Effect of dose intensity of methotrexate, doxorubicin, and ifosfamide on the prognosis of patients with osteosarcoma

Background. The prognosis of patients with osteosarcoma has improved due to the introduction of systemic chemotherapy. The current study tried to identify the effect of each anti-tumor drug on the prognosis of patients with osteosarcoma. Methods. The records of 29 patients with osteosarcoma who received systemic chemotherapy were retrospectively analyzed. All tumors were classified as stage IIB (Enneking's surgical stage) and were located around the knee joint or more distal areas. The histologic response to preoperative chemotherapy was determined in 20 patients: 9 patients had grade 1, 4 grade 2, 5 grade 3, and 2 grade 4. The mean follow-up period was 102 months. Results. The 5-year overall survival and relapse-free survival (RFS) in the 29 patients was 47.7% and 41.4%, respectively. The 5-year RFS for the 7 good responders (grade 3 and 4) was 85.7%, and that for the 13 poor responders (grade 1 and 2) was 23.1% (P = 0.008). The mean preoperative dose intensity (DI) of methotrexate (MTX) for good responders was significantly higher than that for poor responders (P = 0.028). In 23 patients who received MTX and doxorubicin (ADR) but not ifosfamide (IFOS), the DI of MTX significantly influenced the RFS (P = 0.0128). In the 13 poor responders, 6 of whom received IFOS, the DI of IFOS and ADR significantly influenced RFS (P = 0.0112, 0.0395). Conclusion. The preoperative DI of MTX was related to the histologic response rate. The DI of MTX was significartly associated with the patients' RFS. In poor responders, the DI of IFOS and ADR influenced the patients' RFS. Received: November 17, 1997 / Accepted: July 9, 1998     

Combined pre-operative chemotherapy with intra-arterial cisplatin and continuous intravenous adriamycin for high grade osteosarcoma

Osteosarcoma is one of the most common juvenile malignant tumors in Korea. Combined modality treatment (pre-operative chemotherapy + limb salvage surgery + adjuvant therapy) improved the patients' overall survival and quality of life. We evaluated the efficacy and feasibility of pre-operative chemotherapy with intra-arterial (IA) cisplatin plus continuous intravenous infusion (CI) of adriamycin. We assessed the rate of limb salvage, recurrence pattern and the survival impact based on the histologic response of pre-operative chemotherapy. Fourty-one patients with histologically-proven high grade osteosarcoma of the extremities were enrolled from January 1990 to June 1995. Pre-operative chemotherapy, cisplatin 120 mg/m2 IA and adriamycin 75 mg/m2/72 h CI was administered every 3 weeks for 3 cycles, followed by limb salvage surgery if possible or by amputation. According to the histologic tumor response, if the tumor necrosis was >90%, the same regimen was administered for 3 cycles as an adjuvant therapy. A salvage regimen (Ifosfamide 7.5 gm/m2/5 d IV + high dose MTX 10 gm/m2 IV+VP-16 360 mg/m2/3 d IV) was administered every 3 weeks for 6 cycles if the tumor necrosis was <90%. Of 41 patients, 37 patients were evaluable for efficacy and toxicities, because 4 patients refused chemotherapy after 1 or 2 cycles. Twenty-one patients were male and 16 were female with median age of 16 years (range 8-41). The tumor locations were: distal femur 20, proximal tibia 8, humerus 6, distal tibia 2 and 1 in proximal femur. All but one patient, who died of neutropenic sepsis, completed the planned pre-operative therapy. Of the 36 patients who received surgery, limb salvage surgery was possible in 30 patients (83.3%) and 27 patients (75%) showed a good response (grade III 10; 27.8%, grade IV 17; 47.2%). With a median follow-up of 23 months, 3-year disease-free survival rate was 54.7% and overall survival rate was 78.3%. Of the 15 patients who recurred, the major metastatic site was the lung. No operation-related mortality was observed. Most patients experienced grade III-IV nausea, vomiting and hematologic toxicities, which were reversible with supportive cares. Pre-operative chemotherapy with IA DDP+CI ADR followed by surgery showed 75% histologic tumor response rate, 83% limb salvage rate and 54.7% 3-year disease-free survival rate with tolerable side effects. To improve the survival rate, the possible role of good salvage chemotherapy with a non-cross resistance regimen in poor responders should be evaluated.     

