Sex- and Age-Related Chemotherapy Toxicity in Patients with Non-Metastatic Osteosarcoma

Abstract

The influence of age and sex on chemotherapy-related toxicity was evaluated in children and adults with non metastatic osteosarcoma. Treatment consisted of methotrexate (MTX, 12 g/m²), cisplatin (CDP 120 mg/m²) and doxorubicin (ADM 75-90 mg/m²) and high-dose ifosfamide (HDIFO). Toxicity data from 1,051 courses (295 with MTX, 756 based on doxorubicin, cisplatin and high-dose ifosfamide) were analyzed. Children (4-14 yrs) and females showed a higher incidence of grade 4 neutropenia and thrombocytopenia and were more frequently hospitalized for neutropenic fever compared to adolescents and young adults (AYA, 15-19 yrs) and adults (>20-40 yrs). Delayed MTX excretion was higher in adults than AYA and children. Adults (up to 40 years) can be treated with pediatric protocols for osteosarcoma and they experience lower hematologic toxicity compared to pediatric population. Further investigations on sex-related susceptibility to chemotherapy in osteosarcoma patients are recommended.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

洛铂联合阿霉素、异环磷酰胺化疗方案新辅助治疗骨肉瘤的剂量探索

目的 探讨洛铂（LBP）联合阿霉素（ADM）、异环磷酰胺（IFO）化疗方案新辅助治疗骨肉瘤的最大耐受量（MTD）,并观察其毒副反应。方法 LBP设定3个剂量水平,分别为45mg／m²、50mg／m²、55mg／m²,ADM和IFO剂量固定（ADM 60mg／m²、IFO 12g／m²）,观察到出现剂量限制性毒性（DLT）即终止试验,或至55mg／m²未出现DLT,试验亦终止。结果 共有6例患者完成了爬坡试验,当试验进行到第1个剂量组时,出现2例DLT,试验终止。从而确定联合化疗方案的MTD为LBP 45mg／m²、ADM 60mg／m²和IFO 12g／m²。主要不良反应为骨髓抑制,血小板减少的发生率为66.6％（4/6）,3级发生率为33.3％（2/6）;白细胞减少的发生率为83.3％（5/6）,未发生4级白细胞减少;中性粒细胞减少的发生率为83.3％（5/6）,4级发生率为33.3％（2/6）。所有患者经对症治疗后均好转,未影响继续治疗。结论 LBP联合ADM、IFO化疗方案新辅助治疗骨肉瘤的MTD为LBP 45mg／m²、ADM 60mg／m²和IFO12g／m²,毒副反应可耐受,建议以此为依据开展进一步临床研究。     

Adjuvant six cycles of high-dose adriamycin,cyclophosphamide, methotrexate, 5-fluorouracil (ACMF) vs. 12 cycles of low-dose acmf with tamoxifen for premenopausal,node-positive breast cancer patients: Results of a prospective randomized study

A prospective randomized study was conducted to compare the adjuvant efficacy of six cycles of high-dose ACMF (Adriamycin, ADM; cyclophosphamide, CPA; methotrexate, MTX; 5-fluorouracil, 5-FU) with that of 12 cycles of low-dose ACMF in premenopausal, node-positive breast cancer patients. The six-cycle ACMF group (93 patients) received, intravenously (iv), 130 mg/m² CPA, 26 mg/m² MTX, and 600 mg/m² 5-FU on days 1 and 8, and 26 mg/m² ADM on day 1 of each cycle. The 12-cycle ACMF group (97 patients) received, iv, 65 mg/m² CPA, 13 mg/m² MTX, and 300 mg/m² 5-FU on days 1 and 8, and 13 mg/m² ADM on day 1 of each cycle. These treatments were repeated every 4 weeks, and all the patients took tamoxifen (30 mg/day) for 2 years. The background factors of the two groups were comparable. There were non-significant trends toward better disease-free and overall survival rates in the high-dose, six-cycle ACMF group. Both treatments were well tolerated, but more patients in the low-dose, 12-cycle group refused to continue to receive chemotherapy. These data suggest that escalating doses of ACMF over a shorter period, even with doses within the conventional range, are superior to low-dose, prolonged therapy. © 1995 Wiley-Liss, Inc.     

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.     

