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At least 19 recordsLinked to original sources

PubMed1981

A controlled prospective trial of adjuvant razoxane in resectable colorectal cancer.

Following resection of their tumour, 162 patients with colorectal cancer entered a prospective randomized controlled clinical trial of adjuvant oral razoxane. Thirty-one patients were Duke's group A; 49 group B; 61 group C; and 17 group D; an additional four patients were randomized in error. The adjuvant group received the usual clinical care and 125 mg razoxane twice daily for 5 consecutive days (monday-friday) every week indefinitely. Control patients received the same clinical care as the adjuvant group, but no razoxane. At 3 years, 134 patients (84%) are evaluable. The recurrence rate in the first 6 months was 20% and 28% respectively in the Duke's B and C controls compared with 4% and 9% in the corresponding razoxane treated patients. Most recurrences occurred within the first 6 months from randomization. When all patients as randomized are included in the analysis of survival, irrespective of whether they were cured by surgery (Duke's A), had advanced cancer (Duke's D), or took no razoxane when randomized to take it, then as might be expected any differences there may be between the razoxane-treated and control patients with minimal residual disease (Duke's B and C) are so distorted that the p value of the difference in survival was 0.93. If however only patients with Duke's group B or C are taken (49 controls and 47 treated), log-rank analysis reveals a difference in the cancer mortality curves (p = 0.07). If patients who had been randomized to take razoxane, but who had not taken it at any time (and therefore received the same treatment as controls) are analysed with the controls, the difference between the two groups increases further, with p less than 0.05. The razoxane-treated patients experienced no significant toxicity apart from a readily reversible mild leukopenia in 52% while gastrointestinal symptoms necessitated stopping the drug in only four patients. These four all took the drug for less than 4 weeks. Because there was no toxicity to subtract from any benefit razoxane adjuvant treatment produced and the quality of life was not impaired, the therapeutic benefit of surgery wsa increased to the extent that razoxane increased survival of patients with Duke's B and C tumours.

Clinical Trials as Topic↗

PubMed1984

Inhibition of experimental colorectal cancer by razoxane (ICRF-159).

Large bowel cancer induced in rats by dimethylhydrazine (DMH) closely resembles human disease both histologically and clinically. In this study it has been used to assess the antimitotic drug razoxane (ICRF-159). Dimethylhydrazine induced benign colorectal tumours after 20 weeks and adenocarcinomas from 30 weeks. Razoxane was given from week 25 until the end of experiment (week 35) to see if this drug could inhibit the development of tumours. Animals were randomly allocated to four groups: DMH + razoxane (26), DMH + control (26), control + razoxane (25), control + control (25). There were fewer malignant colorectal tumours in rats receiving razoxane than in the controls (10 vs. 24; P = 0.04). Some animals developed malignant tumours of the small intestine as well as the large bowel and the number of malignant tumours for the whole intestinal tract was also reduced in animals receiving razoxane (15 vs. 32; P = 0.025). This study demonstrates inhibition of the development of malignant tumours in rats by razoxane. This finding may have relevance to colorectal cancer in man where razoxane has been used in disseminated disease and as an adjuvant to surgery.

1,2-Dimethylhydrazine↗

PubMed2005

Combined razoxane and radiotherapy for melanoma brain metastases. a retrospective analysis.

We retrospectively compared the efficacy of razoxane and radiotherapy with radiotherapy alone or in combination with a non-razoxane based medication in patients with melanoma brain metastases. From 19 assessable patients receiving whole brain irradiation with or without a boost (mean total dose 40.5 Gy) for measurable brain metastases, 8 patients underwent an additional razoxane therapy with 125 mg per os twice daily started 5 days before radiotherapy and given throughout the whole radiation period. The median razoxane dose was 6.25 g (range 3.2-8.0 g). Endpoints included radiation response rates, median survival time and 1-year survival rates. To generate reliable prognostic parameters for this non-randomized study population, the Score Index for Stereotactic Radiosurgery and the Radiation Therapy Oncology Group Recursive Partitioning Analysis score were applied. Radiotherapy with razoxane led to higher response rates (62% vs. 27%) and a lower percentage of progressive disease (12.5% vs. 36%) if compared with radiotherapy alone or with a non-razoxane based medication. This combination was associated with a longer median survival (5 months vs. 2.2 months; P=0.052) and a 1-year survival rate of 37.5% vs. 0% (P=0.027). Both treatment groups belonged to similar prognosis subsets. The treatment was well tolerated. Taken together our data support the therapeutic concept of a combined razoxane radiation therapy in melanoma patients with brain metastases. The favorable treatment effects are probably due to the radiosensitizing and the cytorallentaric mode of action of razoxane. Since the patient numbers are low, confirmatory studies are certainly necessary.

