Methotrexate and Radiation in the Treatmentof Patients with Cancer*
P. T. CONDIT, G. R. RIDINGS,! J. W. COIN,ÎG. R. WILLIAMS,D. MITCHELL,JR.§AND G. W. BOLES
(Oklahoma Medical Research Institute; Departments of Medicine, Radiology and Surgery, University of Oklahoma Schoolof Medicine; and Department of Radiology, St. Anthony Hospital, Oklahoma City, Oklahoma)
SUMMARYAbout one-third of patients with squamous carcinoma of the head and neck treated
with methotrexate experience partial regression of tumors with associated symptomatic relief for a period of 1-3 months. Complete regression for longer periods canoccur but is unusual. About two-thirds derive temporary symptomatic relief,particularly reduction of pain. These results can be achieved by large, infrequentintravenous doses with little or no drug toxicity. Intra-arterial administration ofmethotrexate confers no obvious advantage.
Methotrexate added to conventional protracted schedules of radiation therapy results in unacceptable drug toxicity but can be combined with short intensive coursesof radiation without appreciable toxicity. The occurrence of prolonged remissionsin patients with squamous carcinoma of the head and neck after treatment with lessthan curative doses of radiation plus methotrexate suggests that the drug potentiatesthe therapeutic effects of radiation.
An earlier study of the effects of large doses of methotrexate in patients with cancer indicated not only that anintermittent dosage regimen was feasible but also that ithad some value in the management of these patients (3).One-third of the patients with squamous carcinomasshowed objective evidence of tumor regression, whereashalf had subjective improvement. A group of patientsreported by Sullivan et al. (9) with squamous carcinomaslimited to the head and neck showed an even higher incidence of transient response.
The present investigation was designed to provide moreinformation about the role of methotrexate in the management of patients with squamous carcinoma, particularlyof the head and neck. Methotrexate alone produced thesame incidence of response as in the previous study (3),but the responses were still disappointingly short in duration. In an attempt to improve therapeutic results, thestudies were extended to explore the therapeutic potentialities and toxic effects of combinations of methotrexate withradiation therapy.
* Supported by Grants No. T-118 and T-119 and by a FlorenceL. Fenton Memorial Grant for Cancer Research from the American Cancer Society, and by Grant No. CA-05815from the NationalInstitutes of Health.
Presented at the 54th Annual Meeting of the American Association for Cancer Research, Toronto, Canada, May 24, 1963.
t Present address: Department of Radiology, School of Medicine, University of Missouri, Columbia, Missouri.
Methotrexate.—Methotrexate (amethopterin; 4-amino-10-methylpteroylglutamic acid; MTX) was prepared in aconcentration of 50 mg/ml. Four routes of administration were used: all 43 patients received intravenous doses;in addition, four patients were given intra-arterial doses,one patient received a subcutaneous dose, and one patienthad two courses of small, daily, oral doses.
Intravenous and intra-arterial doses were given rapidlyas single large (1.3-23 mg/kg) doses over a period of 1-2minutes. For intra-arterial administration, a polyethylene catheter was placed in the external carotid arteryjust distal to its origin, either retrograde via the superficialtemporal artery or percutaneously via the common carotidartery under fluoroscopic control as described by Seldinger(7). The position of the catheter was established byangiography, and the area infused was localized by inspection under ultraviolet light after the injection offluorescein.
Radiation therapy.—Radiation therapy was given eitherby a 2 Mev. van de Graaff generator at 250 ¿tamp.,12.5
* All with squamous carcinoma except if5, who had basal-cell carcinoma.|W = white; N = Negro; I = Indian.ÎIncludes one subcutaneous dose.§Includes two oral courses of 45 and 35 days' duration.
mm. Cu HVL, 100 cm. TSD, or by a Theratron Jr. Co60unit with a 1200-curie source at 55-60 cm. SSD.
The three dosage schedules are shown schematically inChart 1. Schedule I: daily, protracted at about 200 radsper dose, 5 times a week for 5 weeks to a total tumor dose of5000 rads; Schedule II: twice weekly, protracted at 500rads per dose, twice a week for 5 weeks to a total tumordose of 5000 rads; Schedule III: short, intensive at a rateof 400-800 rads tumor dose per dose for (usually) 3 days.In four cases a repeat course was given after an averageinterval of 19 days.
Large, intravenous doses of methotrexate were given atintervals of about 2 weeks during the 5 weeks of radiationtherapy by Schedules I and II, for a planned total ofthree doses. With Schedule III, a dose of methotrexatewas given with each course of radiation therapy.
Criteria for response.—Responseswere classified as complete or partial. A response was considered completewhen all evidence of tumor disappeared ; partial responseswere determined as described in Reference 3.