High Dose Ifosfamide in Combination with High Dose Methotrexate,Adriamycin and Cisplatin in the Neoadjuvant Treatment of Extremity Osteosarcoma: Preliminary Results of an Italian Sarcoma Group/Scandinavian Sarcoma Group Pilot Study

Abstract

With the intention of starting an international protocol between Italy and Scandinavia on neoadjuvant treatment of extremity osteosarcoma using the four active drugs at maximum doses (doxorubicin 75 mg/m² pre-operatively, and 90 mg/m² post-operatively, cisplatin 120 mg/m², methotrexate 12 g/m², and ifosfamide 15 g/m²), a single center (the Rizzoli institute) performed a pilot study to closely monitor toxicity, safety, and tumor necrosis. Only 7 patients (10%) had a reduced number of the scheduled cycles. A total of 1050 of the expected 1076 cycles (98%) were administered. Delays and dose reduction were minimal, leading to a mean received dose intensity of 89%. Limb salvage surgery was performed in 59 cases (87%), with 6 amputations and 3 rotation plasties. Chemotherapy-induced necrosis higher than 95% was observed in 38 patients (56%). Eleven patients had total necrosis (16%). At a median follow-up of 60 months (range 50-65 months), 53 patients (73%) were continuously disease-free. Six of the relapsed patients were rescued with further treatments leading to an overall survival of 87%. Hematological toxicity was remarkable despite the use of G-CSF and hospitalization due to febrile neutropenia occurred in 25 patients (37%). Platelet transfusions were required in 77 of the 194 episodes of grade 4 thrombocytopenia, but no case of major bleeding was observed. Red blood cell transfusions were necessary in all patients (in 15 cases perioperatively only). Non-hematological toxicity comprised grade 1-2 nephrotoxicity in 3 cases, CNS toxicity in 2 cases, and dilatative cardiopathy leading to heart transplantation in 1 case. In conclusion, the pilot study was feasible in the vast majority of cases with toxicity not superior to that of the previous protocols where chemotherapy was given in lower doses. The rate of limb salvage procedures, event-free survival and overall survival seemed to be higher than in previous protocols. On the basis of this study, in March 1997 the Italian and Scandinavian Sarcoma Groups started a new protocol for osteosarcoma of the extremities.     

Frontline treatment of localized osteosarcoma without methotrexate: results of the St. Jude Children's Research Hospital OS99 trial

BACKGROUND:

The standard treatment of osteosarcoma includes cisplatin and high‐dose methotrexate (HDMTX); both agents exert significant toxicity, and HDMTX requires complex pharmacokinetic monitoring and leucovorin rescue. In the previous OS91 trial, the treatment of localized disease with carboplatin, ifosfamide, doxorubicin, and HDMTX yielded outcomes comparable to those of cisplatin‐based regimens and caused less toxicity. To build on this experience, the authors conducted a multi‐institutional trial (OS99) that evaluated the efficacy of carboplatin, ifosfamide, and doxorubicin without HDMTX in patients with newly diagnosed, localized, resectable osteosarcoma.

METHODS:

Treatment was comprised of 12 cycles of chemotherapy administered over 35 weeks: 3 cycles of carboplatin (dose targeted to area under the concentration‐time curve of 8 mg/mL × min on Day 1) and ifosfamide (at a dose of 2.65 g/m² daily ×3 days) and 1 cycle of doxorubicin (at a dose of 25 mg/m² daily ×3 days) before surgical resection, followed by 2 additional cycles of the combination of carboplatin and ifosfamide and 3 cycles each of doxorubicin (25 mg/m² daily ×2 days) combined with ifosfamide or carboplatin.

RESULTS:

A total of 72 eligible patients (median age, 13.4 years) were enrolled between May 1999 and May 2006. Forty of the 66 (60.6%) evaluable patients had good histologic responses (>90% tumor necrosis) to preoperative chemotherapy. The estimated 5‐year event‐free survival rate was 66.7% ± 7.0% for the OS99 trial compared with 66.0% ± 6.8% for the OS91 trial (P = .98). The estimated 5‐year survival rate was 78.9% ± 6.3% for the OS99 trial and 74.5% ± 6.3% for the OS91 trial (P = .40).

CONCLUSIONS:

The regimen used in the OS99 trial was found to produce outcomes comparable to those of cisplatin‐containing or HDMTX‐containing regimens. This therapy offers a good alternative for patients, particularly those who demonstrate an intolerance of HDMTX, and for institutions that cannot provide pharmacokinetic monitoring for MTX. Cancer 2011. © 2011 American Cancer Society.     

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).     