Preoperative cisplatin for initial treatment of limb osteosarcoma: its local effect and impact on prognosis

PURPOSE: The significance of preoperative cisplatin (CDDP) as a single agent has not been assessed in terms of its effect on prognosis. The purpose of this multi-institution study was to assess the local effect of preoperative CDDP as a single agent as well as its impact on the prognosis of limb osteosarcoma. PATIENTS AND METHODS: The study group comprised 44 patients with stage IIB limb osteosarcoma who were treated with single-agent CDDP as initial preoperative chemotherapy. Two to five courses of CDDP (mean 2.4 courses) were administered intravenously and/or intraarterially as an initial preoperative treatment. The mean dose of CDDP was 3.0 mg/kg (2.5-3.4 mg/kg). The effect of the treatment was evaluated clinically and histologically. RESULTS: The clinical and histological response rates to preoperative CDDP were 56.8% and 47.6%, respectively. The survival rate was 59.1% among all patients in the study, 64.0% among those with a grade III or IV clinical response, and 52.6% among those with a grade I or II clinical response, with no significant differences between the groups. The survival rate was 70% among patients with a grade III or IV histological response, and 54.5% among those with a grade I or II histological response, with no statistical differences between the groups. CONCLUSIONS: We consider that CDDP is a useful chemotherapeutic agent for preoperative induction therapy for osteosarcoma because of the excellent local effect observed. Good responders to preoperative CDDP showed a better survival rate, but a correlation between the local response to CDDP and the survival rate was not demonstrated statistically. Systemic multidrug chemotherapy should follow preoperative CDDP to diminish the microscopic foci of metastatic disease.     

Prognostic factors in the response of primary osteogenic sarcoma to preoperative chemotherapy (high-dose methotrexate with citrovorum factor)

Forty-three patients, ranging in age from 7 to 30 years (median age, 17 yr), with primary osteogenic sarcoma (OS), confirmed by biopsies and with no evidence of metastatic disease at the time of diagnosis, received T-7 chemotherapy for an average of 4 months before surgery, including high-dose methotrexate (HDMTX) and citrovorum factor rescue (CFR) (median, 7 courses), and 1 course each of bleomycin, cyclophosphamide, and dactinomycin, and adriamycin. At the time of definitive surgery, the surgical specimen showed a good histologic response to chemotherapy (grade III or IV response) in 29 (67%) of 43 patients and a poor histologic response (grade I or II response) in 14 (33%) of 43 patients. Among those who responded well, no patient relapsed, as all received a complete course of preoperative and postoperative chemotherapy for more than 5 to over 28 months after the initiation of treatment (medium, 13 mo). Among those who responded poorly, 6 of 14 patients relapsed with pulmonary metastases (a thoracotomy was beneficial to 1), 4 of 6 patients are alive with disease, and 1 patient died of progressive disease. On retrospective analysis, we observed that good and poor responders did not differ in the distribution of sex, age, race, primary site of disease, or histologic subtype of OS. An elevated alkaline phosphatase level that returned to normal under preoperative chemotherapy indicated a good response. Neither the 24-, 48-, and 72-hour serum MTX levels nor the fluid intake and urinary output during 3 days that followed HDMTX with CFR correlated significantly with tumor response. Based on our studies with this form of therapy, we concluded that the response of OS to preoperative chemotherapy is of prognostic value.     

Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor

BACKGROUND: In primary central high-grade osteosarcoma, a number of distinct subtypes have been identified, but little is known about the response to chemotherapy. METHODS: The authors investigated whether the subtypes correlated with histologic response to chemotherapy in 1058 patients with osteosarcoma of the extremities who were treated with neoadjuvant chemotherapy over the last 20 years. The tumors were classified as osteoblastic (70%), chondroblastic (13%), fibroblastic (9%), and telangiectatic (6%). At diagnosis, 911 patients had localized disease and 147 had resectable lung metastases. RESULTS: The response to preoperative chemotherapy was good (90% or more tumor necrosis) in 59% of patients and poor (< 90% tumor necrosis) in 41% of patients. The rate of good responses was significantly higher (P = 0.0001) in the fibroblastic (83%) and telangiectatic (80%) tumors and significantly lower in chondroblastic tumors (43%). Prognosis was significantly correlated with the histologic subtypes. The 5-year overall survival rate was significantly higher (P = 0.0001) in fibroblastic (83%) and telangiectatic (75%) tumors than in osteoblastic (62%) and chondroblastic (60%) tumors. In all subtypes, except for the chondroblastic subtype, the 5-year overall survival rate was significantly higher (P = 0.0001) in good responders P = 0.0001 (68%) than in poor responders (52%). CONCLUSIONS: The authors concluded that the histologic subtype of primary central high-grade osteosarcoma of the extremity was strictly correlated with histologic response to chemotherapy and probably, as a consequence, also with prognosis. Further studies are needed to establish whether these results justify a specific therapeutic approach based on the histologic subtype of the tumor.     

