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High dose methotrexate as a preoperative adjuvant in the treatment of epidermoid carcinoma of the head and neck
High Dose Methotrexate as a Preoperative Adjuvant in the Treatment of Epidermoid Carcinoma of the Head and Neck A Feasibility Study and Clinical Trial John L. Tarpley, MD, Bethesda, Maryland Paul B. Chretien, MD, Bethesda, Maryland John C. Alexander, Jr, MD, Bethesda, Maryland Robert C. Hoye, MD, Bethesda, Maryland Jerome B. Block, MD, Bethesda, Maryland Alfred S. Ketcham, MD, Bethesda, Maryland
The treatment of carcinoma of the head and neck presents the difficult problem of both local and systemic control. To improve survival rates over those achieved with surgery or radiotherapy alone, radiotherapy has been used as a preoperative adjuvant. The primary goal of these regimens was to reduce local recurrences; however, conclusive evidence that this has been achieved is lacking thus far. Preoperative irradiation, however, is frequently associated with significant morbidity, such as impaired healing of the surgical wound, formation of fistulas, and, at least in one study, evidence of an increased incidence of systemic metastases [l31. To avoid the morbidity associated with radiation therapy used prior to surgery, trials of postoperative radiation therapy are in progress. Thus far, sufficient data have not accrued to determine the efficacy of these regimens. Chemotherapy has been used in the treatment of carcinoma of the head and neck primarily for inoperable and recurrent tumors. When administered systemically, a significant number of cases of tumor regression in inoperable patients has been achieved with methotrexate [4-71. Local arterial infusion of chemotherapeutic agents, especially methotrexate, has effected marked tumor regression and, as seen in limited follow-up studies, has reduced local recurrence rates after subsequent surgical resection. As with adjunctive radiation therapy, the ultimate effect of this combination on survival has not been assessed [8-121. From the Surgery Branch. National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Reprint requests should be addressed to Paul B. Chretien. MD. Surgery Branch, National Cancer Institute. National Institutes of Health, Sethesda. Maryland 20014. Presented at the Combined Meeting of the James Ewing Sodety and the Society of Head and Neck Surgeons, New Orleans, Louisiana, March 25-29.1975.
V&an.
130, octobar 1975
The beneficial effects of adjuvant chemotherapy in the management of malignant lesions classically treated by surgery alone are found in the experiences with osteogenic sarcoma, rhabdomyosarcoma, soft tissue sarcoma, and breast cancer [13-191. Of these, the most dramatic effects have been achieved in the management of osteogenic sarcoma. Methotrexate administered in extremely high doses immediately after amputation has reduced the incidence of recurrence from a historical rate of approximately 80 per cent in two years to projected rates of 20 to 30 per cent [I&16]. The demonstrated efficacy of preoperative chemotherapy in the treatment of other forms of malignancy and the regressions in inoperable tumors of the head and neck achieved with methotrexate led to this study to determine the effects of high dose methotrexate with leucovorin rescue when used preoperatively in patients with operable epidermoid carcinoma of the head and neck.
Material and Methods Thirty consecutive patients with operable, previously untreated epidermoid carcinoma of the head and neck who had no medical contraindications to the administration of systemic methotrexate were studied. There were thirteen oral, four pharyngeal, and thirteen laryngeal tumors. A control population of patients with similar tumors who met all the medical and other criteria for eligibility for preoperative methotrexate were selected from the patients treated by surgery alone at the National Cancer Institute prior to the institution of this protocol. The tumor site, TNM classification, stage, and status of the methotrexate-treated patients is presented in Table I and the controls in Table II. A comparison of the two groups by these parameters is presented in Table III.
481
Tarpley et al
or lymph node metastases. In thirteen patients, regression of the primary tumor occurred, in four regression of lymph node metastases occurred, and in six regression of both primary tumor and the nodal metastases occurred. In seven patients, or 23 per cent, regression of tumor was not documented. (Table IV.) Methotrexate toxicity was evaluated by laboratory and clinical indexes. The laboratory indexes of toxicity are shown in Table V. The mean of the lowest platelet counts occurring in a two week interval after operation was 164,000 per mm3 with a range of 63,000 to 274,000. The mean of the lowest white blood cell counts during the same interval was 5,660 per mm3 with a range of 2,100 to 11,100. The mean of the highest white blood cell counts was 12,200 per mm3 with a range of 6,600 to 17,200. No renal or hepatic toxicity was documented. The clinical indexes used to determine possible methotrexate toxicity and a comparison of the same parameters in the controls are shown in Table VI. The average number of intraoperative blood transfusion in the methotrexate-treated
