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Primary Treatment of Pelvic Osteosarcoma Report of Five Cases J. Estrada-Aguilar, MD,* H. Greenberg, MD,t A. Walling, MD,$ K. Schroer, MD,§ T. Black, MD,7 S. Morse, MD,[I and E. Hvizdala, MD*
Five patients, ages 12 to 20 years, with nonresectable primary (Patients 2,3, and 5) and metastatic (Patients 1 and 4) pelvic osteosarcomas were treated with intraarterial cisplatin and concurrent radiation therapy from 1983 to 1987. Long-term local tumor control was achieved in all five patients. Patients 1 and 3 are alive with no evidence of local recurrence or metastatic disease at 77 and 56 months of follow-up, respectively, since diagnosis of the pelvic tumor. Patients 2,4,and 5 died of metastatic lung disease at 25,39, and 12 months, respectively, after diagnosis of the pelvic tumor. Patient 4 had no clinical or radiologic evidence of local recurrence. Control of tumor growth in patients with pelvic osteosarcomas can be achieved with regional chemotherapy and concurrent radiation therapy. These patients also should receive adjuvant intensive systemic chemotherapy to increase the probability of eliminating potential subclinical metastatic disease. Cancer 1992; 691137-1145.
control of osteosarcomas that arise or metastasize to axial bones has required extensive and often mutilating surgical procedures.2Most of these patients will die of local recurrences or metastatic disease. Like osteosarcomas of the spine, pelvic osteosarcomasoften are considered nonresectable because of the significant surgical complication. In this study, we report our experience in treating five patients with both primary and metastatic osteosarcoma of the pelvis with a program that combined regional chemotherapy and concurrent radiation therapy. Two of these patients refused surgical resection of the tumor (hemipelvectomy), whereas the tumors in the other three patients were considered nonresectable because of their size and location.
Primary osteosarcomas of the pelvic bones are uncommon. Dahlin and Unni' reported an incidence of 9.5% in their extensive series of 1274 osteosarcomas at the Mayo Clinic. This group included 12 patients with tumors that arose from the sacrum, 89 from the ilium, 14 from the acetabulum, and 6 from the ischium. Because the definitive treatment of the primary tumor in patients with osteosarcomas is surgical resection, the local
Five patients, ages 12 to 20 years, with primary (Patients 2, 3, and 5) and metastatic (Patients l and 4) pelvic osteosarcomas (Table 1) were treated with intraarterial (IA) cisplatin and concurrent radiation therapy at our institution from 1983 to 1987. Patients 1 and 4 had pelvic metastasis from distal femoral tumors, whereas Patients 2 and 3 presented with primary tumors. Patient 5 had an aggressive osteosarcoma of the right ilium secondary to radiation therapy for a recurrent malignant fibrous histiocytoma 7 years earlier. Twenty-six courses (mean, 5; range, 4 to 7) of L4 cisplatin (100 to 150 mg/m2/dose) were administered to this group of patients at a mean interval between courses of 25 days plus or minus 7.7 days (range, 15 to 41 days). Nineteen of the 26 courses (73%) were administered at 21 days plus or minus 2-day intervals. Patient 1also received two doses of IA doxorubicin (45 mg/m2) after six courses of cisplatin, and Patient 2 received one dose of IA doxorubicin (45 mg/m2) after five courses of IA cisplatin. Cisplatin was administered in 500 ml 0.9% NaCl with heparin 3000 units and vera-
From the Departments of *Pediatrics,tRadiotherapy, Sorthopedic Surgery, §Pathology, and ][Radiology,H. Lee Moffitt Cancer & Research Institute, University of South Florida, Tampa, and the llDepartment of Radiology, Tampa General Hospital, Tampa, Florida. The authors thank N. Jaffe, MD, for the suggestion of using chemotherapy and radiation therapy concurrently in the first patient and for helpful advice, Mary Dustin for editing the manuscript, and Shelley Coleman and Pat Harrell for typing the manuscript. Address for reprints: J. Estrada-Aplar, MD, USF College of Medicine, MDC-15,12901 Bruce B. Downs Boulevard, Tampa, Florida 33612-4799. Accepted for publication May 31, 1991.
Subjects and Methods
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CANCER March 1, 1992, Volume 69, No. 5
Table 1.Patient Characteristics and Prior T h e r a p y
Patient no. Sex
Age at diagnosis of pelvic tumor (yr)
1
M
16
2
M
20
3
M
18
4
F
18
5
F
12
Site of pelvic tumor Rtiliumand acetabulum, with large soft tissue mass Lt iliac wing and acetabulum Lt pubic ramus and acetabulum Rt pubic ramus and acetabulum
Rt ilium, acetabulum and ischium
Other disease at time of pelvic presentation
Disease status
Primary tumor
Interval to development of pelvic mass (mo)
None
Metastatic
Lt distal femur
19
None
Primary
-
-
None
Primary
-
-
None
Metastatic
Rt lung nodule
2nd malignancy*
Lt distal femur
-
Prior therapy Amputation, adjuvant chemotherapy (HDM, AD, CDP, CTX, BLE, DACT)
Presurgery chemotherapy, amputation, adjuvant, chemotherapy (HDM, VCR, CTX, BLE, CDP, AD, DACT) Combination IV chemotherapy (HDM, VCR, CTX, DACT, AD, CDP, IFO, ETO)
HDM high-dose methotrexate; A D adriamycin; CDP: cisplatin; CTX: cyclophosphamide; B L E bleomycin; DACT dactinomycin; I F 0 ifosphamide;ETO: etoposide; Rt: right; Lt: left. Osteosarcoma presented as a second malignancy in area irradiated for malignant fibrous histiocytoma 7 years earlier.
pamil 5 mg into the arterial catheter during 2 hours at 250 ml/h according to a modification of the procedure described by Jaffeet aL3 A high urine flow was maintained during and after the cisplatin infusion with forced hydration and mannitol diuresis. Hydration was continued for 48 hours with 5% dextrose in 0.45% NaCl with 20 meq KCL, 1 g MgS04, and 500 mg Ca
gluconate per liter at twice the maintenance rate. Magnesium was given orally in gluconate form (1 to 1.5 g twice a day) at discharge from the hospital to prevent hypomagnesemia. Catheter placement for IA chemotherapy was performed under intravenous (IV) sedation. According to the tumor location, the catheters were advanced into
Figure 1. Patient 1. (Left) CT scan image through the femoral heads demonstrates the large pelvic osteosarcoma involving the medial aspect of the right ilium and acetabulum with a large soft tissue component displacing the bladder. (Right) Follow-up CT scan image of the pelvis through the right femoral head 4 years after diagnosis of the pelvic recurrence shows the response to the treatment.