Adult↗

PubMedDate not supplied

Therapeutic efficacy of two different cytostatic-linked phosphonates in combination with razoxane in the transplantable osteosarcoma of the rat.

Two new compounds, 4-[4-[bis-(2-chloroethyl)-amino-]phenyl]-1- hydroxybutane-1,1-bisphosphonic acid (BAD) and aminotris-(methylenephosphonato)-diamminoplatinum(II) (ADP) that both have cytostatic and osteotropic properties, have shown good therapeutic efficacy against an osteosarcoma which metastasizes and kills by lung metastases. We therefore combined each of these drugs with the antimetastic agent razoxane. Razoxane (20 mg/kg i.p., 5 days/week for 6 weeks) was administered in combination with either BAD (30 mg/kg i.p.) or ADP (37.5 mg/kg i.v.) twice weekly for 3 weeks. Tumour volumes, body weight, survival time and occurrence of metastases were recorded, in addition to the measurement of the metastasis area compared to the total lung area in serial histological lung samples. In both experiments, razoxane effected a significant increase in life span while being ineffective in tumour inhibition. Razoxane in combination with BAD displayed an enhanced anticancer activity which was not significant. ADP had a good antineoplastic activity and a large increase in survival time (144 per cent ILS). Razoxane used in combination with ADP did not influence antitumour efficacy. Median survivals of both ADP-treated groups were significantly longer than the razoxane-treated group. Analysis of the lung metastasis area showed a maximum of 57 per cent for the controls while all treated groups occupied a lesser area. The lowest metastases area was found with the combination treatment BAD + RAZ (18 per cent). This was considered an antimetastatic effect, while ADP treatment effected a time delay only. No change in metastatic pattern was observed in any of the treatment groups. Histological examination showed no effect on the capillaries in the proliferating region of the tumours that could account for the lower occurrence of metastases.

Animals↗

PubMed1985

The mutagenic activity of razoxane (ICRF 159): an anticancer agent.

The mutagenic activity of razoxane (ICRF 159) was studied using the Salmonella/microsome assay and rodent bone-marrow micronucleus and metaphase assays. Razoxane (up to 5000 micrograms/plate) did not cause an increase in the mutation frequency in the Salmonella/microsome assay. In the mouse micronucleus assay razoxane (200 and 400 mg kg-1 i.p.) was cytotoxic to the bone marrow cells (which limited the analysis) but an increase in micronucleated polychromatic erythrocytes was observed in razoxane dosed animals (5-fold compared to control value). In the Chinese hamster metaphase assay razoxane (up to 500 mg kg-1 orally) induced abnormal chromosome condensation and an increase in structural chromosome aberrations (7 fold compared to control value) as well as an increase in the number of polypoid cells (8-fold compared to control value). The mutagenic effect of razoxane was restricted to eukaryotic organisms and was associated with specific chromosomal changes.

Animals↗

PubMedDate not supplied

Prospective serial liver ultrasound scanning in resectable colorectal cancer treated with adjuvant razoxane.

Prospective serial ultrasound scanning (U/S) of the liver at 3-monthly intervals has been used to detect the presence of hepatic metastases from successfully resected Dukes' A, B and C grade colorectal carcinomas in a trial of the antimetastatic agent razoxane (ICRF 159). One hundred and twenty-six consecutive patients were randomly allocated to either adjuvant razoxane treatment (61) or to no further treatment (65). Twenty-six patients, 15 in the control group (23 per cent) and 11 in the razoxane treatment group (18 per cent) have developed hepatic metastases. All but three patients in the treated group and four in the controls were detected by U/S. In the control group four patients had definite metastases when metastases were first seen by ultrasound and three more, among the eight who initially had probable metastases, became definite metastases on ultrasound. In the treated group four patients had definite metastases and four more developed them amongst 12 who had probable metastases. The remaining eight of these 12 all regressed completely. This compared with only one complete regression (additionally on 5-FU for lung secondaries) amongst the eight controls who had probable metastases. The median time to development of liver metastases detected by U/S and other means was 59 weeks in the control group and 91 weeks in the razoxane treatment group. Ultrasound has proved to be a safe, sensitive and acceptable serial imaging technique for detecting colorectal liver metastases. Used prospectively, U/S has been valuable in monitoring the natural history of liver metastases and their behaviour during razoxane treatment.

