Role Of Ifosfamide Research Articles

The role of ifosfamide and etoposide in Ewing sarcoma

The EICESS-92 Trial compared the efficacy of cyclophosphamide and ifosfamide in patients with Ewing sarcoma. Subgroup analysis suggested that patients with large, localized tumors benefited from the addition of etoposide, whereas patients with metastases did not.

Sarcomatoid (metaplastic) carcinoma of the breast: The U.T. M.D. Anderson Cancer Center (MDACC) and SEER database experience

614 Background: Sarcomatoid (metaplastic) carcinoma of the breast is a rare disease which contains overtly carcinomatous and sarcoma-like elements on light microscopy; its clinical behaviour is not well documented. Methods: To better define the clinical features of sarcomatoid breast carcinoma, MDACC records were searched for patients diagnosed from 1985–2002. We also searched the SEER database for patients with this disease registered between 1988 and 2001. Descriptive statistics were used to summarize patient characteristics. Results: From the MDACC records, we identified 100 sarcomatoid breast cancer patients. Their median follow-up was 55 months (range, 4–252).The median age at diagnosis was 48 years (range, 26–77), 76% had grade 3 disease, 66% had node-negative disease, and 57% had stage 2 disease. Six percent had ER-positive and 9% had PR-positive tumors. Of 26 patients with a known HER2/neu status, 24 were HER2/neu-negative. Of 94 patients with localized disease at diagnosis, all but 1 had surgery, 82% received adjuvant chemotherapy, and 54% radiotherapy. The median recurrence-free survival (RFS) of these patients was 74 months (range, 3 to 252), with a 52% RFS rate at 5 years. The median overall survival (OS) of these patients was not reached, with 64% alive at 5 years. Fifty percent of first recurrences were local. Median survival from the time recurrent disease was recognized was only 14 months (range, 1 to 50). The 5-year RFS was low and not statistically different between patients who did and did not receive adjuvant chemotherapy, although all 3 patients treated with an anthracycline/ifosfamide-based regimen did remain recurrence-free. The SEER database registered 213 cases of sarcomatoid breast cancer of a total of 281,382 breast cancers. Information from this database was remarkably consistent with our findings. Conclusions: Sarcomatoid (metaplastic) cancer of the breast is rare, usually receptor-negative, and often aggressive and treatment-refractory. The role of ifosfamide with standard chemotherapy should be explored. The biology of this disease needs to be better defined with the aid of gene array and other new technologies to develop targeted therapies. No significant financial relationships to disclose.

The Role of Ifosfamide in the Treatment of Lymphomas

Over the last few decades, progress has been made in classification and treatment guidelines for patients with lymphoma with differing prognostic factors. As investigators look for alternatives to current standard therapy there has been a resurgence of interest in the alkylat-ing agent ifosfamide. A basic tenet of lymphoma therapy has been to use combinations of non-cross resistant agents in an effort to avoid tumor resistance. Ifosfamide is at least partially non-cross resistant with cyclophosphamide, and because it is often only modestly myelosup-pressive, it is useful in combination regimens. Other toxicities of ifosfamide, including urinary bladder toxicity and neurotoxicity, are generally predictive and seldom occur in clinical practice with standard ifosfamide doses and proper screening and preventive therapy.Several regimens incorporating ifosfamide in a variety of doses and schedules have demonstrated clinical efficacy in the treatment of lymphomas. Ifosfamide is most commonly used in regimens for patients with relapsed or refractory disease, although there has been interest in ifosfamide as part of initial therapy regimens. Ifosfamide is an active agent as part of combination therapy for patients with both indolent and aggressive relapsed lymphomas, and has also been used in high-dose therapy regimens followed by stem cell or bone marrow rescue. Future studies incorporating ifosfamide should be directed towards its use in outpatient regimens as initial therapy for patients with lymphoma and in regimens designed for patients with relapsed or refractory disease.

The role of ifosfamide in paediatric cancer.

Ifosfamide is an active drug in the therapy of paediatric tumours such as rhabdomyosarcoma, Ewings' sarcoma, Wilms' tumour, neuroblastoma, germ cell tumours and lymphomas. Myelosuppression is the major toxicity along with haemorrhagic cystitis. The latter is largely prevented by the use of concomitant mesna.

