed excretion, in three patients renal failure followed the CDP cycle, and in three patients it followed the cycle with HDIFO. Twelve patients (75%) are alive at present: 10 (62.5%) are in continuous complete remission, one is alive with disease, one is in a second complete remission, and four died as a result of disease. Chronic renal failure has developed in four of the patients, but none required dialysis. Acute renal failure developed 4 years after chemotherapy completion in one patient. At the end of the treatment, the tests of renal function were within a normal range, and no causal factors other than previous chemotherapy were identified.
Acute heart failure due to chemotherapy-associated cardiomyopathy developed in one patient, 4 months after completion of chemotherapy. She is currently alive and receiving medication to prevent heart failure.
No occurrences of severe ototoxicity or clinically evident hearing loss were reported during the treatment, but at the audiogram performed at the end of treatment, hearing loss for high frequency without clinical relevance was found in 40% of patients.
During IFO infusion, the reported incidence of microhematuria was negligible. In nine patients, CNS toxicity was reported, but the subsequent IFO was not administered only in one patient. In one patient, convulsive seizures appeared during the first day of infusion of HDIFO. That patient, a 30-year-old man, had suffered from epilepsy in childhood, and he was not taking neurologic therapy since postpuberty. No additional cycles of chemotherapy were given. For the remaining patients, CNS toxicity was mild, with transient confusion, somnolence, and mood alteration.
Fifteen male patients (median age at the start of treatment, 22 years; range 14 to 40 years) who had received chemotherapy after the time of puberty underwent seminal analysis 1 to 3 years after chemotherapy completion. Azoospermia was recorded in all patients. Given that only a group of patients underwent the test, we cannot exclude a selection bias toward patients who experienced difficulties in conceiving a child. Permanent amenorrhea was recorded only in two patients, both 40 years old at the time of the treatment, and menarche occurred in all the patients who received chemotherapy before puberty.
With regard to hematologic toxicity, all patients experienced grade 4 platelet and leukocyte toxicity. Overall, 52% of the cycles were followed by grade 4 leucopenia and 31% grade 4 thrombocytopenia (MTX excluded). After 21% of the cycles, a neutropenic fever that required hospitalization was reported.
Surgery and Histologic Response
No occurrences of tumor progression during preoperative chemotherapy were recorded. Three patients did not undergo surgery because of adverse events during the preoperative phase. Of the remaining 179 patients, 164 (92%) underwent conservative surgical procedures, 11 (6%) underwent amputation, and four (2%) underwent rotation plasty. The percentage of resection was similar in Italian (93%) and in Scandinavian patients (89%). The quality of the surgical margins was reported in 157 patients, and it was adequate (radical or wide) in 147 patients (94%), whereas in eight patients (5%) the surgical margins were marginal, and in two patients (1%) the margins were intralesional.
Chemotherapy-induced tumor necrosis was total in 17 (10%) patients, and almost total in 13 (7%) patients. Some pathology forms reported also the local pathology evaluation: in 42 patients the histologic response was graded according to Huvos' classification, with one (2%) grade 4 response 24 (57%) grade 3 responses, and 17 (41%) grade 2 responses. In 121 patients, the percentage of tumor necrosis was reported: 45 (37%) reported less than 90% and 76 (63%) reported more than 90%. Nonetheless, according to study requirements, these data were not revised by the panel of pathologists.
Follow-Up
With a median follow-up of 55 months (range, 23 to 78 months), 119 patients (65%) were continuously event free; 59 patients (32%) had local recurrence or distant relapse, three died as a result of chemotherapy-related toxicity, and one died as a result of pulmonary embolism. The 5-year probability of EFS (Fig 1) was 64% (95% CI, 57% to 71%) without any difference between patients treated in the ISG centers (5-year EFS, 65%; 95% CI, 56% to 73%) and SSG centers (5-year EFS, 64%; 95% CI, 51% to 76%). A total of 140 patients were alive, and the 5-year probability of OS was 77% (95% CI, 67% to 81%; Fig 1).
The median time to relapse was 21 months (range, 3 to 54 months); 52 of the patients who experienced relapse (88%) developed lung metastases, combined with local recurrence in two patients and other locations in five patients. In two patients the primary site of distant relapse was the skeleton, whereas five patients first developed local recurrence. Overall, the local recurrence rate was 4% (seven of the 179 patients who underwent surgery with an estimated 5-year risk of local recurrence of 5%).