Definitions of toxicity.—The toxicity produced by methotrexate was classified as mild, moderate, or severe. Mildtoxicity consisted of anorexia, nausea, occasional vomiting,oral ulcers, but did not require interruption of radiationtherapy. Moderate toxicity consisted of the same symptoms and signs, but of a more severe degree—or withleukocytes below 2000 cells per cu. mm., platelets below50,000 cells per cu. mm., or combinations of these findings
II. TV/ICE WEEKLY, PROTRACTED. 500 rads/dose , 5000 rads total.
-»« il 11 11 11 11
1 1 1 1 15 WEEKS|—
MIX ÃŽ ÃŽIII. SHORT,INTENSIVE. 400-800 rods/dose.
*— 111 111
3 DAYS | 1 1 1 1
MTX ÃŽ \
CHART1.—Treatment schedules used. See text for details.
sufficient to require interruption or termination of radiation therapy. Severe toxicity included all the precedingfindings or leukocytes below 1000 cells per cu. mm. orplatelets below 25,000 cells per cu. mm.; and in severalcases survival was in doubt for a period of time. Onedeath did occur (v. infra).
RESULTSMethotrexate alone.—The21 patients treated by metho
trexate are presented in Table 1. More than half had
* All with squamous carcinoma except as marked.t Tumor dose.Ì.Lost to follow-up.§Primary unknown.# + means still in remission on 4/1/64.IfDays between courses.
advanced disease with extensive recurrent tumor, weightloss, pain, and limitation of activity.
The doses varied in number from one to eleven, in sizefrom 1.3 to 23 mg/kg, in total amounts from 230 to 5415
mg., and were separated by intervals of from 9 to 30 days.Drug toxicity was not a problem, because nine had notoxicity, six had mild symptoms, five had moderate andonly one had severe toxicity (consisting of asymptomatic
CHART2.—Case15. Changes in hematocrit, platelets, and leukocytes due to seven intra-arterial, one subcutaneous, and four intravenous doses are shown.
Only one patient had a complete remission, and he wasnot symptom-free because of chronic osteomyelitis of theexposed mandible (Patient #21, Figs. 1 and 2). He wasclinically free of tumor for 5 months. SLxpatients showedpartial responses varying from 3 weeks to 3 months induration. The incidence of objective response was sevenout of 21, or 33 per cent, with an average duration of 2.3months.
Four patients were given methotrexate by the intra-arterial route as well as intravenously. There was noobvious difference between these two routes in the production of systemic drug toxicity or in anti-tumor effects.One patient's course is summarized in Chart 2. The
changes in hematocrit, leukocyte, and platelet countsduring the administration of seven intra-arterial, one subcutaneous, and four intravenous doses of methotrexateare presented. Only the last intravenous dose, 27 daysbefore death, produced marked depression of leukocytesand platelets, and even this drop was transient and followed by a rise to above normal counts. No gastrointestinal toxicity occurred. Another patient was given2 mg/kg into the internal carotid artery. For the next 5days he was semistuporous and partially blind but eventually recovered completely.
Six patients experienced symptomatic improvementwithout apparent change in their lesions. Relief of pain,increase in appetite and spirits, as well as activity wereobserved.
Methotrexate plus radiation therapy.—The 25 patientstreated by combinations of methotrexate and radiation
therapy are summarized in Table 2. Three of thesepatients received additional methotrexate at other times(Table 1: Patients No. 5, 11, and 19).
Methotrexate toxicity for each of the three treatmentschedules is listed in Table 3. With Schedules I and IIdrug toxicity was a serious problem, with eleven of 22patients developing moderate or severe toxicity, includingone death. Schedule III, however, produced little toxicity, with only one patient classified as having moderatetoxicity.
with toxicity. All the patients treated by Schedule IIIresponded for an average of 15.7 months, and two of theseven are still in remission.
CASE REPORTSCase 81, a 65-year-old white male, had a 3-year history of a
lump at the left corner of his mouth. He was treated with x-rayon two occasions, receiving 4400 r in 5 days 100 kvP and later4400 r in 24 days, 2 Mev., and presented on 1/30/62 with alarge recurrent tumor over the left mandible (Fig. 1). Biopsy:recurrent squamous carcinoma of the lip. He was treated withmethotrexate as follows: 2/2/62, 7 mg/kg (500 mg.) intravenously; 2/12/62, 3 mg/kg (210 mg.) intra-arterially(left); 2/23/62, 5 mg/kg (340 mg.) intra-arterially (left);3/7/62, 5 mg/kg (335 mg.) intra-arterially (right); 3/22/62,6 mg/kg (400 mg.) intravenously; 4/6/62, 7.6 mg/kg (500 mg.)intravenously; 4/25/62, 5 mg/kg (325 mg.) intravenously;5/21/62, 5 mgAg (375 mg.) intravenously; 6/19/62, 8.3 mg/kg(500 mg.) intra-arterially (left) ; 7/8/62,9 mg/kg (500 mg.) intravenously. Complete regression of the tumor occurred by 4/5/62(Fig. 2) and was maintained until death on 7/28/62. Chronicosteomyelitis of the exposed mandible remained a troublesomecomplication. He died at home, and details of his terminalillness are not available.
