Chemotherapy for Nonmetastatic Osteogenic Sarcoma: The Memorial Sloan-Kettering Experience By Paul A. Meyers, Glenn Heller, John Healey, Andrew Huvos, Joseph Lane, Ralph Marcove, Anne Applewhite, Vaia Vlamis, and Gerald Rosen Purpose: Adjuvant chemotherapy improves diseasefree survival (DFS) for patients with osteogenic sarcoma (OS). We reviewed our experience with OS to determine prognostic factors, the role of preoperative chemotherapy and subsequent histologic response, and the role of salvage chemotherapy after poor initial response. Methods: From 1975 to 1984, we saw 279 patients with previously untreated OS without metastasis. All patients received intensive chemotherapy and underwent surgical resection of primary tumor. Chemotherapy included high-dose methotrexate; Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH); and bleomycin, cyclophosphamide, and dactinomycin (BCD). Selected patients also received cisplatin. Results: DFS was not affected by use of preoperative chemotherapy versus immediate surgery, by use of limbsparing surgery versus amputation, age, sex, or dose intensity of chemotherapy. DFS did correlate with serum lactate dehydrogenase (LDH), alkaline phosphatase, pri-
OSTEOGENIC
SARCOMA (OS) treated by surgi-
cal ablation of the primary tumor will progress to metastatic disease in 80% to 90% of patients in a median
of 5 months.' Many investigators have reported improved disease-free survival (DFS) and overall survival
for patients treated with chemotherapy compared with these historical controls. A prospective randomized trial
of adjuvant chemotherapy versus observation after surgery for OS was performed at the Mayo Clinic (Rochester, MN).2 The results were surprising on two counts:
mary tumor site, race, and histologic response to preoperative chemotherapy. There was no difference in DFS for patients with a poor histologic response who did or did nor receive cisplatin, although patients who did receive cisplatin had a longer time to relapse. The 5-year DFS was 76% for patients aged < 21 years who had extremity primary tumor and were treated with the T10 protocol. Conclusions: Intensive chemotherapy can achieve DFS for a high proportion of patients with OS. Although it is a powerful predictor of DFS, histologic response to preoperative chemotherapy cannot be assessed at diagnosis. We have not shown an ability to salvage patients with an unfavorable response. We need to increase the proportion of patients with a favorable response, identify the patients who will have an unfavorable response, and develop novel treatments to salvage poor responders. J Clin Oncol 10:5-15. c 1992 by American Society of Clinical Oncology.
quent DFS, is it possible to alter therapy for poor responders to improve their prognosis? From 1975 to 1984, we evaluated 612 patients with OS at the Memorial Sloan-Kettering Cancer Center (MSKCC). In this review we will only examine the group of patients who presented to MSKCC with fully malignant, high-grade, newly diagnosed, and previously untreated OS. The analysis is also limited to those patients who did not have metastatic disease detected at diagnosis by conventional diagnostic imaging techniques.
there was no difference in outcome between the two groups, and the observational group achieved a DFS of
40%. A subsequent, larger trial performed by the Pediatric Oncology Group documented markedly superior DFS with the use of adjuvant chemotherapy.3 The 2-year actuarial DFS was 66% for patients randomly assigned to receive chemotherapy and 17% for patients randomly assigned to observation. The value of adjuvant chemotherapy for OS seems well established. Several crucial questions remain unanswered. What factors best
predict outcome for the patient with OS? What is the optimal chemotherapy for OS? Is a period of chemotherapy before definitive surgery ("neoadjuvant" or preoper-
ative chemotherapy) superior to immediate surgery followed by adjuvant chemotherapy? If histologic response to preoperative chemotherapy predicts subse-
METHODS Patients A comprehensive list of patients with the diagnosis of OS was generated. The medical record and histopathology of each patient were reviewed. Inclusion was restricted to patients first seen at MSKCC between January 1, 1975, and April 30, 1984. The former
From the Departmentsof Pediatrics,Biostatistics,Orthopedics, and Pathology, Memorial Sloan-Kettering Cancer Center,New York, NY, and Cedars-SinaiComprehensive CancerCenter,Los Angeles, CA. SubmittedApril 22, 1991; acceptedJuly 30, 1991. Address reprint requests to Paul A. Meyers, MD, Department of Pediatrics,Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. 0 1992 by American Society of Clinical Oncology. 0732-183X/92/1001-0018$3.00/0
Journalof Clinical Oncology, Vol 10, No 1 (January), 1992: pp 5-115
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5
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MEYERS ET AL
date was chosen arbitrarily as a date by which OS treatment strategy was accepted to include aggressive multiagent chemotherapy, preferably before definitive surgery, and wide en bloc resection or amputation of primary disease. On the latter date, patients seen at MSKCC began participation in a national trial and will be reported elsewhere. Patients with preexisting Paget's disease, with metastatic disease at first presentation, with OS arising in a prior irradiation field, with OS recurrent after prior therapy, and with OS that had already been treated for more than 3 weeks were excluded from the analysis. Patients who had less than 3 weeks of therapy for newly diagnosed OS before beginning treatment at MSKCC are included in the analysis. During the period of this study, we saw 612 patients with OS at MSKCC. Of these, 23 had Paget's disease, 63 had metastatic disease, 23 had OS in a previous irradiation field, 54 had recurrent OS, and 47 had received more than 3 weeks of therapy for OS. Fifty-six patients were seen in consultation only and did not receive treatment at MSKCC. Twenty-three patients had juxtacortical OS, seven patients had multicentric OS. Thirty-seven patients were excluded for a variety of reasons, including extraosseous primary tumor, low- or intermediate-grade histology, or incorrect diagnosis. The remaining 279 patients are the subject of the present analysis. Minimum follow-up in this study was 5 years or until death. The median follow-up for all patients was 7.75 years. Treatment All patients were treated with multiagent chemotherapy and surgery. The objective of surgery was resection of the primary tumor with wide margins. When possible this was accomplished with limb-sparing surgery using an endoprosthesis. During this interval there were five chemotherapy protocols used: T4, T5, T7, 7 T10, and T12.- Treatment did not strictly follow protocol guidelines; patient treatment was individualized using a variety of indicators of patient response to therapy. Patients who had primary chemotherapy before definitive surgery had several parameters that were followed to evaluate their response to preoperative chemotherapy. These included symptoms, tumor size, alkaline phosphatase, radionuclide imaging studies, and histopathologic response of the primary tumor at the time of definitive resection. In the early years of the period included in this study, patients were treated with high-dose methotrexate, doxorubicin, and the threedrug combination of bleomycin, cyclophosphamide, and dactinomycin (BCD). When cisplatin was identified as an active agent against OS, it was incorporated into treatment protocols. Most patients who received cisplatin did so after a poor histologic response to preoperative therapy with the other agents listed above. In four patients, concern about a poor response before definitive surgery was raised by persistent pain, swelling, or persistent elevation of alkaline phosphatase. In these rare individuals, cisplatin was included in preoperative chemotherapy. Patients received treatment according to one of the published treatment protocols, but frequent modifications were made to accommodate toxicity, the requirements of surgical scheduling and prosthesis availability, and assessment by the treating physician of patient response. At the beginning of limb-sparing surgery, all prostheses were custommade; if a prosthesis was not available at the time surgery was called for by protocol, chemotherapy was continued until surgery could be performed. The T7 protocol did not call for the use of cisplatin. Patients who had a poor histologic response to preoperative chemotherapy on the T7 protocol were offered adjuvant cisplatin once that drug demonstrated activity against OS.
Chemotherapy High-dose methotrexate was administered to all patients. The dose was calculated at 8 g/m 2 for patients 13 years or older and at 12 g/m 2 for patients 12 or younger. All doses were rounded up to the next highest full gram of methotrexate. Methotrexate was administered without prior hydration in 1L of 5% dextrose in water with 50 mEq of sodium bicarbonate per liter over 4 hours. Patients who were nauseated received an additional 2 hours of intravenous hydration. In over 90% of administrations, patients were then discharged to be managed as outpatients. Patients were instructed to adjust oral hydration to achieve a urine output of 1,400 to 1,600 mL/m 2 for the first 24 hours after methotrexate and a minimum urine output of 2,000 mL/m 2 for each of the next 24-hour periods. They were taught to take oral sodium bicarbonate to achieve a urine pH in excess of 7.0. Oral leucovorin was begun 20 hours after the start of the methotrexate infusion at a dose of 10 mg every 6 hours until the serum methotrexate level was less than 1.0 x 10mol/L. Patients were seen daily in the outpatient department to monitor renal function and serum methotrexate levels. Methotrexate levels drawn in the morning were available the same day to allow measures to prevent toxicity when necessary. Patients who were nauseated or who were experiencing difficulty with oral hydration received up to 8 hours of intravenous hydration in the outpatient department. Patients whose methotrexate excretion was delayed had increased dose or duration of leucovorin. Doxorubicin was administered as a bolus. When it was given as a single agent, it was given at a dose of 30 mg/m 2/d for 3 days. When it was given in conjunction with cisplatin, it was given at the same dose for 2 days. Dosage modifications were made for patients who experienced sepsis after a course of therapy with doxorubicin. BCD was given on 2 consecutive days. Bleomycin was given at a dose of 15 mg/m2, cyclophosphamide at a dose of 600 mg/im 2, and dactinomycin at a dose of 0.6 mg/m2, with intravenous hydration daily for 2 days. Patients who had significant decreases in pulmonary function received cyclophosphamide and dactinomycin without bleomycin in subsequent courses. Cisplatin was administered at a dose of 120 mg/m2 with intravenous hydration and mannitol diuresis. Creatinine clearance was measured before each course of cisplatin. If the clearance was less than 70 mL/min, cisplatin administration was postponed. Clearance was determined weekly. If renal function improved, cisplatin was administered. If the clearance remained below 70 mL/min for more than 3 weeks, cisplatin was discontinued. For each patient we determined dose intensity of high-dose methotrexate, BCD, doxorubicin, and cisplatin. Dose intensity was derived by dividing the total dose administered for each individual agent by intended dose. The resulting fraction of intended dose was then divided by the actual time of administration. The protocol called for surgery and chemotherapy totaling 40 weeks; as noted, the actual treatment period varied considerably. Patients who failed before the end of chemotherapy treatment had dose intensity calculated using actual time to failure. Patients who failed within 20 weeks of diagnosis were excluded from the dose-intensity analysis.
