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 high grade osteosarcoma of the extremities: long-term results for patients treated according to the Rizzoli IOR/OS-3b protocol

The results of the Rizzoli IOR/OS-3b neoadjuvant protocol for the treatment of osteosarcoma of the extremity are reported. Preoperative chemotherapy consisted of two cycles of high-dose methotrexate (HDMTX i.v.), followed by a combination of cisplatin (CDP i.a.)/ doxorubicin (ADM i.v.). Postoperatively all patients, regardless of the histologic response, received 3 more cycles of MTX, CDP/ADM alternated with 3 cycles of ifosfamide. In the study performed between January and December 1992 43 patients were enrolled and limb salvage was performed in 39 of them (91%). The histologic response to chemotherapy was good (90% or more tumor necrosis) in 24 patients (56%) and poor (less than 90% tumor necrosis) in 19 (44%). With a minimum follow-up of 7 years, 23 pts (53%) remained continuously free of disease, 19 relapsed and one died due to unrelated cause. In spite of the high number of limb salvages performed, only 2 local recurrences were registered. The 7-year event-free survival and overall survival were, respectively, 53% and 68%. The hematopoietic and extrahematopoietic toxicity experienced by the patients during the entire treatment was relatively mild. These long-term results confirm that, with neoadjuvant chemotherapy, it is possible to cure more than 60% of patients with osteosarcoma of the extremities, avoiding amputation in most of them. These results, however, are no better than those achieved in our previous study IOR/OS-3a, in which only poor responder patients received ifosfamide during the postoperative treatment.     

Neoadjuvant chemotherapy for osteosarcoma of the extremity: long-term results of the Rizzoli's 4th protocol

From January 1993 to March 1995, 162 patients with osteosarcoma of extremities were treated according to the IOR/OS-4 protocol. 133 patients had localised disease, while 29 had metastases at diagnosis. These last patients were simultaneously operated upon for their primary and metastatic lesions. Chemotherapy consisted preoperatively of two cycles of high dose methotrexate (HDMTX) and one cycle each of cisplatin (CDP)-doxorubicin (ADM), CDP/ifosfamide (IFO) and IFO/ADM. After surgery, patients were treated with the aforementioned drugs used as single agents. The mean follow-up of all patients was 6.5 years (5.5-8 years). Surgery was a limb salvage in 94% of cases, and the 5-year event-free survival (EFS) and overall survival (OS) rates were 56 and 71% for patients with localised disease, and 17 and 24% for patients with metastases at diagnosis. These results did not differ from those achieved in our previous study (IOR/OS-3) in which IFO was used only postoperatively in poor responders.     

Neoadjuvant Chemotherapy for High Grade Osteosarcoma of the Extremities: Long-Term Results for Patients Treated According to the Rizzoli IOR/OS-3b Protocol

Abstract

The results of the Rizzoli IOR/OS-3b neoadjuvant protocol for the treatment of osteosarcoma of the extremity are reported. Preoperative chemotherapy consisted of two cycles of high-dose methotrexate (HDMTX i.v.), followed by a combination of cisplatin (CDP i.a.)/ doxorubicin (ADM i.v.). Postoperatively all patients, regardless of the histologic response, received 3 more cycles of MTX, CDP/ADM alternated with 3 cycles of ifosfamide. In the study performed between January and December 1992 43 patients were enrolled and limb salvage was performed in 39 of them (91%). The histologic response to chemotherapy was good (90% or more tumor necrosis) in 24 patients (56%) and poor (less than 90% tumor necrosis) in 19 (44%). With a minimum follow-up of 7 years, 23 pts (53%) remained continuously free of disease, 19 relapsed and one died due to unrelated cause. In spite of the high number of limb salvages performed, only 2 local recurrences were registered. The 7-year event-free survival and overall survival were, respectively, 53% and 68%. The hematopoietic and extrahematopoietic toxicity experienced by the patients during the entire treatment was relatively mild.

These long-term results confirm that, with neoadjuvant chemotherapy, it is possible to cure more than 60% of patients with osteosarcoma of the extremities, avoiding amputation in most of them. These results, however, are no better than those achieved in our previous study IOR/OS-3a, in which only poor responder patients received ifosfamide during the postoperative treatment.     