Treatment of Pelvic Osteosarcoma/Estrada-Aguilaret al.
the common iliac artery through a femoral artery puncture, and arteriograms of the tumor were obtained to gain information about specific tumor feeders, tumor neovascularity, and tumor stain in the capillary phase after the contrast injection. Radiographs were obtained for documentation of tumor response. When possible, selective catheterization of the major tumor artery was performed for a more detailed study of the tumor vascularity and for the chemotherapy infusion. Radiation therapy with photons was given using a 15 MEV linear accelerator to anterior and posterior parallel opposed fields that included all of the radiographically evident tumor plus a generous margin for microscopic and subclinical extension of disease. Daily 200 cGy fractions to a total of 4000 cGy, plus conned down boosts to totals of 6000 cGy to Patient 1, 6,600 cGy to Patient 2, and 6,000 cGy to Patient 3 were given during a course of 6 to 10 weeks, starting on day 1after the first course of IA cisplatin. An accelerated fractionation schedule, consisting of 120 cGy twice a day, 4 hours
1139
apart, for 7 days, with each course of IA cisplatin was used for Patients 4 and 5 to totals of 7,000 and 7,560 cGy, respectively, also starting on day 1. This new schedule was based on clinical and experimental evidence that multiple daily fractions could amplify the inhibition of sublethal radiation damage repair by cispiatin.4-7 Results
Local tumor control as measured by clinical and radiographic criteria was achieved in all five patients after this combined technique treatment (Table 2, Figs. 1 to 5). In addition, Patient 2 underwent an open biopsy that showed no evidence of viable tumor after the patient completed treatment. Patients l and 3 are alive and well with no evidence of local recurrence or metastatic disease at 77 and 56 months of follow-up since diagnosis of the pelvic tumor, respectively. Patient 1 underwent resection of a solitary pleural-based right
Figure 2. Patient 2. (Left) Plain film of the right side of the pelvis shows a typical "sunburst" appearance of this large osteosarcoma of the left ilium. (Right) Plain film of the tumor shows the increase in dystrophic calcification of the tumor with treatment.
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CANCER March 1, 1992, Volume 69, No. 5
Figure 3. Patient 3. (Left) Plain film of the pelvis shows a sclerosing lesion with permeative destruction of the cortex of the left superior pubic ramus. Two smaller sclerosing lesions also are seen in the ischium and in the inferior pubic ramus. (Right) Follow-up film of the pelvis after treatment shows the extensive calcification of the tumor with perfect delimitation of the tumor extent.
lung metastasis 18 months after completion of treatment for the pelvic recurrence. Patient 3’s disease remains in complete remission after 6 months of adjuvant chemotherapy that was given after treatment of his primary pelvic osteosarcoma. Patients 2 and 4 died of metastatic lung disease at 25 and 39 months, respectively, after treatment of the pelvic tumor. Patient 4 had no clinical or radiologic evidence of local recurrence at the time of death. Patient 2 complained of pain, and there was an apparent increase in the size of the pelvic tumor radiographically at the time of death. Patient 2 refused adjuvant chemotherapy after treatment of the primary pelvic tumor, whereas Patient 4 had an initial poor response to preoperative chemotherapy with vincristine, high-dose methotrexate, bleomycin, cyclophosphamide, and dactinomycin for a primary distal femur osteosarcoma. The disease-free survival of these two patients after completing treatment of the pelvic tumor was 17 and 19 months, respectively. Despite evidence of response in the primary tumor (Fig. 5, bottom), Patient 5 died of rapid and extensive tumor growth in the lungs and paraspinal tissues adjacent to the infused area 12 months after diagnosis of the pelvic tumor. The mean disease-free survival time for the first four patients after diagnosis of the pelvic malignancy is 24.7 months (range, 7 to 56 months). Because of the appearance of paraspinal lumbar disease and lung metastasis, Patient 5 was never free of disease after treatment of
the pelvic tumor. The overall survival time for the five patients after diagnosis of the pelvic tumor is 41.8 months (range, 12 to 77 months).
Toxicity Mild-to-moderate myelosuppression was seen in Patients l, 2, and 3 during treatment of the pelvic tumor, whereas Patients 4 and 5, who had been previously treated, experienced moderate to severe neutropenia. Two absolute neutrophil counts (ANCs) of less than 500 cells/dl were seen in these two patients. In one of these episodes (ANC 432), the patient required hospitalization for treatment of fever and neutropenia; only Patient 5 required red blood cell and platelet transfusion support during the treatment. Renal function was adequate in all patients during the treatment; a mild increase in serum creatinine levels was seen in Patients 2 and 4 after the 6th and 1st doses of IA cisplatin, respectively, with normalization thereafter. Patient 1had a 20% decrease in creatinine clearance after three doses of cisplatin. All patients were orally supplemented for mild-tomoderate hypomagnesemia and hypocalcemia. Peripheral neuropathy was seen in three patients; it was mild in Patients 1 and 3, and severe in Patient 2. High-frequency hearing loss occurred in Patient 4. Significant weight loss occurred in all patients during treatment; it
Treatment of Pelvic Osteosarcoma/Estrada-Aguilar et al.
1141
Figure 4. Patient 4. (Top left) Plain film of the lower pelvis shows a permeative destructive lesion involving the superior pubic ramus. (Top right) Plain film shows partial remodeling of the superior pubic ramus after treatment and a healed pathologic fracture across the ischium. (Bottom left) CT scan image through the femoral head shows the soft tissue component displacing the bladder. (Bottom right) Follow-up CT scan image through the right femoral head shows the resolution of the soft tissue component after treatment.
was severe (25% weight loss) in Patient 1, moderate (15% loss) in Patients 3 and 4, and mild in Patients 2 and 5 (7% to 9% loss). Hip contractures developed in two patients: mild in Patient 3 and severe in Patient 1. Atrophy of the soft tissues of the right buttock occurred in Patient 4. This patient also had a pathologic fracture across the right ischium during the last part of the treatment that healed well without fixation (Fig. 4, top right). No significantradiation-induced skin toxicity was seen. Discussion
Because of their rarity and poor prognosis, osteosarcomas of the pelvis traditionally have been grouped with
other nonresectable sarcomas for treatment purposes. Thus, relativelylittle information is available in the literature concerning the response of pelvic osteosarcomas to systemic and regional chemotherapy. Mavligit et al.' first used IA cisplatin as a single agent to treat a group of patients with inoperable skeletal tumors. Nine of them had primary pelvic osteosarcomas.After an average number of courses of three (range, one to five), there were four partial responses (PR), lasting from 12 to 63 weeks. Needle biopsy of the patient who had a 63+ weeks' response showed 100% tumor necrosis, whereas the patient who had a PR for 12 weeks showed only 25% to 40% necrosis. The response rate of this group of patients was 44%, with a median duration of 30+ weeks (range, 8 to 63 weeks). The usual course of these patients is exemplified by the case of a 29-year-
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CANCER March I , 1992, Volume 69, No. 5
Figure 5 . Patient 5. (Top left) CT scan image shows the extensive iliac osteosarcoma with large soft tissue component.(Top right) Right iliac arteriogram shows the extensive tumor neovascularity and stain at presentation. (Bottom) Right hypogastric arteriogram shows significant decrease in the tumor neovascularity and stain after the third intraarterial chemotherapy infusion.
old woman with a large osteosarcoma of the left ilium treated with IA doxorubicin and cisplatin by Stephens et aL9 Despite an initial response that was followed by local resection and radiation therapy, the tumor recurred in the pubic bone outside the infused region 18 months later. The patient died with local recurrence and pulmonary metastasis 3 years after diagnosis. Recently, Paredes ef aZ.* reported ten patients with osteosarcoma of the pelvis, nine of them chondroblastic, treated with systemic doxorubicin, 75 to 90 mg/m2 continuous 96-h infusion days 1 to 4, and IA cisplatin, 120 to 160 mg/m2 on day 6. After a median number of courses of four (range, two to six), six patients had surgery (three hemipelvectomies, two internal hemipelvectomies, and one whose tumor could not be resected) and four were given radiation therapy. Ne-
crosis in all of the resected specimens was less than 90%. Despite the suboptimal response to chemotherapy, three of five patients with resections and three of four patients who received radiation therapy had prolonged survival (6 to 53 months). The poor response of pelvic osteosarcomas to chemotherapy may be related to the predominantly chondroblastic nature of these tumors.*,2The two patients with primary osteosarcomas in our series had tumors with chondroblastic differentiation (Patients 2 and 3). However, in both of them there was a good response of the primary tumor to the combination of IA cisplatin and radiation therapy as indicated by progressive calcification of the tumors and disappearance of the tumor neovascularity. Patient 3 is one of the long-term survivors, whereas Patient 2, who died of metastatic lung
Treatment of Pelvic Osteosarcoma/Estrada-Aguilaret al.