StatisticalAnalysis The following parameters were analyzed by univariate analysis for their ability to predict both DFS and overall survival: primary tumor site, age, race, sex, pretreatment serum alkaline phosphatase and lactate dehydrogenase (LDH), histologic response to
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OSTEOSARCOMA AT MEMORIAL SLOAN-KETTERING preoperative chemotherapy, dose-intensity of doxorubicin, highdose methotrexate, cisplatin, and BCD. Univariate comparisons were made using the score test based on the Cox proportional hazards model. The estimated DFS probabilities were calculated using the method of Kaplan and Meier. Failures were defined by relapse or death. DFS was measured from the start of chemotherapy to either the last follow-up or failure. The proportional hazards model equates the relative risk (RR) of (disease-free) survival with the exponential of a constant times the covariate of interest: h(t,x)/ho(t) = exp(xp), where x is the value of the covariate, t is the time to failure or last follow-up, P is the regression parameter assessed with the covariate, h(t,x) is the hazard function for an individual at time t with covariate value x, and h 0(t) is the baseline hazard corresponding to a covariate value of 0 (or the average covariate value if x is continuous). This model generalizes to more than one covariate by considering a linear combination of covariates on the right side of the equation. Approximate 95% confidence intervals for the RR were calculated using standard asymptotic methods; with RR = exp(xp). The variance of RR (for a given value of x) is approximately equal to var (RR) = Ix*exp(xb)t2*var(b), where b is the proportional hazards estimate of the regression parameter p. Thus, the approximate 95% confidence interval for the RR is RR ± 2[var(RR)]"2 . To display the relationship of a continuous covariate and the time a patient is alive free of disease, a predictive plot was generated. 8 The predictive plot is more descriptive of this relationship than a Kaplan-Meier plot, because the Kaplan-Meier plot is based on an arbitrary grouping of a continuous covariate and, therefore, assumes that all individuals in one group are at equivalent risk of relapse or death. The predicted 80th percentile DFS for a given covariate x is the time t, such that: S(t) = (0.8)exp(xb),
where S(t) is a smoothed version of the overall Kaplan-Meier estimate. The 80th percentile is used as a summary measure (rather than the 50th percentile or median), because greater than 70 percent of the patients in this study were censored. Subsequent to the univariate analysis, a multivariate analysis using the proportional hazards model noted above was performed. The purpose of considering a multiple variable model in this exploratory analysis is to eliminate redundancy among highly correlated covariates, each of which may be individually significant.
7 patients who did or did not have preoperative chemotherapy (P = .29; Fig 1). When possible, limb-sparing surgery was performed. Reasons to perform amputation included neurovascular compromise by the tumor, tumor size, considerations of soft tissue and skin closure, and site of the tumor. Clinical features that suggested a poor response to preoperative chemotherapy were also considered. Amputation was performed when there was a strong clinical suspicion of a poor histologic response. There was no difference by univariate analysis in outcome between the patients who underwent limb-sparing surgery and the patients who had amputation (P = .34; Fig 2). Age We examined the effect of age at diagnosis on DFS (Fig 3). Patients aged 13 to 21 years at diagnosis had a higher probability of DFS than those aged < 12 years, who in turn did better than patients older than 21 years (P = .064).
Sex Patient sex had no effect on DFS. Race Patients were classified as white, black, Hispanic, and other. The number of patients in the last group was too small to permit analysis. Black patients had a relative risk of relapse or death 1.9-fold greater than white patients (P = .04; 95% confidence interval (CI), 1.0 to 4.0; Fig 4).
RESULTS
For all the variables examined, DFS and overall survival were equivalent; thus, we will only report the results in terms of DFS. Surgery The intent of the treatment strategy was to administer a period of initial chemotherapy to all patients following diagnostic biopsy and before definitive surgery. Some patients were referred to MSKCC after a primary amputation; others had primary amputation performed at MSKCC because of tumor size, pathologic fracture, or pain. Sixty-three patients underwent primary surgery and did not receive preoperative chemotherapy. Univariate analysis showed no difference in outcome between
".0030.00
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time (months) Fig 1. DFS for patients who received any preoperative chemotherapy (0; 216 patients, 143 censored) v no preoperative chemotherapy (0; 63 patients, 39 censored). Tick marks indicate last follow-up.
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8
MEYERS ET AL
0
C
00
time
(months)
time
Fig 2. DFS for patients who underwent amputation (0; 132 patients, 85 censored) v limb-sparing en bloc resection (0; 127 patients, 86 censored) for definitive surgery. Tick marks indicate last follow-up.
Primary Site The site of the primary tumor correlated with DFS (P = .008; Fig 5). The most favorable sites were the proximal humerus and proximal tibia. We treated 56 patients with OS of the proximal tibia; 45 (80%) remained continuously free of disease. For 34 patients with OS of the proximal humerus, 25 (74%) remain in continuous DFS. The distal femur was the next most
(months)
Fig 4. DFS as a function of race: white (L; 188 patients, 128 censored), black (0; 46 patients, 23 censored), and Hispanic (A; 25 patients, 17 censored). Tick marks indicate last follow-up.
favorable site, with 75 of 122 patients (61%) continuously free of disease, with a similar experience for 26 of 43 patients (60%) for all other extremity sites. The worst prognosis was associated with an axial primary; only 11 of 24 patients (46%) remain continuously free of disease. Patients with an axial skeletal primary tumor had a 3.9-fold greater risk of relapse or death than the patients with a proximal humerus tumor (95% CI, 1.4 to 10.6).
o
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oo
time
time (months)
(months)
Fig 3. DFS as a function of age at diagnosis: < 12 years (L0; 51 patients, 32 censored), from 12 to 21 years (0; 168 patients, 117 censored), and older than 21 years (A; 60 patients, 33 censored). Tick marks indicate last follow-up.
Fig 5. DFS as a function of primary site: distal femur (D; 122 patients, 75 censored), proximal tibia (0; 56 patients, 45 censored), proximal humerus (A; 34 patients, 25 censored), other extremity (O; 43 patients, 26 censored), and axial (a; 24 patients, 11 censored). Tick marks indicate last follow-up.
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OSTEOSARCOMA AT MEMORIAL SLOAN-KETTERING BiochemicalMarkers
EaoX -
Initial baseline, pretreatment serum alkaline phosphatase and LDH were strongly predictive of outcome in our patients (P = .007 and P = .001, respectively; Figs 6 and 7). For both markers, there was a steady increase in risk of relapse or death associated with increasing serum enzyme activity. Because risk of relapse varied continuously as a function of enzyme activity, we show the predicted 80th percentile DFS as a continuous function of LDH or alkaline phosphatase. We cannot use median DFS, as 68% of the patients in this study remain alive and free of disease. Patients with an LDH level less than 100 had a 0.4-fold lower risk of relapse or death than patients with the median LDH level of 256 (95% CI, 0.04 to 0.8), while patients with an LDH level greater than 400 had a risk of relapse or death 1.5-fold greater than the median (95% CI, 1.3 to 1.8). Patients with an alkaline phosphatase level less than 100 had half the risk of relapse or death associated with the median of 205 (95% CI, 0.3 to 0.7), while patients with an alkaline phosphatase level in excess of 400 had a twofold greater risk of relapse or death (95% CI, 1.8 to 2.2). HistologicResponse Patients who underwent a period of initial chemotherapy before definitive resection of their primary tumors had an assessment of their histologic response to preoperative chemotherapy performed at the time of definitive surgery. Histologic response was assessed in 182 patients. Sixty-three patients did not have preoperative ·,oo E &
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alkaline phosphatase Fig 6. Predicted 80th percentile for DFS (in months) as a function of baseline alkaline phosphatase level based on the proportional hazards model.