The importance of dose-intensity in neoadjuvant chemotherapy of osteosarcoma: a retrospective analysis of high-dose methotrexate, cisplatinum and adriamycin used preoperatively

The relationship between dose-intensity and outcome was retrospectively analyzed in 125 patients with osteosarcoma of the extremities treated at our institution with neoadjuvant chemotherapy between 1986 and 1988. Before surgery, chemotherapy was performed with high-dose methotrexate (HDMTX) i.v. followed by cisplatinum (CDP) i.a. and adriamycin (ADM) i.v. Postoperative chemotherapy was tailored according to the necrosis induced by preoperative treatment. Patients who were "good responders" had 31-weeks of chemotherapy with the same drugs utilized preoperatively, while "poor responder" patients received a longer treatment (40 weeks) in which ifosfamide and etoposide (VP-16) were added to HDMTX, CDP and ADM. At a median follow-up of 2 years (1-3 years) 100 patients (80%) remained continuously disease-free and 25 patients relapsed: 24 with lung metastases and 1 with local recurrence. According to the real dose-intensity received, calculated as a percentage of the dose intensity projected by the protocol, the continuously disease-free survival was 87% in the 82 patients who received 80% or more of the scheduled dose-intensity and only 65% for the 43 patients who received less than 80% of the projected dose-intensity. This difference is highly significant (P less than 0.01). These results suggest that in neoadjuvant chemotherapy of osteosarcoma the real dose-intensity delivered is a determinant of treatment outcome and therefore every effort should be made to avoid reductions of doses and delays of cycles of chemotherapy in these patients.     

Adriamycin-methotrexate high dose versus adriamycin-methotrexate moderate dose as adjuvant chemotherapy for osteosarcoma of the extremities: a randomized study

Adjuvant chemotherapy comprising Adriamycin (ADM) and Methotrexate (MTX) with Citrovorum Factor (CF) was administered on a randomization basis to 2 groups of patients with osteosarcoma after surgical ablation of the primary tumor. One group received high dose MTX (regimen I) and the other moderate dose MTX (regimen II). In both groups a short period of heparin treatment was also administered to prevent neoplastic emboli during surgery. All patients were free of metastasis at the beginning of therapy. The efficacy of therapy was determined by recording the percentage of continuously disease-free patients. This was compared to the disease-free survival in 132 patients previously treated with other ADM or ADM-MTX regimens and to a group of 39 patients treated during this period with amputation only. The latter did not receive adjuvant chemotherapy for a variety of reasons and are equated to a concurrent control group. Over the ensuing 27–66 months, 31 of 56 patients (55%) treated with regimen I and 25 of 50 (50%) treated with regimen II were disease-free. The overall disease-free survival in both regimens was 53%. This is similar to the 132 patients treated with previous adjuvant chemotherapy protocols (45–50%). However, the percentage of continuously disease-free patients treated with adjuvant chemotherapy was significantly better than the 39 patients (12%) treated contemporaneously with surgery only (P < 0.0005). Survival in the latter is similar to that of historical control patients. These results do not suggest any change in the natural history of osteosarcoma and reveal benefits which may accrue with adjuvant chemotherapy. These results also demonstrate that in adjuvant treatment of osteosarcoma performed with ADM and MTX the high and the moderate doses of MTX are equally efficacious.     

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).     

Influence of Adriamycin Dose in the Outcome of Patients with Osteosarcoma Treated with Multidrug Neoadjuvant Chemotherapy: Results of Two Sequential Studies