The preoperative methotrexate regimen was. as follows: on day 1 methotrexate, 240 mg/m2, was given intravenously in 1,000 ml of 5 per cent dextrose in water over a twenty-four hour interval. This was followed by leucovorin, 75 mg intravenously, in 500 ml of 5 per cent dextrose in water over twelve hours. Six hours later, leucovorin, 12 mg, was given every six hours for a total of four doses. This regimen was repeated on day 5 and the operation was performed between days 12 and 15. Patients who had intraoperative transection of tumor, tumor in surgical margins, or lymph node metastases demonstrated histologically received postoperative methotrexate. This regimen consisted of methotrexate, 30 mg/m2, intravenously weekly for four doses followed by escalation to 60 mg/m2weekly for twelve doses, then the same dose monthly for two years. The recurrence and survival rates were evaluated using the life table analysis method. Time of recurrence and time of death were evaluated using Student’s t test. Results Of the thirty patients treated with preoperative methotrexate, tumor regression occurred in twenty-three. Tumor regression is defined as any measurable decrease in size of the primary tumor TABLE I
Preoperative Tumor Extent and Current Status of the Patients Treated with Preoperative Methotrexate
Patient 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
LH AB JD BM AR IE JD RM cw JS AS DB GS FD WI-I BG EA HD EC HG LT RC HJ ED MM ES AK JC HB WG
* Recurrence
482
Site
Txf’U’Jx
Larynx Tonsil Floor of the mouth Tongue Buccal mucosa Buccal mucosa Floor of the mouth Floor of the mouth Gingiva Tongue Palate Pyriform sinus Pyriform sinus Pyriform sinus Pyriform sinus Pyriform sinus Larynx Pyriform sinus Larynx Larynx Larynx Pyriform sinus Floor of the mouth Floor of the mouth Floor of the mouth Vallecula Base of the tongue Floor of the mouth Hypopharynx Vallecula in opposite
TaNaM, T,N,Mo T,N,Mo T,N,Mo T,N,Mo T,N,Mo T,N,Mo T,NoMo T,NJ% TJ%Mo T,N,% TJ’J,M, TM% T,N,Mo TJ’J,M, T,N,Mo T&,Mo T,N,W TN’% T,N,% T,W% TAM, T,W% T,W% TAM, T,N,Mo
TJ’J,Mo T,N&‘o T,W% T,N,M,
Status
Stage III
II III III II III III II II III IV IV II II II III IV III II III II IV II I IV III Ill II II III
No evidence No evidence Recurrence, Recurrence, Recurrence, No evidence Recurrence, Recurrence, No evidence No evidence No evidence Recurrence, Recurrence, No evidence Recurrence, Recurrence, No evidence Recurrence, No evidence No evidence No evidence No evidence No evidence No evidence Recurrence, Recurrence, Recurrence, No evidence No evidence Recurrence,
of disease > 36 mo of disease, 20 mo 9 mo; dead of disease, 19 mo 18 mo; dead of disease, 26 mo 5 mo; dead of disease, 10 mo of disease, 26 mo 26 mo; alive with disease, 30 mo 12 mo; dead of disease, 21 mo of disease, 26 mo of disease, 35 mo of disease > 36 mo 13 mo; dead of disease, 20 mo 5 mo; dead of disease, 7 mo of disease, 27 mo 4 mo; dead of disease, 21 mo 9 mo; dead of disease, 21 mo of disease, 14 mo 11 mo; no evidence of disease, 20 mo of disease, 23 mo of disease, 28 mo of disease, 23 mo of disease, 19 mo of disease, 16 mo of disease, 17 mo 6 mo; no evidence of disease, 17 mo 9 mo;* no evidence of disease, 16 mo 9 mo;* no evidence of disease, 11 mo of disease, 9 mo of disease, 10 mo 5 mo; dead of disease, 15 mo
neck.
The Ame&an
Journal d Surguy
Methotrexate in Epidermoid Carcinoma
group was 4.5 units with a range of 0 to 15 and in the controls, 4 units with a range of 0 to 15. Wound hematomas did not occur in the methotrexatetreated group but four occurred in the controls. Infectious complications were divided into two categories, local wound infections and pneumonitis. There were five wound infections in the methotrexate-treated group and nine in the controls. Complications of wound healing led to two orocutaneous fistulas in the methotrexate-treated group and five fist&as in the controls. Postoperative TABLE II
pneumonia developed in four methotrexate-treated patients and in nine controls. Postoperative temperatures greater than 38°C were noted in thirteen treated patients and in fifteen controls. Life table analysis of the disease-free interval in the two groups is presented in Figure 1. There is no statistical difference in the incidence of recurrence in the two groups. However, in the fifteen methotrexate-treated patients in whom recurrences developed, the average postoperative interval before recurrence was 10.13 months and in the
Preoperative Tumor Extent and Current Status of the Control Patients Stage
1. RR 2. RS
Larynx Tonsil
3. HB 4. MD
Floor Floor
5. 6. 7.
MH MS PT
Alveolar Alveolar Tongue
8.
FK
Floor
of the mouth of the mouth ridge ridge
of the mouth
T,W% T,N,Mo
II III
T,N,Mo TJ’J,Mo
III III
TIN,% T,N,‘% T,N,‘“‘o
III III III
T,W%
II
9. AH 10. GM 11. IS 12. WK
Floor of the mouth Tongue Palate Larynx
T,f’W’o T,N,Mo T,N,Mo -f’,N,Mo
I I III III
13.
HP
Pyriform
sinus
T,N,Mo
III
14.
JK
Pyriform
sinus
-f-,N,Mo
III
15.
TD
Vallecula
T,N,Mo
III
16.
JW
Larynx
T,N,W
Ill
17. 18. 19. 20. 21.
ES JP RJ HM cc
Pyriform Larynx Larynx Larynx Larynx
sinus
22.
WT
Pyriform
sinus
TJ’J,Mo
III
23.
OC
Floor
of the mouth
T,NoMo
I
24. 25. 26. 27. 28.
GB WS MH TH LF
Floor of the mouth Floor of the mouth Larnyx Vallecula Floor of the mouth
I III III II III
29. 30.