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chemotherapy, and 34 patients did not have histologic assessment. DFS correlates strongly with the degree of histologic response (P = .016; Fig 8). The best outcome was observed with DFS for 29 of the 32 (91%) patients who had no viable tumor cells detected in the specimen obtained at the time of complete resection (grade IV histologic response). In contrast, the 20 patients with no apparent effect of chemotherapy (grade I response) had a sixfold greater risk of relapse or death than patients with a grade IV response (DFS, 10 of 20 (50%); 95% CI, 1.6 to 22.9). DFS was observed in 57 of 87 (66%) patients with a grade II response and in 31 of 43 (72%) patients with a grade III response. Patients who did not receive an initial period of chemotherapy could not be assessed for histologic response. Although these 63 patients did not fare significantly worse than the overall group of patients who did receive preoperative chemotherapy, they had a risk of relapse or death 5.3-fold greater than the patients with a grade IV response (95% CI, 1.6 to 18.1). We examined the relationship of the duration of the preoperative phase of treatment to histologic response. Patients were divided into three groups of approximately equal size based on the duration of preoperative chemotherapy. This duration was 19 to 60 days for the 57 patients in the first group, 63 to 96 days for the 58 patients in the intermediate group, and greater than 97 days for the 55 patients with the longest duration of preoperative chemotherapy. In univariate analysis, the duration of preoperative chemotherapy did not correlate with DFS. With longer preoperative treatment,
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10
MEYERS ET AL
.o.
time
(months)
Fig 8. DFS as a function of histologic respons e at the time of definitive surgery: grade I (L; 20 patients, 10 censo red), grade II (0; 87 patients, 57 censored), grade III (A; 43 patien ts, 31 censored), grade IV (0; 32 patients, 29 censored), and no preooperative chemotherapy (*; 63 patients, 39 censored). Tick ma rks indicate last follow-up.
however, a greater proportion of patientss had a favorable histologic response (Table 1), but the correlation of that response with outcome decreased. Pat ients who had a favorable histologic response assessed af'ter less than 2 months of preoperative chemotherapy had a high probability of DFS. Patients who had a favora ble histologic response assessed after a greater period o f preoperative chemotherapy had a lower probability of E)FS. For every duration of preoperative therapy, better histologic response predicted better DFS, but the differences between good and poor responders decr eased as the duration increased.
patients who had evaluation of histologic response at definitive surgery. There was no correlation for any of the agents with either histologic response grade or subsequent DFS. The addition of cisplatin to the postoperative management of patients with a poor (grade I or II) histologic response to preoperative chemotherapy did not improve their long-term probability of DFS but may have delayed their relapse (Fig 9). None of the patients was treated with high-dose methotrexate as the only chemotherapeutic agent. A group of 54 patients received only high-dose methotrexate during the preoperative phase of treatment and were assessable for histologic response. Of these patients, four (7%) had a grade IV response and six (11%) had a grade III response. In other words, 10 of 54 patients .(1t0/) achieved a favorable hlstologic response to preoperative chemotherapy at the time of definitive surgery after receiving high-dose methotrexate as a single agent.
This compares with 65 of 128 patients (51%) evaluated who achieved a favorable histologic response after multiagent chemotherapy.
Protocol Patients were enrolled on a series of chemotherapy protocols. The protocols are identified by a number that increased with sequential opening to enrollment, with T4 and T5 being used in the first years of this series, followed by T7, T10, and finally, T12. While DFS improved from the T4 and T5 protocols to the T7 and T10 protocols, the number of patients treated according
Chemotherapy Dose intensity did not correlate with D)FS for any of the chemotherapy agents. We examined tlhe dose intensity of the preoperative chemotherapy for the 182 Table 1. Histologic Response at the Time of Definit ive Surgery as a Function of the Duration of Preoperative Cheomotherapy Response Grade
Days of Preoperative Chemotherapy 19-60 63-96 >96
I II III IV
14 30 10 3
(.50) (.63) (.90) (1.0)
Total
57 (.67)
3 25 13 17
(.33) (.80) (.69) (.88)
58 (.77)
2 24 17 12
All Patients
(1.0) (.58) (.65) (.92)
19(.53) 79 (.67) 40 (.73) 32 (.91)
55 (.69)
170 (.71)
NOTE. P < .005 by X' analysis. Patients were divided into three groups of approximately equal size. Numbers in parentheses are the proportion of patients in each group who remain alive and free of disease.
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Fig 9. DFS for patients with histologic response grade I or II who did (0; 77 patients, 49 censored) or did not (0; 30 patients, 18 censored) receive subsequent cisplatin. Tick marks indicate last follow-up.
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11
OSTEOSARCOMA AT MEMORIAL SLOAN-KETTERING to the former is insufficient to conclude with confidence that the latter are superior therapies (Fig 10). Similarly, the results with T12 appear better than those with T7 and T10, but the numbers are small. Long-term DFS for patients treated with the T7 and T10 protocols are the same, but the average time to relapse was greater in the T10 protocol. The distribution of histologic response grades was different, with a higher rate of good responses seen in the T7 protocol than in the T10. The former called for a longer period of preoperative chemotherapy with more agents than the latter. Fifty-eight percent of the patients treated with the T7 protocol had a grade III or IV response to preoperative chemotherapy, compared with 34% of the patients treated with the T10 protocol (Table 2). IntervalFrom Definitive Surgery to Resumption of Chemotherapy We examined the relationship between delay in resumption of chemotherapy after definitive surgery to subsequent DFS. For patients with a good histologic response to preoperative chemotherapy, there was no correlation. For the patients who had a grade I or grade II (poor) response to preoperative chemotherapy, there was a trend toward poorer DFS for patients with increasing duration between definitive surgery and resumption of chemotherapy (Fig 11). For this group, a delay of more than 24 days in resumption of chemotherapy was associated with a higher risk of relapse or death (P = .15).
Table 2. Histologic Response at the Time of Surgery: Protocols T7 and T10 Protocol
Response Grade
T7
T10
I II III IV
1 10 12 8
16 67 21 21
MultivariateAnalysis As a result of the univariate analyses, five covariates appeared to be predictive of DFS: tumor site, race, histologic response, LDH level, and alkaline phosphatase level. Multivariate analysis using Cox's proportional hazards model was undertaken to determine which variables were predictive of DFS (Table 3). The model indicates that the risk of relapse or death increases as the LDH or alkaline phosphatase level increases. In addition, the risk increases as the histologic response grade decreases. The primary tumor site retains its prognostic significance, with axial primaries conferring the greatest relative risk. Race, identified in univariate analysis as a prognostic factor, did not achieve statistical significance in multivariate analysis. This appears to be the result of a correlation between race and histologic response to preoperative chemotherapy. A greater proportion of black patients had a grade I or II histologic response at the time of definitive surgery than did white patients. DISCUSSION Prognostic factors are dependent on treatment as well as the intrinsic biology of a tumor. Factors of strong significance in predicting outcome with one treatment regimen may no longer be predictive with improved treatment. Taylor et al 9 reported the results of a survey of 13 cancer centers that treated patients with OS during an interval similar to that of our study. They were not able to identify a prognostic advantage for chemotherapy. In their study, 350 patients with classical OS (excluding juxtacortical OS and OS arising in Paget's disease) had an overall survival of 57% and DFS of 36%. Our results for a comparable group of 279 patients were an overall survival of 71% and DFS of 65% with a longer median follow-up. It is possible that their failure to
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Fig 10. DFS as a function of treatment protocol: T4 and T5 (0[; 32 patients, 15 censored); T7 (0; 75 patients, 54 censorred), T10 (V; 153 patients, 106 censored), and T12 (0; 17 patients, 1I4 censored). Tick marks indicate last follow-up.
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inclusion of some less-tnan-optimal chemotherapy regimens. We identified several factors that could predict outcome for patients with OS. The primary site of the tumor has a strong influence on outcome, with axial primaries
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12
MEYERS ET AL
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having the greatest risk of progression and death. Definitive surgery achieving wide margins of resection is almost never possible for axial primaries. To allow comparison with other published series of patients with OS treated with multiagent chemotherapy, we examined the outcome for our patients with OS of the extremities who were less than 22 years old at diagnosis and were treated with the T10 protocol. The 5-year DFS for this group is 76% (95% CI, 68% to 84%; Fig 12). This compares with the published 2-year DFS of 66% in the Multiinstitutional Osteosarcoma Study and the DFS of 58% with a median follow-up of 34 months in the Cooperative Osteogenic Sarcoma Study (COSS)-82 study.3' 10 In contrast to the observations of some other groups, we found the proximal humerus to be a relatively favorable site, comparable to the proximal tibia. Both alkaline phosphatase and LDH levels correlated strongly Table 3. Proportional Hazards Model for DFS (n = 230) Covariate
RR
In LDH Histologic response grade
exp((In LDH - 5.44)*0.561
II 11I IV No preoperative chemotherapy Primary site Proximal humerus Proximal tibia Distal femur Other extremity Axial In Alk phos
P .001 .018
6.49 3.53 3.06 1.00 5.37 .038 1.00 1.01 1.77 1.88 3.67 exp{(In AP - 5.32)*0.311
.072
Abbreviations: Alk phos, AP, alkaline phosphatase; In, natural logarithm.
1 180
Fig 11. DFS for patients with histologic response grade I or II who had prompt (_< .8 months, 0; 64 patients, 47 censored) or delayed (> .8 months, 0; 43 patients, 24 censored) resumption of chemotherapy after definitive surgery. Vertical bars represent 95% CIs; tick marks indicate last follow-up.
and independently with outcome. White and Hispanic patients had a greater likelihood of DFS and overall survival than black patients in univariate analysis. An older series previously reported by this institution reported no difference in outcome between black and white patients." That report examined 100 black patients with OS seen between 1921 and 1979; the majority of these patients were treated with surgery alone. The multivariate analysis suggests that the poorer outcome for black patients was the consequence of a higher incidence of unfavorable histologic response to preoperative chemotherapy among that group. Histologic response to preoperative chemotherapy assessed at the time of definitive surgery strongly predicted subsequent DFS and overall survival. Similar results have been reported from the Childrens Cancer Study Group (CCSG) and European trials. 10 '2 In these trials there was a strong correlation between histologic response and subsequent DFS. The proportion of patients achieving a good histologic response was substantially lower in both studies than we observed. Poor histologic response to preoperative chemotherapy predicts an increased likelihood of progression and death. It is possible that poor response to initial therapy identifies a group of patients unresponsive to chemotherapy who will do poorly, regardless of treatment used. It is also possible that a poor initial response allows persistence of tumor cells with a greater probability for emergence of drug-resistant clones and spread, increasing the probability of subsequent failure. One way to discriminate between these hypotheses is to compare the outcome for patients treated with immediate definitive surgery followed by adjuvant chemotherapy with those treated with initial chemotherapy and delayed definitive surgery. In
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13
OSTEOSARCOMA AT MEMORIAL SLOAN-KETTERING 1.o0.9-
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Fig 12. DFS for patients with extremity primary aged _< 21 years at diagnosis and treated on the T10 protocol (104 patients, 77 censored). Vertical bars represent 95% CIs; tick marks indicate last follow-up.