1143
Table 2. Patient Treatment and Results Patient no.
Therapy
1
CDP 100 mg/m2 X6 IA; AD 45 mg/m2 x 2 IA; XRT 6600 CGY
2
CDP 150 mg/mz X5 IA; AD 45 mg/m2 x 1 IA; XRT 6600 CGY
3
CDP 150 mg/m2 X7; XRT 6000 CGY CDP 150 mg/m2 X4; XRT 7000 CGY
4
5
CDP 100 mg/m2 X4; XRT 7560 CGY
Local tumor response Reduction in size of soft tissue mass and neovascularity; calcification of residual mass Decrease in neovascularity and tumor size; increase in dystrophic calcification Open Bx negative for viable tumor Increase in dystrophic calcification Increase in dystrophic calcification; decrease in size of soft tissue mass Decrease in neovascularity; increase in calcification
Disease-free survival (mo)
Survival after pelvic tumor (mo)
Status NED
Metastasis
Rx for mets
32
Rt lung nodule
Surgical resection
77f
17
Bilateral lung nodules
None (refused)
25
Dead
56+
NED
40
Dead
12
Dead
56+
19
Rt lung and mediastinum
0
Paraspinal mass, lung nodules
Surgical resection
-
-
CDP: cisplatin; AD: adriamycin; IA: intraarterial;NED no evidence of disease; Rt: right; Lt: left.
disease, had no radiologic or clinical evidence of local recurrence for 21 months after diagnosis of the pelvic tumor. In addition to a direct cytotoxic effect of the cisplatin, the response seen in our patients might be explained by a possible potentiation of the radiation therapy effect by cisplatin, a potent inhibitor of the sublethal radiation damage repair (SLDR) in both bacterial and mammalian cells.'o*" Because of the pronounced SLDR inhibition by cisplatin, fractionated radiation therapy schedules may lead to strong amplification of the radiation enhan~ement.~,~,'~ There also may be a correlation between the sensitivity of the cells to the cytotoxic action of cisplatin and its radiation sensitizing effect." Several studies in adult patients with a variety of malignancies suggest therapeutic synergismbetween cisplatin and radiation therapy administered concurrently.6,7,13-19 Likewise, nonconventional fractionation schedules or radiation therapy combined with radiation-sensitizing drugs have achieved better local effect than radiation therapy alone in the treatment of osteosarcomas and other types of solid tumor^.^*^*^^ Despite significant local toxicity, local tumor control was achieved in seven of nine patients with nonresectable ~ IA infusion of osteosarcomas by Martinez et ~ l . , *using
the radiation sensitizer 5'-bromodeoxyuridine (BudR) combined with hypofractionated radiation therapy and adjuvant systemic chemotherapy. Our experience in the treatment of five patients with primary and metastatic osteosarcomas of the pelvis suggests that long-term control of the pelvic tumor can be achieved in these patients with the combined use of cisplatin and radiation therapy. Two of the five patients are alive with no evidence of locoregional recurrence or metastatic disease. However, Patient 1 uses a wheel chair because of a severe right hip contracture and the amputation of the other leg, whereas Patient 3 ambulates with only a slight limp caused by a mild, residual contracture of the left hip. Early institution of physical therapy during the treatment may help avoid crippling osteomuscular contractures and residual deformities, particularly those related to the function of the hip joints in these patients. Three patients died of metastatic disease. Because no postmortem examinations were performed on these patients, we could not determine with certainty whether local recurrences had occurred at the time of death. Patient 2, who moved elsewhere after completing treatment for his pelvic tumor, was thought to have a recurrence because he complained of pain and there was evidence of enlargement
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CANCER March 1, 1992, Volume 69, No. 5
of the pelvic mass on plain radiographs obtained by another physician. However, Patients 3 and 4 had no clinical or radiologic evidence of pelvic tumor activity from the end of the regional treatment to the time of death. The mean survival time of these three patients was 25.3 months (range, 12 to 39 months) after diagnosis of the pelvic malignancy. A controversy exists between the effectiveness of IA versus IV cisplatin in the treatment of patients with osteosarcoma of the extremities. In the only published found no difference prospective study, Winkler ef dZ1 in terms of percent of tumor necrosis between IA and IV administered cisplatin in a group of 109 patients with high-risk osteosarcoma of the extremities. Cisplatin was part of a four-drug regimen given preoperatively that included ifosfamide, high-dose methotrexate, and doxorubicin. The increased drug exposure of the tumor during IA infusion caused by the selective catheterization of the pelvic tumor arteries for the cisplatin infusion may explain the enhancement of the radiation effect in our patient^.^^,^^ A study comparing the efficacy of IA administered cisplatin with IV administered cisplatin in patients with pelvic osteosarcomas may be warranted but remains impractical because of the small number of available patients. Our protocol for the treatment of patients with primary and metastatic osteosarcomas of the pelvis incorporates four doses of IA cisplatin, 100 mg/m2 every 2 weeks while delivering concurrent radiation therapy with 120 to 140 cGy fractions twice a day, 6 hours apart,24for a total of 6500 cGy over 6 to 7 weeks. Although development of metastatic disease could occur during treatment of the primary pelvic tumor, studies by Jaffe and ~ t h e r in~patients ~ ~ ~with ~ osteosarco~ - ~ ~ mas of the extremities treated preoperatively with IA cisplatin indicate that substantial cisplatin concentrations enter the systemic circulation after IA cisplatin administration with apparent similar therapeutic efficacy upon micrometastatic disease.28 At the completion of the treatment to the pelvic tumor, a full clinical and radiologic evaluation of the tumor response is done. When possible, pathologicevaluation is obtained through an open biopsy of the tumor. Evidence of viable tumor is an indication for immediate surgical resection. Because the nonsurgical approach to treatment of pelvic osteosarcomas is investigational, surgical treatment of the pelvic tumor, including external/intemal hemipelvectomy or even limited resections, should still be offered to the patients at the completion of the combined treatment technique to the pelvic tumor. Surgery also should be considered when clinical or radiologic evidence indicates lack of response or tumor progression at any time during treatment of the pelvic tumor.
