Neoadjuvant Chemotherapy and Local Radiotherapy for High-Grade

Mayo Clin Proc, February 2003, Vol 78

Combination Therapy for High-Grade Osteosarcoma

147

Original Article

Neoadjuvant Chemotherapy and Local Radiotherapy for High-Grade Osteosarcoma of the Extremities GENNADY N. MACHAK, MD; SERGEY I. TKACHEV, MD; YURIY N. SOLOVYEV, MD, PHD; PAVEL A. SINYUKOV, MD; STANISLAV M. IVANOV, MD; NATALYA V. KOCHERGINA, MD; ALEXEY D. RYJKOV, MD; VALERY V. TEPLIAKOV, MD; BENJAMIN Y. BOKHIAN, MD; AND VALERIA V. GLEBOVSKAYA tively, but it was only 35%±15% and 42%±13% in the nonresponders (P=.005 and P=.005, respectively). Local control was also related to response after induction chemotherapy. None of the 11 patients with both a good imaging and a good biochemical response had local relapse; median follow-up was 67 months. The estimated local progression–free survival among nonresponders was 31%±16% at 3 years and 0% at 5 years. Of 22 patients surviving without local disease progression, 19 (86%) had excellent limb function (Enneking score between 90% and 100%) at the time of most recent evaluation. • Conclusion: When used after effective induction chemotherapy for osteosarcoma of the extremities, radiation therapy can be a reliable modality to control local disease and preserve limb function. Mayo Clin Proc. 2003;78:147-155

• Objective: To determine the effectiveness of radiation therapy for local control of nonmetastatic osteosarcoma of the extremities after induction chemotherapy. • Patients and Methods: Of 187 patients with nonmetastatic osteosarcoma of the extremities treated with induction chemotherapy since 1986, 31 refused surgery and underwent standard, fractionated external beam radiotherapy for local control. The median radiation dose to the limb was 60 Gy (range 40-68 Gy). Records were reviewed through April 2002, and outcomes including radiologic and biochemical response, local control, limb function, and survival were analyzed. The end points were local progression–free survival, metastases-free survival, and overall survival. • Results: Overall survival, local progression–free survival, and metastases-free survival at 5 years were a mean ± SD of 61%±11%, 56%±12%, and 62%±10%, respectively. The outcome correlated significantly with patients’ imaging and biochemical response. In patients who had a pronounced response, overall survival and metastases-free survival at 5 years were 90%±9% and 91%±9%, respec-

CI = confidence interval; CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography

N

ods for replacing segmental bone and joint loss are used, the incidence of postoperative short- and long-term complications continues to be high.6,8-11 Therefore, local treatment of osteosarcoma of the extremities remains a problem for some patients. Nonsurgical management of the primary tumor is attractive but highly controversial and poorly investigated in the modern chemotherapeutic era. Experience at the M. D. Anderson Cancer Center, Houston, Tex, showed that only a small number of patients with osteosarcoma achieved disease control with intra-arterial chemotherapy alone, even when efficacy was proved by clinical and imaging methods.12 As a single modality, radiation therapy has not been found to be successful in either reliably controlling the primary tumor or preventing the appearance of lung metastases.13-16

eoadjuvant chemotherapy combined with complete surgical excision is the gold standard in the treatment of osteosarcoma of the extremities.1-4 In the past, treatment of the primary tumor was amputation, whereas a high percentage of patients are currently being treated by limb salvage surgery.1,2,5,6 Intensive multiagent induction chemotherapy contributes to more widespread use of such procedures, yielding complete or subtotal tumor sterilization ranging from 28% to 50%.1,2,4,7 Although various methFrom the Department of Bone and Soft Tissue Tumors (G.N.M., P.A.S., V.V.T., B.Y.B.), Department of Radiation Oncology (S.I.T., S.M.I., V.V.G.), Department of Pathological Anatomy (Y.N.S.), Department of Radiology (N.V.K.), and Department of Nuclear Medicine (A.D.R.), N. N. Blokhin Cancer Research Center of AMS, Moscow, Russia. This work was supported by the Russian Foundation of Basic Research grants N96-15-98040 and N99-04-48018.