EM RP
Floor Floor
II IV
III II II II II
of the mouth of the mouth
Status No evidence of disease > 36 mo Recurrence, 6 mo; dead of disease, 15 mo No evidence of disease > 36 mo Recurrence, 5 mo; dead of disease, 7 mo No evidence of disease > 36 mo No evidence of disease > 36 mo No evidence of disease, 26 mo; dead, 26 mo* No evidence of disease, 8 mo; dead, 8 mot No evidence of disease > 36 mo No evidence of disease > 36 mo No evidence of disease > 36 mo Recurrence, 6 mo; dead of disease, 21 mo Recurrence, 7 mo; dead of disease, 13 mo Recurrence, 12 mo; no evidence of disease > 36 mo Recurrence, 7 mo; dead of disease, 12 mo Recurrence, 4 mo; dead of disease, 11 mo No evidence of disease > 36 mo No evidence of disease > 36 mo No evidence of disease > 36 mo No evidence of disease > 36 mo Recurrence, 5 mo; dead of disease, 17 mo Recurrence, 11 mo; dead of disease, 25 mo Recurrence, 7 mo; dead of disease, 9 mo No evidence of disease > 36 mo Recurrence, 1 mo; dead, 1 mot No evidence of disease > 36 mo No evidence of disease > 36 mo Recurrence, 11 mo; dead of disease, 28 mo No evidence of disease > 36 mo Recurrence, 9 mo; dead of disease, 9 mo
* Dead of second primary lesion (malignant melanoma). t Dead of unrelated cause (myocardial infarction in both). $ Recurrence in opposite neck.
vohmo 130. Octobar 1975
463
Tarpley et al
TABLE III
Comparison of Tumor Extent in the Controt and Methotrexate-Treated Patients
Patients
Site
Controls
Methotrexatetreated
TABLE V
Oropharynx Pharynx Larynx
13 3 12
Oropharynx Pharynx Larynx
13 4 13
Tumor
Nodes
Stage
T, T, T, T, T, T, T, T,
10 5 13 2 2
N, N, N, N, N,
11
N, 11
15 2
N, N,
I 4 II 8 III 17 IV 1 I 1 II 12 III 12 IV 5
12 17 1 0 14 4 1
Laboratory index of Toxicity of Preoperative Methotrexate Average 164
Lowest platelet count (per mm3) Lowest white blood cell count (per mmJ) Highest white blood cell count (per mm3) Hepatic renal toxicity
TABLE VI
Range (63-174)
5,660
(2,100-11,100)
12,220
(6,600-17,200)
None
Clinical index of Toxicity of Preoperative Methotrexate
Index
Controls
Transfusions Wound hematoma Fistula Wound infection Total wound complications Pneumonitis Temperature > 38°C
MethotrexateTreated Patients
K = 4.0 (O-15) 2 5 4 9
R = 4.5 (O-15) 0 2 3 5
9 15
4 13
METHOTREXATE
01 0
I
I
4
a
I
I
,
I
12 18 20 24 TIME POST-OP IN MONTHS
1
1
I
28
32
36
Figure 1. Lite tabts ana&sts of postoperative d&easefree lntervats tn the cm&at and methotrexate-treated pathts.
484
TABLE IV
Preoperative Clinical Responses of Tumor to Methotrexate in Thirty Patients Response
Positive response Tumor only Nodal only Tumor and nodal No response
Number of Patients 23 (77%) 13 4 6 7 (23%)
fourteen controls it was 6.78 months. The difference is significant (p < 0.05). (Figure 2.) Life table analysis of survival in the two groups is presented in Figure 3. The mean survival of the methotrexate-treated patients who thus far have died with disease was 16.4 months compared with 12.5 months in the controls. A trend toward longer survival in patients in whom recurrence develops after methotrexate treatment is suggested; however, only eighteen of the treated patients have been followed up two years or longer compared with a follow-up interval of three years or longer for all controls. Thus, valid statistical comparison of the two groups by this parameter must await completion of the follow-up period in the treated group. (Figure 4.) Comments The goal of the use of methotrexate as an adjuvant in the surgical treatment of epidermoid carcinoma of the head and neck was to improve both recurrence and survival rates. The data show that there was no difference in recurrence rates compared with those in retrospective controls, but the postoperative disease-free interval was longer in the treated patients in whom recurrences developed. Survival in the two groups did not differ significantly; however, there was a trend toward a longer survival in the treated patients who eventually died of recurrent tumor. These two observations consider different aspects of the clinical course of patients after treatment. Thus, although methotrexate did not improve the cure rate, it appeared to change the dynamics of tumor recurrence. At this dose level, methotrexate did not eradicate residual tumor, but it appeared to retard the growth rate of tumor that persisted after operation. Immunologic reactivity was not monitored in the postoperative interval in patients who received methotrexate after operation. However, correlations between immunologic reactivity and clinical course and the previously demonstrated immunosuppressive effects
lho Amerkan Journal ol Surgery
Methotrexate in Epidermoid Carcinoma
MTX
VS CDNT
t-2.066 df = 27 P
. . . -
x = 10.134 l
9.0
SEM-1.37 N-
0
.
4
a
12 16 .ZO 24 TIME POST-OP IN MONTiiS
15
26
32
36
... w l l
. .
.
. . . .
x-6.70 SEM - 0.02 N-
14
FIgwe 3. Life tabts anatysts of po&toperattve survtval In control and methotrexate-treated pattsnis.
. 24 METMOTREXAT~
CONTROL
GROUP
GROUP
Ft#ure 2. Compartson of the post@erattve iniervats befom tumor recwkcB h ftftaen conttvl and fourteen methotrexMe-treated pattents tn whoni recurkences havb developed.
r
20-
Y 5
.