C
0.2SC-
go.o"o 0.0rF 12
24
F 36
our experience there was no difference in outcome for these two groups of patients. Our study was not randomized, however, and it is possible that selection bias could obfuscate this issue. We originally described histologic response as a qualitative assessment of tumor necrosis; no quantitation was defined. Patients with total necrosis (grade IV) or only scattered foci of viable tumor cells (grade III) were considered to have a good response to preoperative chemotherapy. Beginning with the T10 protocol, patients with a grade I and II response had cisplatin added to their postoperative treatment. The designation of grade III and IV as good response was operational and was used to decide for subsequent treatment. With longer follow-up, it is apparent that grade IV response is clearly predictive for superior DFS. DFS for patients with grade III response is not significantly superior to that for patients with a grade II response. Other investigators have used different definitions of "good" histologic response. In the COSS-80 study, good response was defined as > 50% necrosis in the resected tumor; this may explain the observation of a 67% "good" response rate reported in this series. 13 In the COSS-82 study good response was defined as > 90% necrosis."o In the design of future interventions aimed at improving outcome for poor responders, it will be critical to assess the definitions of good and poor response. Patients who are treated with preoperative chemotherapy similar to that given to the patients in this series who have less than a grade IV response would be appropriate candidates for a postoperative intervention designed to improve DFS. We examined the potential of the addition of cisplatin to the treatment of OS. Patients who had a poor
48
60 Months
72
from start
84
96
10
120
132
l
" 144
of protocol
response to initial therapy and were at increased risk for relapse or death received cisplatin. We were not able to demonstrate any improvement in 5-year DFS for this group of patients compared with a similar group who had not received cisplatin. It is possible that this failure was related to the relatively late introduction of cisplatin in the treatment regimen. Most patients who received cisplatin after initial poor response began cisplatin after 20 weeks of therapy. This result differs from our previously published observation6 that the addition of cisplatin could improve the 2-year DFS for patients with a poor response to preoperative chemotherapy. In retrospect, that observation was premature; with more patients and longer follow-up, there is no evidence for improved outcome with modification of postoperative chemotherapy on the basis of histologic response to preoperative chemotherapy. The COSS-82 study was also unable to demonstrate the ability to salvage poor responders to initial therapy by the addition of alternative agents.'o The drugs that have been active in the treatment of OS include doxorubicin, high-dose methotrexate, and cisplatin. The three-drug combination BCD was incorporated into our treatment after demonstrating limited activity in patients with recurrent OS.14 A more recent examination of BCD for recurrent OS performed at St Jude Children's Research Hospital was not able to show any activity for this combination in patients with metastatic OS." Nonetheless, the inclusion of BCD in the treatment of our patients did not appear to have a detrimental effect on outcome. Both DFS and overall survival for our patients are among the best reported. The relative merits of high-dose methotrexate have been questioned by several investigators. When high-
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MEYERS ET AL
dose methotrexate therapy was first introduced it was expensive and associated with a risk of severe toxicity. The CCSG performed a trial that did not show any advantage of high-dose methotrexate over moderatedose methotrexate.16 Unfortunately, both arms of that trial achieved a DFS significantly inferior to that of the subsequent trial incorporating high-dose methotrexate, and inferior to our present results. When administered with appropriate rescue, high-dose methotrexate is considerably less toxic than moderate-dose methotrexate, and can be administered in a period of less than 1 week, allowing for the rapid administration of other active agents. The CCSG 782 study was an attempt to reproduce in a cooperative group the results of the MSKCC T10 trial. Although the study confirmed the importance of histologic response, DFS and overall survival were inferior to the present results. The preponderance of high-dose methotrexate in the early weeks of treatment in both treatment approaches suggests that a possible explanation for differences in outcome may lie in differences in administration of high-dose methotrexate. High-dose chemotherapy differs from other chemotherapy in its sensitivity to a wider variety of variables in administration, including dose, rate of administration, hydration, alkalinization, dose timing, and route of administration of leucovorin rescue. Concern about the potential toxicity of high-dose methotrexate has led many treating physicians to use more hydration or more leucovorin than we have found to be necessary. For example, the CCSG 782 study called for the administration of leucovorin 15 mg per dose instead of the 10 mg we have routinely used. It is possible that differences in the administration of high-dose methotrexate and/or leucovorin could explain the superior outcome that we have observed. The concept that early intensive treatment is critical to a successful outcome for patients with OS is further supported by the examination of the interval between definitive surgery and the resumption of chemotherapy. Reasons for a delay in the resumption of chemotherapy included the need for additional time to permit wound healing, wound infections, and patient request. Patients who had a good response to preoperative chemotherapy did not suffer from a delay in resuming treatment. Patients with a poor initial response and a delay in resumption of chemotherapy did worse than those patients who promptly resumed treatment. We were unable to demonstrate any correlation between dose intensity for any of the agents used in this
study and histologic response at definitive surgery, overall survival, and DFS. This finding must be interpreted with caution. Conventional examination of dose intensity is performed using a protocol in which all patients receive identical numbers of courses of identical agents. Dose intensity, then, varies as a result of predetermined dose reductions and treatment delays for toxicity. Our patients received different sequences and doses of chemotherapy based both on histologic response to preoperative chemotherapy and the treating physician's judgment. This may obscure the ability to detect a relationship between dose intensity and outcome. It is also possible, however, that OS has an intrinsic sensitivity or resistance to chemotherapy at diagnosis. This sensitivity could be revealed by the histologic response to preoperative chemotherapy, which would explain the strong correlation between histologic response and subsequent DFS. Histologic response to preoperative chemotherapy strongly predicts subsequent DFS and overall survival. This observation, strongly supported by other studies, is of limited clinical value to an individual patient. Neither we nor other investigators have demonstrated the ability to salvage the poor responder by subsequent modification of chemotherapy. An obvious alternative strategy would be to use additional agents during preoperative chemotherapy in an attempt to increase the proportion of patients who will achieve a good histologic response. With this in mind, it is critical to examine the relationship of histologic response to outcome. We found that longer periods of preoperative chemotherapy achieved a higher proportion of good responses, but that the good responses so achieved did not translate into the same survival advantage as good responses achieved with shorter treatment. The T7 protocol called for longer preoperative chemotherapy with more agents than the T10 protocol. Grade III and IV histologic responses to preoperative chemotherapy were seen in 54% of the patients treated with T7 and 34% of patients treated with T10; DFS for the two trials is the same. Reports of high rates of good response must be carefully examined in light of these observations. With prolonged periods of preoperative chemotherapy, it is theoretically possible that the correlation between histologic response and outcome will be lost. It cannot be presumed that a treatment that results in a higher rate of good histologic response will automatically translate into improved survival. Multiagent chemotherapy coupled with aggressive surgical resection can produce durable survival for
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OSTEOSARCOMA AT MEMORIAL SLOAN-KETTERING
15
almost three fourths of patients with OS who present without clinically detectable metastatic disease. Prognostic factors can predict some of the patients who are destined to do poorly with the therapies described in this report. The most powerful predictor of DFS-histologic
response to preoperative chemotherapy-cannot be determined at the time of diagnosis. We need additional techniques to identify those patients who will respond poorly to chemotherapy and to develop novel therapies for this group.
REFERENCES 1. Marcove R, Mike V, Haych JV, et al: Osteogenic sarcoma under the age of twenty-one: A review of 145 operative cases. J Bone Joint Surg 52:411-492, 1970 2. Edmonson JH, Green SJ, Ivins JC, et al: A controlled pilot study of high-dose methotrexate as postsurgical adjuvant treatment for primary osteosarcoma. J Clin Oncol 2:152-156, 1984 3. Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314:1600-1606, 1986 4. Rosen G, Murphy ML, Huvos AG, et al: Chemotherapy, en bloc resection and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 37:1-11, 1976 5. Rosen G, Marcove RC, Caparros B, et al: Primary osteogenic sarcoma. The rationale for preoperative chemotherapy and delayed surgery. Cancer 43:2163-2177, 1979 6. Rosen G, Caparros B, Huvos AG, et al: Preoperative chemotherapy for osteogenic sarcoma: Selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 49:1221-1230, 1982 7. Rosen G: Pre-operative (neo-adjuvant) chemotherapy for osteogenic sarcoma: A ten year experience. Orthopedics 8:659-664, 1985 8. Heller G, Simonoff JS: Prediction in censored survival data: A comparison of the proportional hazards and linear regression models. Biometrics (in press) 9. Taylor WF, Ivins JC, Unni KK, et al: Prognostic variables in
osteosarcoma: A multi-institutional study. J Natl Cancer Inst 81:21-30, 1989 10. Winkler K, Beron G, Delling G, et al: Neoadjuvant chemotherapy of osteosarcoma: Results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol 6:329-337, 1988 11. Huvos AG, Butler A, Bretsky SS: Osteogenic sarcoma in the American Black. Cancer 52:1959-1965, 1983 12. Provisor A, Nachman J, Krailo M, et al: Treatment of non-metastatic osteogenic sarcoma (OS) of the extremities with pre- and post-operative chemotherapy. Proc Am Soc Clin Oncol 6:217, 1987 (abstr) 13. Winkler K, Beron G, Kotz R, et al: Neoadjuvant chemotherapy for osteogenic sarcoma: Results of a cooperative German/ Austrian study. J Clin Oncol 2:617-624, 1984 14. Mosende C, Gutierrez M, Caparros B, et al: Combination chemotherapy with bleomycin, cyclophosphamide and dactinomycin for the treatment of osteogenic sarcoma. Cancer 40:2779-2786, 1977 15. Pratt CB, Epelman S, Jaffe N: Bleomycin, cyclophosphamide, and dactinomycin in metastatic osteosarcoma: Lack of tumor regression in previously treated patients. Cancer Treat Rep 71:421423, 1987 16. Krailo M, Ertel E, Makley J, et al: A randomized trial comparing high dose methotrexate with moderate dose methotrexate as components of adjuvant chemotherapy in childhood nonmetastatic osteosarcoma. Med Ped Oncol 15:69-77, 1987
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OSTEOGENIC
SARCOMA (OS) treated by surgi-
cal ablation of the primary tumor will progress to metastatic disease in 80% to 90% of patients in a median
of 5 months.' Many investigators have reported improved disease-free survival (DFS) and overall survival
for patients treated with chemotherapy compared with these historical controls. A prospective randomized trial
of adjuvant chemotherapy versus observation after surgery for OS was performed at the Mayo Clinic (Rochester, MN).2 The results were surprising on two counts:
mary tumor site, race, and histologic response to preoperative chemotherapy. There was no difference in DFS for patients with a poor histologic response who did or did nor receive cisplatin, although patients who did receive cisplatin had a longer time to relapse. The 5-year DFS was 76% for patients aged < 21 years who had extremity primary tumor and were treated with the T10 protocol. Conclusions: Intensive chemotherapy can achieve DFS for a high proportion of patients with OS. Although it is a powerful predictor of DFS, histologic response to preoperative chemotherapy cannot be assessed at diagnosis. We have not shown an ability to salvage patients with an unfavorable response. We need to increase the proportion of patients with a favorable response, identify the patients who will have an unfavorable response, and develop novel treatments to salvage poor responders. J Clin Oncol 10:5-15. c 1992 by American Society of Clinical Oncology.