Case 26, a 57-year-old Negro female, appeared for the firsttime on 10/20/60 with a 4- to 5-month history of enlargementof the jaw (Fig. 3). Biopsy showed squamous carcinoma; siteof origin could not be determined. She was given 5 mg/kg(250 mg.) methotrexate intravenously on 10/20/60 and 1450rads from 10/24/60 to 10/25/60. She returned on 11/2/60with considerable reduction in size of the tumor (Fig. 4) andwas treated again with 5 mg/kg (250 mg.) methotrexate intravenously on 11/2/60, together with 1450 rads from 11/3/60 to11/4/60. Further extensive tumor regression was apparentwhen she returned on 11/23/60 (Fig. 5). She was treated subsequently with more methotrexate and radiation and died ofrecurrent tumor hi July, 1961.
Case 34, a 62-year-old white male, presented on 12/29/60 witha 2-year history of squamous carcinoma of the left lower lip,treated on two occasions by surgical excision, and with a largerecurrent tumor involving the left alveolar ridge destroyingmuch of the underlying mandible. He was treated with methotrexate, 7.5 mg/kg (475 mg.) intravenously on 1/7/61, 5 mg/kg(325 mg.) intravenously on 2/10/61, and radiation therapy,2200 rads from 12/29/60 to 1/3/61 (3 treatments), and 550 radson 2/6/61. He developed moderate erythema in the radiatedarea, but no systemic toxicity. Complete regression of thetumor ensued which lasted until 4/5/62 (Fig. 6) when it recurred as before. He was retreated with methotrexate: 4/9/62,5 mg/kg (300 mg.) intravenously; 4/26/62, 4 mg/kg (220 mg.)intravenously; 5/10/62, 4 mg/kg (250 mg.) intravenously andradiation therapy, 4850 rads from 4/16/62 to 5/25/62. Complete regression again occurred, this time without toxicity (Fig.7 11/7/62). Destruction of the mandible progressed to pathologic fracture (Fig. 8, 8/29/61), which healed and recalcifiedafter therapy (Fig. 9, 11/7/62). He was free of disease on3/1/63, 26 months after his initial combination therapy but hasbeen lost to follow-up.
Case 35, a 50-year-old white female, was begun on combined
therapy with methotrexate and radiation for squamous carcinoma of the palate of 6 months' duration on 10/16/62. Radia
tion therapy was given twice a week from 10/16/62 to 11/23/62,for a total of 5100 rads. Methotrexate was given on 10/19/62,3 mg/kg (180 mg.) intravenously, 11/1/62, 3 mg/kg (177 mg.)intravenously, and on 11/23/62, 2 mg/kg (112 mg.) intravenously. The first dose produced no toxicity, but because ofmoderate toxicity after the second dose 12 days later the thirdwas delayed for 22 days and reduced to two-thirds the previousdoses. Despite these precautions she rapidly developed overwhelming methotrexate toxicity and died on 11/29/62, 6 daysafter the last dose of methotrexate.