The probability of 5-year EFS did not differ according to sex, site of the tumor, histologic subtype, or baseline serum level of LDH. The serum level of alkaline phosphatase influenced the EFS, which was significantly (P = .02) better for those patients with normal baseline values (5-year EFS, 75%; 95% CI, 66% to 95%) than that of patients with high baseline values (5-year EFS, 52%; 95% CI, 41% to 64%). The mean tumor volume, calculated in 140 patients, was significantly (P = .002) higher in patients who experienced relapse (274 mL) than in patients who were continuously event free (162 mL). With a cutoff at 100 mL, a significant (P = .04) difference in EFS was observed. The 5-year EFS was 71% (95% CI, 58% to 85%) in patients with tumors smaller than 100 mL and 54% (95% CI, 44% to 65%) in patients with larger tumors.
According to the type of local treatment, patients who underwent amputation had a 5-year EFS of 22% (95% CI, 0% to 48%), which was significantly (P = .005) worse than that observed in patients who underwent resection (67%; 95% CI, 60% to 75%). The tumor volume in these groups of patients was significantly (P =.003) higher in patients who underwent amputation (mean tumor volume, 436 mL) than in patients who underwent resection (mean tumor volume, 189 mL).
Patients with primary chemotherapy-induced total necrosis had a 5-year EFS of 81% (95% CI, 62% to 100%), patients with evidence of no more than 10 foci containing not more than 30 cells/focus (almost total necrosis) had a 5-year EFS of 61.5% (95% CI, 35% to 88%), and those with a higher persistence of viable tumor cells had a 5-year EFS of 64% (95% CI, 55% to 72%; P = .3).
Protocol compliance had no impact on EFS, given that the mean received cumulative dose was similar in patients who were continuously event free (0.92) compared with those who experienced relapse (0.93). A similar analysis was carried out for the mean cumulative dose/relative duration ratio, which was 0.82 ± 0.13 in patients who experienced relapse and 0.8 ± 0.12 in those who were continuously event free.
Postrelapse Survival
With a median postrelapse survival time of 26.5 months, 21 patients (36%) are alive—13 (22%) without evidence of disease, and eight (14%) with disease. Thirty-eight patients (64%) died as a result of disease, with a median postrelapse survival of 14.6 months.
The 3-year probability of postrelapse survival was 27% (95% CI, 14% to 40%). Additional chemotherapy treatment based on high-dose carboplatin and etoposide with stem-cell support was given in 28 patients according to a second-line chemotherapy protocol.24 In this subset of patients, the 3-year probability of postrelapse survival was 28% (95% CI, 7% to 50%).
DISCUSSION
This study is the first with HDIFO given in the preoperative phase, in combination with MTX, CDP, and ADM for the treatment of patients with nonmetastatic osteosarcoma of the extremity. We report a 5-year EFS of 63% and a 5-year OS of 77%. The oncologic results are in the same range as those reported by collaborators16,17,25 and by other groups,10,13,14 with IFO used at standard dose, and similar cumulative doses of MTX and CDP, but a higher cumulative dose of ADM. In the fourth neoadjuvant study,26 carried out at the Rizzoli Institute, standard-dose IFO was used in the preoperative phase; the 5-year EFS was 56% and the 5-year overall survival was 71%. In the SSG VIII study,25 carried out from 1990 to 1997, standard-dose IFO combined with etoposide was used in the postoperative phase for poor responders, and a 5-year metastases-free survival of 61% and 5-year overall survival of 74% were reported. Because the current study was not randomized, no definitive conclusions can be drawn; nonetheless, the comparison with previous studies suggests no benefit in using HDIFO compared with standard-dose IFO.