For editorial comment, see page 145.

Individual reprints of this article are not available. Address correspondence to Gennady N. Machak, MD, Department of Bone and Soft Tissue Tumors, N. N. Blokhin Cancer Research Center of AMS, Kashirskoye sh. 24, Moscow, 115478, Russia (e-mail: machak [email protected]).

Because osteosarcoma is highly responsive to currently used drug protocols, the combination of radiation and chemotherapy can be predicted to be more effective than radiation alone. Several clinical and experimental studies have

Mayo Clin Proc. 2003;78:147-155

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© 2003 Mayo Foundation for Medical Education and Research

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

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shown benefit of simultaneous or alternating radiotherapychemotherapy schedules for solid tumors, in particular for osteosarcoma.17-21 However, the potential value of radiotherapy-based local treatment of osteosarcoma of the extremities with modern neoadjuvant chemotherapy remains unclear. During the past 16 years, we have examined a group of patients with osteosarcoma of the extremities treated with neoadjuvant chemotherapy at the N. N. Blokhin Cancer Research Center, Moscow, Russia, who refused surgery and preferred radiation therapy as local treatment. Our study was undertaken to evaluate the outcome of these patients and to discuss some problems associated with this treatment modality. PATIENTS AND METHODS Between January 1986 and February 1999, our protocol for osteosarcoma consisted of preoperative intra-arterial monodrug chemotherapy, surgery, and response-adapted adjuvant chemotherapy. In March 1999, a new protocol with more aggressive chemotherapy and surgical local control was instituted. Twenty-seven of 157 patients from the first protocol and 4 of 30 patients from the second protocol refused recommended surgery for the primary tumor but accepted local radiotherapy as an alternative. These 31 patients had the following characteristics: biopsy-proven diagnosis of high-grade osteosarcoma, tumor located in an extremity, receipt of at least 3 cycles of induction chemotherapy, and no disease progression before local treatment. The ages of the 16 male and 15 female patients ranged from 14 to 36 years, with a mean and median of 18 and 16 years, respectively. Of the 31 bone tumors, 3 were stage IIA, 25 were stage IIB, and 3 were stage IIIB. The distribution by anatomical site was as follows: 17 tumors (55%) were located in the proximal tibia, 9 (29%) in the distal femur, 1 in the diaphysis of the femur, 2 in the diaphysis of the tibia, 1 in the distal tibia, and 1 in the fibula. Tumor volume ranged from 60 to 1061 cm3 with a mean and median of 324 and 257 cm3, respectively (Table 1). All patients and their relatives were informed about the investigational nature of local treatment by radiation therapy, and informed consent was obtained. The initial staging included radiographs, computed tomography (CT) and magnetic resonance imaging (MRI) of the primary lesion, CT of the chest, and total-body bone scan. Treatment Neoadjuvant (Induction) Chemotherapy.—In the first protocol, induction chemotherapy comprised 3 to 5 monthly cycles of cisplatin, 120 to 150 mg/m2 (19 patients), or doxorubicin, 90 mg/m2 (8 patients). Cisplatin was administered in a 4-hour intra-arterial continuous infu-


