Prevalence and management of methotrexate-induced neurotoxicity in pediatric patients with osteosarcoma: a single-center experience

Aims

To determine the incidence, clinical presentation, and outcome of methotrexate (MTX) associated neurotoxicity in pediatric patients treated for osteosarcoma, with the aim of identifying possible risk factors and suggesting recommended treatment for these sequelae.

Materials and methods

All medical files of patients treated for osteosarcoma in a single pediatric haemato-oncology center between November 2011 and August 2021 were retrospectively reviewed. All patients were treated according to the EURAMOS AOST0331 protocol, using cisplatin, doxorubicin, and high-dose MTX at a dose of 12 g/m² over 4 h.

Results

Seventy-eight patients with osteosarcoma were identified (age range 5 to 23 years, 42 males). Seven patients (9%) sustained neurotoxicity following treatment with high-dose MTX. Manifestations of neurotoxicity included among others, generalized seizures, confusion, encephalopathy, dysarthria, and choreiform movements. All but one episode occurred following two sequential cycles of high-dose MTX. All 7 had subacute toxicity, 5–10 days following MTX administration, and 1 had both acute and subacute toxicity. Brain MRI was performed for all patients and demonstrated typical MRI changes attributed to MTX neurotoxicity in 4 of them. Two patients received aminophylline; one patient received dextromethorphan. Patients with normal MRI imaging resumed MTX therapy without any sequels. No risk factors were found for high-dose MTX-related toxicity occurrence.

Conclusions

The time of risk of neurotoxicity due to high-dose MTX treatment for osteosarcoma is days 5–10 following two sequential treatment cycles. These findings together with treatment options for these adverse effects should be detailed in the therapeutic protocol of MTX use among pediatric patients with osteosarcoma.

     

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 with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups.

PURPOSE: To explore the effect of high-dose ifosfamide in first-line treatment for patients < or = 40 years of age with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS: From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m2), methotrexate (12 g/m2), cisplatin (120 mg/m2), and doxorubicin (75 mg/m2). Postoperatively, patients received two cycles of doxorubicin (90 mg/m2), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m2). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination. RESULTS: No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence. CONCLUSION: The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.     

Methotrexate Serum Concentration and Histological Response to Multiagent Primary Chemotherapy for Osteosarcoma of the Limbs

Abstract

The authors investigated the influence of methotrexate (MTX) serum concentration on (histologically evaluated) tumor necrosis, induced by a primary multiagent chemotherapy, including MTX, for osteosarcoma. MTX serum peaks in 151 patients, preoperatively treated with MTX (8-12g/m²), cisplatin (120 mg/m²) and Adriamycin (60mg/m²), were analyzed.

Significantly (p<0.01) higher serum MTX mean peaks were observed in patients with complete tumor necrosis (MTX 773.8 umol/1) compared to patients with 90-99% tumor necrosis (639.8 umol/1), 50-89% tumor necrosis (649.1 μmol/1) or less than 50% tumor necrosis (610μmol/l). Complete tumor necrosis was observed in 9% of patients with MTX peaks of less than 600μmol/l, in 27% of patients with serum MTX peaks between 600 and 699μmol/l and in 37% of those with MTX peaks ranging from 700 to 799μmol/l. Higher MTX peaks (800-899, 900-999, >1000μmol/l) were not associated with a further increase of cases with complete tumor necrosis. 40% of patients with an MTX peak greater than 700 μmol/1 had complete tumor necrosis, compared to 15.5% of patients who did not reach this value (p < 0.002). At a multivariant analysis including age, sex, tumor site and volume, pretreatment serum alkaline phosphatase and lactic dehydrogenase levels, MTX peaks of 700 umol/1 and, less significantly, the histologic type (telangiectatic osteosarcoma), were independent factors influencing tumor necrosis.

The authors conclude that MTX serum peaks significantly influence chemotherapy-induced tumor necrosis in osteosarcoma. In a primary treatment consisting of cisplatin, Adriamycin and MTX, complete tumor necrosis can be obtained in 40% of patients with MTX peak concentrations > 700 μmol/1.     

Can molgramostim enhance the antitumor effects of cytotoxic drugs in patients with advanced sarcomas?