High-dose methotrexate for elderly patients with primary CNS lymphoma

The introduction of methotrexate (MTX)-based chemotherapy has improved median survival for patients with primary CNS lymphoma (PCNSL). Older age is a negative prognostic marker in patients with PCNSL and may increase the likelihood of MTX toxicity. We studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. We identified 31 patients at our institution diagnosed with PCNSL at age > or =70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m(2)) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrast-enhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survival were 7.1 months and 37 months, respectively. Grade I-IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL.     

Neoadjuvant Chemotherapy for Osseous Malignant Fibrous Histiocytoma of the Extremity: Results in 18 Cases and Comparison with 112 Contemporary Osteosarcoma Patients Treated with the Same Chemotherapy Regimen

Abstract

Eigthteen patients with high grade malignant fibrous histiocytoma (MFH) of bone and 112 patients with high grade osteosarcoma (OS) of the extremity were treated with neoadjuvant chemotherapy comprised of methotrexate, cisplatinum, doxorubicin and ifosfamide. For the 18 patients with MFH, surgery involved amputation in 2 cases and limb salvage in 16 (89%); the 112 osteosarcoma patients had amputation in 8 cases and limb salvage procedure in 104 cases (93%). The rate of good histologic response to preoperative chemotherapy (90% or more tumor necrosis) was significantly higher in patients with osteosarcoma than in patients with MFH (74% vs 28%; p<0.003). However, at a median follow-up of 38 months (range 25-61), the 3-year event-free survival (EFS) did not differ in the two groups (MFH 77.8%, OS 70.5%; p=ns). In patients with MFH, no local recurrences were registered, whereas in the osteosarcoma group there were 6 local relapses (5.%).

The effectiveness of neoadjuvant chemotherapy in the treatment of osteosarcoma has been assessed during the last 15 years. The results of the present study seem to indicate that, in spite of a usually poor histologic response to preoperative treatment, neoadjuvant chemotherapy is very effective also in MFH of bone.     

Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: Analogies and differences between the two tumors

Background: Malignant fibrous histiocytoma (MFH) is a rare bone tumor usually treated like osteosarcoma. Studies on analogies and differences between the two tumors have seldom been reported.Patients and methods: Between March 1982 and December 1994, 51 patients with high-grade MFH of bone and 390 with high-grade osteosarcoma were treated with the same regimen of neoadjuvant chemotherapy. All of the tumors in both groups were located in the limbs. Preoperative chemotherapy was performed according to three different, successively activated, regimens consisting of MTX/CDP intraarterially, MTX/CDP/ADM, and MTX/CDP/ADM//IFO.Results: The rate of limb salvage was the same in both the MFH (92%) and osteosarcoma (85%) patients. MFH showed a statistically significantly lower rate of good histologic response, 90% or more tumor necrosis (27% vs. 67%, P = 0.00001) for all three regimens. Despite this low chemosensitivity, the disease-free survivals of the two neoplasms were similar (67% vs. 65%).Conclusions: In terms of histologic response to primary chemotherapy, MFH has a lower chemosensitivity than osteosarcoma. Nevertheless, the two tumors have similar prognoses when treated with chemotherapy regimens based on MTX, CDP, ADM and IFO.     