Five-year results of cyclic semi-high dose neoadjuvant chemotherapy supported by autologous peripheral blood stem-cell transplantation in patients with advanced ovarian cancer

Background To achieve anti-ovarian tumor responses similar to those obtained with high-dose chemotherapy but with milder side effects, we developed a treatment protocol in which semi-high dose multi-cycle neoadjuvant chemotherapy was supported by autologous peripheral blood stem-cell transplantation (auto-PBSCT).Methods Seventeen patients with advanced ovarian cancer were enrolled in this study. Two cycles of semi-high dose neoadjuvant chemotherapy, using carboplatin (AUC, 8.75; average dose, 621mg/m²) and etoposide (average dose, 960mg/m²) were supported by auto-PBSCT and followed by cytoreductive surgery and further chemotherapy. Each patient was followed for at least 5 years.Results This treatment schedule achieved an overall response rate of 70.6% in 17 patients with stage III or stage IV ovarian cancer. The 5-year disease-free survival rate was 52.9% (95% confidence interval, 29.2%–76.6%) and the median survival time was 63 months (95% confidence interval, 16–79 months). Thus, we obtained superior treatment outcomes in these 17 patients in comparison with published conventional protocols.Conclusion Cyclic semi-high dose neoadjuvant chemotherapy supported by auto-PBSCT may be tolerable and favorable for patients with advanced ovarian cancer.     

Dose-intense therapy with etoposide, ifosfamide, cisplatin, and epirubicin (VIP-E) in 107 consecutive patients with limited- and extensive-stage non-small-cell lung cancer

Background: We conducted a phase I/II trial to assess the feasibilityand activity of combination chemotherapy with etoposide, ifosfamide,cisplatin, and epirubicin in limited-stage (LS, stage I–IIIB) andextensive-stage (ES, stage IV) non-small-cell lung cancer (NSCLC). End-pointswere treatment-related morbidity and mortality, response rate, duration ofresponse, and survival.Patients and methods: Chemotherapy followed by granulocytecolony-stimulating factor was given at a dose of etoposide (500mg/m²), ifosfamide (4000 mg/m²), cisplatin (50mg/m²), and epirubicin (50 mg/m²) (VIP-E) to107 patients with NSCLC. Twenty-five patients with qualifying responsesproceeded to high-dose chemotherapy with autologous peripheral blood stem celltransplantation after etoposide (1500 mg/m²), ifosfamide(12,000 mg/m²), carboplatin (750 mg/m²) andepirubicin (150 mg/m²) (VIC-E) conditioning.Results of conventional-dose VIP-E: 35 of 102 (34%) evaluablepatients responded (2 CR's, 33 PR's), 33/102 patients (33%) showed nochange (NC); the remainder of patients progressed with therapy (PD). Objectiveresponse rate was 68% (4% CR, 64% PR) in LS-NSCLC and23% (1.4% CR, 21.4% PR) in ES-NSCLC. Median duration ofsurvival was 13 months in LS-NSCLC and 5.5 months in ES-NSCLC. Two-yearsurvival was 26% in LS and 2% in ES-NSCLC.Results of high-dose VIC-E: 23 of 24 evaluable patients improved ormaintained prior responses (92%), 1 patient showed NC. Treatmentmortality was 4%. Median duration of survival was 17 months in LS-NSCLCand 10 months in ES-NSCLC. Two-year survival was 30% in LS and8% in ES-NSCLC.Conclusion: Response-rates and survival after conventional-dose VIP-Echemotherapy are comparable to other published trials of combinationchemotherapy in NSCLC. Toxicity and mortality is acceptable in limited stage,but unacceptably high in extensive stage NSCLC. Although better response-rateswere achieved in the high-dose arm, they did not translate into improvedsurvival. Most stage IV NSCLC-patients will neither benefit from VIP-Econventional dose, nor from VIC-E high dose chemotherapy. Whether selectedLS-patients with partial or complete responses to VIP-E induction chemotherapycould benefit from dose intensification in an adjuvant or neo-adjuvant settingremains to be determined.     

Dose-intense therapy with etoposide, ifosfamide, cisplatin, and epirubicin (VIP-E) in 100 consecutive patients with limited- and extensive-disease small-cell lung cancer