Because most patients with pelvic osteosarcomas ultimately die of metastatic disease, an important component of the treatment of these patients should be an intensive systemic chemotherapy program after the initial treatment of the pelvic tumor, as was done for Patient 3. This approach may succeed in eliminating potential metastatic disease, particularly in untreated patients with primary pelvic osteosarcomas. However, previously treated patients who present with pelvic recurrence may not benefit from additional systemic chemotherapy because of the development of multidrug resistance. An aggressive surgical approach to metastatic lung disease appears to be the best treatment option for these patients. Although our results need to be confirmed in a larger series of patients, it appears that a model for the treatment of the primary tumor in patients with osteosarcomas of the extremities could be drawn from a combined approach based on the use of effective cytotoxic/radiation-sensitizing drugs, such as cisplatin, and concurrent radiation therapy. This approach may benefit, in particular, patients with large tumors and eventually could make surgical resection obsolete in patients who have completed their osseous growth. References 1. Dahlin DC, Unni KK. Osteosarcoma. In: Dahlin DC, Unni KK, eds. Bone Tumors. General Aspects and Data on 8,542 Cases. Springfield, Illinois: Charles C. Thomas, 1986; 269-307. 2. Paredes J, Chawla SP, Raymond AK et al. Chemotherapy of osteosarcoma of the pelvis (Abstr). Proc Am Assoc Cancer Res 1988; 29:A885. 3. JaffeN, Knapp J, Chuang VP et al. Osteosarcomas: Intra-arterial treatment of the primary tumor with Cis-diammine-dichloroplatinum I1 (CDP). Angiogaphic, pathologic, and pharmacologic studies. Cancer 1983; 51:402-407. 4. Stratford IJ, Williamson C, Adams GE. Combination studies with misonidazole and a cis-platinum complex: Cytotoxicity and radiosensitizationin vitro. Br ] Cancer 1980; 41:517-522. 5. Carde P, Lava1 F. Effect of cis-diamminedichloroplatinum(11) and x-rays on mammalian cell survival. Int ] Radiat Oncol Biol Phys 1981; 7929-933. 6. Arcangeli G, Mauro F, Morelli D, Nervi C. Multiple daily fractionation in radiotherapy: Biological rationale and preliminary clinical experiences.Eur ] Cancer 1979; 15:1077-1083. 7. Douglas BG, Worth AJ.Superfractionationin glioblastomamultiforme. Results of a phase I1 study. Int ] Radiat Oncol Biol Phys 1982; 8~1787-1794. 8. Mavligit GM, Benjamin R, Patt YZ et al. Intraarterial cis-platinum for patients with inoperable skeletal tumors. Cancer 1981; 481-4. 9. Stephens FO, Tattersall MH, Marsden W et al. Regional chemotherapy with the use of cisplatin and doxorubicin as primary treatment for advanced sarcomas in shoulder, pelvis and thigh. Cancer 1987; 60:724-735. 10. Richmond RC. Toxic variability and radiation sensitization by dichlorodiammineplatinum (11) complexes in SalmonetIa typhimuriurn cells. Radiat Res 1984; 99:596-608.
Treatment of Pelvic Osteosarcoma/Estrada-Aguilaret al. 11. Begg AC, van der Kolk H, Dewit L e f al. The interaction of cisplatin and radiation on RIF-1 tumor cells in vitro. Int IRadiaf Biol 1986; 5:871-884. 12. Dewit L. Combined treatment of radiation and cis-diamminedichloroplatinum (11): A review of experimental and clinical data. Inf ] Radiat Oncol Biol Phys 1987; 13:403-426. 13. Haselow RE, Adams GS, Oken MM, Goudsmit A, Lemer HJ, Marsh JC. Simultaneous cis-platinum (DdP) and radiation therapy (RT) for locally advanced unresectable head and neck cancer (Abstr). Proc Am Soc Clin Oncol 1983; 2:160. 14. Schmitt G, Higi M, Stupp H, Scherer E. Ein neues interdisziplinares behandlungskonzept bei fortgeschrittenen interdisziplinares behandlungskinzept bei fortgeschrittenen Kopf-Hals-Tumoren. Strahlentherapie 1983; 159:470-473. 15. Shipley WU, Coombs LJ, Einstein AB Jr, Soloway MS, Wajsman Z, Prout GR. National Bladder Cancer Collaborative Group A Cisplatin and full dose irradiation for patients with invasive bladder carcinoma: A preliminary report of tolerance and local response. ] Urol 1984; 132:899-903. 16. Eapen L, Stewart D, Danjoux C et al. Intraarterial cisplatin and concurrent radiation for locally advanced bladder cancer. Clin O ~ C1989; O ~ 7230-235. 17. Rettenmaier MA, Moran MF, Ramsinghani NF. Treatment of advanced and recurrent squamous carcinoma of the uterine cervix with constant intraarterial infusion of cisplatin. Cancer 1988; 61:1301-1303. 18. Tobias JS, Smith BJ, Blackman G, Finn G. Concurrent daily cisplatin and radiotherapy in locally advanced squamous carcinoma of the head-and-neck and bronchus. Radiofher Oncol 1987; 9~263-268. 19. Raghavan D, Grundy R, Grenaway TM. Pre-emptive (neo-adjuvant) chemotherapy prior to radical radiotherapy for fit septuagenarians with bladder cancer: Age itself is not a contra-indication. Br Urol 1988; 62:154-159.
1145 20. Martinez A, Goffinet DR, Donaldson SS, Bagshaw MA, Kaplan HS. Intraarterial infusion of radiosensitizer (BudR) combined with hypofractionated irradiation and chemotherapy for primary treatment of osteogenic sarcoma. Int ] Radiaf Oncol Biol P h y ~1985; 11:123-128. 21. Winkler K, Bielack S, Delling G et al. Effect of intraarterial versus intravenous cisplatin in addition to systemic doxorubicin, highdose methotrexate, and ifosfamide on histologic tumor response in osteosarcoma (Study COSS-86). Cancer 1990; 66:1703-1710. 22. Stewart DJ, Benjamin RS, Zimmerman S el al. Clinical pharmacology of intraarterial cis-diamminedichloroplatinum (11). Cancer Res 1983; 43:917-920. 23. Campbell TN, Howell SB, Pfeifle CE, Wung WE, Bookstein J. Clinical pharmacokinetics of intraarterial cisplatin in humans. J Clin Oncol 1983; 1:755-762. 24. Cox JD, Pajak TF, Marcia1 VA e f al. Interfraction interval is major determinant of late effects, but not acute effects or tumor control, with hyperfractionated irradiation (HFX) of carcinomas of upper respiratory and digestive tracts (URDT) (Abstr). Int ] Radiaf Oncol Biol Phys 1990; 19:196. 25. Jaffe N, Robertson R, Ayala A e f al. Comparison of intra-arterial cis-diamminedichloroplatinum-I1 with high dose methotrexate and citrovorum factor rescue in the treatment of primary osteosarcoma. ] Clin Oncol 1985; 3:llOl-1104. 26. Jaffe N, Raymond AK, Ayala A e f al. Effect of cumulative courses of intraarterial cis-diamminedichloroplatinum-I1on the primary tumor in osteosarcoma. Cancer 1989; 63:63-67. 27. Bielack S, Erttmann R, Purfurst C et al. Platinum (PT) levels in plasma (PL), ultrafiltrate (UF), urine, and tumor-tissue after intraarterial (IA) vs intravenous (IV) infusion of cis-diamminedichloroplatinum (CDDP) for osteosarcoma (0s)Proc ASCO 1988; 7A211. 28. Hudson M, Jaffe MR, Jaffe N et al. Pediatric osteosarcoma: Therapeutic strategies, results, and prognostic factors derived from a 10-year experience. J Clin Oncol 1990; 8:1988-1997.