quent DFS, is it possible to alter therapy for poor responders to improve their prognosis? From 1975 to 1984, we evaluated 612 patients with OS at the Memorial Sloan-Kettering Cancer Center (MSKCC). In this review we will only examine the group of patients who presented to MSKCC with fully malignant, high-grade, newly diagnosed, and previously untreated OS. The analysis is also limited to those patients who did not have metastatic disease detected at diagnosis by conventional diagnostic imaging techniques.
there was no difference in outcome between the two groups, and the observational group achieved a DFS of
40%. A subsequent, larger trial performed by the Pediatric Oncology Group documented markedly superior DFS with the use of adjuvant chemotherapy.3 The 2-year actuarial DFS was 66% for patients randomly assigned to receive chemotherapy and 17% for patients randomly assigned to observation. The value of adjuvant chemotherapy for OS seems well established. Several crucial questions remain unanswered. What factors best
predict outcome for the patient with OS? What is the optimal chemotherapy for OS? Is a period of chemotherapy before definitive surgery ("neoadjuvant" or preoper-
ative chemotherapy) superior to immediate surgery followed by adjuvant chemotherapy? If histologic response to preoperative chemotherapy predicts subse-
METHODS Patients A comprehensive list of patients with the diagnosis of OS was generated. The medical record and histopathology of each patient were reviewed. Inclusion was restricted to patients first seen at MSKCC between January 1, 1975, and April 30, 1984. The former
From the Departmentsof Pediatrics,Biostatistics,Orthopedics, and Pathology, Memorial Sloan-Kettering Cancer Center,New York, NY, and Cedars-SinaiComprehensive CancerCenter,Los Angeles, CA. SubmittedApril 22, 1991; acceptedJuly 30, 1991. Address reprint requests to Paul A. Meyers, MD, Department of Pediatrics,Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. 0 1992 by American Society of Clinical Oncology. 0732-183X/92/1001-0018$3.00/0
Journalof Clinical Oncology, Vol 10, No 1 (January), 1992: pp 5-115
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5
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MEYERS ET AL
date was chosen arbitrarily as a date by which OS treatment strategy was accepted to include aggressive multiagent chemotherapy, preferably before definitive surgery, and wide en bloc resection or amputation of primary disease. On the latter date, patients seen at MSKCC began participation in a national trial and will be reported elsewhere. Patients with preexisting Paget's disease, with metastatic disease at first presentation, with OS arising in a prior irradiation field, with OS recurrent after prior therapy, and with OS that had already been treated for more than 3 weeks were excluded from the analysis. Patients who had less than 3 weeks of therapy for newly diagnosed OS before beginning treatment at MSKCC are included in the analysis. During the period of this study, we saw 612 patients with OS at MSKCC. Of these, 23 had Paget's disease, 63 had metastatic disease, 23 had OS in a previous irradiation field, 54 had recurrent OS, and 47 had received more than 3 weeks of therapy for OS. Fifty-six patients were seen in consultation only and did not receive treatment at MSKCC. Twenty-three patients had juxtacortical OS, seven patients had multicentric OS. Thirty-seven patients were excluded for a variety of reasons, including extraosseous primary tumor, low- or intermediate-grade histology, or incorrect diagnosis. The remaining 279 patients are the subject of the present analysis. Minimum follow-up in this study was 5 years or until death. The median follow-up for all patients was 7.75 years. Treatment All patients were treated with multiagent chemotherapy and surgery. The objective of surgery was resection of the primary tumor with wide margins. When possible this was accomplished with limb-sparing surgery using an endoprosthesis. During this interval there were five chemotherapy protocols used: T4, T5, T7, 7 T10, and T12.- Treatment did not strictly follow protocol guidelines; patient treatment was individualized using a variety of indicators of patient response to therapy. Patients who had primary chemotherapy before definitive surgery had several parameters that were followed to evaluate their response to preoperative chemotherapy. These included symptoms, tumor size, alkaline phosphatase, radionuclide imaging studies, and histopathologic response of the primary tumor at the time of definitive resection. In the early years of the period included in this study, patients were treated with high-dose methotrexate, doxorubicin, and the threedrug combination of bleomycin, cyclophosphamide, and dactinomycin (BCD). When cisplatin was identified as an active agent against OS, it was incorporated into treatment protocols. Most patients who received cisplatin did so after a poor histologic response to preoperative therapy with the other agents listed above. In four patients, concern about a poor response before definitive surgery was raised by persistent pain, swelling, or persistent elevation of alkaline phosphatase. In these rare individuals, cisplatin was included in preoperative chemotherapy. Patients received treatment according to one of the published treatment protocols, but frequent modifications were made to accommodate toxicity, the requirements of surgical scheduling and prosthesis availability, and assessment by the treating physician of patient response. At the beginning of limb-sparing surgery, all prostheses were custommade; if a prosthesis was not available at the time surgery was called for by protocol, chemotherapy was continued until surgery could be performed. The T7 protocol did not call for the use of cisplatin. Patients who had a poor histologic response to preoperative chemotherapy on the T7 protocol were offered adjuvant cisplatin once that drug demonstrated activity against OS.
Chemotherapy High-dose methotrexate was administered to all patients. The dose was calculated at 8 g/m 2 for patients 13 years or older and at 12 g/m 2 for patients 12 or younger. All doses were rounded up to the next highest full gram of methotrexate. Methotrexate was administered without prior hydration in 1L of 5% dextrose in water with 50 mEq of sodium bicarbonate per liter over 4 hours. Patients who were nauseated received an additional 2 hours of intravenous hydration. In over 90% of administrations, patients were then discharged to be managed as outpatients. Patients were instructed to adjust oral hydration to achieve a urine output of 1,400 to 1,600 mL/m 2 for the first 24 hours after methotrexate and a minimum urine output of 2,000 mL/m 2 for each of the next 24-hour periods. They were taught to take oral sodium bicarbonate to achieve a urine pH in excess of 7.0. Oral leucovorin was begun 20 hours after the start of the methotrexate infusion at a dose of 10 mg every 6 hours until the serum methotrexate level was less than 1.0 x 10mol/L. Patients were seen daily in the outpatient department to monitor renal function and serum methotrexate levels. Methotrexate levels drawn in the morning were available the same day to allow measures to prevent toxicity when necessary. Patients who were nauseated or who were experiencing difficulty with oral hydration received up to 8 hours of intravenous hydration in the outpatient department. Patients whose methotrexate excretion was delayed had increased dose or duration of leucovorin. Doxorubicin was administered as a bolus. When it was given as a single agent, it was given at a dose of 30 mg/m 2/d for 3 days. When it was given in conjunction with cisplatin, it was given at the same dose for 2 days. Dosage modifications were made for patients who experienced sepsis after a course of therapy with doxorubicin. BCD was given on 2 consecutive days. Bleomycin was given at a dose of 15 mg/m2, cyclophosphamide at a dose of 600 mg/im 2, and dactinomycin at a dose of 0.6 mg/m2, with intravenous hydration daily for 2 days. Patients who had significant decreases in pulmonary function received cyclophosphamide and dactinomycin without bleomycin in subsequent courses. Cisplatin was administered at a dose of 120 mg/m2 with intravenous hydration and mannitol diuresis. Creatinine clearance was measured before each course of cisplatin. If the clearance was less than 70 mL/min, cisplatin administration was postponed. Clearance was determined weekly. If renal function improved, cisplatin was administered. If the clearance remained below 70 mL/min for more than 3 weeks, cisplatin was discontinued. For each patient we determined dose intensity of high-dose methotrexate, BCD, doxorubicin, and cisplatin. Dose intensity was derived by dividing the total dose administered for each individual agent by intended dose. The resulting fraction of intended dose was then divided by the actual time of administration. The protocol called for surgery and chemotherapy totaling 40 weeks; as noted, the actual treatment period varied considerably. Patients who failed before the end of chemotherapy treatment had dose intensity calculated using actual time to failure. Patients who failed within 20 weeks of diagnosis were excluded from the dose-intensity analysis.