Background: We conducted a phase I/II trial to assess the feasibilityand activity of VIP-E chemotherapy in small-cell lung cancer. End-points weretreatment-related morbidity and mortality, response to treatment, duration ofresponse, and survival.Patients and methods: Two cycles of combination chemotherapy followedby granulocyte colony-stimulating factor (G-CSF) were given at a dose ofetoposide (500 mg/m²), ifosfamide (4000mg/m²), cisplatin (50 mg/m²), and epirubicin(50 mg/m²) to 100 consecutive patients with SCLC. Thirtypatients (19 with LD, and 11 with ED SCLC) proceeded to VIC-E high-dosechemotherapy with autologous peripheral blood stem cell transplantation(PBSCT) at a cumulative dose of etoposide 1500 mg/m²,ifosfamide 12,000 mg/m², carboplatin 750 mg/m²and epirubicin 150 mg/m² (VIC-E). Surgical resection ofprimary tumor was attempted at the earliest feasible point. Thoracicirradiation was given after completion of chemotherapy.Results of conventional-dose VIP-E: 97 patients were evaluable forresponse. Objective response rate was 81% in LD-SCLC (33% CR,48% PR; excluding patients in surgical CR) and 77% in ED-SCLC(18% CR, 58% PR). Treatment mortality was 2%. Mediansurvival was 19 months in LD-SCLC and 6 months in ED-SCLC. Two-year survivalwas 36% in LD and 0% in ED SCLC.Results of high-dose VIC-E: All 30 patients improved on or maintainedprior responses. Four patients (13%) died of treatment-relatedcomplications. Median survival was 26 months in LD-SCLC and 8 months inED-SCLC. Two-year survival was 53% in LD and 9% in ED SCLC.Conclusion: VIP-E chemotherapy is an effective induction therapy forSCLC. Compared with traditional protocols such as ACO orcarboplatin/etoposide, response rates are slightly improved, while survivalis not different. In the LD SCLC subgroup, high-dose chemotherapy improvedresponse rates and survival, especially for patients in surgical CR prior tohigh-dose therapy. In ED SCLC, however, higher response-rates did nottranslate into improved survival. Selected LD-SCLC patients with good partialor complete remissions after prior therapy may benefit from HDC and PBSCT.     

肢体骨肉瘤的新辅助化疗：异环磷酰胺、甲氨蝶呤、表柔吡星化疗的初步结果

目的评价新辅助化疗的疗效和在骨肉瘤保肢手术方面的作用。方法2001年9月～2005年4月治疗53例肢体骨肉瘤患者。化疗方案：异环磷酰胺2．0g／m^2，第1～5天；甲氨蝶呤8g／m^2，第3天；表柔吡星60mg／m^2，第5天。每3～4周重复1次。评价化疗反应和化疗毒性。术前化疗3次，术后化疗6次。结果2例患者死于化疗毒性反应。完全缓解（CR）23例，部分缓解（PR）15例、稳定（SD）9例、进展（PD）5例。44例患者进行保肢手术，8例进行截肢。3年生存率为77．36％。结论异环磷酰胺、甲氨蝶呤、表柔吡星联合化疗方案有利于保肢手术，改善患者的预后，可以作为一种较理想的化疗方案。     

Neoadjuvant Chemotherapy for Extremity Osteosarcoma: Preliminary Results of the Rizzoli's 4th Study

A neoadjuvant chemotherapy protocol (1/93-1/95) for extremity osteosarcoma preoperatively using high-dose methotrexate (HDMTX) as single agent per cycle and three different combinations of other drugs (CDP/IFO,CDP/ADM,IFO/ADM) is reported. The four drugs were used postoperatively as single agents. Treatment was uniform, but suspended earlier if total necrosis was attained. An improvement was found in the results of the previous study using only IFO postoperatively, with 16/119 patients (97%) avoiding amputation, and 38 (32%) attaining complete necrosis. At a 3-year (2-4 years) mean follow-up, 92 patients (76%) remained continuously disease-free, 2 died of chemotherapy-related toxicity and 25 suffered relapse. Projected 3-year DFS also improved (75% vs. 60%; p=0.04). Despite limb salvage, local recurrences (6.3%) and infections were few, although postoperative chemotherapy was restarted within a week. Therefore, until new effective drugs are found, expertise in using the four known drugs may improve cure rate and help to avoid amputation in almost all patients.     

Combination chemotherapy with irinotecan and adriamycin for refractory and relapsed non-Hodgkin's lymphoma

Twenty-five patients with relapsed or refractory non-Hodgkin's lymphomawere treated by combination chemotherapy with irinotecan hydrochloride(CPT-11) and adriamycin (ADM): CPT-11, 25 mg/m² on days 1 and 2;ADM, 40 mg/m² on day 3. Nine (36%) of twenty-five patientsachieved CR. Fairly good responses were seen in relapsed B-cell lymphomas (4of 8 in diffuse large B-cell lymphoma and 2 of 2 in follicular lymphoma grade1), and substantial responses in T-cell lymphomas (1 of 4 in peripheral T-celllymphoma and 2 of 7 in adult T-cell leukemia/lymphoma). Leukopenia wasfrequent but tolerable, and diarrhea minimal. Combination chemotherapy witha reduced dose CPT-11 and ADM was useful in the treatment of relapsednon-Hodgkin's lymphoma.