Ifosfamide and Actinomycin-D, Added in the Induction Phase to Vincristine, Cyclophosphamide and Doxorubicin, Improve Histologic Response and Prognosis in Patients with Non Metastatic Ewing's Sarcoma of the Extremity

The role of ifosfamide as first-line chemotherapy treatment of non metastatic Ewing's sarcoma of the extremity is still under discussion. The purpose of this paper is to report the results achieved in a neoadjuvant protocol (REN-3) in which ifosfamide, added to the conventional VACA regimen, was employed since the induction phase. Induction chemotherapy consisted of vincristine, cyclophosphamide, doxorubicin, actinomycin-D and ifosfamide. After local treatment, patients received the drugs used in the induction phase and etopo-side. Between November 1991 and November 1994, 61 patients with non metastatic Ewing's sarcoma of the extremity were treated. Forty-nine patients underwent surgery and 73.5% of them had a good histologic response. At a median follow-up of 60 months (range 32-76), 48 patients (79%) remained continuously disease-free. The 5-year event-free and overall survival were 77% and 87%, respectively. These results were significantly better both in terms of histologic response or event-free and overall survival than those obtained in 58 patients with non metastatic Ewing's sarcoma of the extremity treated in a previous protocol (REN-2) in which the same drugs were used, but ifosfamide was employed only in the maintenance phase. The present study suggests the importance of early use of ifosfamide in the treatment of patients with non metastatic Ewing's sarcoma of the extremity.

Standard and high dose chemotherapy for advanced soft tissue sarcomas.

While significant improvements have been made in the management of localized soft tissue sarcomas, enabling the realization of better functional results and a better overall outcome, progress in metastatic disease has been less than impressive. Adriamycin and DTIC based chemotherapy programs have resulted in response rates of upto 50%, with a small but finite cure fraction, especially in conjunction with surgical resection of residual abnormalities. The decade of the 80s experienced a considerable amount of enthusiasm in exploring the role of ifosfamide and mesna, and identified its definite usefulness as an effective salvage regimen with response rates of approximately 25%-30% in adriamycin failures. Studies evaluating the role of ifosfamide as up-front line agent in combination with adriamycin have met with increased toxicities without a significant additive therapeutic benefit, probably as a result of compromised dose intensity of each individual agent. The steep linear log-dose response relationship of alkylating agents and adriamycin constitutes the theoretical rationale for use of higher doses of chemotherapy, which have become feasible, with the advent of growth factors for bone marrow support. While this approach seems promising in its infancy, with improved complete and overall response, its ultimate effect on survival is anxiously awaited. The limited experience available in the literature with even more aggressive approaches like marrow ablative doses of chemotherapy followed by bone marrow transplantation, have been uniformly disappointing, with extremely short lived responses and extremely high morbidity and cost. As clinical research continues to improve our understanding and ability to implement the currently available therapeutic armamentarium, the search for newer and better drugs needs to continue.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of ifosfamide plus cisplatin-based chemotherapy as salvage therapy for patients with refractory germ cell tumors

A prospective study of four cycles of etoposide with ifosfamide and cisplatin (VIP) chemotherapy was conducted in 42 germ cell tumor (GCT) patients who were refractory to cisplatin with etoposide/vinblastine-based therapy. Forty patients were evaluable for response. Ten patients (25%) had a complete response: seven to chemotherapy alone and an additional three patients after surgical resection of viable GCT. With a median follow-up of 15 months, four complete responders relapsed, and six patients (15%) remain in remission. Hematologic and nephrotoxicity were moderately severe. Durable complete responses with VIP as second salvage were achieved and suggests that ifosfamide adds efficacy to standard first-salvage therapy. The observed nephrotoxicity and myelotoxicity are considerations in the design of ifosfamide-cisplatin-based regimens. Hematopoietic growth factors may be useful in ameliorating myelotoxicity. The early use of ifosfamide-based chemotherapy may reduce the nephrotoxicity exacerbated by prior cisplatin. A trial of VIP as first salvage after a relapse from a complete response to platinum-based induction therapy is warranted. The modest proportion of patients who achieve a durable remission to VIP as second salvage emphasizes the need for more efficacious salvage therapy for patients who do not achieve a durable complete response.