Summary

The results of two sequential studies of neoadjuvant chemotherapy for osteosarcoma of the extremities performed at Rizzoli Institute between 1986 and 1991 in 228 patients are presented. In both studies preoperative chemotherapy consisted of two cycles of high dose methotrexate (HDMTX), cisplatinum (CDP) and adriamycin (ADM). Postoperatively the good responder patients were treated with the same drugs used before surgery while in the poor responder patients ifosfamide was added to these three drugs. The preoperative treatment was the same in both studies while after surgery in the second protocol either the cumulative dose of ADM (270 mg/m² instead of 360 mg/m²) or the single dose per cycle of this drug (60 mg/m² instead of 90 mg/m²) was reduced. These changes in the last protocol were done to reduce the cardiotoxicity of ADM that was high in the first study (2 deaths and 1 heart transplantation). Since in the last protocol – in comparison with the first protocol – after surgery chemotherapy was restarted earlier and ADM was administered not as a single drug but in combination with the CDP the dose intensity of ADM was unchanged while the dose intensity of MTX, CDP and ifosfamide was higher than in the first study. The preliminary results of the 84 patients treated in the second study show a 2-year disease free survival significantly lower than that achieved in the 144 patients treated in the first study (37/51 – 73% vs 123/144 – 85%: P < 0.008). In addition, even if in the last study there were no cases of clinical cardiotoxicity due to ADM, there was a significantly higher percentage of severe myelodepression that led to two deaths for infectious complications. These results suggest that in neoadjuvant treatment of osteosarcoma the total dose of ADM and/or the single dose per cycle of the same drug are an important determinant of outcome and that increasing the dose-intensity of less toxic but less active agents, MTX, CDP and ifosfamide, at the expense of the more active and more toxic agent, ADM, can lead to a poorer outcome without reducing toxicity.     

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.     

Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy

Background: Most of the studies of the treatment of non-metastaticosteosarcoma of the extremity have reported results in terms of probabilityof survival up to five years with a minimum follow-up of less than two tothree years. Definition of reliable indicators of prognosis and predictivefactors for survival require mature data derived from a long-term survivalanalysis.Patients and methods: A review of 127 patients with non-metastaticosteosarcoma of the extremity, treated between March 1983 and June 1986, wasperformed. The treatment protocol consisted of primary chemotherapy with MTX(randomization to high vs. moderate dosages) and CDP followed by surgery.Postoperatively, patients with <60% tumor necrosis received ADMand BCD; those with tumor necrosis 60% < 90% (FairResponders FR) were given MTX, CDP and ADM. Up to January 1984, patientswith tumor necrosis >90% received MTX and CDP only, and after thenthey were given the same treatment as for FR. A multivariate analysis totest predictive factors for survival was performed.Results: With a median follow-up of 134 months (range 114–153), the12-year DFS was 46%. A good histologic response, an LDH baselinevalue within the normal range, and the use of high-dose MTX were positivepredictive factors for DFS. With a median time of observation for survivorsof 130 months, the 12-year overall survival was 53%. None of thepatients who relapsed with local or distant recurrences other than lungmetastasis are now alive. Patients with a relapse-free interval longer than24 months had a significantly better post-relapse survival than those with ashorter relapse-free interval (40% vs. 7%; P = 0.0159). All ofthe patients who were not surgically treated had disease progression anddied within 40 months after the first recurrence. The surgically-treatedpatients had a 30% post-relapse survival probability.Conclusions: In non-metastatic osteosarcoma of the extremity,chemotherapy-induced tumor necrosis, the baseline LDH serum value and the useof HDMTX are significant predictive factors for DFS. The relapse-free intervaland the possibility of metastasectomy are significant factors conditioning thepost-relapse survival.     

A comparison of methods of loco-regional chemotherapy combined with systemic chemotherapy as neo-adjuvant treatment of osteosarcoma of the extremity.

AIM: Our experience of pre-operative intraarterial (i.a.) vs intravenous (i.v.) infusion of cisplatinum (CDP) in a multiagent neo-adjuvant chemotherapy for osteosarcoma of the extremity is reported. METHODS: Two successive randomized studies were performed. In the first, pre-operatively, CDP i.a. vs CDP i.v. was applied in combination with high-dose methotrexate (HDMTX) and adriamycin (ADM) within a three-drug regimen. In the second, a combination of HDMTX, ADM and IFO, within a four-drug regimen was tested. RESULTS: The rate of responses to chemotherapy (tumour necrosis > or = 90%) was significantly higher (P<0.04) for the 142 patients treated with the four-drug regimen than in the 79 patients treated with a three-drug regimen (76%vs 62%). According to the route of CDP infusion, in the three-drug regimen the rate of responses was significantly higher (P=0.004) in patients treated with i.a. CDP (77%) than in patients treated i.v. (46%); with the four-drug regimen the rate of response was not significantly different in patients treated i.a. (81%) and in patients treated i.v. (71%). No significant differences in the rates of limb salvages, local recurrence and event-free survival (EFS) were seen between the i.a. and the i.v. groups. CONCLUSION: In the treatment of osteosarcoma of the extremity, the i.a. infusion of CDP does not offer any significant advantage when this drug is used within an aggressive, multiagent, pre-operative four-drug regimen. Copyright Harcourt Publishers Limited.     

Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report.

PURPOSE: To provide an estimate of long-term prognosis for patients with osteosarcoma of the extremity treated in a single institution with neoadjuvant chemotherapy and observed for at least 10 years. PATIENTS AND METHODS: Patients with nonmetastatic osteosarcoma of the extremity were preoperatively treated with high-dose methotrexate, cisplatin, and doxorubicin (ADM). Postoperatively, good responders (90% or more tumor necrosis) received the same three drugs used before surgery, whereas poor responders (less than 90% tumor necrosis) received ifosfamide and etoposide in addition to those three drugs. RESULTS: For the 164 patients who entered the study between September 1986 and December 1989, surgery was a limb salvage in 136 cases (82%) and a good histologic response was observed in 117 patients (71%). At a follow-up ranging from 10 to 13 years (median, 11.5 years), 101 patients (61%) remained continuously free of disease, 61 relapsed, and two died of ADM-induced cardiotoxicity. There were no differences in prognosis between good and poor responding patients. ADM-induced cardiotoxicity (six patients), male infertility (10 of the 12 assessable patients), and second malignancies (seven patients) were the major complications of chemotherapy. Despite the large number of limb salvages performed, only four local recurrences (2.4%) were registered. CONCLUSION: With an aggressive neoadjuvant chemotherapy, it is possible to cure more than 60% of patients with nonmetastatic osteosarcoma of the extremity and amputation may be avoided in more than 80% of them. Because local or systemic relapses, myocardiopathies, and second malignancies are possible even 5 years or more after the beginning of treatment, a long-term follow-up is recommended for these patients.     

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.     

Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for telangiectatic osteogenic sarcoma of the extremities

Twelve patients with telangiectatic osteogenic sarcoma (TOS) of the extremities were treated with neoadjuvant chemotherapy, according to two different protocols. Preoperatively the patients received high-dose methotrexate(HD-MTX)/cisplatinum(CPD) or HD-MTX/CPD/adriamycin(ADM). CPD was delivered intra-arterially, the other drugs intravenously. Limb salvage surgery was performed in eight instances and four patients underwent amputation. Post operative chemotherapy was tailored according to the grade of necrosis determined by preoperative treatment on the primary tumor. In ten cases (83%) the grade of necrosis resulted higher than 95%. The mean length of follow-up was 3.5 years with a range of 18 to 72 months. Ten patients (83%) remained continuously disease-free, while two patients developed lung metastases and died of uncontrolled disease. No local recurrences were observed. These results are better than those observed in 167 contemporary cases of conventional osteosarcoma treated with the same protocols. This study confirms that TOS is not always a lethal tumor as suggested by prior reports. Employing neoadjuvant chemotherapy a high percentage of patients with TOS can be cured and in most of them, limb sparing surgery is possible and safe.     

Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian Sarcoma Group study.