StatisticalAnalysis The following parameters were analyzed by univariate analysis for their ability to predict both DFS and overall survival: primary tumor site, age, race, sex, pretreatment serum alkaline phosphatase and lactate dehydrogenase (LDH), histologic response to
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OSTEOSARCOMA AT MEMORIAL SLOAN-KETTERING preoperative chemotherapy, dose-intensity of doxorubicin, highdose methotrexate, cisplatin, and BCD. Univariate comparisons were made using the score test based on the Cox proportional hazards model. The estimated DFS probabilities were calculated using the method of Kaplan and Meier. Failures were defined by relapse or death. DFS was measured from the start of chemotherapy to either the last follow-up or failure. The proportional hazards model equates the relative risk (RR) of (disease-free) survival with the exponential of a constant times the covariate of interest: h(t,x)/ho(t) = exp(xp), where x is the value of the covariate, t is the time to failure or last follow-up, P is the regression parameter assessed with the covariate, h(t,x) is the hazard function for an individual at time t with covariate value x, and h 0(t) is the baseline hazard corresponding to a covariate value of 0 (or the average covariate value if x is continuous). This model generalizes to more than one covariate by considering a linear combination of covariates on the right side of the equation. Approximate 95% confidence intervals for the RR were calculated using standard asymptotic methods; with RR = exp(xp). The variance of RR (for a given value of x) is approximately equal to var (RR) = Ix*exp(xb)t2*var(b), where b is the proportional hazards estimate of the regression parameter p. Thus, the approximate 95% confidence interval for the RR is RR ± 2[var(RR)]"2 . To display the relationship of a continuous covariate and the time a patient is alive free of disease, a predictive plot was generated. 8 The predictive plot is more descriptive of this relationship than a Kaplan-Meier plot, because the Kaplan-Meier plot is based on an arbitrary grouping of a continuous covariate and, therefore, assumes that all individuals in one group are at equivalent risk of relapse or death. The predicted 80th percentile DFS for a given covariate x is the time t, such that: S(t) = (0.8)exp(xb),
where S(t) is a smoothed version of the overall Kaplan-Meier estimate. The 80th percentile is used as a summary measure (rather than the 50th percentile or median), because greater than 70 percent of the patients in this study were censored. Subsequent to the univariate analysis, a multivariate analysis using the proportional hazards model noted above was performed. The purpose of considering a multiple variable model in this exploratory analysis is to eliminate redundancy among highly correlated covariates, each of which may be individually significant.
7 patients who did or did not have preoperative chemotherapy (P = .29; Fig 1). When possible, limb-sparing surgery was performed. Reasons to perform amputation included neurovascular compromise by the tumor, tumor size, considerations of soft tissue and skin closure, and site of the tumor. Clinical features that suggested a poor response to preoperative chemotherapy were also considered. Amputation was performed when there was a strong clinical suspicion of a poor histologic response. There was no difference by univariate analysis in outcome between the patients who underwent limb-sparing surgery and the patients who had amputation (P = .34; Fig 2). Age We examined the effect of age at diagnosis on DFS (Fig 3). Patients aged 13 to 21 years at diagnosis had a higher probability of DFS than those aged < 12 years, who in turn did better than patients older than 21 years (P = .064).
Sex Patient sex had no effect on DFS. Race Patients were classified as white, black, Hispanic, and other. The number of patients in the last group was too small to permit analysis. Black patients had a relative risk of relapse or death 1.9-fold greater than white patients (P = .04; 95% confidence interval (CI), 1.0 to 4.0; Fig 4).
RESULTS
For all the variables examined, DFS and overall survival were equivalent; thus, we will only report the results in terms of DFS. Surgery The intent of the treatment strategy was to administer a period of initial chemotherapy to all patients following diagnostic biopsy and before definitive surgery. Some patients were referred to MSKCC after a primary amputation; others had primary amputation performed at MSKCC because of tumor size, pathologic fracture, or pain. Sixty-three patients underwent primary surgery and did not receive preoperative chemotherapy. Univariate analysis showed no difference in outcome between
".0030.00
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time (months) Fig 1. DFS for patients who received any preoperative chemotherapy (0; 216 patients, 143 censored) v no preoperative chemotherapy (0; 63 patients, 39 censored). Tick marks indicate last follow-up.
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8
MEYERS ET AL
0
C
00
time
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time
Fig 2. DFS for patients who underwent amputation (0; 132 patients, 85 censored) v limb-sparing en bloc resection (0; 127 patients, 86 censored) for definitive surgery. Tick marks indicate last follow-up.
Primary Site The site of the primary tumor correlated with DFS (P = .008; Fig 5). The most favorable sites were the proximal humerus and proximal tibia. We treated 56 patients with OS of the proximal tibia; 45 (80%) remained continuously free of disease. For 34 patients with OS of the proximal humerus, 25 (74%) remain in continuous DFS. The distal femur was the next most
(months)
Fig 4. DFS as a function of race: white (L; 188 patients, 128 censored), black (0; 46 patients, 23 censored), and Hispanic (A; 25 patients, 17 censored). Tick marks indicate last follow-up.
favorable site, with 75 of 122 patients (61%) continuously free of disease, with a similar experience for 26 of 43 patients (60%) for all other extremity sites. The worst prognosis was associated with an axial primary; only 11 of 24 patients (46%) remain continuously free of disease. Patients with an axial skeletal primary tumor had a 3.9-fold greater risk of relapse or death than the patients with a proximal humerus tumor (95% CI, 1.4 to 10.6).
o
C
o o c o a D o
oo
time
time (months)
(months)
Fig 3. DFS as a function of age at diagnosis: < 12 years (L0; 51 patients, 32 censored), from 12 to 21 years (0; 168 patients, 117 censored), and older than 21 years (A; 60 patients, 33 censored). Tick marks indicate last follow-up.
Fig 5. DFS as a function of primary site: distal femur (D; 122 patients, 75 censored), proximal tibia (0; 56 patients, 45 censored), proximal humerus (A; 34 patients, 25 censored), other extremity (O; 43 patients, 26 censored), and axial (a; 24 patients, 11 censored). Tick marks indicate last follow-up.
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OSTEOSARCOMA AT MEMORIAL SLOAN-KETTERING BiochemicalMarkers
EaoX -
Initial baseline, pretreatment serum alkaline phosphatase and LDH were strongly predictive of outcome in our patients (P = .007 and P = .001, respectively; Figs 6 and 7). For both markers, there was a steady increase in risk of relapse or death associated with increasing serum enzyme activity. Because risk of relapse varied continuously as a function of enzyme activity, we show the predicted 80th percentile DFS as a continuous function of LDH or alkaline phosphatase. We cannot use median DFS, as 68% of the patients in this study remain alive and free of disease. Patients with an LDH level less than 100 had a 0.4-fold lower risk of relapse or death than patients with the median LDH level of 256 (95% CI, 0.04 to 0.8), while patients with an LDH level greater than 400 had a risk of relapse or death 1.5-fold greater than the median (95% CI, 1.3 to 1.8). Patients with an alkaline phosphatase level less than 100 had half the risk of relapse or death associated with the median of 205 (95% CI, 0.3 to 0.7), while patients with an alkaline phosphatase level in excess of 400 had a twofold greater risk of relapse or death (95% CI, 1.8 to 2.2). HistologicResponse Patients who underwent a period of initial chemotherapy before definitive resection of their primary tumors had an assessment of their histologic response to preoperative chemotherapy performed at the time of definitive surgery. Histologic response was assessed in 182 patients. Sixty-three patients did not have preoperative ·,oo E &
00 >0
0) qo.
0(O
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ae 0
0)
.00
9
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300.00
450.00
600.00
750.00
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alkaline phosphatase Fig 6. Predicted 80th percentile for DFS (in months) as a function of baseline alkaline phosphatase level based on the proportional hazards model.
>2
o
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Idh Fig 7. Predicted 80th percentile for DFS (in months) as a function of baseline LDH level based on the proportional hazards model.
chemotherapy, and 34 patients did not have histologic assessment. DFS correlates strongly with the degree of histologic response (P = .016; Fig 8). The best outcome was observed with DFS for 29 of the 32 (91%) patients who had no viable tumor cells detected in the specimen obtained at the time of complete resection (grade IV histologic response). In contrast, the 20 patients with no apparent effect of chemotherapy (grade I response) had a sixfold greater risk of relapse or death than patients with a grade IV response (DFS, 10 of 20 (50%); 95% CI, 1.6 to 22.9). DFS was observed in 57 of 87 (66%) patients with a grade II response and in 31 of 43 (72%) patients with a grade III response. Patients who did not receive an initial period of chemotherapy could not be assessed for histologic response. Although these 63 patients did not fare significantly worse than the overall group of patients who did receive preoperative chemotherapy, they had a risk of relapse or death 5.3-fold greater than the patients with a grade IV response (95% CI, 1.6 to 18.1). We examined the relationship of the duration of the preoperative phase of treatment to histologic response. Patients were divided into three groups of approximately equal size based on the duration of preoperative chemotherapy. This duration was 19 to 60 days for the 57 patients in the first group, 63 to 96 days for the 58 patients in the intermediate group, and greater than 97 days for the 55 patients with the longest duration of preoperative chemotherapy. In univariate analysis, the duration of preoperative chemotherapy did not correlate with DFS. With longer preoperative treatment,
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MEYERS ET AL
.o.
time
(months)
Fig 8. DFS as a function of histologic respons e at the time of definitive surgery: grade I (L; 20 patients, 10 censo red), grade II (0; 87 patients, 57 censored), grade III (A; 43 patien ts, 31 censored), grade IV (0; 32 patients, 29 censored), and no preooperative chemotherapy (*; 63 patients, 39 censored). Tick ma rks indicate last follow-up.
however, a greater proportion of patientss had a favorable histologic response (Table 1), but the correlation of that response with outcome decreased. Pat ients who had a favorable histologic response assessed af'ter less than 2 months of preoperative chemotherapy had a high probability of DFS. Patients who had a favora ble histologic response assessed after a greater period o f preoperative chemotherapy had a lower probability of E)FS. For every duration of preoperative therapy, better histologic response predicted better DFS, but the differences between good and poor responders decr eased as the duration increased.
patients who had evaluation of histologic response at definitive surgery. There was no correlation for any of the agents with either histologic response grade or subsequent DFS. The addition of cisplatin to the postoperative management of patients with a poor (grade I or II) histologic response to preoperative chemotherapy did not improve their long-term probability of DFS but may have delayed their relapse (Fig 9). None of the patients was treated with high-dose methotrexate as the only chemotherapeutic agent. A group of 54 patients received only high-dose methotrexate during the preoperative phase of treatment and were assessable for histologic response. Of these patients, four (7%) had a grade IV response and six (11%) had a grade III response. In other words, 10 of 54 patients .(1t0/) achieved a favorable hlstologic response to preoperative chemotherapy at the time of definitive surgery after receiving high-dose methotrexate as a single agent.