sion along with vigorous hydration and mannitol diuresis. Doxorubicin was also delivered intra-arterially in a 72hour continuous infusion. Four patients received primary chemotherapy according to the second protocol: 4 cycles of 96-hour continuous intravenous infusion of doxorubicin, 90 mg/m2, and a 2-hour intra-arterial infusion of cisplatin, 120 mg/m2 at day 5. Radiotherapy.—Standard external beam radiation therapy was administered by using a cobalt Co 60 source or a 6- to 18-MeV linear accelerator and initiated 2 to 3 weeks after completion of induction chemotherapy. Parallel opposing fields were used. The shrinking-field technique was used in all patients. Initial ports included margins 10 to 15 cm greater than the bone lesion treated with a dose of 35 to 40 Gy followed by a 20- to 25-Gy boost dose delivered to the tumor volume. Tumor margins were assessed by means of standard radiographs, CT, MRI, and planar scintigraphy. The tumor was irradiated to a median dose of 60 Gy (range 40-68 Gy). Two regimens of dose fractionation were used. Eight patients (26%) were treated by conventional fractionation. Daily fractions of 2.5 to 3.0 Gy were administered 5 days per week. Twenty-three patients (74%) were treated by hyperfractionated radiotherapy with a single fraction of 1.25 to 1.5 Gy delivered twice daily at an interval of at least 4 hours (10 fractions per week). Adjuvant Chemotherapy.—Seventeen patients from the first protocol adjuvant chemotherapeutic regimen were given 6 cycles of CAP (cisplatin, 120 mg/m2; doxorubicin, 50 mg/m2; and cyclophosphamide, 600 mg/m2). Three patients were treated with doxorubicin alone at a dose of 90 mg/m2. Two patients from the second protocol continued with cisplatin and doxorubicin; the other 2 patients received 6 cycles of ifosfamide, 1.8 g/m2, and etoposide, 100 mg/m2, on days 1 through 5 because of moderate response to induction chemotherapy. Seven patients received no adjuvant chemotherapy. Evaluation of Response The following factors were used to monitor the response to induction chemotherapy: (1) pain profile, (2) limb function, (3) tumor volume, (4) radiographic appearance of extraskeletal tumor masses, (5) tumor neovascularization, (6) tumor perfusion, and (7) serum alkaline phosphatase level. Functional results were evaluated according to the functional evaluation system proposed by Enneking et al.22 Tumor volume was determined on the basis of MRI, CT, and arteriograms of the affected bone by calculating the product of the maximum diameters of altered tissues in 3 planes, corrected by the factor of 0.52 for spherical or irregular tumors and by the factor of 0.78 for cylindrical tumors. Tumor neovascularization was qualitatively assessed on the arteriograms. A modification of the standard23 3-phase




149

Table 1. Characteristics of Patients With Osteosarcoma of the Extremities Treated With Chemotherapy and Radiotherapy Without Surgery* Follow-up

Stage

Tumor volume (cm3)

I

Femur

IIB

632

Yes

Femur

IIA

254

Yes

3/14/M

Tibia

IIB

262

Yes

4/16/F

Tibia

IIB

568

5/16/F

Tibia

IIB

6/16/M

Femur

IIB

Patient No./ age (y)/sex

Site

1/29/F 2/16/F

Response Both

Dose (Gy)

AP

Yes

40

112

Cen

94

Cen

94

Cen

AP

Yes

45

120

Cen

114

Cen

114

Cen

Yes

Yes

60

91

Cen

87

Cen

87

No

Yes

No

60

20

Comp

16

Cen

9

277

No

No

No

40

69

Comp

48

Comp

65

Comp

328

No

No

No

50

44

Comp

15

Comp

19

Comp

B

Survival (mo)

Status†

SURVREC (mo)

Status†

SURVMTS (mo)