Neoadjuvant chemotherapy for radioinduced osteosarcoma of the extremity: The Rizzoli experience in 20 cases

PURPOSE: Evaluate treatment and outcome of 20 patients with radioinduced osteosarcoma (RIO). Because of previous primary tumor treatment, RIO protocols were different from others we used for non-RIO. PATIENTS AND METHODS: Between 1983 and 1998, we treated 20 RIO patients, ages 4-36 years (mean 16 years), with chemotherapy (two cycles before surgery, three postoperatively). The first preoperative cycle consisted of high-dose Methotrexate (HDMTX)/Cisplatinum (CDP)/Adriamycin (ADM) and the second of HDMTX/CDP/Ifosfamide (IFO). The three postoperative treatments were performed with cycles of MTX/CDP; IFO was used as single agent per cycle repeated three times. RESULTS: Two patients received palliative treatment because their osteosarcoma remained unresectable after preoperative chemotherapy. The remaining 18 patients had surgery (7 amputations, 11 resections); histologic response to preoperative chemotherapy was good in 8 patients, poor in 10. At a mean follow-up of 11 years (range, 7-22 years), 9 patients remained continuously disease-free, 10 died from osteosarcoma and 1 died from a third neoplasm (myeloid acute leukemia). These results are not significantly different from those achieved in 754 patients with conventional osteosarcoma treated in the same period with protocols used for conventional treatment. However, this later group had an 18% 3-year event-free survival after treatment of relapse vs. 0% in the RIO group. CONCLUSION: Treated with neoadjuvant chemotherapy RIO seem to have an outcome that is not significantly different from that of comparable patients with conventional primary high grade osteosarcoma (5-year event-free survival: 40% vs. 60%, p = NS; 5-year overall survival 40% vs. 67%, p < 0.01).     

Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities. The Istituto Rizzoli Experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin

Between March 1983 and June 1986 127 patients with localized osteosarcoma of the extremity were treated with neoadjuvant chemotherapy. Preoperative chemotherapy consisted of two cycles of methotrexate (MTX) (high or moderate doses) followed by 6 days by cisplatin (CDP). Surgery was an amputation or a rotation plasty, or a limb salvage. Necrosis was good in 52% of cases, fair in 36%, and poor in 12%. Postoperative chemotherapy consisted of Adriamycin (doxorubicin [ADM]) and bleomycin (BCD) for poor responders; and ADM, MTX, and CDP for fair responders. Good responders were treated as fair responders or with only MTX and CDP. At a 47-month follow-up, 66 patients remained continuously disease free and 61 patients developed metastases. Six of these patients had also a local recurrence. According to the grade of necrosis, the cumulative disease-free probability at 5 years was 67% for good responders, 42% for fair responders, and for poor responders 10% at 45 months. According to the doses of MTX, survival at 5 years was 58% for patients who received high doses and 42% for patients treated with moderate doses. No differences in the rate of survivors were observed between amputated patients and patients treated with limb salvage. The authors conclude that (1) a limb salvage procedure is possible in about 70% of cases and as safe as demolitive surgery, if adequate surgical margins are achieved; (2) good responders have a better prognosis than fair and poor responders if postoperative chemotherapy is sufficiently prolonged and also includes ADM; (3) a different postoperative chemotherapy for poor responders did not improve their prognosis; and (4) a multidrug regimen using high doses of MTX is probably more effective than moderate doses.     

A pilot study of cyclical chemotherapy with high-dose methotrexate and CHOP (MTX-CHOP) in poor-prognosis non-Hodgkin's lymphoma (NHL)

Summary In a pilot study of cyclical chemotherapy in patients with poor-prognosis non-Hodgkin's lymphoma (NHL), high-dose methotrexate (MTX) 1 g/m² with folinic acid rescue was given as initial treatment and then between cycles of a single-arm CHOP combination administered every 4 weeks. Of 21 patients with previously untreated or minimally treated grade 2 (high-grade) histology stage II/III/IV NHL, 13 (62%) achieved complete remission (CR); the CR rate for stage III/IV patients was 56%. Of all 25 patients with grade 2 stage II/III/IV NHL, including previously treated patients, 16 (64%) achieved CR. The median folow-up of patients who completed treatment is currently 22 months and only 1 relapse has been recorded in the CR group. Only five of 24 grade 2 patients given the initial test MTX failed to show any response, and eight patients achieved partial remission (PR) as a result of this single treatment. The response to MTX-CHOP in nine patients with grade 1 (low-grade) histology NHL was poor; only two achieved CR. These findings lend support to other data which indicate a useful role for MTX in the induction chemotherapy of advanced high-grade NHL, though the optimum dosage and drug sequence have yet to be determined.for the Yorkshire Lymphoma Group (YLG)     

A phase II trial evaluating the feasibility of adding bevacizumab to standard osteosarcoma therapy

Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received two courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab‐related targeted toxicity (grade 4 hypertension, proteinuria or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2–4 major wound complications). Thirty‐one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4‐year event‐free survival (EFS) rate and overall survival rate were 57.5 ± 10.0% and 83.4 ± 7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (<5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma.     