Background: A phase I study was designed for the amalgamation of twopreviously studied antisarcoma regimens (ifosfamide + doxorubicin andmitomycin + doxorubicin + cisplatin) supported by molgramostim. Thus, we hopedto develop a better regimen for the treatment of advanced sarcomas.Patients and methods: Fifteen adult advanced sarcoma patients and six otherpatients were registered and sequentially assigned to receive threeprogressively more myelosuppressive levels of chemotherapy: level I –ifosfamide 2500 mg/m² + doxorubicin 40 mg/m²+ cisplatin 60 mg/m² all given on day 0, followed bymolgramostim 5 µg/kg every 12 hours for 14 days; level II –exactly the same chemotherapy from level I given on day 1 preceded on day 0by ifosfamide 2500 mg/m² and an additional four days ofmolgramostim given on days –6 through –3; level III – sameas level II except for the addition of mitomycin 4 mg/m²immediately prior to cisplatin on day 1. MESNA 500 mg/m² wasgiven five times on each day that involved ifosfamide treatment. For alllevels, treatment was repeated at four-week intervals.Results: Preliminary results and toxicity were reported three years ago (JNatl Cancer Inst 86: 312–4, 1994). Mature results confirm theseunexpectedly favorable results with five advanced sarcoma patients stillsurviving after more than three years (four more than four years).Hypothesis: Molgramostim given subcutaneously in a relatively intensiveschedule might enhance the antitumor effects initiated by cytotoxic drugs inpatients with advanced sarcomas. This idea should be tested formally in phaseIII studies.     

Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials

BackgroundNeoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted.Patients and methodsBetween 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m² and cisplatin 100 mg/m². Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome.ResultsFive- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3–40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival.ConclusionsLocalised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments.     

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.     

Mitomycin,ifosfamide and cisplatin in non-small-cell lung cancer

Summary Chemotherapy with mitomycin C, ifosfamide and cisplatin (MIC) is reported to produce responses of 56% and 69% in inoperable non-small-cell lung cancer (NSCLC) [1,2]. We evaluated the regimen in 45 similar patients who received up to six courses of 6 mg/m² mitomycin C, 3 g/m² ifosfamide, and 50 mg/m² cisplatin every 3 weeks. In all, 18 patients had limited disease (LD) and 27 had extensive disease (ED). A total of 18 patients responded (40%), 9/18 with LD and 9/27 with ED; there were 4 complete responders. The median duration of response was 25 weeks, and median survival was 32 weeks (range, 2–96 weeks). Toxicity was moderate. Nausea and vomiting were controlled with i.v. dexamethasone and high-dose metoclopramide. Other toxicities included myelosuppression and alopecia. This study confirms that MIC is one of the most active regimens for treatment of NSCLC, with acceptable toxicity.Supported by the Cancer Research Campaign     

Docetaxel,cisplatin and 5-fluorouracil-based induction chemotherapy followed by intensity-modulated radiotherapy concurrent with cisplatin in locally advanced EBV-related nasopharyngeal cancer

BackgroundThis monocentric study evaluates the activity and tolerability of docetaxel (Taxotere), cisplatin and 5-fluorouracil (5-FU) (TPF) induction chemotherapy followed by intensity-modulated radiotherapy (IMRT) concurrent with high-dose cisplatin in Epstein–Barr virus -related locally advanced undifferentiated nasopharyngeal cancer.Patients and methodsWe retrospectively reviewed the records of patients who received induction docetaxel 75 mg/m² and cisplatin 75 mg/m² on day 1, and 5-FU 750 mg/m²/day (96-h continuous infusion). Following induction, patients received full doses of IMRT concurrently with cisplatin 100 mg/m² every 21 days for three cycles.ResultsThirty patients received three TPF cycles (median). Induction was well tolerated; the main toxicity was neutropenia (33%, grade 3–4). During chemoradiotherapy, neutropenia (40%) and mucositis (43%) were the most frequent grade 3–4 adverse events. Mean dose of IMRT was 68.8 Gy. Worst late toxicity was xerostomia. Complete response rate was 93%. At 35 months, two patients had locoregional recurrence, three had distant metastases, and one had both. Three-year progression-free survival and overall survival were 79% [95% confidence interval (CI) 64% to 94%] and 87% (95% CI 74%– to 100%), respectively.ConclusionsIn this high-stage nonendemic cancer population, TPF followed by high-dose cisplatin IMRT was promising; this treatment approach deserves evaluation in randomized trials.     

Carboplatin/ifosfamide window therapy for osteosarcoma: results of the St Jude Children's Research Hospital OS-91 trial.