.. . .
.
-
X=
16-
16.4
SEM = 2.1
.
N=7
E”
. .
r E
of methotrexate provoke the speculation that the doses of methotrexate used postoperatively had a deleterious effect by suppressing immune competence while failing to eradicate residual tumor. The major conclusion of this study is that patients with head and neck carcinoma, despite their relatively poor nutrition and susceptibility to postoperative pneumonia, undergo tumor resection without increased postoperative morbidity after high dose preoperative methotrexate therapy. The adjuvant did not increase the incidence of local infection, wound complications, or systemic infection. This contrasts sharply with the morbidity of preoperative radiation therapy reported in several trials. These results warrant a determination of the adjunctive effect of other agents when used preoperatively; alone or in combination, which have a therapeutic effect on epidermoid carcinoma. Summary Thirty patients with operable epidermoid carcinoma of the head and neck were treated with intravenous high dose methotrexate and leucovorin rescue prior to resection. Their clinical courses were compared with those of thirty randomly selected patients matched for tumor site and clinical stage who were treated by surgery alone. No medical or surgical complications associated with methotrexate were encountered. An objective vohmm 130. ociobu 1975
IZ-
ii
I=
.
SEM = 1.73
. . 0-
12.5
N-
;; i F
:
.
10
.
. .
4
t METHOTREXATE
CONTROL
TOTAL
TOTAL
N-
16
FOLLOWED
FOLLOWED
N-36
Fwrre 4. Comparfson of the posto#eratlve interval befiwe death of the ten controt and seven methotrexate-treateU path?nts who have d&d.
decregse. in tumor size (primary lesion or nodal metastases) was noted prior to resection in twentythree patients (77 per cent). The number of recurrences in the two groups was similar. However, there was a significantly greater disease-free interval in the methotrexate-treated patients (p < 0.05). No significant differences in survival have been noted to date between the two groups. In view of the absence of complications, the regressions in tumor size, and the increase in postoperative disease-free interval in this trial, evaluation as preoperative adjuvants of higher doses of methotrexate and of other chemotherapeutic agents in combination with methotrexate appears warranted. 485
Tarpley et al
References 1. Tucker HM, Rabuzti DD. Sagerman RH, Reed GF: Prevention of complications of composite resection after high dose preoperative radiotherapy. Laryngoscope 84: 933, 1974. 2. Marchetta FC, Sako K. Maxwell W: Complications after radical head and neck surgery performed through previously irradiated tissues. Am J Surg 114: 835, 1967. 3. Ogura JH, Biller HF: Preoperative irradiation for laryngeal and laryngopharyngeal cancers. Laryngoscope 80: 802,197O. 4. Capizzi RL, DeConti RC, March JC, Bertino JR: Methotrexate therapy of head and neck cancer: improvement in therapeutic index by the use of leucovorin “rescue.” Cancer Res30: 1782, 1970. 5. Sealy R, Helman P: Treatment of head and neck cancer with intraarterial cytotoxic drugs and radiotherapy. Cancer 30: 187, 1972. 6. Sullivan RD: Chemotherapy in head and neck cancer. JAMA 217: 461, 1971. 7. Vogler WR, Jacobs J: Toxic and therapeutic effects of methotrexate-folinic acid (leucovorin) in advanced cancer and leukemia. Cancer 28: 894, 197 1. 8. Donegan WL. Harris HS: Factors influencing the success of arterial infusion chemotherapy for cancer of the head and neck. Am J Surg 123: 549, 1972. 9. Freckman HA: Results in 169 patients with cancer of the head and neck treated by intra-arterial infusion therapy. Am J Sufg 124: 501, 1972. 10. Couture J. Deschenes L: Intraarterial infusion: an adjuvant to the treatment of oral carcinoma. Cancer 29: 1632.
488
1972. 11. Desprez JD, Kiehn CL, Sciotto C, Raniirez-Gonzales M: Response of oral carcinoma to preoperative methotrexate infusion therapy. Am J Surg 120: 461, 1970. 12. Oberfield RA: The role of chemotherapy in the treatment of carcinoma of the oral cavity. Otokwyngol C/in North Am 5: 365. 1972. 13. Fisher B, Carbone P, Economou SG, Frelick R, Glass A, Lerner H, Redmond C, Zelen M. Band P, Katrych DL, Wolmark N, Fisher ER: L-phenyhlanine mustard in the management of primary breast cancer. N Engl J Med 292: 117.1975. 14. Haskell CM, Silverstein MI. Rangel DM, Hunt JS, Sparks FC, Morton DL: Muitimodafii cancer therapy in man: a pilot study of adriamycin by arterial infusion. Cancer 33: 1485. 1974. 15. Jaffe N, Frei E, Traggis D, Bishop Y: Adjuvant rnethotrexate and citrovorum-factor treatment of osteogenic sarcoma. N Eng JMed291: 994, 1974. 16. Cartes EP, Holland JF, Wang JJ, Sinks LF. Blom J, Senn H, Bank, A. Glidewell 0: Amputation ahd adriamycin in primary osteosarcoma. N En@ J A&d 291: 998, 1974. 17. Kilman JW. Clatworthy HW Jr,,lJewton WA Jr, Grosfeki JL: Reasonable surgery for rhabdomyosarcoma: a study of 67 cases. Ann Surg 178: 346, 1973. 18. Hoiton CP, Chapman KE, Lackey RW, Hatch El, Baum ES, Favara BE: Extended combination therapy of childhood rhabdomyosarcoma. Cancer32: 1310, 1973. 19. McBride CM: Sarcomas of the limbs: results of adjuvant chemotherapy using isolation perfusion. Arch Surg 109: 304, 1974.