From 1982 to 1989, 97 patients with extremity-localized, high-grade osteosarcoma were treated according to the T-10 protocol. Two thirds of the patients consisted of the near-complete national patient materials from Norway and Finland. Eighty patients (82%) received four courses of high-dose methotrexate (HD MTX, 8 to 12 g/m2) at weekly intervals as their only preoperative treatment, and 77 patients (79%) were assessable for histologic response grading according to Rosen et al (Cancer 49:1221-1230, 1991). Observed histologic response was no certain chemotherapy effect (grade I) in 21%, grade II effect in 62%, and grade III or IV effect in 17%. Nonresponders had significantly lower serum MTX concentrations after 24 and 48 hours than responders; the significance of the difference at 48 hours was maintained in a multivariate analysis. After a median follow-up of 45 months, projected 5-year overall and relapse-free survival for all patients were 64% and 54%, respectively. Patients with a good response to preoperative chemotherapy (grade III/IV) had a significantly better survival than grade I/II responders, despite a switch to postoperative cisplatin/doxorubicin chemotherapy in the latter group. These results were obtained in a largely nonselected group of patients. We conclude that a good initial chemotherapy effect is important for the final outcome in osteosarcoma, and that HD MTX alone is insufficient preoperative treatment for the majority of patients. The individual MTX excretion rate is of importance for tumor response, suggesting a dose-response relationship for HD MTX treatment.     

Comparative Outcome of Thai Pediatric Osteosarcoma Treated with Two Protocols: the Role of High-Dose Methotrexate (HDMTX) in a Single Institute Experience

Background: High-dose methotrexate (HD-MTX) is recognized as an efficient component of therapy againstpediatric osteosarcoma in combination with other drugs such as cisplatin (CDP), carboplatin (CBDCA),doxorubicin (ADM), etoposide (VP-16) and ifosfamide (IFO). Objectives: To demonstrate the feasibility andeffectiveness of the HD-MTX/CDP/DOX/VP-16/IFO [MTX(+)] protocol comparable to CDP/ADM/CBDCA/IFO[MTX(-)] for treating childhood osteosarcoma at Ramathibodi Hospital (1999-2014). Materials and Methods:A retrospective analysis was conducted of osteosarcoma patients aged less than 18 years treated with twochemotherapeutic regimens between 1999 and 2014. A total of 45 patients received the MTX(-) and 21 the MTX(+)protocol. Results: Overall limb-salvage and amputation rate were 12.9% and 77.7%, respectively. Kaplan-Meier analysis results for 3-year disease free survival (DFS) and overall survival (OS) regardless of treatmentregimens were 43.4±6.0% and 53.2±6.1% respectively. The 3-year DFS and OS were improved significantlywith the MTX(+) protocol compared to MTX(-) protocol (p=0.010 and p=0.009, log rank test) [69.8±10.5%,79.8±9.1% for MTX(+) and 31.1±6.9%, 42.2±7.4% for MTX(-) protocol, respectively]. Patients with metastaticosteosarcoma treated with the MTX(+) protocol had statistically significant higher 3-year DFS and OS thanthose treated with the MTX(-) protocol (66.7±13.6% and 15.0±8.0% for 3-year DFS, p=0.010, 73.3±13.2% and20±8.9% for 3-year OS, p=0.006, respectively). The independent risk factors for having inferior 3-year DFSand OS were poor histological response (tumor necrosis <90%) and treatment with the MTX(-) protocol. Themultivariate analysis identified only the treatment with the MTX(-) protocol as an independent predictor ofinferior OS with a hazard ratio (HR) of 3.53 (95% confidence interval of 1.2-10.41, p=0.022). Conclusions: Ourstudy demonstrated the tolerability, feasibility and efficacy of the HDMTX-based regimen improving the survivalrate in pediatric osteosarcoma cases, in line with reports from developed countries.     

Combination chemotherapy of UFT with adriamycin (ADM) and cisplatin (CDDP) for advanced gastrointestinal cancer