Colonic Neoplasms↗

PubMed1983

The effects of razoxane (ICRF 159) on the production of collagenase and inhibitor (TIMP) by stimulated rabbit articular chondrocytes.

Monolayer cultures of rabbit chondrocytes were stimulated to produce collagenase with conditioned medium from human peripheral blood mononuclear cells (MCM), and the ability of Razoxane to modulate the production of collagenase and specific tissue inhibitor of metalloproteinases (TIMP) was studied. Collagenase production was inhibited and TIMP increased by Razoxane, in a dose-dependent manner, when cells were treated daily for 3 days. Over this period the effect of Razoxane was progressive; 50 micrograms/ml or less had no effect at day 1 but 50 micrograms/ml was effective by day 3. The effectiveness of Razoxane was inversely related to the degree of MCM stimulation and the confluency of the culture. On removal of the drug, chondrocytes stimulated with MCM recovered their ability to produce collagenase, and TIMP production returned to near normal. The results suggest that the ability of Razoxane to reduce collagenase and increase TIMP production may correlate with its effectiveness in treating psoriatic arthritis.

Animals↗

PubMed1982

Interaction of razoxane and radiation on cultured Chinese hamster cells.

Razoxane [(+/-)-1,2-bis(3,5-dioxopiperazine-1-yl)propane] was investigated for its effects on the survival of irradiated Chinese hamster fibroblasts in vitro. Razoxane alone produced cytotoxicity that was dependent upon drug concentration and pulse exposure time, with a preferential lethality for cells treated while in the DNA-synthetic phase. Razoxane enhanced radiation-induced cell killing when used as either a pulse exposure or a continuous treatment. In asynchronous populations of cells, this was expressed as an increase in the slope and a reduction in the shoulder of the radiation dose-survival curve. In synchronous populations of cells, a modest increase in cell killing was observed for those cells treated in G1 and G2, with a greater enhancement for cells treated in the S-phase. Overall, razoxane may potentiate the radiation-induced killing of cultured mammalian cells by a number of mechanisms: 1) a blockade of cell cycle progression causing an accumulation of cells in radiosensitive phases of the cell cycle; 2) selective cytotoxicity of cells in radioresistant phases of the cell cycle; 3) inhibition of the accumulation of sublethal radiation damage; or 4) interaction of the damages induced by each agent so as to produce an enhanced effect. These mechanisms may need to be considered if razoxane and radiation therapy are to be used in combined modality therapeutic approaches.

Animals↗

PubMed1996

Radiotherapy vs. radiotherapy and razoxane in the treatment of soft tissue sarcomas: final results of a randomized study.

PURPOSE: The effect of the sensitizer razoxane on soft tissue sarcomas (STS) was prospectively evaluated in a randomized, controlled trial. The main purpose of the study was to determine the response rates and local control under the combined treatment compared to irradiation alone. METHODS AND MATERIALS: Between 1978 and 1988, 144 patients entered the study; 130 were evaluable for response, toxicity, or survival. The patients were randomized to receive radiotherapy alone or radiotherapy with razoxane. They were divided into postoperative cases and patients with gross disease (unresectable primaries, recurrent disease, or metastatic disease). The median radiation dose was 60 Gy postoperatively, and 56-58 Gy in patients with gross disease. The dose difference has palliative reasons. Razoxane was given orally at a daily dose of 150 mg/m2 during the time of the radiotherapy, starting 5 days before the first irradiation. In general, the groups were comparable as to their prognostic factors. There was some imbalance, however, in favor of the postoperative group reveiving radiotherapy alone. RESULTS: Between the patient groups treated postoperatively in an adjuvant form, there were no substantial differences in local control and survival. Among 82 patients with gross disease, the treatment with radiotherapy and razoxane led to an increased response rate compared to photon irradiation alone (74 vs. 49%). The local control rate was likewise improved (64 vs. 30%;p < 0.05). The acute toxicity was somewhat higher in the sensitizer arm, but there was no difference in the occurrence of late complications. CONCLUSIONS: Radiotherapy combined with razoxane seems to improve the local control in inoperable, residual, or recurrent STS compared to radiotherapy alone. The combined treatment is a fairly well tolerated procedure at low costs. It can be recommended for inoperable primary STS or gross disease after incomplete resection, conditions which are still associated with limited local control and a grave prognosis.