The Amrksn
Journal of Suqery
The treatment of carcinoma of the head and neck presents the difficult problem of both local and systemic control. To improve survival rates over those achieved with surgery or radiotherapy alone, radiotherapy has been used as a preoperative adjuvant. The primary goal of these regimens was to reduce local recurrences; however, conclusive evidence that this has been achieved is lacking thus far. Preoperative irradiation, however, is frequently associated with significant morbidity, such as impaired healing of the surgical wound, formation of fistulas, and, at least in one study, evidence of an increased incidence of systemic metastases [l31. To avoid the morbidity associated with radiation therapy used prior to surgery, trials of postoperative radiation therapy are in progress. Thus far, sufficient data have not accrued to determine the efficacy of these regimens. Chemotherapy has been used in the treatment of carcinoma of the head and neck primarily for inoperable and recurrent tumors. When administered systemically, a significant number of cases of tumor regression in inoperable patients has been achieved with methotrexate [4-71. Local arterial infusion of chemotherapeutic agents, especially methotrexate, has effected marked tumor regression and, as seen in limited follow-up studies, has reduced local recurrence rates after subsequent surgical resection. As with adjunctive radiation therapy, the ultimate effect of this combination on survival has not been assessed [8-121. From the Surgery Branch. National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Reprint requests should be addressed to Paul B. Chretien. MD. Surgery Branch, National Cancer Institute. National Institutes of Health, Sethesda. Maryland 20014. Presented at the Combined Meeting of the James Ewing Sodety and the Society of Head and Neck Surgeons, New Orleans, Louisiana, March 25-29.1975.
V&an.
130, octobar 1975
The beneficial effects of adjuvant chemotherapy in the management of malignant lesions classically treated by surgery alone are found in the experiences with osteogenic sarcoma, rhabdomyosarcoma, soft tissue sarcoma, and breast cancer [13-191. Of these, the most dramatic effects have been achieved in the management of osteogenic sarcoma. Methotrexate administered in extremely high doses immediately after amputation has reduced the incidence of recurrence from a historical rate of approximately 80 per cent in two years to projected rates of 20 to 30 per cent [I&16]. The demonstrated efficacy of preoperative chemotherapy in the treatment of other forms of malignancy and the regressions in inoperable tumors of the head and neck achieved with methotrexate led to this study to determine the effects of high dose methotrexate with leucovorin rescue when used preoperatively in patients with operable epidermoid carcinoma of the head and neck.
Material and Methods Thirty consecutive patients with operable, previously untreated epidermoid carcinoma of the head and neck who had no medical contraindications to the administration of systemic methotrexate were studied. There were thirteen oral, four pharyngeal, and thirteen laryngeal tumors. A control population of patients with similar tumors who met all the medical and other criteria for eligibility for preoperative methotrexate were selected from the patients treated by surgery alone at the National Cancer Institute prior to the institution of this protocol. The tumor site, TNM classification, stage, and status of the methotrexate-treated patients is presented in Table I and the controls in Table II. A comparison of the two groups by these parameters is presented in Table III.
481
Tarpley et al
or lymph node metastases. In thirteen patients, regression of the primary tumor occurred, in four regression of lymph node metastases occurred, and in six regression of both primary tumor and the nodal metastases occurred. In seven patients, or 23 per cent, regression of tumor was not documented. (Table IV.) Methotrexate toxicity was evaluated by laboratory and clinical indexes. The laboratory indexes of toxicity are shown in Table V. The mean of the lowest platelet counts occurring in a two week interval after operation was 164,000 per mm3 with a range of 63,000 to 274,000. The mean of the lowest white blood cell counts during the same interval was 5,660 per mm3 with a range of 2,100 to 11,100. The mean of the highest white blood cell counts was 12,200 per mm3 with a range of 6,600 to 17,200. No renal or hepatic toxicity was documented. The clinical indexes used to determine possible methotrexate toxicity and a comparison of the same parameters in the controls are shown in Table VI. The average number of intraoperative blood transfusion in the methotrexate-treated