Status†

Cen Comp

7/16/M

Tibia

IIB

203

Yes

Yes

Yes

62

91

Cen

83

Cen

83

Cen

8/15/F

Femur

IIB

100

Yes

Yes

Yes

65

93

Comp

80

Cen

80

Cen

9/20/F

Femur

IIB

186

No

Yes

No

68

27

Comp

10

Comp

10

Comp

10/18/M

Tibia

IIB

187

Yes

Yes

Yes

57

23

Comp

13

Cen

8

Comp

11/17/M

Tibia

IIB

955

Yes

Yes

Yes

55

68

Cen

60

Cen

60

Cen

12/16/M

Tibia

IIA

228

Yes

Yes

Yes

57.5

75

Cen

67

Cen

67

Cen

13/20/F

Femur

IIB

140

No

No

No

60

53

Cen

47

Cen

47

Cen

14/21/M

Femur

IIB

160

Yes

AP

Yes

60

52

Cen

35

Cen

35

Cen

15/15/F

Tibia

IIB

240

No

Yes

No

60

51

Comp

21

Comp

17

Comp

16/15/M

Tibia

IIB

156

No

No

No

50

10

Comp

1

Comp

1

Comp

17/16/M

Tibia

IIB

322

No

Yes

No

60

49

Comp

15

Comp

24

Comp

18/17/F

Tibia

IIB

163

No

Yes

No

60

39

Cen

31

Comp

36

Cen

19/16/F

Tibia

IIB

180

No

Yes

No

60

25

Cen

19

Cen

13

Comp

20/14/M

Tibia

IIB

398

Yes

No

No

60

42

Cen

21

Comp

31

Cen

21/17/M

Tibia

IIB

491

No

Yes

No

60

10

Cen

1

Cen

1

Comp

22/36/F

Femur

IIIB

458

No

Yes

No

52.5

23

Comp

15

Cen

0

Comp

23/17/F

Tibia

IIB

257

No

No

No

60

53

Cen

24

Cen

24

24/25/M

Tibia

IIB

480

No

Yes

No

60

24

Cen

17

Cen

5

25/15/F

Tibia

IIA

100

Yes

AP

Yes

60

35

Cen

29

Cen

29

Cen

26/17/M

Femur

IIB

60

Yes

Yes

Yes

60

20

Cen

14

Cen

14

Cen

27/15/M

Tibia

IIB

418

No

No

No

60

28

Cen

14

Comp

20

28/16/M

Femur

IIIB

1061

No

Yes

No

60

19

Comp

13

Cen

2

29/16/F

Tibia

IIB

398

No

Yes

No

60

17

Cen

11

Cen

11

30/16/F

Fibula

IIIB

96

No

AP

No

60

10

Cen

4

Cen

0

31/25/M

Tibia

IIB

280

No

No

No

60

21

Cen

15

Cen

15

Cen Comp

Cen Comp Cen Comp Cen

*AP = alkaline phosphate level remained normal; B = biochemical; Cen = censored; Comp = complete; I = imaging; SURVMTS = free of metastases; SURVREC = free of local disease progression. †At last examination.

bone scan with technetium Tc 99m was developed to allow quantification of tracer activity (blackness) during each phase: arterial, blood pool, and early bone uptake phase. Uptake in the region of the tumor was compared to uptake of the contralateral nontumor region during each phase. A dynamic scan was recorded at 21 minutes followed by static images at 3 hours. Clinical response was defined as complete remission of pain and restoration of limb function. Patients were considered to have achieved a good imaging response to induction

chemotherapy if their tumor volume regressed or remained unchanged or extraskeletal tumor masses became ossified and clearly delineated, hypervascularity and tumor stain completely disappeared, or tumor perfusion could not be demonstrated. A good biochemical response required that the alkaline phosphatase level normalized. Follow-up and Statistical Analysis Clinical examinations, to detect progression of disease or delayed complications related to therapy, were per-



150


Table 2. Imaging and Biochemical Response After Induction Chemotherapy but Before Irradiation for Local Control of Osteosarcoma of the Extremities (N=31) Both imaging and biochemical response

No. (%) of patients

Estimated 5-year overall survival* (%)

Good Poor

11 (35) 20 (65)

90±9 35±15

P value .005

*Values are mean ± SD.