The results achieved by this study were inferior compared with the preceding pilot study.21 In the pilot study, a 4-year EFS of 73% and OS of 87% in the 68 patients included in the study were reported. Compared with ISG/SSG I, the only difference was the cumulative dose of ADM. Because of the occurrence of severe cardiomyopathy in one patient in the pilot study, ADM was reduced from 420 to 330 mg/m2 in ISG/SSG I. We cannot exclude that the different outcome might be related to this cumulative dose reduction. The importance of ADM in the treatment of osteosarcoma is well known,27 and most of the protocols for nonmetastatic osteosarcoma used cumulative doses higher than 400 mg/m2.11,12,14,16
Surgical results are an important aspect of this study: 92% of the patients underwent resection, 2% of patients underwent a rotation plasty, and only 6% of patients underwent amputation. The incidence of local recurrence was 4%. The percentage of conservative surgery performed is the highest ever reported in the treatment of osteosarcoma in multicenter studies with two orthopaedic centers in Italy (Istituto Ortopedico Rizzoli, Bologna, and Centro Traumatologico Ortopedico, Firenze) and 12 Scandinavian centers involved in the surgical treatment of the patients. The surgical expertise probably explains the good results obtained, but we cannot exclude that the primary chemotherapy powered by the addition of HDIFO might have facilitated such an extensive use of limb salvage.
The addition of HDIFO to MTX, CDP, and ADM is possible, although related toxicity was remarkable. In fact, in terms of protocol-received dose-intensity, 57% of the patients received 80% or more of the protocol-planned dose-intensity, which is similar to previous protocols using standard-dose IFO.28 The reduction in dose-intensity compared with protocol is due mainly to a prolongation of chemotherapy treatment and not to dose reduction. Even with mandatory use of growth factor support, there was a tendency to longer delay throughout the treatment period due to prolonged hematologic reconstitution.
When compliance with the chemotherapy protocol was evaluated in relation to the oncologic outcome, it was observed that the received dose-intensity did not have an impact on the probability of EFS. Similar findings have been reported in an analysis of the impact of received dose-intensity on outcome in patients with nonmetastatic osteosarcoma treated with a chemotherapy protocol based on cisplatin and ADM.29 Furthermore, the fact that patients who received a reduced cumulative dose of MTX, CDP, and IFO due to renal impairment (which occurred mainly in the postoperative phase) had a prognosis similar to those who received the full drug dose, makes the need of prolonged postoperative use of these drugs in the chemotherapy treatment of osteosarcoma questionable.
The acute toxicity was considerable, and was characterized mainly by hematologic and renal toxicity. With the exclusion of the patient who died as a result of pulmonary embolism, the incidence of treatment-related death was 1.6%. All deaths occurred after administration of HDIFO, and all patients developed a combined pattern of neutropenic fever and Fanconi-like syndrome. However, the percentage of toxic deaths was equal and even lower than in previous studies by ISG and SSG or other groups with similar oncologic results.14,16,17
The incidence of ototoxicity was negligible in contrast to what has been reported with short infusion delivery of cisplatin,14 confirming the relation between ototoxicity and the duration of administration of cisplatin.30
Chemotherapy against osteosarcoma harbors a risk of long-term toxicity. The addition of IFO to a three-drug combination of MTX, ADM, and CDP is likely to induce azoospermia in males, especially at the high-dose level. All male patients examined who had received chemotherapy after the time of puberty were diagnosed with azoospermia. Similar figures have been reported previously in long-term follow-up studies of Italian patients receiving standard-dose IFO.31 The incidence of chronic renal failure in survivors is 3.6% (five of 140) at a median follow-up of 55 months. Continuous follow-up of these patients will be important to assess the frequency and seriousness of chronic renal failure, and results should be compared with patients receiving chemotherapy without IFO or standard-dose IFO.
The total dose of ADM in the protocol (330 mg/m2) was considered to harbor a low risk of cardiomyopathy,32 and only one patient developed cardiac malfunction requiring medical treatment. Acute cardiac toxicity related to HDIFO has been reported recently,18 and a combined effect of doxorubicin and HDIFO cannot be excluded. It is important to note that the incidence of cardiotoxicity in this study is low (one in 181), and that the strategy of reducing the total dose of ADM did not negatively affect the oncologic results, which were similar to those achieved in protocols based on a higher total dose of ADM, leading to higher incidence of cardiotoxicity.14,31 This could suggest that the increased cumulative dose of IFO might compensate for the reduction of the cumulative dose of ADM.
The ISG/SSG I study showed that the use of HDIFO first-line chemotherapy added to MTX, CDP, and ADM is feasible, even with considerable acute toxicity in a multicentric setting, and that more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery with a risk of local failure lower than 5%. Compared with studies in which four drug regimens with standard-dose IFO have been used, the rate of major toxicity was not increased, but the oncologic results were not improved. Continuous follow-up of the patients will be important for assessment of long-term toxicity.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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