The preoperative methotrexate regimen was. as follows: on day 1 methotrexate, 240 mg/m2, was given intravenously in 1,000 ml of 5 per cent dextrose in water over a twenty-four hour interval. This was followed by leucovorin, 75 mg intravenously, in 500 ml of 5 per cent dextrose in water over twelve hours. Six hours later, leucovorin, 12 mg, was given every six hours for a total of four doses. This regimen was repeated on day 5 and the operation was performed between days 12 and 15. Patients who had intraoperative transection of tumor, tumor in surgical margins, or lymph node metastases demonstrated histologically received postoperative methotrexate. This regimen consisted of methotrexate, 30 mg/m2, intravenously weekly for four doses followed by escalation to 60 mg/m2weekly for twelve doses, then the same dose monthly for two years. The recurrence and survival rates were evaluated using the life table analysis method. Time of recurrence and time of death were evaluated using Student’s t test. Results Of the thirty patients treated with preoperative methotrexate, tumor regression occurred in twenty-three. Tumor regression is defined as any measurable decrease in size of the primary tumor TABLE I
Preoperative Tumor Extent and Current Status of the Patients Treated with Preoperative Methotrexate
Patient 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
LH AB JD BM AR IE JD RM cw JS AS DB GS FD WI-I BG EA HD EC HG LT RC HJ ED MM ES AK JC HB WG
* Recurrence
482
Site
Txf’U’Jx
Larynx Tonsil Floor of the mouth Tongue Buccal mucosa Buccal mucosa Floor of the mouth Floor of the mouth Gingiva Tongue Palate Pyriform sinus Pyriform sinus Pyriform sinus Pyriform sinus Pyriform sinus Larynx Pyriform sinus Larynx Larynx Larynx Pyriform sinus Floor of the mouth Floor of the mouth Floor of the mouth Vallecula Base of the tongue Floor of the mouth Hypopharynx Vallecula in opposite
TaNaM, T,N,Mo T,N,Mo T,N,Mo T,N,Mo T,N,Mo T,N,Mo T,NoMo T,NJ% TJ%Mo T,N,% TJ’J,M, TM% T,N,Mo TJ’J,M, T,N,Mo T&,Mo T,N,W TN’% T,N,% T,W% TAM, T,W% T,W% TAM, T,N,Mo
TJ’J,Mo T,N&‘o T,W% T,N,M,
Status
Stage III
II III III II III III II II III IV IV II II II III IV III II III II IV II I IV III Ill II II III
No evidence No evidence Recurrence, Recurrence, Recurrence, No evidence Recurrence, Recurrence, No evidence No evidence No evidence Recurrence, Recurrence, No evidence Recurrence, Recurrence, No evidence Recurrence, No evidence No evidence No evidence No evidence No evidence No evidence Recurrence, Recurrence, Recurrence, No evidence No evidence Recurrence,
of disease > 36 mo of disease, 20 mo 9 mo; dead of disease, 19 mo 18 mo; dead of disease, 26 mo 5 mo; dead of disease, 10 mo of disease, 26 mo 26 mo; alive with disease, 30 mo 12 mo; dead of disease, 21 mo of disease, 26 mo of disease, 35 mo of disease > 36 mo 13 mo; dead of disease, 20 mo 5 mo; dead of disease, 7 mo of disease, 27 mo 4 mo; dead of disease, 21 mo 9 mo; dead of disease, 21 mo of disease, 14 mo 11 mo; no evidence of disease, 20 mo of disease, 23 mo of disease, 28 mo of disease, 23 mo of disease, 19 mo of disease, 16 mo of disease, 17 mo 6 mo; no evidence of disease, 17 mo 9 mo;* no evidence of disease, 16 mo 9 mo;* no evidence of disease, 11 mo of disease, 9 mo of disease, 10 mo 5 mo; dead of disease, 15 mo
neck.
The Ame&an
Journal d Surguy
Methotrexate in Epidermoid Carcinoma
group was 4.5 units with a range of 0 to 15 and in the controls, 4 units with a range of 0 to 15. Wound hematomas did not occur in the methotrexatetreated group but four occurred in the controls. Infectious complications were divided into two categories, local wound infections and pneumonitis. There were five wound infections in the methotrexate-treated group and nine in the controls. Complications of wound healing led to two orocutaneous fistulas in the methotrexate-treated group and five fist&as in the controls. Postoperative TABLE II
pneumonia developed in four methotrexate-treated patients and in nine controls. Postoperative temperatures greater than 38°C were noted in thirteen treated patients and in fifteen controls. Life table analysis of the disease-free interval in the two groups is presented in Figure 1. There is no statistical difference in the incidence of recurrence in the two groups. However, in the fifteen methotrexate-treated patients in whom recurrences developed, the average postoperative interval before recurrence was 10.13 months and in the
Preoperative Tumor Extent and Current Status of the Control Patients Stage
1. RR 2. RS
Larynx Tonsil
3. HB 4. MD
Floor Floor
5. 6. 7.
MH MS PT
Alveolar Alveolar Tongue
8.
FK
Floor
of the mouth of the mouth ridge ridge
of the mouth
T,W% T,N,Mo
II III
T,N,Mo TJ’J,Mo
III III
TIN,% T,N,‘% T,N,‘“‘o
III III III
T,W%
II
9. AH 10. GM 11. IS 12. WK
Floor of the mouth Tongue Palate Larynx
T,f’W’o T,N,Mo T,N,Mo -f’,N,Mo
I I III III
13.
HP
Pyriform
sinus
T,N,Mo
III
14.
JK
Pyriform
sinus
-f-,N,Mo
III
15.
TD
Vallecula
T,N,Mo
III
16.
JW
Larynx
T,N,W
Ill
17. 18. 19. 20. 21.
ES JP RJ HM cc
Pyriform Larynx Larynx Larynx Larynx
sinus
22.
WT
Pyriform
sinus
TJ’J,Mo
III
23.
OC
Floor
of the mouth
T,NoMo
I
24. 25. 26. 27. 28.
GB WS MH TH LF
Floor of the mouth Floor of the mouth Larnyx Vallecula Floor of the mouth
I III III II III
29. 30.