Adolescent↗

PubMedDate not supplied

Combined radiotherapy and razoxane in the treatment of chondrosarcomas and chordomas.

BACKGROUND: Chondrosarcomas and chordomas are reported to have low radio-sensitivity. Therefore, a study was undertaken to explore the radioresponsiveness of these tumours using the sensitising agent razoxane. PATIENTS AND METHODS: Thirteen chondrosarcomas and five chordomas were irradiated with high-energy photons and razoxane in the period from 1984 to 2003. The median tumour dose was 60 Gy in the chondrosarcomas and 63 Gy in chordomas. Razoxane tablets were given at a dose of 125 mg twice daily starting 5 days before the first irradiation. The drug was continued on radiation days. RESULTS: Eight out of the 13 chondrosarcomas had unresectable or recurrent measurable disease. There were one complete and five partial responses, while two tumours remained unchanged (response rate 75%). The median duration of response was 22 months. Three out of four patients without clear surgical margins and one patient with clear margins had locally controlled disease. Overall, local control was achieved in seven out of twelve patients who were not radically resected. All five patients with chordomas survived 5 years and remained locally controlled at that time. Among four measurable tumours, two complete and one partial regression were noted. Razoxane was well tolerated; the dose limiting toxicity was leukopenia. CONCLUSION: Photon irradiation together with razoxane induces major responses in a majority of patients with chondrosarcomas and chordomas. This combination therapy seems to be more effective than photon irradiation alone.

Adolescent↗

PubMed1997

Suppression of metastatic potential and up-regulation of gelatinases and uPA in LLC by protracted in vivo treatment with dacarbazine or razoxane.

Treatment of mouse Lewis lung carcinoma with razoxane or dacarbazine was protracted for 10 transplant generations. While the capacity of the treated tumors to grow locally in immuno-competent or in immuno-depressed hosts was retained and not significantly modified, the metastatic phenotype was eliminated when the treated tumor cells were transplanted into immuno-competent hosts. The reduction in metastatic potential was slightly less pronounced, in terms of both number and volume of metastases, when the treated tumor cells were transplanted into immuno-depressed hosts. These properties were retained after 3 transplant generations without treatment. Northern blotting and zymography of primary-tumor crude extracts revealed that treatment with either razoxane or dacarbazine for one generation approximately doubled the expression of MMP-2 and MMP-9, while lacking any effect on that of 1.0 and of 3.5 kb TIMP-2. When the treatment was maintained for 10 generations, the expression of MMP-2 and MMP-9 for both drugs showed up-regulation of approximately 10- and 2-fold respectively. TIMP-2 mRNA of 1.0 kb doubled its expression, while that of 3.5 kb registered just above the control. Dacarbazine doubled the expression of uPA after 10 generations, while razoxane boosted it approximately 3-fold after either 1 or 10 generations. The permanent loss of metastatic phenotype induced in Lewis lung carcinoma by dacarbazine and razoxane is thus attributable to biological mechanisms independent of down-regulation of expression and/or activation of the 2 gelatinases.

Animals↗

PubMed1986

Randomized trial of oral adjuvant razoxane (ICRF 159) in resectable colorectal cancer: five-year follow-up.

Razoxane is one of the few agents which has shown activity in the treatment of advanced colorectal cancer. The drug has therefore been evaluated in a prospective randomized controlled trial as an adjuvant to surgery for resectable colorectal cancer. The results to median follow-up of 5 years are reported here. Accrual has ceased and a total of 272 patients entered the trial (133 control, 139 treatment). Treated patients received razoxane postoperatively on a continuous, long-term basis while control patients received identical clinical care but no adjuvant chemotherapy. Analysis of the results shows a significant prolongation of the time to recurrence for Dukes' C patients. All other groups including the overall analysis show no benefit although there is a consistent trend in favour of the treated patients except in Dukes' group 'D'. Razoxane is tolerated well by patients and causes minimal side-effects. However acute leukaemia occurred in three patients (2.45 per cent) after prolonged exposure to the drug and further evaluation should be in patients who are at high risk of developing recurrent cancer, in whom such a risk may be acceptable. It is concluded that razoxane is suitable for further evaluation in colorectal cancer and for incorporation into combination chemotherapy regimens.