Primary chemotherapy with the Rosen T10 protocol before conservative surgery in limb primitive osteosarcomas: results about 56 cases

We report the results of a prospective Tunisian study using primary chemotherapy followed by conservative surgery in primitive limb osteosarcoma. From January 1988 to January 1998, 56 patients affected by limb osteosarcoma entered in a prospective study of neoadjuvant chemotherapy with the T10 protocol before surgery with a conservative intent. Initial work-up include: clinical exam with tumor measurements, chest and limb X-rays, limb CT-scan or MRI, chest CT-scan, bone scintigraphy and hematological and renal biological exams. Patients receive pre- and post-operative chemotherapy according to the T10 modified protocol. Fifty-six patients (33 M/23 F) with a mean age of 19 years (8 to 28) are included. Mean clinical and radiological tumor size is around 14 cm. Main histologic type is classic osteosarcoma (50% of cases) and 10 patients (9%) presented with initial metastasis; 42 patients on 56 receive the whole pre-operative protocol. Treatment is well tolerated excluding 18 episodes of mucositis, 29 of leucopenia (< grade 3), 7 of thrombopenia (< grade 3), 4 of cutaneous toxicity, 2 of pulmonary toxicity and 3 of nausea-vomiting. We observe 36% of good histological responders and 64% of bad responders to primary chemotherapy, 27 patients on 49 operated (53%) have a conservative surgery and 18 (47%) a radical surgery. With a median follow-up of 51 months (8 to 128), 29 patients remain alive free of disease (15/17 GR and 14/30 BR), 2 are alive with disease, 2 died by toxicity, 14 died by progressive disease and 9 are lost to follow-up with evolutive disease. Five year disease-free survival is 55% for the 46 non metastatic patients. In univariate analysis, seric alkaline phosphatase level (p = 0.0014) and histological response to chemotherapy (p = 0.0218) are significant factors for prognosis.     

Reduced folate carrier protein expression in osteosarcoma: implications for the prediction of tumor chemosensitivity

BACKGROUND: High-dose methotrexate (MTX) is an important component of current protocols for the treatment of osteosarcoma. Although MTX uptake proceeds primarily through the reduced folate carrier (RFC) protein and efflux occurs via multidrug resistance protein 1 (MRP1), RFC protein expression in osteosarcoma remains unexamined. METHODS: RFC and MRP1 expression (normalized to beta-actin expression) was examined with Western blot analysis in 11 osteosarcoma specimens obtained at diagnosis and 9 osteosarcoma specimens obtained on recurrence. RESULTS: The average RFC level in specimens obtained on recurrence was significantly higher than the level in specimens obtained at diagnosis (P = 0.0005). Furthermore, in all three matched pairs of diagnosis and recurrence specimens, RFC levels were higher in recurrence specimens than in the corresponding diagnosis specimens. Potential correlations between RFC and MRP1 expression and histologic response to preoperative chemotherapy were examined. Tumors with poor histologic responses (i.e., 相似文献   

Nonmetastatic osteosarcoma of the extremity: results of a neoadjuvant chemotherapy protocol (IOR/OS-3) with high-dose methotrexate, intraarterial or intravenous cisplatin, doxorubicin, and salvage chemotherapy based on histologic tumor response

AIMS AND BACKGROUND: From 1986 to 1989, a study for the treatment of nonmetastatic osteosarcoma of the extremity (IOR/OS-2) was carried out at the Rizzoli Institute. The cumulative dose of doxorubicin delivered was 480 mg/m2, and severe heart failure developed in 5 (3%) of the 164 treated patients. The specific aim of the subsequent study was to assess the efficacy of a protocol, similar to IOR/OS-2, but with a reduced cumulative dose of doxorubicin (390 mg/m2). Additional aims were to assess the role of the route of infusion (intraarterial or intravenous) of cisplatin on histologic response of the primary tumor and the use of ifosfamide as salvage chemotherapy in poor responders. METHODS: The new chemotherapy regimen (IOR/OS-3) was comprised of a preoperative phase with methotrexate (10 g/m2), cisplatin (120 mg/m2 intraarterially or intravenously), and doxorubicin (60 mg/m2). After surgery, the same drugs were administered, with the addition of ifosfamide (10 g/m2) in patients who had a poor histologic response to primary chemotherapy. RESULTS: Ninety-five patients entered the study. The rate of good histologic response was 64% with intraarterial cisplatin and 43% with intravenous cisplatin (P = 0.05). The 8-year event-free survival and overall survival were 54% and 61%, respectively, with no significant difference according to the histologic response. No cases of clinical doxorubicin-induced cardiopathy were recorded. Event-free and overall survival did not significantly differ from those achieved with IOR/OS-2 (8-year disease-free and overall survival, respectively 63% and 72%). CONCLUSIONS: The reduction in the doxorubicin cumulative dose avoided episodes of cardiotoxicity, without consequences on the efficacy of treatment. The addition of ifosfamide was an effective "salvage" therapy for poor responders. A better histologic response with intraarterial cisplatin was observed, but owing to the availability of an effective salvage therapy for poor responders, the advantages in terms of histologic response did not compensate for the cost and discomfort for the patients of this modality of infusion of cisplatin.     