EM RP
Floor Floor
II IV
III II II II II
of the mouth of the mouth
Status No evidence of disease > 36 mo Recurrence, 6 mo; dead of disease, 15 mo No evidence of disease > 36 mo Recurrence, 5 mo; dead of disease, 7 mo No evidence of disease > 36 mo No evidence of disease > 36 mo No evidence of disease, 26 mo; dead, 26 mo* No evidence of disease, 8 mo; dead, 8 mot No evidence of disease > 36 mo No evidence of disease > 36 mo No evidence of disease > 36 mo Recurrence, 6 mo; dead of disease, 21 mo Recurrence, 7 mo; dead of disease, 13 mo Recurrence, 12 mo; no evidence of disease > 36 mo Recurrence, 7 mo; dead of disease, 12 mo Recurrence, 4 mo; dead of disease, 11 mo No evidence of disease > 36 mo No evidence of disease > 36 mo No evidence of disease > 36 mo No evidence of disease > 36 mo Recurrence, 5 mo; dead of disease, 17 mo Recurrence, 11 mo; dead of disease, 25 mo Recurrence, 7 mo; dead of disease, 9 mo No evidence of disease > 36 mo Recurrence, 1 mo; dead, 1 mot No evidence of disease > 36 mo No evidence of disease > 36 mo Recurrence, 11 mo; dead of disease, 28 mo No evidence of disease > 36 mo Recurrence, 9 mo; dead of disease, 9 mo
* Dead of second primary lesion (malignant melanoma). t Dead of unrelated cause (myocardial infarction in both). $ Recurrence in opposite neck.
vohmo 130. Octobar 1975
463
Tarpley et al
TABLE III
Comparison of Tumor Extent in the Controt and Methotrexate-Treated Patients
Patients
Site
Controls
Methotrexatetreated
TABLE V
Oropharynx Pharynx Larynx
13 3 12
Oropharynx Pharynx Larynx
13 4 13
Tumor
Nodes
Stage
T, T, T, T, T, T, T, T,
10 5 13 2 2
N, N, N, N, N,
11
N, 11
15 2
N, N,
I 4 II 8 III 17 IV 1 I 1 II 12 III 12 IV 5
12 17 1 0 14 4 1
Laboratory index of Toxicity of Preoperative Methotrexate Average 164
Lowest platelet count (per mm3) Lowest white blood cell count (per mmJ) Highest white blood cell count (per mm3) Hepatic renal toxicity
TABLE VI
Range (63-174)
5,660
(2,100-11,100)
12,220
(6,600-17,200)
None
Clinical index of Toxicity of Preoperative Methotrexate
Index
Controls
Transfusions Wound hematoma Fistula Wound infection Total wound complications Pneumonitis Temperature > 38°C
MethotrexateTreated Patients
K = 4.0 (O-15) 2 5 4 9
R = 4.5 (O-15) 0 2 3 5
9 15
4 13
METHOTREXATE
01 0
I
I
4
a
I
I
,
I
12 18 20 24 TIME POST-OP IN MONTHS
1
1
I
28
32
36
Figure 1. Lite tabts ana&sts of postoperative d&easefree lntervats tn the cm&at and methotrexate-treated pathts.
484
TABLE IV
Preoperative Clinical Responses of Tumor to Methotrexate in Thirty Patients Response
Positive response Tumor only Nodal only Tumor and nodal No response
Number of Patients 23 (77%) 13 4 6 7 (23%)
fourteen controls it was 6.78 months. The difference is significant (p < 0.05). (Figure 2.) Life table analysis of survival in the two groups is presented in Figure 3. The mean survival of the methotrexate-treated patients who thus far have died with disease was 16.4 months compared with 12.5 months in the controls. A trend toward longer survival in patients in whom recurrence develops after methotrexate treatment is suggested; however, only eighteen of the treated patients have been followed up two years or longer compared with a follow-up interval of three years or longer for all controls. Thus, valid statistical comparison of the two groups by this parameter must await completion of the follow-up period in the treated group. (Figure 4.) Comments The goal of the use of methotrexate as an adjuvant in the surgical treatment of epidermoid carcinoma of the head and neck was to improve both recurrence and survival rates. The data show that there was no difference in recurrence rates compared with those in retrospective controls, but the postoperative disease-free interval was longer in the treated patients in whom recurrences developed. Survival in the two groups did not differ significantly; however, there was a trend toward a longer survival in the treated patients who eventually died of recurrent tumor. These two observations consider different aspects of the clinical course of patients after treatment. Thus, although methotrexate did not improve the cure rate, it appeared to change the dynamics of tumor recurrence. At this dose level, methotrexate did not eradicate residual tumor, but it appeared to retard the growth rate of tumor that persisted after operation. Immunologic reactivity was not monitored in the postoperative interval in patients who received methotrexate after operation. However, correlations between immunologic reactivity and clinical course and the previously demonstrated immunosuppressive effects
lho Amerkan Journal ol Surgery
Methotrexate in Epidermoid Carcinoma
MTX
VS CDNT
t-2.066 df = 27 P
. . . -
x = 10.134 l
9.0
SEM-1.37 N-
0
.
4
a
12 16 .ZO 24 TIME POST-OP IN MONTiiS
15
26
32
36
... w l l
. .
.
. . . .
x-6.70 SEM - 0.02 N-
14
FIgwe 3. Life tabts anatysts of po&toperattve survtval In control and methotrexate-treated pattsnis.
. 24 METMOTREXAT~
CONTROL
GROUP
GROUP
Ft#ure 2. Compartson of the post@erattve iniervats befom tumor recwkcB h ftftaen conttvl and fourteen methotrexMe-treated pattents tn whoni recurkences havb developed.
r
20-
Y 5
.
.. . .
.
-
X=
16-
16.4
SEM = 2.1
.