Clinical Trials as Topic↗

PubMedDate not supplied

Antimetastatic effects of razoxane in a rat osteosarcoma model.

The cytostatic and antimetastatic activities of 1,2-di(3,5-dioxopiperazin-1-yl) propane (ICRF-159, razoxane) were studied in a transplantable, slowly growing osteosarcoma in Sprague-Dawley rats. This tumor model is characterized by osteoid formation and spontaneous metastasization to lungs, kidneys and lymph nodes. Razoxane given intraperitoneally (i.p.) from 2 days before to 14 days after tumor transplantation (30 mg/kg or 10 mg/kg per day) resulted in a dose-dependent prolongation of median survival time (83 or 48 days respectively, versus 38 days for the control group), but showed no influence on the growth of the primary tumor. Early treatment with razoxane (30 mg/kg i.p. from day -2 to +14) showed a greater inhibition of pulmonary metastases than later treatment (30 mg/kg i.p. from day +14 to +28 after transplantation). Whereas 59.9 per cent of the total sectional area of the lungs in the control animals was covered by osteosarcoma metastases, only 3.4 per cent and 26.1 per cent respectively was affected in the early and late razoxane treatment groups. Toxic side-effects of these treatment schedules were reversible diffuse alopecia, but no retardation of body weight gain.

Animals↗

PubMed1982

Razoxane penetration into the cerebrospinal fluid of rats.

Razoxane (100 mg/kg) was administered to rats as a single IP dose. Plasma and CSF samples were obtained at intervals varying from 15 min to 24 h after dosing, and the razoxane was assayed by a new and simple high performance liquid chromatography (HPLC) technique. Razoxane was absorbed quickly from the peritoneal cavity; it reached a peak concentration within 0.5 h and decayed with a half-life of 1.6 h. Only 10% of the plasma razoxane available entered the CSF, reaching a peak concentration by 2h, which was maintained for a further 4 h, and finally decaying to reach 10% of its peak value by 8 h.

Animals↗

PubMed1993

An evaluation of the effectiveness and safety of razoxane when used as an adjunct to surgery in colo-rectal cancer. Report of a controlled randomised study of 603 patients.

A prospective controlled randomised trial to evaluate the effectiveness and safety of razoxane is reported. Some 603 patients with colo-rectal cancer having curative surgery entered the study, and all have been followed up for a minimum of five years. Statistical analysis showed that razoxane treatment had no effect either beneficial or adverse on the rates of recurrence or on five year survival of patients with colo-rectal cancer. It is possible that a more prolonged course of razoxane might have significantly influenced survival. The incidence of severe adverse reaction was low but it is of concern that one patient developed leukaemia. Should razoxane be considered for future use it is recommended that continuous low dose therapy be given for no longer than 12 months. No renal, hepatic, pulmonary or cardiac toxicity was noted.

Aged↗

PubMed2003

A small prospective study of chordomas treated with radiotherapy and razoxane.

PURPOSE: To evaluate the local effect of conventional photon irradiation in chordomas if the radiosensitizing agent razoxane is added. The rationale for this procedure were improved results previously seen in soft tissue and chondrosarcomas with this combination. PATIENTS AND METHODS: Between 1988 and 1996, five patients with histologically confirmed chordomas of the skull base or the spine (three females, two males) were irradiated with 6- and 25-MeV photons under razoxane medication, one patient was treated with a telecobalt unit. Single doses of 180-200 cGy were given five times a week. The median total tumor dose was 63 Gy (range 54-67 Gy). Concomitantly, the radiosensitizer razoxane was administered at a dose of 125 mg twice daily p.o., median total dose 7.6 g. The drug was started 3-5 days before the first irradiation, and continued until the end of radiotherapy. RESULTS: After a potential median follow-up time of 10 years, three of the five patients are alive and show neither symptoms nor signs of recurrence in CT or MR images. One patient with persistent sacral chordoma died after 8 years from cardiac insufficiency, and another patient died after 6.5 years from a bleeding complication following surgery for recurrence. The patients remained locally controlled for 5, 5.5+, 6.4, 11+, and 13+ years, respectively. Objective tumor regressions were noted in three of four patients with measurable disease. Acute side effects included mucosal reactions, two of five patients developed a leukopenia WHO grade 3 due to razoxane. Serious long-term complications were not observed. CONCLUSIONS: Although the patient series is small, there is an interesting trend in local control and survival. The cases are unselected, and the follow-up time is of considerable duration. The treatment can easily be performed at any institution and is tolerated fairly well.