Prognostic factors in non-metastatic limb osteosarcoma: A 20-year experience of one center.

The purpose of this study was to evaluate the prognostic significance of variables in osteosarcoma. We performed a retrospective analysis of 35 patients with non-metastatic limb osteosarcoma that were treated between 1973 and 1994. The following variables were evaluated: age, sex, ethnic group, tumor histology and primary site, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels at diagnosis, treatment regimen, and the histologic response to treatment. Three variables showed significant correlation with prognosis: i) histologic response to preoperative treatment. Disease-free survival (DFS) was 89% in patients with grade III-IV histologic response after a median follow-up (MFU) of 64 months, 67% in patients with grade II after an MFU of 64 months, the patients with grade I response died within 15 months (p<0.0001); ii) treatment regimen. DFS was 83% after an MFU of 42 months, 62% after an MFU of 82 months, and 30% after an MFU of 177 months in patients treated by the 90's, 80's, and 70's protocols, respectively (p<0.05); iii) corrected ALP (cALP) levels at diagnosis. DFS was 78% after an MFU of 88 months in patients with cALP levels <200, and 32% after an MFU of 56 months in patients with cALP levels >200 (p=0.01). Low ALP levels, good histologic response to preoperative chemotherapy, and the new therapeutic regimen correlated with good prognosis in patients with osteosarcoma.     

Serum Methotrexate (MTX) Concentrations and Prognosis in Patients with Osteosarcoma of the Extremities Treated with a Multidrug Neoadjuvant Regimen

Summary

The relationship between the serum concentration of methotrexate and the prognosis has been studied in 108 patients with osteosarcoma of the extremities treated from September 1986 to December 1989 at the Chemotherapy Department of Rizzoli Hospital.

The protocol of neoadjuvant chemotherapy included high doses of methotrexate (HDMTX) adriamycin, cisplatinum, ifosfamide and VP-16. After a median follow-up of 40.4 months (range 24-62), 84 (77.7%) of the patients studied remained continuously disease-free (CDF) and 24 relapsed. Significantly higher mean serum MTX concentrations were observed in the patients who remained CDF (669.5 μmol/1) than in the patients who relapsed (571.9 μmol/1) ( p < .004). The breaking point of prognostic significance for the serum MTX levels seems to be 700 μmol/1. In fact, according to the mean MTX concentrations, the patients with less than 700 μmol/1 showed a significantly lower disease-free survival than the patients with higher mean MTX concentrations (68.12% vs 94.87% p < .0013). The distribution of prognostic variables between the two groups was the same in terms of site and histological type of tumor and alkaline phosphatase serum levels at diagnosis. In the group which had more than 700μmol/1 MTX, a higher percentage of good histological response after primary chemotherapy was observed. This is probably independent from the MTX because no significant preoperative MTX serum levels between good and partially responding patients were observed.

These data suggest that in neoadjuvant chemotherapy of osteosarcoma there is a correlation, even in patients treated with multidrug regimens, between serum concentrations of MTX and the prognosis; for this reason the patients who show low MTX serum concentrations should be treated with increased amounts of MTX to achieve upper 700 μmol/1 MTX serum levels.     

Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response

Following observation of the predictive value of the histologic extent of tumor cell destruction after preoperative chemotherapy for metastasis-free survival (MFS) in osteosarcoma, a randomized study was undertaken with the aim of (1) sparing some patients the unpleasant side effects of highly toxic drugs like doxorubicin (DOX) and cisplatin (CPDD) by administering these drugs postoperatively only after poor response with a milder preoperative regimen, and (2) improving the prognosis of patients responding poorly to the initial treatment by use of a salvage chemotherapy postoperatively. The available patients were divided into two groups. Those in the study arm received a preoperative chemotherapy consisting of high-dose methotrexate (HDMTX) and the triple drug combination of bleomycin, cyclophosphamide, and dactinomycin (BCD) and were switched to DOX/CPDD postoperatively in case of poor response. DOX/CPDD was used besides HDMTX for initial treatment in the control arm, and BCD alternatively with CPDD/ifosfamide (IFO) for postoperative salvage treatment. The response rate of the study arm was significantly inferior to the control arm (26% v 60%; P less than .001). The actuarial 4-year MFS rate of poor responders after salvage chemotherapy also was poorest in the study arm (41%); it was unchanged in the control arm (53%) as compared with that of poor responders from the COSS-80 study without salvage chemotherapy (52%). The actuarial 4-year MFS rate of good responders was 73% in the study arm, 79% in the control arm, and not significantly different from that of the COSS-80 study (84%), although postoperative chemotherapy of good responders had been markedly shortened as compared with the COSS-80 study. The actuarial 4-year MFS rate of the study arm as a whole was inferior to that of the control arm (49% v 68%; P less than .1) and also inferior to the COSS-80 study (68%; P less than .01), indicating a failure of the employed salvage strategy in general and especially of the effort to restrict the use of the very effective but highly toxic drugs DOX and CPDD to patients resistant to a less toxic initial treatment.     

Therapeutic response of various histological osteosarcoma subtypes to high-dose methotrexate treatment

The successful or unsuccessful chemotherapy of osteosarcoma has given rise to the division of these tumors into responders and non responders from the clinical point of view. In order to work out drug sensitive tumor components we studied 9 osteosarcomas by a histological subdivision of the osteosarcoma tissue into 6 subtypes. Seven of the 9 osteosarcoma patients had developed lung metastases under adjuvant high dosage methotrexate (HDMTX) therapy. The aim was to identify the components of the primary tumors which had endured HDMTX-therapy as lung metastases. As HDMTX-sensitive histologic differentiation form of osteosarcoma tissue we regarded the no matrix producing-subtype (III), because it did not occur in the lung metastases. The classical subtype (IV) seems to be only partially sensitive because the corresponding lung metastases showed a higher osteoblastic differentiation with increased osteoid production. No therapeutic effect could be observed in the chondromatous (I) and in the sarcomatous (II) subtypes as well as in the two subtypes with intensive osteoid production being termed trabecularly sclerosing (V) and massively osteoid producing subtypes (VI).     

Imaging assessment of the responses of osteosarcoma patients to preoperative chemotherapy: angiography compared with thallium-201 scintigraphy.

BACKGROUND: Assessment of the responses of osteosarcoma patients to preoperative chemotherapy is of clinical importance. The purpose of this study was to estimate the accuracy of angiography and thallium-201 scintigraphy, compared with histology, in assessing the responses of patients with osteosarcoma to preoperative chemotherapy. METHODS: Nineteen patients with osteosarcoma who were diagnosed between 1992 and 1997 were studied. The findings of angiography and thallium-201 scintigraphy before and after preoperative chemotherapy were compared with the percentage of necrosis of tumor cells and the response grade as determined histologically. Quantitative analysis of the isotopic uptake by thallium-201 scintigraphy before and after chemotherapy, defined as the alteration ratio, was correlated with the percentage of tumor necrosis. RESULTS: Angiography yielded a sensitivity of 88%, a specificity of 73%, and a predictive accuracy of positive test of 70%, whereas thallium-201 scintigraphy achieved 88%, 100%, and 100%, respectively. Both angiographic and scintigraphic assessment showed a significant correlation with response grade as determined histologically (P < 0.05 and P < 0.0003, respectively). The alteration ratio of thallium-201 scintigraphy showed a strong, highly significant correlation with the percentage of tumor necrosis (P < 0.0001). CONCLUSIONS: A change in the tumor uptake of thallium-201 scintigraphy after preoperative chemotherapy can predict the tumor necrosis in osteosarcoma precisely. Thallium scintigraphy is a noninvasive technique and seems to be more useful than angiography in assessing the response of osteosarcoma to preoperative chemotherapy.