Primary Treatment of Pelvic Osteosarcoma Report of Five Cases J. Estrada-Aguilar, MD,* H. Greenberg, MD,t A. Walling, MD,$ K. Schroer, MD,§ T. Black, MD,7 S. Morse, MD,[I and E. Hvizdala, MD*
Five patients, ages 12 to 20 years, with nonresectable primary (Patients 2,3, and 5) and metastatic (Patients 1 and 4) pelvic osteosarcomas were treated with intraarterial cisplatin and concurrent radiation therapy from 1983 to 1987. Long-term local tumor control was achieved in all five patients. Patients 1 and 3 are alive with no evidence of local recurrence or metastatic disease at 77 and 56 months of follow-up, respectively, since diagnosis of the pelvic tumor. Patients 2,4,and 5 died of metastatic lung disease at 25,39, and 12 months, respectively, after diagnosis of the pelvic tumor. Patient 4 had no clinical or radiologic evidence of local recurrence. Control of tumor growth in patients with pelvic osteosarcomas can be achieved with regional chemotherapy and concurrent radiation therapy. These patients also should receive adjuvant intensive systemic chemotherapy to increase the probability of eliminating potential subclinical metastatic disease. Cancer 1992; 691137-1145.
control of osteosarcomas that arise or metastasize to axial bones has required extensive and often mutilating surgical procedures.2Most of these patients will die of local recurrences or metastatic disease. Like osteosarcomas of the spine, pelvic osteosarcomasoften are considered nonresectable because of the significant surgical complication. In this study, we report our experience in treating five patients with both primary and metastatic osteosarcoma of the pelvis with a program that combined regional chemotherapy and concurrent radiation therapy. Two of these patients refused surgical resection of the tumor (hemipelvectomy), whereas the tumors in the other three patients were considered nonresectable because of their size and location.
Primary osteosarcomas of the pelvic bones are uncommon. Dahlin and Unni' reported an incidence of 9.5% in their extensive series of 1274 osteosarcomas at the Mayo Clinic. This group included 12 patients with tumors that arose from the sacrum, 89 from the ilium, 14 from the acetabulum, and 6 from the ischium. Because the definitive treatment of the primary tumor in patients with osteosarcomas is surgical resection, the local
Five patients, ages 12 to 20 years, with primary (Patients 2, 3, and 5) and metastatic (Patients l and 4) pelvic osteosarcomas (Table 1) were treated with intraarterial (IA) cisplatin and concurrent radiation therapy at our institution from 1983 to 1987. Patients 1 and 4 had pelvic metastasis from distal femoral tumors, whereas Patients 2 and 3 presented with primary tumors. Patient 5 had an aggressive osteosarcoma of the right ilium secondary to radiation therapy for a recurrent malignant fibrous histiocytoma 7 years earlier. Twenty-six courses (mean, 5; range, 4 to 7) of L4 cisplatin (100 to 150 mg/m2/dose) were administered to this group of patients at a mean interval between courses of 25 days plus or minus 7.7 days (range, 15 to 41 days). Nineteen of the 26 courses (73%) were administered at 21 days plus or minus 2-day intervals. Patient 1also received two doses of IA doxorubicin (45 mg/m2) after six courses of cisplatin, and Patient 2 received one dose of IA doxorubicin (45 mg/m2) after five courses of IA cisplatin. Cisplatin was administered in 500 ml 0.9% NaCl with heparin 3000 units and vera-
From the Departments of *Pediatrics,tRadiotherapy, Sorthopedic Surgery, §Pathology, and ][Radiology,H. Lee Moffitt Cancer & Research Institute, University of South Florida, Tampa, and the llDepartment of Radiology, Tampa General Hospital, Tampa, Florida. The authors thank N. Jaffe, MD, for the suggestion of using chemotherapy and radiation therapy concurrently in the first patient and for helpful advice, Mary Dustin for editing the manuscript, and Shelley Coleman and Pat Harrell for typing the manuscript. Address for reprints: J. Estrada-Aplar, MD, USF College of Medicine, MDC-15,12901 Bruce B. Downs Boulevard, Tampa, Florida 33612-4799. Accepted for publication May 31, 1991.
Subjects and Methods
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CANCER March 1, 1992, Volume 69, No. 5
Table 1.Patient Characteristics and Prior T h e r a p y
Patient no. Sex
Age at diagnosis of pelvic tumor (yr)
1
M
16
2
M
20
3
M
18
4
F
18
5
F
12
Site of pelvic tumor Rtiliumand acetabulum, with large soft tissue mass Lt iliac wing and acetabulum Lt pubic ramus and acetabulum Rt pubic ramus and acetabulum
Rt ilium, acetabulum and ischium
Other disease at time of pelvic presentation
Disease status
Primary tumor
Interval to development of pelvic mass (mo)
None
Metastatic
Lt distal femur
19
None
Primary
-
-
None
Primary
-
-
None
Metastatic
Rt lung nodule
2nd malignancy*
Lt distal femur
-
Prior therapy Amputation, adjuvant chemotherapy (HDM, AD, CDP, CTX, BLE, DACT)
Presurgery chemotherapy, amputation, adjuvant, chemotherapy (HDM, VCR, CTX, BLE, CDP, AD, DACT) Combination IV chemotherapy (HDM, VCR, CTX, DACT, AD, CDP, IFO, ETO)
HDM high-dose methotrexate; A D adriamycin; CDP: cisplatin; CTX: cyclophosphamide; B L E bleomycin; DACT dactinomycin; I F 0 ifosphamide;ETO: etoposide; Rt: right; Lt: left. Osteosarcoma presented as a second malignancy in area irradiated for malignant fibrous histiocytoma 7 years earlier.
pamil 5 mg into the arterial catheter during 2 hours at 250 ml/h according to a modification of the procedure described by Jaffeet aL3 A high urine flow was maintained during and after the cisplatin infusion with forced hydration and mannitol diuresis. Hydration was continued for 48 hours with 5% dextrose in 0.45% NaCl with 20 meq KCL, 1 g MgS04, and 500 mg Ca
gluconate per liter at twice the maintenance rate. Magnesium was given orally in gluconate form (1 to 1.5 g twice a day) at discharge from the hospital to prevent hypomagnesemia. Catheter placement for IA chemotherapy was performed under intravenous (IV) sedation. According to the tumor location, the catheters were advanced into
Figure 1. Patient 1. (Left) CT scan image through the femoral heads demonstrates the large pelvic osteosarcoma involving the medial aspect of the right ilium and acetabulum with a large soft tissue component displacing the bladder. (Right) Follow-up CT scan image of the pelvis through the right femoral head 4 years after diagnosis of the pelvic recurrence shows the response to the treatment.