PURPOSE: To determine the activity of carboplatin/ifosfamide in patients with previously untreated osteosarcoma and to estimate patient outcomes after a multiagent chemotherapy protocol that eliminated cisplatin. PATIENTS AND METHODS: Sixty-nine patients with newly diagnosed, previously untreated osteosarcoma received three cycles of carboplatin (560 mg/m(2) x 1) and ifosfamide (2.65 g/m(2)/d x 3). Assessment of response was evaluated after two (week 6) and three (week 9) chemotherapy cycles. At week 9, histologic response was assessed. Adjuvant therapy comprised two additional carboplatin/ifosfamide cycles, doxorubicin, and high-dose methotrexate. Patients were stratified at enrollment: stratum A, resectable primary tumor without metastases; stratum B, unresectable primary tumor; and stratum C, metastatic disease at diagnosis. Week 6 response was compared with that of a historic group that received only ifosfamide during the initial window evaluation. RESULTS: The clinical and radiographic response rate to three cycles of carboplatin/ifosfamide was 67.7% (95% confidence interval, 55.0% to 78.8%). Compared with the historic population who received only ifosfamide, the combination of carboplatin and ifosfamide reduced the progressive disease rate at week 6 (31.9% v 9%, P: = .003). For patients in stratum A, the 3-year event-free survival and survival were 72.3% +/- 6.7% and 76.4% +/- 6.4%, respectively. Patients who received carboplatin-based therapy had less long-term renal toxicity and ototoxicity. CONCLUSION: This pilot trial suggests that carboplatin/ifosfamide combination chemotherapy has substantial antitumor activity. In the context of a multiagent chemotherapy protocol comprising high-dose methotrexate and doxorubicin, we found that the addition of carboplatin/ifosfamide resulted in patient outcomes comparable to trials using cisplatin-based therapy with less long-term toxicity.     

Dose-intense ifosfamide/doxorubicin/cisplatin based chemotherapy for osteosarcoma in adults

The efficacy of neoadjuvant and adjuvant chemotherapy has been clearly established in the treatment of osteosarcoma; however, the most active regimen remains to be identified. This prospective study evaluated the efficacy and toxicity of a dose-intense ifosfamide, doxorubicin, and cisplatin-based neoadjuvant regimen in adults with osteosarcoma. We prospectively treated 20 patients with osteogenic sarcoma with two cycles of ifosfamide/doxorubicin followed by two cycles of doxorubicin/cisplatin every 2 weeks. Surgical specimens were analyzed for percent tumor necrosis. Patients who demonstrated a "good response" (GR) to chemotherapy received the same combination postoperatively at a lower dose rate. Patients who demonstrated a "poor response" (PR) received four cycles of high-dose methotrexate alternating with two cycles of ifosfamide/etoposide and two cycles of cisplatin/etoposide after the surgery. Neoadjuvant chemotherapy was well tolerated with moderate hematologic toxicity. Twelve of 19 evaluable patients (63%) were treated according to the GR arm and 7 according to the PR arm. At median follow-up of 5.5 years, disease-free survival (DFS) and overall survival (OS) are 68% and 74%, respectively. Patients treated on the GR arm had DFS and OS of 75% and 83%, respectively, whereas patients on the PR arm had DFS and OS of 57%. Intensive neoadjuvant chemotherapy is effective and moderately well tolerated in patients with de novo osteosarcoma. The outcome data suggest that lack of a near complete response to preoperative chemotherapy reflects inherent biologic resistance to chemotherapy and hence a poor prognosis.     

A Three-Drug Regimen (Gemcitabine,Ifosfamide and Cisplatin) for Advanced Non-Small-Cell Lung Cancer

Abstract

We have carried out a pilot study on 25 non-small cell lung cancer patients, administering the combination of gemcitabine at the dose of 1000 mg/m² on days 1 and 8, ifosfamide 1500 mg/m² on days 1 and 2 (plus mesna as uropro-tector) and cisplatin 40 mg/m² on days 1 and 2, every 21 days. Granulocyte Colony Stimulating Factor was employed in all cases from day 10 to day 18 at the dose of 300 μg daily. An objective response was observed in 11 cases (44%). The regimen was active, but toxicity was remarkable with some cases of severe myelosuppression and mucositis.     

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.     

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.     

Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis

Purpose: To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis. Methods: Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200–1500 mg/m², followed by a 23-h infusion of 800–6000 mg/m². Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease. Results: Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 μM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 ± 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 ± 41 ml/min per m²) versus without CNS disease (59 ± 38 ml/min per m²). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF. Conclusion: This trial demonstrates that potentially cytotoxic CSF MTX concentrations (>1 μM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m² and a 23-h infusion of 2800 mg/m² with leucovorin in less heavily pretreated patients with carcinomatous meningitis. Received: 4 May 1999 / Accepted: 14 February 2000     

High-dose VP 16 cisplatinum in soft tissue sarcoma of children

Nine children with soft tissue sarcomas, five of them rhabdomyosarcomas with initial metastatic disease, (one patient, partial response, one patient), refractory primary, (two patients, relapse, five patients) were treated with a combination of high-dose VP 16 (100 mg/m² daily for 5 days) and cisplatin (40 mg/m² daily for 5 days). The response rate was five out of nine or 55% (±32%) (two complete and three partial, responses). Three of the five responders had rhabdomyosarcomas. The duration of response was 4–58 months (median 11 months). The toxicity was mainly hematological. Thus, the high-dose VP 16-cisplatin association warrants further evaluation in soft tissue sarcoma in children.     