formed monthly for the first 6 months, then every 3 months during months 7 through 24, and every 6 months thereafter. These examinations included radiographs of the primary skeletal lesion and of the chest, laboratory tests, and 3phase and planar bone scans. The end points selected for analysis were local progression–free survival, metastasesfree survival, and overall survival. Overall survival was calculated from the date of diagnosis to the date of death due to osteosarcoma or to the date of the patient’s most recent consultation. Local progression–free survival was the time interval from the date of completion of local therapy to the date of local failure and metastases-free survival, the time interval to distant metastases. Local progression was defined as posttreatment new clinical impairment of the extremity (eg, mass effect or pain) or radiologic imaging signs of tumor reactivation and was always confirmed morphologically. Patterns of survival were estimated by the Kaplan-Meier method, and differences between groups were assessed by the log-rank test. The χ2 test was used to compare qualitative variables. RESULTS After induction chemotherapy but before local control irradiation of the extremity, a clinical response and limb

function restoration were observed in 24 (77%) of the 31 patients. The imaging response was defined as good in 12 patients, and the biochemical response was defined as good in 18. Among the 12 patients with a good imaging response, the initial alkaline phosphatase level remained normal in 4, normalized in 7, and increased in 1. Of 19 patients with a poor imaging response, the initial alkaline phosphatase level remained normal in 1, normalized in 11, and increased in 7. Only 11 patients had both a good imaging and a good biochemical response (Table 2). Of the 20 nonresponders to induction chemotherapy, 15 (75%) had signs of bone healing, including ossification and decrease of tumor perfusion after irradiation. Follow-up of the patients alive at last contact ranged from 10 to 120 months, with a median follow-up of 39 months. As of April 2002, 20 patients (65%) were alive, 16 of whom were free of disease; 9 patients died of osteosarcoma, 1 patient with solitary lung metastasis died of a chemotherapy-related complication, and 1 patient died of a second neoplasm. This last-mentioned patient, a female adolescent aged 15 years with osteosarcoma of the distal femur, developed a lymphosarcoma 7 years after radiation therapy and died of this disease 4 months later. At last examination, 4 survivors had distant metastases. Three patients are alive without metastases after amputation due to local treatment failure. Overall survival of the cohort at 5 years was 61%±11% (95% confidence interval [CI], 59%-95%) (Figure 1, left). It correlated significantly with patients’ imaging and biochemical response (Table 2; Figure 1, right). In patients who had a pronounced response, 5-year overall survival was 90%±9% (95% CI, 81%-123%), but it was only 35%±15% (95% CI, 36%-58%) in the nonresponders (P=.005).

100

100

Cumulative survival (%)


90 80 70 60 50 40 30

Complete Censored

20

Responders (n=11)

80

60

Nonresponders (n=20)

40

20

Complete Censored

10

0

0 0

20

40

After diagnosis (mo)

60

0

20

40

60

80

After diagnosis (mo)

Figure 1. Survival of patients with nonmetastatic osteosarcoma of the extremities treated with chemotherapy-radiotherapy. Left, Overall survival. Right, Survival according to response to induction chemotherapy (Kaplan-Meier method).






100 90 80 70 60 50 40 30 20 10

Complete Censored 0

100 90

80 70 60 50 40 30 20 10 0

0 20

40

60

After local treatment (mo)

151

Complete Censored 0

10

20

30

40

50

60


Figure 2. Local progression–free survival of patients with nonmetastatic osteosarcoma of the extremities treated with chemotherapyradiotherapy. Left, All 31 patients. Right, Nonresponders to induction chemotherapy. Among imaging responders, survival estimates cannot be computed because all observations were censored.

Local Progression Nineteen patients with localized osteosarcoma and 3 patients with stage IIIB osteosarcoma (22/31) had no clinical, radiographic, scintigraphic, or biochemical signs of local disease progression at last examination or at date of death. An evident local treatment failure occurred in 8 patients, from 10 to 48 months (median 18 months) after completion of irradiation. The patient who died of chemotherapy-related toxicity 10 months after 68 Gy of radiation had no clinical or radiographic signs of local disease activity except continued increased isotope uptake in the lesion area on bone scan. At autopsy, sections showed more than 90% tumor necrosis. This case was considered a local treatment failure. No patient had disease progression during radiation treatment, and only 1 nonresponder to induction chemotherapy of 20 such high-risk patients developed local disease progression immediately after completion of irradiation. Local progression–free survival of the cohort at 5 years was 56%±12% (95% CI, 54%-95%) (Figure 2, left). Three patients had simultaneously local treatment failure and lung metastases; 3 patients developed systemic disease progression several months after local relapse. The 3 patients who had local relapse underwent amputation and then received additional chemotherapy. They are currently alive and free of disease at 2, 6, and 10 months from the event. Local control correlated significantly with response to induction chemotherapy. Of note, no local relapses occurred in the 11 patients who had both a good imaging and a good biochemical response. Follow-up in this group ranged from 13 to 114 months, with a median follow-up of 67 months. Of 20 patients with nonresponsive tumors, 9 developed local treatment failure. The estimated local progression–free survival in this group was 31%±16% at 3 years and 0% at 5 years (95% CI, 19%-38%) (Figure 2, right).