Treatment of Pelvic Osteosarcoma/Estrada-Aguilaret al.
the common iliac artery through a femoral artery puncture, and arteriograms of the tumor were obtained to gain information about specific tumor feeders, tumor neovascularity, and tumor stain in the capillary phase after the contrast injection. Radiographs were obtained for documentation of tumor response. When possible, selective catheterization of the major tumor artery was performed for a more detailed study of the tumor vascularity and for the chemotherapy infusion. Radiation therapy with photons was given using a 15 MEV linear accelerator to anterior and posterior parallel opposed fields that included all of the radiographically evident tumor plus a generous margin for microscopic and subclinical extension of disease. Daily 200 cGy fractions to a total of 4000 cGy, plus conned down boosts to totals of 6000 cGy to Patient 1, 6,600 cGy to Patient 2, and 6,000 cGy to Patient 3 were given during a course of 6 to 10 weeks, starting on day 1after the first course of IA cisplatin. An accelerated fractionation schedule, consisting of 120 cGy twice a day, 4 hours
1139
apart, for 7 days, with each course of IA cisplatin was used for Patients 4 and 5 to totals of 7,000 and 7,560 cGy, respectively, also starting on day 1. This new schedule was based on clinical and experimental evidence that multiple daily fractions could amplify the inhibition of sublethal radiation damage repair by cispiatin.4-7 Results
Local tumor control as measured by clinical and radiographic criteria was achieved in all five patients after this combined technique treatment (Table 2, Figs. 1 to 5). In addition, Patient 2 underwent an open biopsy that showed no evidence of viable tumor after the patient completed treatment. Patients l and 3 are alive and well with no evidence of local recurrence or metastatic disease at 77 and 56 months of follow-up since diagnosis of the pelvic tumor, respectively. Patient 1 underwent resection of a solitary pleural-based right
Figure 2. Patient 2. (Left) Plain film of the right side of the pelvis shows a typical "sunburst" appearance of this large osteosarcoma of the left ilium. (Right) Plain film of the tumor shows the increase in dystrophic calcification of the tumor with treatment.
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CANCER March 1, 1992, Volume 69, No. 5
Figure 3. Patient 3. (Left) Plain film of the pelvis shows a sclerosing lesion with permeative destruction of the cortex of the left superior pubic ramus. Two smaller sclerosing lesions also are seen in the ischium and in the inferior pubic ramus. (Right) Follow-up film of the pelvis after treatment shows the extensive calcification of the tumor with perfect delimitation of the tumor extent.
lung metastasis 18 months after completion of treatment for the pelvic recurrence. Patient 3’s disease remains in complete remission after 6 months of adjuvant chemotherapy that was given after treatment of his primary pelvic osteosarcoma. Patients 2 and 4 died of metastatic lung disease at 25 and 39 months, respectively, after treatment of the pelvic tumor. Patient 4 had no clinical or radiologic evidence of local recurrence at the time of death. Patient 2 complained of pain, and there was an apparent increase in the size of the pelvic tumor radiographically at the time of death. Patient 2 refused adjuvant chemotherapy after treatment of the primary pelvic tumor, whereas Patient 4 had an initial poor response to preoperative chemotherapy with vincristine, high-dose methotrexate, bleomycin, cyclophosphamide, and dactinomycin for a primary distal femur osteosarcoma. The disease-free survival of these two patients after completing treatment of the pelvic tumor was 17 and 19 months, respectively. Despite evidence of response in the primary tumor (Fig. 5, bottom), Patient 5 died of rapid and extensive tumor growth in the lungs and paraspinal tissues adjacent to the infused area 12 months after diagnosis of the pelvic tumor. The mean disease-free survival time for the first four patients after diagnosis of the pelvic malignancy is 24.7 months (range, 7 to 56 months). Because of the appearance of paraspinal lumbar disease and lung metastasis, Patient 5 was never free of disease after treatment of
the pelvic tumor. The overall survival time for the five patients after diagnosis of the pelvic tumor is 41.8 months (range, 12 to 77 months).
Toxicity Mild-to-moderate myelosuppression was seen in Patients l, 2, and 3 during treatment of the pelvic tumor, whereas Patients 4 and 5, who had been previously treated, experienced moderate to severe neutropenia. Two absolute neutrophil counts (ANCs) of less than 500 cells/dl were seen in these two patients. In one of these episodes (ANC 432), the patient required hospitalization for treatment of fever and neutropenia; only Patient 5 required red blood cell and platelet transfusion support during the treatment. Renal function was adequate in all patients during the treatment; a mild increase in serum creatinine levels was seen in Patients 2 and 4 after the 6th and 1st doses of IA cisplatin, respectively, with normalization thereafter. Patient 1had a 20% decrease in creatinine clearance after three doses of cisplatin. All patients were orally supplemented for mild-tomoderate hypomagnesemia and hypocalcemia. Peripheral neuropathy was seen in three patients; it was mild in Patients 1 and 3, and severe in Patient 2. High-frequency hearing loss occurred in Patient 4. Significant weight loss occurred in all patients during treatment; it
Treatment of Pelvic Osteosarcoma/Estrada-Aguilar et al.
1141
Figure 4. Patient 4. (Top left) Plain film of the lower pelvis shows a permeative destructive lesion involving the superior pubic ramus. (Top right) Plain film shows partial remodeling of the superior pubic ramus after treatment and a healed pathologic fracture across the ischium. (Bottom left) CT scan image through the femoral head shows the soft tissue component displacing the bladder. (Bottom right) Follow-up CT scan image through the right femoral head shows the resolution of the soft tissue component after treatment.
was severe (25% weight loss) in Patient 1, moderate (15% loss) in Patients 3 and 4, and mild in Patients 2 and 5 (7% to 9% loss). Hip contractures developed in two patients: mild in Patient 3 and severe in Patient 1. Atrophy of the soft tissues of the right buttock occurred in Patient 4. This patient also had a pathologic fracture across the right ischium during the last part of the treatment that healed well without fixation (Fig. 4, top right). No significantradiation-induced skin toxicity was seen. Discussion
Because of their rarity and poor prognosis, osteosarcomas of the pelvis traditionally have been grouped with
other nonresectable sarcomas for treatment purposes. Thus, relativelylittle information is available in the literature concerning the response of pelvic osteosarcomas to systemic and regional chemotherapy. Mavligit et al.' first used IA cisplatin as a single agent to treat a group of patients with inoperable skeletal tumors. Nine of them had primary pelvic osteosarcomas.After an average number of courses of three (range, one to five), there were four partial responses (PR), lasting from 12 to 63 weeks. Needle biopsy of the patient who had a 63+ weeks' response showed 100% tumor necrosis, whereas the patient who had a PR for 12 weeks showed only 25% to 40% necrosis. The response rate of this group of patients was 44%, with a median duration of 30+ weeks (range, 8 to 63 weeks). The usual course of these patients is exemplified by the case of a 29-year-
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CANCER March I , 1992, Volume 69, No. 5
Figure 5 . Patient 5. (Top left) CT scan image shows the extensive iliac osteosarcoma with large soft tissue component.(Top right) Right iliac arteriogram shows the extensive tumor neovascularity and stain at presentation. (Bottom) Right hypogastric arteriogram shows significant decrease in the tumor neovascularity and stain after the third intraarterial chemotherapy infusion.
old woman with a large osteosarcoma of the left ilium treated with IA doxorubicin and cisplatin by Stephens et aL9 Despite an initial response that was followed by local resection and radiation therapy, the tumor recurred in the pubic bone outside the infused region 18 months later. The patient died with local recurrence and pulmonary metastasis 3 years after diagnosis. Recently, Paredes ef aZ.* reported ten patients with osteosarcoma of the pelvis, nine of them chondroblastic, treated with systemic doxorubicin, 75 to 90 mg/m2 continuous 96-h infusion days 1 to 4, and IA cisplatin, 120 to 160 mg/m2 on day 6. After a median number of courses of four (range, two to six), six patients had surgery (three hemipelvectomies, two internal hemipelvectomies, and one whose tumor could not be resected) and four were given radiation therapy. Ne-
crosis in all of the resected specimens was less than 90%. Despite the suboptimal response to chemotherapy, three of five patients with resections and three of four patients who received radiation therapy had prolonged survival (6 to 53 months). The poor response of pelvic osteosarcomas to chemotherapy may be related to the predominantly chondroblastic nature of these tumors.*,2The two patients with primary osteosarcomas in our series had tumors with chondroblastic differentiation (Patients 2 and 3). However, in both of them there was a good response of the primary tumor to the combination of IA cisplatin and radiation therapy as indicated by progressive calcification of the tumors and disappearance of the tumor neovascularity. Patient 3 is one of the long-term survivors, whereas Patient 2, who died of metastatic lung
Treatment of Pelvic Osteosarcoma/Estrada-Aguilaret al.