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas

Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover.Patients and methods: Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m² by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m² i.v. bolus divided on two days, then to 60 mg/m² bolus divided on three days. Ifosfamide was reduced to 10 g/m² and doxorubicin was further escalated up to 90 mg/m². GM-CSF (5 µg/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days.Results: The MTD was reached with the combination of ifosfamide at 12 g/m² and doxorubicin at 60 mg/m². But with ifosfamide 10 g/m² and doxorubicin 90 mg/m² the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m² and doxorubicin 90 mg/m² induced WHO grade 4 leukopenia in 58%, grade 3–4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%–73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years.Conclusions: The dose level of ifosfamide 10 g/m² and doxorubicin 90 mg/m² with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosuppression should be accepted in order to obtain a high anti-tumor activity of this regimen and a potential improvement in survival.     

Ifosfamide plus doxorubicin in previously untreated patients with advanced soft tissue sarcoma

The objective of this phase II trial was to assess the therapeutic activity and toxicity of doxorubicin plus ifosfamide in previously untreated patients with advanced soft tissue sarcoma. Treatment was doxorubicin 50 mg/m² followed by a 24 h infusion of ifosfamide 5 g/m² plus mesna 2.5 g/m² repeated every 3 weeks until disease progression or unacceptable toxicity occurred. Of 203 patients entered, 175 were evaluable for response. The response rate was 35% (95% CI 28–42%), with 9% of the patients achieving a complete remission and 26% a partial remission. The median time to progression was 29 weeks for all evaluable patients, and 67, 40 and 28 weeks for complete and partial responders and patients with stable disease, respectively. The median duration of survival was 58 weeks. Myelosuppression was the dose-limiting toxicity, resulting in leukopenia (WHO grade 3 and 4) in 73% of evaluable treatment courses. Other side-effects were rare and usually well manageable.     

Synchronous radiochemotherapy in unfavorable brain tumors of children and young adults

The prognosis of patients with incompletely resected malignant brain tumors is almost fatal. In an attempt to improve the outcome of children and young adults with unfavorable brain tumors an intensive multimodal therapeutic strategy was developed combining simultaneous (hyper)fractionated external beam irradiation and conventional adjuvant chemotherapy after initial surgery. 17 patients aged between 2.10 and 25.11 years were entered into the study. 16/17 patients were treated according to the German/Austrian Pediatric Brain Tumor Study Group multicenter trial HIT '91. They are not protocol patients of this HIT '91 trial. Induction chemotherapy consisted of 2 courses of ifosfamide (3 g/m²/d) on days 1–3, etoposide (150 mg/m²/d) on days 4–6, methotrexate (5 g/m²) on days 15 and 22, cisplatin (40 mg/m²/d) and cytarabine (400 mg/m²/d) on days 29–31. Three weeks after the last dose of cisplatin/cytarabine the second course of chemotherapy was started. The last patient entered into the study received a modified therapy containing ifosfamide, cisplatin and etoposide. Synchronously at a median of 12 days after initiation of chemotherapy 12/17 patients received local radiotherapy (6000–7040 cGy) to the brain and 5/17 patients craniospinal irradiation (3520 cGy with a tumor boost of 1400–2000 cGy). 4–6 weeks after completion of the second course of chemotherapy maintenance therapy was started with carmustine (CCNU) (75 mg/m²) and carboplatin (400 mg/m²) each on day 1 and vincristine (1.5 mg/m²) on day 1, 8, 15. This course was repeated eight times every six weeks. 9/17 patients are alive at a median follow-up of 25 months (range 5–50) with 4 complete remissions, 2 partial remissions and 1 stable disease lasting 42 + months. Two patients, who initially had stable disease, progressed, but are still alive at 31 + and 41 + months after diagnosis. Median progression-free survival and median overall survival is 19 and 36 months, respectively. Hematologic and methotrexate-induced toxicity were severe and resulted in one therapy-related death. However, radiotherapy concomitant to chemotherapy appears to be an effective method of treatment for brain tumors with poor prognosis, though toxicity is severe in some cases.