We analyzed the local disease evolution in 18 high-risk nonresponders who completed 5 to 6 cycles of adjuvant chemotherapy after irradiation. In patients who had an amplified local response after irradiation (eg, calcification and decreased tumor vascularity), the incidence of local progression was 38% (5/13) compared with 60% (3/5) in patients whose condition remained refractory after they received adjuvant chemotherapy. In terms of radiation therapy doses, the incidence of local relapses was higher when the dose was 50 Gy or less (3/5 [60%]) than when the dose was more than 50 Gy (6/26 [23%]). No definite correlation was found between the rate of local failure and regimen of fractionation. The progression of primary tumor after radiotherapy seemed to be associated with and perhaps influenced by pathologic fracture within the radiation field. Local treatment failed in 4 of 5 patients with fracture, including both patients who sustained a fracture during treatment. Of the 2 patients with delayed fractures and subsequent local progression, 1 had local and systemic relapse shortly after a traumatic fracture that occurred in the lesion area 48 months after irradiation. The treatment of local relapses (8/31) consisted of amputation in 2 patients, amputation and chemotherapy in 3 patients, bone resection with endoprosthetic replacement and chemotherapy in 1 patient, and symptomatic treatment only in 2 patients. Distant Metastases Of 28 patients with stage IIB osteosarcoma, 11 developed distant metastases 1 to 65 months (median 10 months) after completion of local radiation treatment to an extremity. Of these 11 patients, 8 died (1 from chemotherapeutic toxicity), and 3 are alive with metastatic osteosarcoma. Metastases-free survival of patients with osteosarcoma with localized disease is shown in Figure 3. The probability




100

100

90

90



152

80 70 60 50 40 30 20

Complete Censored

10

80 70 60 50

Nonresponders (n=19)

40 30

Complete Censored

20 10

0

Responders (n=11)

11 20

9 7

7 2

4 0

20

40

60

0

0

40

20

60


0


Figure 3. Metastases-free survival of patients with localized osteosarcoma of the extremities treated with chemotherapy-radiotherapy. Left, All 28 patients. Right, According to response to induction chemotherapy (Kaplan-Meier method). The number of patients at risk is in bold.

to remain without distant metastases was 62%±10% at 5 years (95% CI, 51%-90%) (Figure 3, left). Metastases-free survival was significantly related to the tumor response after induction treatment (Figure 3, right). In those patients who had a pronounced imaging response and normalization of the alkaline phosphatase level, metastases-free survival was 91%±9% at 5 years (95% CI, 86%-122%) compared with 42%±13% (95% CI, 20%-48%) in nonresponders (P=.005). Limb Function Limb function was excellent in most patients (Table 3). Patients without local progression were rated according to the Enneking score as follows: 19 patients had a score between 90% and 100%, and 3 had a score between 75% and 89%. Before local relapse, 5 patients had a score between 90% and 100%, and 4 had a score lower than 80%; 2 maintained a score of 100% before local complications occurred. Complications Two patients with lytic bone lesions sustained pathologic fractures during the chemotherapy-radiotherapy treatment sequence, which previously seemed moderately Table 3. Limb Function After Chemotherapy-Radiotherapy Without Surgery* No. (%) of patients Enneking score (%)