This compares with 65 of 128 patients (51%) evaluated who achieved a favorable histologic response after multiagent chemotherapy.
Protocol Patients were enrolled on a series of chemotherapy protocols. The protocols are identified by a number that increased with sequential opening to enrollment, with T4 and T5 being used in the first years of this series, followed by T7, T10, and finally, T12. While DFS improved from the T4 and T5 protocols to the T7 and T10 protocols, the number of patients treated according
Chemotherapy Dose intensity did not correlate with D)FS for any of the chemotherapy agents. We examined tlhe dose intensity of the preoperative chemotherapy for the 182 Table 1. Histologic Response at the Time of Definit ive Surgery as a Function of the Duration of Preoperative Cheomotherapy Response Grade
Days of Preoperative Chemotherapy 19-60 63-96 >96
I II III IV
14 30 10 3
(.50) (.63) (.90) (1.0)
Total
57 (.67)
3 25 13 17
(.33) (.80) (.69) (.88)
58 (.77)
2 24 17 12
All Patients
(1.0) (.58) (.65) (.92)
19(.53) 79 (.67) 40 (.73) 32 (.91)
55 (.69)
170 (.71)
NOTE. P < .005 by X' analysis. Patients were divided into three groups of approximately equal size. Numbers in parentheses are the proportion of patients in each group who remain alive and free of disease.
26.00
52.00
Fig 9. DFS for patients with histologic response grade I or II who did (0; 77 patients, 49 censored) or did not (0; 30 patients, 18 censored) receive subsequent cisplatin. Tick marks indicate last follow-up.
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11
OSTEOSARCOMA AT MEMORIAL SLOAN-KETTERING to the former is insufficient to conclude with confidence that the latter are superior therapies (Fig 10). Similarly, the results with T12 appear better than those with T7 and T10, but the numbers are small. Long-term DFS for patients treated with the T7 and T10 protocols are the same, but the average time to relapse was greater in the T10 protocol. The distribution of histologic response grades was different, with a higher rate of good responses seen in the T7 protocol than in the T10. The former called for a longer period of preoperative chemotherapy with more agents than the latter. Fifty-eight percent of the patients treated with the T7 protocol had a grade III or IV response to preoperative chemotherapy, compared with 34% of the patients treated with the T10 protocol (Table 2). IntervalFrom Definitive Surgery to Resumption of Chemotherapy We examined the relationship between delay in resumption of chemotherapy after definitive surgery to subsequent DFS. For patients with a good histologic response to preoperative chemotherapy, there was no correlation. For the patients who had a grade I or grade II (poor) response to preoperative chemotherapy, there was a trend toward poorer DFS for patients with increasing duration between definitive surgery and resumption of chemotherapy (Fig 11). For this group, a delay of more than 24 days in resumption of chemotherapy was associated with a higher risk of relapse or death (P = .15).
Table 2. Histologic Response at the Time of Surgery: Protocols T7 and T10 Protocol
Response Grade
T7
T10
I II III IV
1 10 12 8
16 67 21 21
MultivariateAnalysis As a result of the univariate analyses, five covariates appeared to be predictive of DFS: tumor site, race, histologic response, LDH level, and alkaline phosphatase level. Multivariate analysis using Cox's proportional hazards model was undertaken to determine which variables were predictive of DFS (Table 3). The model indicates that the risk of relapse or death increases as the LDH or alkaline phosphatase level increases. In addition, the risk increases as the histologic response grade decreases. The primary tumor site retains its prognostic significance, with axial primaries conferring the greatest relative risk. Race, identified in univariate analysis as a prognostic factor, did not achieve statistical significance in multivariate analysis. This appears to be the result of a correlation between race and histologic response to preoperative chemotherapy. A greater proportion of black patients had a grade I or II histologic response at the time of definitive surgery than did white patients. DISCUSSION Prognostic factors are dependent on treatment as well as the intrinsic biology of a tumor. Factors of strong significance in predicting outcome with one treatment regimen may no longer be predictive with improved treatment. Taylor et al 9 reported the results of a survey of 13 cancer centers that treated patients with OS during an interval similar to that of our study. They were not able to identify a prognostic advantage for chemotherapy. In their study, 350 patients with classical OS (excluding juxtacortical OS and OS arising in Paget's disease) had an overall survival of 57% and DFS of 36%. Our results for a comparable group of 279 patients were an overall survival of 71% and DFS of 65% with a longer median follow-up. It is possible that their failure to
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time
(months)
Fig 10. DFS as a function of treatment protocol: T4 and T5 (0[; 32 patients, 15 censored); T7 (0; 75 patients, 54 censorred), T10 (V; 153 patients, 106 censored), and T12 (0; 17 patients, 1I4 censored). Tick marks indicate last follow-up.
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inclusion of some less-tnan-optimal chemotherapy regimens. We identified several factors that could predict outcome for patients with OS. The primary site of the tumor has a strong influence on outcome, with axial primaries
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12
MEYERS ET AL
1.00.9 0.8i
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having the greatest risk of progression and death. Definitive surgery achieving wide margins of resection is almost never possible for axial primaries. To allow comparison with other published series of patients with OS treated with multiagent chemotherapy, we examined the outcome for our patients with OS of the extremities who were less than 22 years old at diagnosis and were treated with the T10 protocol. The 5-year DFS for this group is 76% (95% CI, 68% to 84%; Fig 12). This compares with the published 2-year DFS of 66% in the Multiinstitutional Osteosarcoma Study and the DFS of 58% with a median follow-up of 34 months in the Cooperative Osteogenic Sarcoma Study (COSS)-82 study.3' 10 In contrast to the observations of some other groups, we found the proximal humerus to be a relatively favorable site, comparable to the proximal tibia. Both alkaline phosphatase and LDH levels correlated strongly Table 3. Proportional Hazards Model for DFS (n = 230) Covariate
RR
In LDH Histologic response grade
exp((In LDH - 5.44)*0.561
II 11I IV No preoperative chemotherapy Primary site Proximal humerus Proximal tibia Distal femur Other extremity Axial In Alk phos
P .001 .018
6.49 3.53 3.06 1.00 5.37 .038 1.00 1.01 1.77 1.88 3.67 exp{(In AP - 5.32)*0.311
.072
Abbreviations: Alk phos, AP, alkaline phosphatase; In, natural logarithm.
1 180
Fig 11. DFS for patients with histologic response grade I or II who had prompt (_< .8 months, 0; 64 patients, 47 censored) or delayed (> .8 months, 0; 43 patients, 24 censored) resumption of chemotherapy after definitive surgery. Vertical bars represent 95% CIs; tick marks indicate last follow-up.
and independently with outcome. White and Hispanic patients had a greater likelihood of DFS and overall survival than black patients in univariate analysis. An older series previously reported by this institution reported no difference in outcome between black and white patients." That report examined 100 black patients with OS seen between 1921 and 1979; the majority of these patients were treated with surgery alone. The multivariate analysis suggests that the poorer outcome for black patients was the consequence of a higher incidence of unfavorable histologic response to preoperative chemotherapy among that group. Histologic response to preoperative chemotherapy assessed at the time of definitive surgery strongly predicted subsequent DFS and overall survival. Similar results have been reported from the Childrens Cancer Study Group (CCSG) and European trials. 10 '2 In these trials there was a strong correlation between histologic response and subsequent DFS. The proportion of patients achieving a good histologic response was substantially lower in both studies than we observed. Poor histologic response to preoperative chemotherapy predicts an increased likelihood of progression and death. It is possible that poor response to initial therapy identifies a group of patients unresponsive to chemotherapy who will do poorly, regardless of treatment used. It is also possible that a poor initial response allows persistence of tumor cells with a greater probability for emergence of drug-resistant clones and spread, increasing the probability of subsequent failure. One way to discriminate between these hypotheses is to compare the outcome for patients treated with immediate definitive surgery followed by adjuvant chemotherapy with those treated with initial chemotherapy and delayed definitive surgery. In
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13
OSTEOSARCOMA AT MEMORIAL SLOAN-KETTERING 1.o0.9-
r
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Fig 12. DFS for patients with extremity primary aged _< 21 years at diagnosis and treated on the T10 protocol (104 patients, 77 censored). Vertical bars represent 95% CIs; tick marks indicate last follow-up.
