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"Radiosensitisers and Radioprotectors"

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Chemo-Radiotherapy combined with Methotrexate trials
Study Patients Course of irradiation Methotrexate and other drug treatment Toxicity DLT Findings of study Reference
152 patients with parameningeal sarcoma intrathecal chemotherapy with cytosine arabinoside, methotrexate, and hydrocortisone, during and after radiation therapy 8 patients paralyzing ascending myelitis Chemoradiotoxicity-associated spinal cord injury appears to be more likely to occur in adolescents than in younger or older ages. [1]
Phase II study patients with Brain and Central Nervous System Tumors external beam radiotherapy once daily, 5 days a week, for approximately 6 weeks. high-dose methotrexate(5 g/m2) IV over 24 hours on days 1 and 15 with chemotherapy drugs(cisplatin, etoposide, ifosfamide, vincristine sulfate) Giving two cycles of high-dose methotrexate prior to radiochemotherapy was feasible. [2]
Phase II study 19 patients with primary CNS lymphoma Radiation therapy begins no later than 3 weeks after completing chemotherapy Methotrexate, IV is administered over 40-60 minutes on days 1 and 15. Cytarabine is administered intrathecally on days 1 and 15. The second course of chemotherapy begins on day 29 or after bone marrow recovery. Cognitive impairment in 12 patients, White matter abnormalities, cortical atrophy. 1. Cognitive impairment was found in 12 patients (63%) despite a complete tumor response.
2. Combined modality treatment for primary CNS lymphoma is associated with cognitive impairment even in patients aged <60 years.
randomized trial 104 patients with stage III or IV inoperable head and neck cancer 7,000 cGy to the involved areas and 5,000 cGy to uninvolved neck at 180 cGy/fraction, five fractions/wk bleomycin, 5 U intravenously (IV), twice weekly during RT, followed by bleomycin, 15 U IV, and methotrexate, 25 mg/m2 IV weekly for 16 weeks after completion of RT 1. The local-regional complete response rate was 45% v 67% .
2. The 2-year local-regional control rate, including salvage surgery, was 26% v 64%
3. The incidence of distant metastasis was 24% v 38%, for the RT alone and RT plus CT groups, respectively.
a retrospective study 50 breast cancer patients with brain metastases whole brain radiation therapy before drug treatment Carmustine 100 mg/m2 on day 1 and Methotrexate 600 mg/m2 on day 1 and 15 of a 28 day cycle. One patient developed febrile neutropenia 1. Median progression-free survival and overall survival were 4.2 and 6.9 months respectively, with a one-year OS rate of 32%.
2. This combination appears to be effective and well tolerated in good performance status Breast cancer patients presenting with brain metastasis.
multicenter phase II study Immunocompetent patients with newly diagnosed Primary CNS lymphoma reduced dose WBRT (23.4 Gy), or, standard WBRT was offered (45 Gy). induction chemotherapy with rituximab, methotrexate, procarbazine, and vincristine (five to seven cycles); and cytarabine after radiotherapy rituximab, methotrexate, procarbazine, and vincristine (R-MPV) combined with consolidation reduced dose WBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity. [6]
non-randomized Phase II study Patients With Primary Testicular NonHodgkin's Lymphoma Drug therapy is followed by radiotherapy CHOP + Rituximab, With Intrathecal Methotrexate Disease-free survival, Progression-free survival, Event-free survival rate has been determined. [7]
12 patients with untreated verrucous carcinoma of the head and neck equivalent tumor dose of 44–70 Gy (median, 56 Gy) concomitant chemotherapy consisted of prolonged intravenous infusions of Vinblastine 2 mg (day 1); Methotrexate 50 mg (day 2); Bleomycin 15 mg (days 2 and 3), and repetition at 2–3 week intervals. 1. Combined radiochemotherapy with Vinblastine, Methotrexate, and Bleomycine is highly effective in the treatment of VC of the head and neck.
2. It could be successfully used in the patients with inoperable VC or as an alternative to surgery.
Phase II study patients with untreated, Advanced-stage, Follicular Lymphoma Iodine I131 tositumomab (Bexxar) lowdose methotrexate Use of lowdose methotrexate in combination with I131 tositumomab for its ability to lower the rate of (human antimouse antibody) HAMA formation in patients with previously untreated low-grade follicular lymphoma has been evaluated. [9]
randomized phase II trial patients with primary CNS lymphoma whole-brain radiotherapy High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone Grade 3-4 haematological toxicity was more common in the methotrexate plus cytarabine group 1. 7 patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% and 46%, respectively.