N=7
E”
. .
r E
of methotrexate provoke the speculation that the doses of methotrexate used postoperatively had a deleterious effect by suppressing immune competence while failing to eradicate residual tumor. The major conclusion of this study is that patients with head and neck carcinoma, despite their relatively poor nutrition and susceptibility to postoperative pneumonia, undergo tumor resection without increased postoperative morbidity after high dose preoperative methotrexate therapy. The adjuvant did not increase the incidence of local infection, wound complications, or systemic infection. This contrasts sharply with the morbidity of preoperative radiation therapy reported in several trials. These results warrant a determination of the adjunctive effect of other agents when used preoperatively; alone or in combination, which have a therapeutic effect on epidermoid carcinoma. Summary Thirty patients with operable epidermoid carcinoma of the head and neck were treated with intravenous high dose methotrexate and leucovorin rescue prior to resection. Their clinical courses were compared with those of thirty randomly selected patients matched for tumor site and clinical stage who were treated by surgery alone. No medical or surgical complications associated with methotrexate were encountered. An objective vohmm 130. ociobu 1975
IZ-
ii
I=
.
SEM = 1.73
. . 0-
12.5
N-
;; i F
:
.
10
.
. .
4
t METHOTREXATE
CONTROL
TOTAL
TOTAL
N-
16
FOLLOWED
FOLLOWED
N-36
Fwrre 4. Comparfson of the posto#eratlve interval befiwe death of the ten controt and seven methotrexate-treateU path?nts who have d&d.
decregse. in tumor size (primary lesion or nodal metastases) was noted prior to resection in twentythree patients (77 per cent). The number of recurrences in the two groups was similar. However, there was a significantly greater disease-free interval in the methotrexate-treated patients (p < 0.05). No significant differences in survival have been noted to date between the two groups. In view of the absence of complications, the regressions in tumor size, and the increase in postoperative disease-free interval in this trial, evaluation as preoperative adjuvants of higher doses of methotrexate and of other chemotherapeutic agents in combination with methotrexate appears warranted. 485
Tarpley et al
References 1. Tucker HM, Rabuzti DD. Sagerman RH, Reed GF: Prevention of complications of composite resection after high dose preoperative radiotherapy. Laryngoscope 84: 933, 1974. 2. Marchetta FC, Sako K. Maxwell W: Complications after radical head and neck surgery performed through previously irradiated tissues. Am J Surg 114: 835, 1967. 3. Ogura JH, Biller HF: Preoperative irradiation for laryngeal and laryngopharyngeal cancers. Laryngoscope 80: 802,197O. 4. Capizzi RL, DeConti RC, March JC, Bertino JR: Methotrexate therapy of head and neck cancer: improvement in therapeutic index by the use of leucovorin “rescue.” Cancer Res30: 1782, 1970. 5. Sealy R, Helman P: Treatment of head and neck cancer with intraarterial cytotoxic drugs and radiotherapy. Cancer 30: 187, 1972. 6. Sullivan RD: Chemotherapy in head and neck cancer. JAMA 217: 461, 1971. 7. Vogler WR, Jacobs J: Toxic and therapeutic effects of methotrexate-folinic acid (leucovorin) in advanced cancer and leukemia. Cancer 28: 894, 197 1. 8. Donegan WL. Harris HS: Factors influencing the success of arterial infusion chemotherapy for cancer of the head and neck. Am J Surg 123: 549, 1972. 9. Freckman HA: Results in 169 patients with cancer of the head and neck treated by intra-arterial infusion therapy. Am J Sufg 124: 501, 1972. 10. Couture J. Deschenes L: Intraarterial infusion: an adjuvant to the treatment of oral carcinoma. Cancer 29: 1632.
488
1972. 11. Desprez JD, Kiehn CL, Sciotto C, Raniirez-Gonzales M: Response of oral carcinoma to preoperative methotrexate infusion therapy. Am J Surg 120: 461, 1970. 12. Oberfield RA: The role of chemotherapy in the treatment of carcinoma of the oral cavity. Otokwyngol C/in North Am 5: 365. 1972. 13. Fisher B, Carbone P, Economou SG, Frelick R, Glass A, Lerner H, Redmond C, Zelen M. Band P, Katrych DL, Wolmark N, Fisher ER: L-phenyhlanine mustard in the management of primary breast cancer. N Engl J Med 292: 117.1975. 14. Haskell CM, Silverstein MI. Rangel DM, Hunt JS, Sparks FC, Morton DL: Muitimodafii cancer therapy in man: a pilot study of adriamycin by arterial infusion. Cancer 33: 1485. 1974. 15. Jaffe N, Frei E, Traggis D, Bishop Y: Adjuvant rnethotrexate and citrovorum-factor treatment of osteogenic sarcoma. N Eng JMed291: 994, 1974. 16. Cartes EP, Holland JF, Wang JJ, Sinks LF. Blom J, Senn H, Bank, A. Glidewell 0: Amputation ahd adriamycin in primary osteosarcoma. N En@ J A&d 291: 998, 1974. 17. Kilman JW. Clatworthy HW Jr,,lJewton WA Jr, Grosfeki JL: Reasonable surgery for rhabdomyosarcoma: a study of 67 cases. Ann Surg 178: 346, 1973. 18. Hoiton CP, Chapman KE, Lackey RW, Hatch El, Baum ES, Favara BE: Extended combination therapy of childhood rhabdomyosarcoma. Cancer32: 1310, 1973. 19. McBride CM: Sarcomas of the limbs: results of adjuvant chemotherapy using isolation perfusion. Arch Surg 109: 304, 1974.
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