Case 41, a 66-year-old white male, had had a squamous carcinoma of the left maxillary gingival ridge for 2 years, treatedon four occasions by Co60radiation, 5300 r in 32 days, 1250 r in5 days, 2850 r in 10 days, and 600 r in 2 days, with only partialresponse, and then by surgery. On 10/17/61, 4 months aftersurgery, he had a recurrence at the apex of the operative defectbeneath the orbit, proved by biopsy. Treatment consisted ofmethotrexate 7.5 mg/kg (460 mg.) intravenously on 10/27/61,5 mg/kg (310 mg.) intravenously on 11/15/61, 7.5 mg/kg (480mg.) intravenously on 12/1/61, and 5 mg/kg (315 mg.) intravenously on 12/26/61; and radiation therapy, 1150 rads from11/14/61 to 11/16/61. The tumor regressed completely andhas not recurred.2
Cose 42, a 63-year-old white male, appeared on 12/15/60 withan 18-month history of squamous carcinoma of the nose. Previous therapy had consisted of 673 mg. hours of radium and 4400 r170 kvP x-ray therapy in 22 days to the tip of the nose, followed by a left radical neck dissection. Recurrence was in theright neck attached to the mandible. He was treated with methotrexate: 7.5 mg/kg (475 mg.) intravenously on 12/17/60, and7.5 mg/kg(475 mg.) intravenously on 1/14/61; and with radiation: 1450 rads from 12/16/60 to 12/19/60, and 1450 radsfrom 1/3/61 to 1/5/61. The tumor disappeared and has notrecurred.3
Case 48, a 76-year-old white male, was admitted about 2months after the onset of dysphagia and hoarseness. He hada squamous carcinoma of the hypopharynx, presenting as a4 X 4-cm. mass at the angle of the left mandible and bulginginto the left pyriform sinus. Treatment consisted of methotrexate: 2 mg/kg (125 mg.) intravenously on 12/18/60, and2.8mg/kg (175 mg.) intravenously on 1/10/61; and radiation,1450 rads from 12/16/60 tol2/20/60, and 1000 rads from 1/9/61to 1/10/61. The tumor regressed and had not recurred on8/16/62, but he has been lost to follow-up.
DISCUSSION
Only seven of the 21 patients treated by methotrexatealone showed objective evidence of tumor regression. Theincidence of response of 33 per cent was the same encountered in the previous study (3), but the duration of 2.3months was twice as long. This result was obtained at acost of only one severe and five moderately severe episodesof drug toxicity, an incidence of 29 per cent.
Therapeutic responses were obtained when methotrexate2 Status on 4/1/64.8 Status on 4/1/64.
Fio. 1.—Case 21. Appearance on 1/31/62, prior to therapy.FIG. 2.—Case 21. Appearance on 4/5/62.FIG. 3.—Case 26. Appearance on 10/20/60, prior to therapy.FIG. 4.—Case 26. Appearance on 11/2/60.FIG. 5.—Case 26. Appearance on 11/23/60.
CoNDiT et al.—Methotrexate and Radiation in thà T̈reatment of Cancer 1533
was given by the oral, intravenous, or intra-arterial routes.Since only one patient was treated by the oral route, noconclusions about the general utility of this route can bedrawn, but the experience of others (2, 10) has been disappointing. There was no obvious advantage to the intra-arterial route either in reduction of systemic drug toxicityor in enhancement of local anti-tumor effects. The centralnervous system toxicity following injection into the internal carotid artery emphasizes the necessity for accuratepositioning of the catheter in the external carotid artery.Because of the hazards, the technical difficulties, the lack ofobvious therapeutic advantage, and the fact that onlyeight of the 33 patients with squamous carcinomas of thehead and neck had adequately localized lesions, the intra-arterial approach has been abandoned. For the reasonsdiscussed previously (3) continuous intravenous or intra-arterial infusions of methotrexate were not given.
Based on the experience to date, it is possible to make atentative appraisal of the role of methotrexate in themanagement of patients with squamous carcinomas of thehead and neck. About one-third of them can expectpartial regression of tumors with associated symptomaticrelief for a period of 1-3 months. Complete regression forlonger periods can occur, but is unusual. About two-thirds will derive symptomatic relief for short periods oftime, the most important being reduction of pain. Theseresults can be achieved by large, infrequent intravenousdoses without undue drug toxicity. Administration ofmethotrexate by the intra-arterial route is probably notwarranted.
Because of the obvious limitations of methotrexatealone, the feasibility of combining it with radiation therapywas explored. Schedule I is a conventional protracted,fractionated regimen; Schedule II is a variant of it. Theaddition of methotrexate to either of these schedulesproduced considerable toxicity including one death.Schedule III was initially used for palliation, but it wasfound that methotrexate could be added to this schedulewith no increase in toxicity.
The role of methotrexate in obtaining the remissionsobserved after combined therapy cannot be evaluated fromthe data presented. Some patients achieved remissionsafter doses of radiation somewhat smaller than usuallyconsidered curative. By applying the reasoning used byFriedman (5) based on the time-dose curves of Strandqvist(8), a suggestion of enhancement of the effects of radiationis obtained. None of the studies reported to date, however, provide a clear answer to the contribution of methotrexate to radiation therapy (1, 5, 6). A controlled randomized study designed to answer this question is currentlyin progress.
Doses of methotrexate that would usually cause littleor no toxicity produced severe effects in a number of patients treated by Schedules I and II, but not by Schedule
ACKNOWLEDGMENTSPlacement of the intra-arterial catheters was supervised by
Dr. G. S. Knox. Patient #41 was given radiation therapy byDr. D. C. Lowry. Patient #29 was given radiation therapy byDr. S. M. Classer.
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