Adolescent↗

PubMed1994

Inoperable recurrent rectal cancer: results of a prospective trial with radiation therapy and razoxane.

PURPOSE: The effect of the sensitizer razoxane was prospectively evaluated in recurrent rectal cancer. Endpoints of the study were mainly local response rates and survival. METHODS AND MATERIALS: From 1984 to 1990 razoxane was given together with radiation therapy to 40 patients with recurrent inoperable rectal cancer. Loco-regional relapses in the pelvis were isolated in 24 and associated with distant metastases in 16 patients. Special attention was given to the subset of 24 patients with isolated local recurrences. This group was compared with historical controls treated with radiotherapy alone. The dosage of razoxane was 150 mg/m2 daily orally starting 5 days before the first irradiation. The drug was then given each radiation day until the end of treatment. The median radiation dose was 60 (40-62) Gy in the evaluable patients. The minimum follow-up was 32 months and the median 72 months. RESULTS: The rates of complete plus partial responses were 57% and 54%, respectively, for recurrent patients without and with distant metastasis. The 23 evaluable patients with isolated local relapses had a median survival of 24 months (12-94+); all patients surviving at least 1 year. CONCLUSION: The combination of radiotherapy and razoxane may lead to better local control and improved median survival compared to our historical controls and literature reports where radiotherapy alone was used. The treatment is easy to administer and is associated with a moderate toxicity.

Adult↗

PubMed2003

Measurement of renal tumour and normal tissue perfusion using positron emission tomography in a phase II clinical trial of razoxane.

Measurement of tumour and normal tissue perfusion in vivo in cancer patients will aid the clinical development of antiangiogenic and antivascular agents. We investigated the potential antiangiogenic effects of the drug razoxane by measuring the changes in parameters estimated from H(2)(15)O and C(15)O positron emission tomography (PET) to indicate alterations in vascular physiology. The study comprised 12 patients with primary or metastatic renal tumours >3 cm in diameter enrolled in a Phase II clinical trial of oral razoxane. Perfusion, fractional volume of distribution of water (VD) and blood volume (BV) were measured in tumour and normal tissue before and 4-8 weeks after treatment with 125 mg twice-daily razoxane. Renal tumour perfusion was variable but lower than normal tissue: mean 0.87 ml min(-1) ml(-1) (range 0.33-1.67) compared to renal parenchyma: mean 1.65 ml min(-1) ml(-1) (range 1.16-2.88). In eight patients, where parallel measurements were made during the same scan session, renal tumour perfusion was significantly lower than in normal kidney (P=0.0027). There was no statistically significant relationship between pretreatment perfusion and tumour size (r=0.32, n=13). In six patients scanned before and after razoxane administration, there was no statistically significant change in tumour perfusion: mean perfusion pretreatment was 0.81 ml min(-1) ml(-1) (range 0.46-1.26) and perfusion post-treatment was 0.72 ml min(-1) ml(-1) (range 0.51-1.15, P=0.15). Tumour VD and BV did not change significantly following treatment: mean pretreatment VD=0.66 (range 0.50-0.87), post-treatment VD=0.71 (range 0.63-0.82, P=0.22); pretreatment BV=0.18 ml ml(-1) (range 0.10-0.25), post-treatment BV=0.167 ml ml(-1) (range 0.091-0.24, P=0.55). Tumour perfusion, VD and BV did not change significantly with tumour progression. This study has shown that H(2)(15)O and C(15)O PET provide useful in vivo physiological measurements, that even highly angiogenic renal cancers have poor perfusion compared to surrounding normal tissue, and that PET can provide valuable information on the in vivo biology of angiogenesis in man and can assess the effects of antiangiogenic therapy.

Antineoplastic Agents↗