No local progression (n=22)

Local progression (n=9)

90-100 75-89 5 years) confirmed that the tumor was in fact sterilized. Our series showed that after initial chemotherapy for nonmetastatic osteosarcoma of the extremities, the potential usefulness of radiotherapy may be predicted to be high, medium, or low as follows. 1. High—When the primary tumor was sensitive to induction chemotherapy, the radiotherapy effectively consolidated antitumor effects. In this subgroup of patients, chances to achieve durable local control and excellent limb function were highest (100%). Other data showed that chemotherapy alone is unable to control disease despite good clinical, imaging, and biochemical response (G.N.M., unpublished data, 1998). Similar results were reported by Jaffe et al.12 2. Medium—When the primary tumor responded moderately to induction chemotherapy, radiotherapy had a curative role in some patients. The effectiveness of chemotherapy-radiotherapy in this subgroup was characterized by progressive bone ossification and gradual decrease of tumor perfusion. Nevertheless, the incidence of local relapse was high (38%). If a patient refuses surgery and radiotherapy is provided for local control, meticulous posttreatment monitoring is necessary. In our series, dynamic and static bone scintigraphy, alkaline phosphatase level, and radiographic appearance were the most sensitive methods for early diagnosis of local relapses. Additionally, PET may be useful. 3. Low—In about one half of patients whose tumor was unresponsive to initial chemotherapy, local radiotherapy was ineffective and not associated with continuing or durable clinical responsiveness. In this situation, the risk of developing local disease progression is almost certain. Surgery and extremely aggressive salvage chemotherapy should be recommended. The feasibility of postponed limb salvage procedures after primary chemotherapy and radiotherapy (median dose, 56 Gy) and adjuvant chemotherapy was shown in patients with Ewing sarcoma in a study by Picci et al.31 Our study did not explore this possibility. In our series, after standard induction chemotherapy (eg, cisplatin and doxorubicin), 60 Gy of irradiation was adequate for os-


154


teosarcoma control. Because of recent improvements in noninvasive assessment of tumor necrosis after induction chemotherapy (eg, PET), it may be possible to gain experience regarding the safety of this approach in the selected subgroup of patients with good initial chemotherapeutic responses. Many studies on neoadjuvant therapy for osteosarcomas have shown that the rate of chemotherapy-induced tumor necrosis is associated with better disease-free survival.2,7,33-35 Because we had no histological confirmation of complete response (ie, percent necrosis), we used clinical, imaging, and biochemical criteria to assess the potential effectiveness of induction chemotherapy. Although a less precise response was estimated in this manner, it nevertheless correlated significantly with metastases-free survival. Thus, conventional and modern imaging techniques such as dynamic contrast-enhanced MRI, bone scintigraphy, and PET can provide a useful, qualitative estimate of the chemotherapeutic effect.36-41 Local control in nonmetastatic osteosarcoma of the extremities without surgery is a controversial subject. In our series of 31 patients, satisfactory disease control and excellent limb function were achieved in the 11 patients who had a pronounced response to initial chemotherapy. Although disease control was also achieved in a few patients who did not undergo adjuvant chemotherapy, the role of chemotherapy should not be underestimated. Standard duration chemotherapy is probably required to adequately reduce the incidence of lung metastases. Of note, our results were achieved with standard megavoltage radiation techniques that can be done at most major medical centers. Finally, it is possible that, if local radiotherapy for osteosarcoma is given earlier than in our study (eg, after 2 cycles of induction chemotherapy instead of 3 to 5 cycles) and concurrently with chemotherapy (eg, during ifosfamide/etoposide as currently used as standard treatment of Ewing sarcoma), results could be improved further. CONCLUSION Radiotherapy can be useful for some patients with osteosarcoma. However, further study of effectiveness and function in prospective randomized clinical trials is necessary to better define the most appropriate situations.42


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Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the Istituto Ortopedico Rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000;18:4016-4027.

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