C
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our experience there was no difference in outcome for these two groups of patients. Our study was not randomized, however, and it is possible that selection bias could obfuscate this issue. We originally described histologic response as a qualitative assessment of tumor necrosis; no quantitation was defined. Patients with total necrosis (grade IV) or only scattered foci of viable tumor cells (grade III) were considered to have a good response to preoperative chemotherapy. Beginning with the T10 protocol, patients with a grade I and II response had cisplatin added to their postoperative treatment. The designation of grade III and IV as good response was operational and was used to decide for subsequent treatment. With longer follow-up, it is apparent that grade IV response is clearly predictive for superior DFS. DFS for patients with grade III response is not significantly superior to that for patients with a grade II response. Other investigators have used different definitions of "good" histologic response. In the COSS-80 study, good response was defined as > 50% necrosis in the resected tumor; this may explain the observation of a 67% "good" response rate reported in this series. 13 In the COSS-82 study good response was defined as > 90% necrosis."o In the design of future interventions aimed at improving outcome for poor responders, it will be critical to assess the definitions of good and poor response. Patients who are treated with preoperative chemotherapy similar to that given to the patients in this series who have less than a grade IV response would be appropriate candidates for a postoperative intervention designed to improve DFS. We examined the potential of the addition of cisplatin to the treatment of OS. Patients who had a poor
48
60 Months
72
from start
84
96
10
120
132
l
" 144
of protocol
response to initial therapy and were at increased risk for relapse or death received cisplatin. We were not able to demonstrate any improvement in 5-year DFS for this group of patients compared with a similar group who had not received cisplatin. It is possible that this failure was related to the relatively late introduction of cisplatin in the treatment regimen. Most patients who received cisplatin after initial poor response began cisplatin after 20 weeks of therapy. This result differs from our previously published observation6 that the addition of cisplatin could improve the 2-year DFS for patients with a poor response to preoperative chemotherapy. In retrospect, that observation was premature; with more patients and longer follow-up, there is no evidence for improved outcome with modification of postoperative chemotherapy on the basis of histologic response to preoperative chemotherapy. The COSS-82 study was also unable to demonstrate the ability to salvage poor responders to initial therapy by the addition of alternative agents.'o The drugs that have been active in the treatment of OS include doxorubicin, high-dose methotrexate, and cisplatin. The three-drug combination BCD was incorporated into our treatment after demonstrating limited activity in patients with recurrent OS.14 A more recent examination of BCD for recurrent OS performed at St Jude Children's Research Hospital was not able to show any activity for this combination in patients with metastatic OS." Nonetheless, the inclusion of BCD in the treatment of our patients did not appear to have a detrimental effect on outcome. Both DFS and overall survival for our patients are among the best reported. The relative merits of high-dose methotrexate have been questioned by several investigators. When high-
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14
MEYERS ET AL
dose methotrexate therapy was first introduced it was expensive and associated with a risk of severe toxicity. The CCSG performed a trial that did not show any advantage of high-dose methotrexate over moderatedose methotrexate.16 Unfortunately, both arms of that trial achieved a DFS significantly inferior to that of the subsequent trial incorporating high-dose methotrexate, and inferior to our present results. When administered with appropriate rescue, high-dose methotrexate is considerably less toxic than moderate-dose methotrexate, and can be administered in a period of less than 1 week, allowing for the rapid administration of other active agents. The CCSG 782 study was an attempt to reproduce in a cooperative group the results of the MSKCC T10 trial. Although the study confirmed the importance of histologic response, DFS and overall survival were inferior to the present results. The preponderance of high-dose methotrexate in the early weeks of treatment in both treatment approaches suggests that a possible explanation for differences in outcome may lie in differences in administration of high-dose methotrexate. High-dose chemotherapy differs from other chemotherapy in its sensitivity to a wider variety of variables in administration, including dose, rate of administration, hydration, alkalinization, dose timing, and route of administration of leucovorin rescue. Concern about the potential toxicity of high-dose methotrexate has led many treating physicians to use more hydration or more leucovorin than we have found to be necessary. For example, the CCSG 782 study called for the administration of leucovorin 15 mg per dose instead of the 10 mg we have routinely used. It is possible that differences in the administration of high-dose methotrexate and/or leucovorin could explain the superior outcome that we have observed. The concept that early intensive treatment is critical to a successful outcome for patients with OS is further supported by the examination of the interval between definitive surgery and the resumption of chemotherapy. Reasons for a delay in the resumption of chemotherapy included the need for additional time to permit wound healing, wound infections, and patient request. Patients who had a good response to preoperative chemotherapy did not suffer from a delay in resuming treatment. Patients with a poor initial response and a delay in resumption of chemotherapy did worse than those patients who promptly resumed treatment. We were unable to demonstrate any correlation between dose intensity for any of the agents used in this
study and histologic response at definitive surgery, overall survival, and DFS. This finding must be interpreted with caution. Conventional examination of dose intensity is performed using a protocol in which all patients receive identical numbers of courses of identical agents. Dose intensity, then, varies as a result of predetermined dose reductions and treatment delays for toxicity. Our patients received different sequences and doses of chemotherapy based both on histologic response to preoperative chemotherapy and the treating physician's judgment. This may obscure the ability to detect a relationship between dose intensity and outcome. It is also possible, however, that OS has an intrinsic sensitivity or resistance to chemotherapy at diagnosis. This sensitivity could be revealed by the histologic response to preoperative chemotherapy, which would explain the strong correlation between histologic response and subsequent DFS. Histologic response to preoperative chemotherapy strongly predicts subsequent DFS and overall survival. This observation, strongly supported by other studies, is of limited clinical value to an individual patient. Neither we nor other investigators have demonstrated the ability to salvage the poor responder by subsequent modification of chemotherapy. An obvious alternative strategy would be to use additional agents during preoperative chemotherapy in an attempt to increase the proportion of patients who will achieve a good histologic response. With this in mind, it is critical to examine the relationship of histologic response to outcome. We found that longer periods of preoperative chemotherapy achieved a higher proportion of good responses, but that the good responses so achieved did not translate into the same survival advantage as good responses achieved with shorter treatment. The T7 protocol called for longer preoperative chemotherapy with more agents than the T10 protocol. Grade III and IV histologic responses to preoperative chemotherapy were seen in 54% of the patients treated with T7 and 34% of patients treated with T10; DFS for the two trials is the same. Reports of high rates of good response must be carefully examined in light of these observations. With prolonged periods of preoperative chemotherapy, it is theoretically possible that the correlation between histologic response and outcome will be lost. It cannot be presumed that a treatment that results in a higher rate of good histologic response will automatically translate into improved survival. Multiagent chemotherapy coupled with aggressive surgical resection can produce durable survival for
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OSTEOSARCOMA AT MEMORIAL SLOAN-KETTERING
15
almost three fourths of patients with OS who present without clinically detectable metastatic disease. Prognostic factors can predict some of the patients who are destined to do poorly with the therapies described in this report. The most powerful predictor of DFS-histologic
response to preoperative chemotherapy-cannot be determined at the time of diagnosis. We need additional techniques to identify those patients who will respond poorly to chemotherapy and to develop novel therapies for this group.
REFERENCES 1. Marcove R, Mike V, Haych JV, et al: Osteogenic sarcoma under the age of twenty-one: A review of 145 operative cases. J Bone Joint Surg 52:411-492, 1970 2. Edmonson JH, Green SJ, Ivins JC, et al: A controlled pilot study of high-dose methotrexate as postsurgical adjuvant treatment for primary osteosarcoma. J Clin Oncol 2:152-156, 1984 3. Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314:1600-1606, 1986 4. Rosen G, Murphy ML, Huvos AG, et al: Chemotherapy, en bloc resection and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 37:1-11, 1976 5. Rosen G, Marcove RC, Caparros B, et al: Primary osteogenic sarcoma. The rationale for preoperative chemotherapy and delayed surgery. Cancer 43:2163-2177, 1979 6. Rosen G, Caparros B, Huvos AG, et al: Preoperative chemotherapy for osteogenic sarcoma: Selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 49:1221-1230, 1982 7. Rosen G: Pre-operative (neo-adjuvant) chemotherapy for osteogenic sarcoma: A ten year experience. Orthopedics 8:659-664, 1985 8. Heller G, Simonoff JS: Prediction in censored survival data: A comparison of the proportional hazards and linear regression models. Biometrics (in press) 9. Taylor WF, Ivins JC, Unni KK, et al: Prognostic variables in
osteosarcoma: A multi-institutional study. J Natl Cancer Inst 81:21-30, 1989 10. Winkler K, Beron G, Delling G, et al: Neoadjuvant chemotherapy of osteosarcoma: Results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol 6:329-337, 1988 11. Huvos AG, Butler A, Bretsky SS: Osteogenic sarcoma in the American Black. Cancer 52:1959-1965, 1983 12. Provisor A, Nachman J, Krailo M, et al: Treatment of non-metastatic osteogenic sarcoma (OS) of the extremities with pre- and post-operative chemotherapy. Proc Am Soc Clin Oncol 6:217, 1987 (abstr) 13. Winkler K, Beron G, Kotz R, et al: Neoadjuvant chemotherapy for osteogenic sarcoma: Results of a cooperative German/ Austrian study. J Clin Oncol 2:617-624, 1984 14. Mosende C, Gutierrez M, Caparros B, et al: Combination chemotherapy with bleomycin, cyclophosphamide and dactinomycin for the treatment of osteogenic sarcoma. Cancer 40:2779-2786, 1977 15. Pratt CB, Epelman S, Jaffe N: Bleomycin, cyclophosphamide, and dactinomycin in metastatic osteosarcoma: Lack of tumor regression in previously treated patients. Cancer Treat Rep 71:421423, 1987 16. Krailo M, Ertel E, Makley J, et al: A randomized trial comparing high dose methotrexate with moderate dose methotrexate as components of adjuvant chemotherapy in childhood nonmetastatic osteosarcoma. Med Ped Oncol 15:69-77, 1987
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