1143
Table 2. Patient Treatment and Results Patient no.
Therapy
1
CDP 100 mg/m2 X6 IA; AD 45 mg/m2 x 2 IA; XRT 6600 CGY
2
CDP 150 mg/mz X5 IA; AD 45 mg/m2 x 1 IA; XRT 6600 CGY
3
CDP 150 mg/m2 X7; XRT 6000 CGY CDP 150 mg/m2 X4; XRT 7000 CGY
4
5
CDP 100 mg/m2 X4; XRT 7560 CGY
Local tumor response Reduction in size of soft tissue mass and neovascularity; calcification of residual mass Decrease in neovascularity and tumor size; increase in dystrophic calcification Open Bx negative for viable tumor Increase in dystrophic calcification Increase in dystrophic calcification; decrease in size of soft tissue mass Decrease in neovascularity; increase in calcification
Disease-free survival (mo)
Survival after pelvic tumor (mo)
Status NED
Metastasis
Rx for mets
32
Rt lung nodule
Surgical resection
77f
17
Bilateral lung nodules
None (refused)
25
Dead
56+
NED
40
Dead
12
Dead
56+
19
Rt lung and mediastinum
0
Paraspinal mass, lung nodules
Surgical resection
-
-
CDP: cisplatin; AD: adriamycin; IA: intraarterial;NED no evidence of disease; Rt: right; Lt: left.
disease, had no radiologic or clinical evidence of local recurrence for 21 months after diagnosis of the pelvic tumor. In addition to a direct cytotoxic effect of the cisplatin, the response seen in our patients might be explained by a possible potentiation of the radiation therapy effect by cisplatin, a potent inhibitor of the sublethal radiation damage repair (SLDR) in both bacterial and mammalian cells.'o*" Because of the pronounced SLDR inhibition by cisplatin, fractionated radiation therapy schedules may lead to strong amplification of the radiation enhan~ement.~,~,'~ There also may be a correlation between the sensitivity of the cells to the cytotoxic action of cisplatin and its radiation sensitizing effect." Several studies in adult patients with a variety of malignancies suggest therapeutic synergismbetween cisplatin and radiation therapy administered concurrently.6,7,13-19 Likewise, nonconventional fractionation schedules or radiation therapy combined with radiation-sensitizing drugs have achieved better local effect than radiation therapy alone in the treatment of osteosarcomas and other types of solid tumor^.^*^*^^ Despite significant local toxicity, local tumor control was achieved in seven of nine patients with nonresectable ~ IA infusion of osteosarcomas by Martinez et ~ l . , *using
the radiation sensitizer 5'-bromodeoxyuridine (BudR) combined with hypofractionated radiation therapy and adjuvant systemic chemotherapy. Our experience in the treatment of five patients with primary and metastatic osteosarcomas of the pelvis suggests that long-term control of the pelvic tumor can be achieved in these patients with the combined use of cisplatin and radiation therapy. Two of the five patients are alive with no evidence of locoregional recurrence or metastatic disease. However, Patient 1 uses a wheel chair because of a severe right hip contracture and the amputation of the other leg, whereas Patient 3 ambulates with only a slight limp caused by a mild, residual contracture of the left hip. Early institution of physical therapy during the treatment may help avoid crippling osteomuscular contractures and residual deformities, particularly those related to the function of the hip joints in these patients. Three patients died of metastatic disease. Because no postmortem examinations were performed on these patients, we could not determine with certainty whether local recurrences had occurred at the time of death. Patient 2, who moved elsewhere after completing treatment for his pelvic tumor, was thought to have a recurrence because he complained of pain and there was evidence of enlargement
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CANCER March 1, 1992, Volume 69, No. 5
of the pelvic mass on plain radiographs obtained by another physician. However, Patients 3 and 4 had no clinical or radiologic evidence of pelvic tumor activity from the end of the regional treatment to the time of death. The mean survival time of these three patients was 25.3 months (range, 12 to 39 months) after diagnosis of the pelvic malignancy. A controversy exists between the effectiveness of IA versus IV cisplatin in the treatment of patients with osteosarcoma of the extremities. In the only published found no difference prospective study, Winkler ef dZ1 in terms of percent of tumor necrosis between IA and IV administered cisplatin in a group of 109 patients with high-risk osteosarcoma of the extremities. Cisplatin was part of a four-drug regimen given preoperatively that included ifosfamide, high-dose methotrexate, and doxorubicin. The increased drug exposure of the tumor during IA infusion caused by the selective catheterization of the pelvic tumor arteries for the cisplatin infusion may explain the enhancement of the radiation effect in our patient^.^^,^^ A study comparing the efficacy of IA administered cisplatin with IV administered cisplatin in patients with pelvic osteosarcomas may be warranted but remains impractical because of the small number of available patients. Our protocol for the treatment of patients with primary and metastatic osteosarcomas of the pelvis incorporates four doses of IA cisplatin, 100 mg/m2 every 2 weeks while delivering concurrent radiation therapy with 120 to 140 cGy fractions twice a day, 6 hours apart,24for a total of 6500 cGy over 6 to 7 weeks. Although development of metastatic disease could occur during treatment of the primary pelvic tumor, studies by Jaffe and ~ t h e r in~patients ~ ~ ~with ~ osteosarco~ - ~ ~ mas of the extremities treated preoperatively with IA cisplatin indicate that substantial cisplatin concentrations enter the systemic circulation after IA cisplatin administration with apparent similar therapeutic efficacy upon micrometastatic disease.28 At the completion of the treatment to the pelvic tumor, a full clinical and radiologic evaluation of the tumor response is done. When possible, pathologicevaluation is obtained through an open biopsy of the tumor. Evidence of viable tumor is an indication for immediate surgical resection. Because the nonsurgical approach to treatment of pelvic osteosarcomas is investigational, surgical treatment of the pelvic tumor, including external/intemal hemipelvectomy or even limited resections, should still be offered to the patients at the completion of the combined treatment technique to the pelvic tumor. Surgery also should be considered when clinical or radiologic evidence indicates lack of response or tumor progression at any time during treatment of the pelvic tumor.