2. 9 patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% and 69% respectively.
3. In patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose methotrexate provides improved outcome with acceptable toxicity compared with high-dose methotrexate alone.
randomized trial 96 patients with advanced squamous cell carcinoma of the head and neck radical radiotherapy after methotrexate treatment
minimum total tumor doses were 6000-6600 rads delivered in 6-61/2 weeks at a rate of 1000 rads weekly
intravenous methotrexate, as 0.2 mg/kg per day for five days
increased to 240 mg/m2) on days 1, 5, 9
1. No significant differences were demonstrated in local disease control or actuarial survival rates at three and five years [11]
Radiotherapy combined with Methotrexate trials
Study Patients Course of irradiation Methotrexate treatment Toxicity DLT Findings of study Reference
48 patients with advanced head and neck tumors radiotherapy oral methotrexate(2.5 mg three times a day for 5 day)and IV methtrexate(25 mg every 3 days for a total of five doses) drop in blood count in orally and IV administered patients, severe edema 1. Three-year survival rates by life table analysis show no significant statistical difference between IV Methotrexate plus radiation or radiation alone.
2. Those treated with oral Methotrexate plus radiation have a statistically significant improved survival.
3. The use of either form of Methotrexate correlated with a lower rate of distant metastasis.
34 patients with advanced head and neck cancer radiotherapy synchronous with methotreate methotrexate (100 mg/m2) hematological toxicity was observed in six patients Complete resolution of disease was obtained in 18 patients [13]
pilot study patients with histologically proven advanced squamous cell carcinoma of the head and neck five daily fractions per week to a total of 15-16 fractions in 3 weeks Methotrexate 100mg/m2 was administered as a single intravenous injection 24 h prior to commencing radiotherapy and again 14 days later Haematological toxicity, septicaemia The treatment was well tolerated, with acceptable morbidity [14]
1. Bleyer A et al, Increased vulnerability of the spinal cord to radiation or intrathecal chemotherapy during adolescence: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2009 ;53(7):1205-10.
2. Wolff JE et al, High dose methotrexate for pediatric high grade glioma: results of the HIT-GBM-D pilot study. J Neurooncol. 2011 ;102(3):433-42.
3. Harder H et al, Cognitive status and quality of life after treatment for primary CNS lymphoma. Neurology. 2004 ;62(4):544-7.
4. Fu KK et al, Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial. J Clin Oncol. 1987;5(9):1410-8.
5. Jacot W et al, RCesaearrmch aurtisclteine and methotrexate in combination after whole brain radiation therapy in breast cancer patients presenting with brain metastases: a retrospective study. BMC Cancer. 2010 ;10:257.
6. Morris PG et al, Rituximab, Methotrexate, Procarbazine, and Vincristine followed by consolidation reduced-dose whole-brain adiotherapy and Cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol 2013;31:3971-3979.
7. Phase II study of combined modality treatment in primary testicular non-Hodgkin's lymphoma.
8. Strojan P et al, Radiochemotherapy with Vinblastine, Methotrexate, and Bleomycin in the treatment of verrucous carcinoma of the head and neck. J Surg Oncol. 2005 ;92(4):278-83.
9. Trial of low-dose Methotrexate and I 131 Tositumomab for previously untreated, advanced-stage, follicular lymphoma.
10. Ferreri AJ et al, High-dose cytarabine plus highdose methotrexate versus highdose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009 ;374(9700):1512-20.
11. Knowlton AH et al, Methotrexate and radiation therapy in the treatment of advanced head and neck tumors. Radiology. 1975 ;116(3):709-12.
12. Lustig RA, DeMare PA, Kramer S, Adjuvant methotrexate in the radiotherapeutic management of advanced tumors of the head and neck. Cancer 1976;37(6):2703-8.
13. Pointon RC et al, Treatment of advanced head and neck carcinoma with synchronous irradiation and methotrexate. Cancer Treat Rep. 1981;65 Suppl 1:145-8.
14. Pointon RC et al, Treatment of advanced head and neck cancer using synchronous therapy with methotrexate and irradiation. Clin Radiol. 1983;34(4):459-62.