Thirty four patients with advanced gastric cancer (GC), colon cancer (CC) biliary tract cancer (BC) and pancreatic cancer (PC) were treated with a combined chemotherapy of UFT with ADM (UFT-A), or UFT with ADM and CDDP (UFT-AC). The UFT-A regimen consisted of UFT, 600 mg/body daily. As for ADM, 10 mg/body was given intravenously from day 1-4 and repeated every two weeks. The UFT-AC regimen consisted of UFT 400-600 mg/body daily. As for ADM, 7.5 mg/m2 was given from day 7-9 and CDDP 50 mg/m2 on day 7, repeated every 3-4 weeks. Partial responses (PR) were seen in 7 cases (36.8%) (5 cases of GC, 1 case of CC and 1 case of BC) out of 19 evaluable patients (8 cases of GC, 4 cases of CC, 4 cases of BC and 3 case of PC) treated with UFT-A. Complete response in a case of CC and PR in 6 cases (47.7%) (3 cases of GC and 3 cases of BC) were observed out of 15 evaluable patients (7 cases of GC, 2 cases of CC, 4 cases of BC and 2 cases of PC) treated with UFT-AC. There was no significant difference of survival curve between the two regimens, however, the median survival of responders for both regimens is longer than non-responders with statistical significance. As for side effects, UGI symptoms were recognized in 37% of UFT-A group and in 73% of UFT-AC group. A leukopenia count of less than 2,000/mm3 appeared in 11% of UFT-A group and in 20% of UFT-AC group. Considering these results, UFT-A and UFT-AC therapy appears to be useful in cases of advanced gastrointestinal cancer, especially gastric cancer.     

The Importance of Dose-Intensity in Neoadjuvant Chemotherapy of Osteosarcoma: A retrospective analysis of high-dose methotrexate,cisplatinum and adriamycin used preoperatively

Summary

The relationship between dose-intensity and outcome was retrospectively analyzed in 125 patients with osteosarcoma of the extremities treated at our institution with neoadjuvant chemotherapy between 1986 and 1988. Before surgery, chemotherapy was performed with high-dose methotrexate (HDMTX) i.v. followed by cisplatinum (CDP) i.a. and adriamycin (ADM) i.v. Postoperative chemotherapy was tailored according to the necrosis induced by preoperative treatment. Patients who were «good responders» had 31-weeks of chemotherapy with the same drugs utilized preoperatively, while «poor responder» patients received a longer treatment (40 weeks) in which ifosfamide and etoposide (VP-16) were added to HDMTX, CDP and ADM. At a median follow-up of 2 years (1-3 years) 100 patients (80%) remained continuously disease-free and 25 patients relapsed: 24 with lung metastases and 1 with local recurrence. According to the real dose-intensity received, calculated as a percentage of the dose intensity projected by the protocol, the continuously disease-free survival was 87% in the 82 patients who received 80% or more of the scheduled dose-intensity and only 65% for the 43 patients who received less than 80% of the projected dose-intensity. This difference is highly significant (P < 0.01).

These results suggest that in neoadjuvant chemotherapy of osteosarcoma the real dose-intensity delivered is a determinant of treatment outcome and therefore every effort should be made to avoid reductions of doses and delays of cycles of chemotherapy in these patients.     

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.     

Cosmetic results after surgery, chemotherapy, and radiation therapy for early breast cancer

Adjuvant chemotherapy (CT) is increasingly being used in conjunction with radiation therapy (RT) in the treatment of early stage breast cancer. To assess the effect of CT on the cosmetic outcome of the irradiated breast, we retrospectively reviewed the cosmetic results of patients who received either cyclophosphamide-methotrexate-fluorouracil (CMF) or doxorubicin-based chemotherapy in conjunction with breast irradiation between 1968 and 1985. The overall cosmetic results were evaluated by the physician as "excellent," "good," "fair," or "poor" using a standardized scale. The CT group consisted of 170 patients treated with CT and RT administered either concurrently or sequentially (CT before RT, after RT, or both) with a minimum of 24 months of cosmetic follow-up. These were compared to an RT alone control group of 170 patients who did not receive CT and were matched by tumor size, radiation technique, and year of treatment. At 36 months, the cosmetic scores for the CT group compared to RT alone were 47% versus 71% excellent (p less than 0.01), 36% versus 19% good, and 17% versus 9% fair or poor. For the 50 patients treated with concurrent CMF and RT, the scores were 31% excellent, 45% good, and 24% fair/poor, whereas for the 118 patients treated with sequential RT and CT they were 54%, 31%, and 14%, respectively. There was no difference between those patients who received sequential CMF and those treated with doxorubicin. We conclude that adjuvant chemotherapy adversely affects the cosmetic outcome of breast irradiation, but that this effect is not clinically significant unless CMF is administered concurrently with RT. Patients treated with either sequential CMF or doxorubicin-based CT had only a slight decrement in their cosmetic result compared to patients treated without CT.