Because most patients with pelvic osteosarcomas ultimately die of metastatic disease, an important component of the treatment of these patients should be an intensive systemic chemotherapy program after the initial treatment of the pelvic tumor, as was done for Patient 3. This approach may succeed in eliminating potential metastatic disease, particularly in untreated patients with primary pelvic osteosarcomas. However, previously treated patients who present with pelvic recurrence may not benefit from additional systemic chemotherapy because of the development of multidrug resistance. An aggressive surgical approach to metastatic lung disease appears to be the best treatment option for these patients. Although our results need to be confirmed in a larger series of patients, it appears that a model for the treatment of the primary tumor in patients with osteosarcomas of the extremities could be drawn from a combined approach based on the use of effective cytotoxic/radiation-sensitizing drugs, such as cisplatin, and concurrent radiation therapy. This approach may benefit, in particular, patients with large tumors and eventually could make surgical resection obsolete in patients who have completed their osseous growth. References 1. Dahlin DC, Unni KK. Osteosarcoma. In: Dahlin DC, Unni KK, eds. Bone Tumors. General Aspects and Data on 8,542 Cases. Springfield, Illinois: Charles C. Thomas, 1986; 269-307. 2. Paredes J, Chawla SP, Raymond AK et al. Chemotherapy of osteosarcoma of the pelvis (Abstr). Proc Am Assoc Cancer Res 1988; 29:A885. 3. JaffeN, Knapp J, Chuang VP et al. Osteosarcomas: Intra-arterial treatment of the primary tumor with Cis-diammine-dichloroplatinum I1 (CDP). Angiogaphic, pathologic, and pharmacologic studies. Cancer 1983; 51:402-407. 4. Stratford IJ, Williamson C, Adams GE. Combination studies with misonidazole and a cis-platinum complex: Cytotoxicity and radiosensitizationin vitro. Br ] Cancer 1980; 41:517-522. 5. Carde P, Lava1 F. Effect of cis-diamminedichloroplatinum(11) and x-rays on mammalian cell survival. Int ] Radiat Oncol Biol Phys 1981; 7929-933. 6. Arcangeli G, Mauro F, Morelli D, Nervi C. Multiple daily fractionation in radiotherapy: Biological rationale and preliminary clinical experiences.Eur ] Cancer 1979; 15:1077-1083. 7. Douglas BG, Worth AJ.Superfractionationin glioblastomamultiforme. Results of a phase I1 study. Int ] Radiat Oncol Biol Phys 1982; 8~1787-1794. 8. Mavligit GM, Benjamin R, Patt YZ et al. Intraarterial cis-platinum for patients with inoperable skeletal tumors. Cancer 1981; 481-4. 9. Stephens FO, Tattersall MH, Marsden W et al. Regional chemotherapy with the use of cisplatin and doxorubicin as primary treatment for advanced sarcomas in shoulder, pelvis and thigh. Cancer 1987; 60:724-735. 10. Richmond RC. Toxic variability and radiation sensitization by dichlorodiammineplatinum (11) complexes in SalmonetIa typhimuriurn cells. Radiat Res 1984; 99:596-608.
Treatment of Pelvic Osteosarcoma/Estrada-Aguilaret al. 11. Begg AC, van der Kolk H, Dewit L e f al. The interaction of cisplatin and radiation on RIF-1 tumor cells in vitro. Int IRadiaf Biol 1986; 5:871-884. 12. Dewit L. Combined treatment of radiation and cis-diamminedichloroplatinum (11): A review of experimental and clinical data. Inf ] Radiat Oncol Biol Phys 1987; 13:403-426. 13. Haselow RE, Adams GS, Oken MM, Goudsmit A, Lemer HJ, Marsh JC. Simultaneous cis-platinum (DdP) and radiation therapy (RT) for locally advanced unresectable head and neck cancer (Abstr). Proc Am Soc Clin Oncol 1983; 2:160. 14. Schmitt G, Higi M, Stupp H, Scherer E. Ein neues interdisziplinares behandlungskonzept bei fortgeschrittenen interdisziplinares behandlungskinzept bei fortgeschrittenen Kopf-Hals-Tumoren. Strahlentherapie 1983; 159:470-473. 15. Shipley WU, Coombs LJ, Einstein AB Jr, Soloway MS, Wajsman Z, Prout GR. National Bladder Cancer Collaborative Group A Cisplatin and full dose irradiation for patients with invasive bladder carcinoma: A preliminary report of tolerance and local response. ] Urol 1984; 132:899-903. 16. Eapen L, Stewart D, Danjoux C et al. Intraarterial cisplatin and concurrent radiation for locally advanced bladder cancer. Clin O ~ C1989; O ~ 7230-235. 17. Rettenmaier MA, Moran MF, Ramsinghani NF. Treatment of advanced and recurrent squamous carcinoma of the uterine cervix with constant intraarterial infusion of cisplatin. Cancer 1988; 61:1301-1303. 18. Tobias JS, Smith BJ, Blackman G, Finn G. Concurrent daily cisplatin and radiotherapy in locally advanced squamous carcinoma of the head-and-neck and bronchus. Radiofher Oncol 1987; 9~263-268. 19. Raghavan D, Grundy R, Grenaway TM. Pre-emptive (neo-adjuvant) chemotherapy prior to radical radiotherapy for fit septuagenarians with bladder cancer: Age itself is not a contra-indication. Br Urol 1988; 62:154-159.
1145 20. Martinez A, Goffinet DR, Donaldson SS, Bagshaw MA, Kaplan HS. Intraarterial infusion of radiosensitizer (BudR) combined with hypofractionated irradiation and chemotherapy for primary treatment of osteogenic sarcoma. Int ] Radiaf Oncol Biol P h y ~1985; 11:123-128. 21. Winkler K, Bielack S, Delling G et al. Effect of intraarterial versus intravenous cisplatin in addition to systemic doxorubicin, highdose methotrexate, and ifosfamide on histologic tumor response in osteosarcoma (Study COSS-86). Cancer 1990; 66:1703-1710. 22. Stewart DJ, Benjamin RS, Zimmerman S el al. Clinical pharmacology of intraarterial cis-diamminedichloroplatinum (11). Cancer Res 1983; 43:917-920. 23. Campbell TN, Howell SB, Pfeifle CE, Wung WE, Bookstein J. Clinical pharmacokinetics of intraarterial cisplatin in humans. J Clin Oncol 1983; 1:755-762. 24. Cox JD, Pajak TF, Marcia1 VA e f al. Interfraction interval is major determinant of late effects, but not acute effects or tumor control, with hyperfractionated irradiation (HFX) of carcinomas of upper respiratory and digestive tracts (URDT) (Abstr). Int ] Radiaf Oncol Biol Phys 1990; 19:196. 25. Jaffe N, Robertson R, Ayala A e f al. Comparison of intra-arterial cis-diamminedichloroplatinum-I1 with high dose methotrexate and citrovorum factor rescue in the treatment of primary osteosarcoma. ] Clin Oncol 1985; 3:llOl-1104. 26. Jaffe N, Raymond AK, Ayala A e f al. Effect of cumulative courses of intraarterial cis-diamminedichloroplatinum-I1on the primary tumor in osteosarcoma. Cancer 1989; 63:63-67. 27. Bielack S, Erttmann R, Purfurst C et al. Platinum (PT) levels in plasma (PL), ultrafiltrate (UF), urine, and tumor-tissue after intraarterial (IA) vs intravenous (IV) infusion of cis-diamminedichloroplatinum (CDDP) for osteosarcoma (0s)Proc ASCO 1988; 7A211. 28. Hudson M, Jaffe MR, Jaffe N et al. Pediatric osteosarcoma: Therapeutic strategies, results, and prognostic factors derived from a 10-year experience. J Clin Oncol 1990; 8:1988-1997.