The role of ifosfamide and cyclophosphamide in the multi-modality treatment after surgery for cure for small-cell bronchial carcinomas (SCLC)

For the optimisation of the therapy for small cell bronchial carcinomas (SCLC), surgery is used to eliminate the primary tumor and its regional lymph nodes and chemo- and radiotherapy for the general treatment of micrometastasis. After patho-histological examination of the operation specimen, randomization for two arms is performed for a standard chemotherapy (CAV) or a sequential chemotherapy using three different drug combinations. Thereafter all disease-free patients receive prophylactic cranial irradiation (PCI). Preliminary evaluations in December 1987, of 112 patients from 19 cooperating departments show that the survival rate projected for 2 yr of 43 patients at stage pT1-3 N0 M0 is 76%, of 43 patients at stage pT1-3 N1 M0 it is 63% and of 26 patients at stage pT1-3 N2 M0 it is 38%.

Chemotherapy-radiation interactions in human cervix carcinoma xenografts

The combination of irradiation and four agents of clinical interest in the treatment of cervix carcinoma (bleomycin, etoposide, cisplatin and ifosfamide) have been investigated using two human cervix carcinoma xenografts in nude mice. As a model of clinical brachytherapy regimes, radiation was administered at a continuous low dose rate of 5 cGy min-1 to a total dose of 9 or 12 Gy. No substantial enhancement in tumour growth delay over that observed for radiation alone was observed with bleomycin, etoposide or cisplatin. Ifosfamide, however, led to substantial additional growth delay, an effect which was lost when irradiation was administered at a higher dose rate of 70 cGy min-1. As dose-rates of around 5 cGy min-1 allow greater repair of radiation damage than at the higher dose-rate without significant cell cycling or repopulation, it is possible that ifosfamide may act as an inhibitor of repair processes in this model. It would be of interest to evaluate the role of ifosfamide and brachytherapy regimes in the clinical treatment of carcinoma of the cervix.

Phase II study with ifosfamide in advanced malignant melanoma.

Ifosfamide was tested in a phase II study in 12 evaluable patients with advanced malignant melanoma. The drug was administered at the dose of 3 g/m2 on days one and two every 3-weeks. Seven patients were not previously treated and 5 received only minimal prior chemotherapy. Visceral involvement was present in 9 patients, and the remaining 3 had only soft tissue lesions. No patient showed objective tumor response. Mild vomiting was observed in 75% of patients; alopecia occurred in all of them. No other major side effects were observed, in particular, myelotoxicity and urotoxicity. Lack of response advised us to discontinue patient accrual. Our data do not support a therapeutic role of ifosfamide at the given dose schedule in the treatment of metastatic malignant melanoma.

The role of ifosfamide in paediatric soft tissue sarcomas

Early clinical trials in adults showed favourable results of ifosfamide (IF) in several tumours. In a previous study we used IF and vincristine (VCR) and observed 6 complete responses (CR) among 25 previously heavily treated children. Especially patients with rhabdomyosarcoma (RMS) responded well, with 4 partial responses (PR) and 2 CR among 6 patients. This and the fact that the combination of VCR, actinomycin D (ACD) and cyclophosphamide (CYT) still give good results in RMS patients led us to replace CYT with IF in this combination. This IVA protocol consists of IF 3000 mg/m2 i.v. in 1 h on days 1 and 2, VCR 1.5 mg/m2 by i.v. push on day 1, and ACD 900 micrograms/m2 by i.v. push on days 1 and 2. The course is repeated at 28-day intervals. VCR 1.5 mg/m2 is given on day 14. We used this protocol als induction therapy in 18 newly diagnosed RMS patients. The primary sites were: abdomen (4 patients), bladder and prostate (3), head and neck (9: orbita 5), extremity (1), chest wall (1). At diagnosis, 9 patients had stage I, 4 stage II and 5 stage IV disease. Except for one mixed mesodermal type, all were of the embryonal type. The patients age at diagnosis varied from 2 to 16 years. After three courses, in some patients surgery was performed if radical tumour extirpation seemed possible. The first evaluation took place after three courses. At this point one patient had no response, one had a reduction in tumour mass of less than 50% (partial response PR), 9 patients had greater than 50% tumour-reduction (good partial response [GPR]), and 7 were in complete remission (CR). In 2 of these 7 (CR) no tumour was found on histopathological examination of the specimen. In patients with GPR or CR therapy was continued for 6 months and then stopped. Thirteen patients have been disease-free for 1-20 months from the date of CR. Four patients relapsed 4, 6, 11 and 11 months after CR. There was one therapy-related death. Except for this patient no major toxicity was encountered. These results indicate that by replacing CYT with IF, remission induction can be improved with a major contribution to survival and to enhanced quality of life in these patients.