Br. J. Surg. Vol. 62 (1975) 497-500
Nitrogen mustard as adjunctive chemotherapy for breast carcinoma J A M E S R . H I N E S A N D J O H N S. W I L L I A M S SUMMARY
A retrospective study is reported of 38 patients with breast carcinoma treated by radical mastectomy and a short course of nitrogen mustard. They were followed up j o r an average of 10 years. There were no serious untoward reactions to the drug, The 5- and 10-year corrected survival rates were 74 and 71 per cent respectively. There would appear to be a renewal of interest in adjuvant chemotherapy Jor patients with breast carcinoma.
POSTOPERATIVE adjunctive chemotherapy for patients with breast carcinoma is being reappraised. There have been at least 32 different studies using single drugs or combinations of drugs as adjuvant treatment in patients with ‘surgically resectable’ breast cancer and many new studies are in progress (Tormey and Geelhoed, 1975). Impetus for improved primary treatment of breast carcinoma comes from disappointment in the results of extended operations, pre- and postoperative irradiation, prophylactic oophorectomy and exogenous hormones. Immunotherapy has not yet had a significant impact as it is just beginning to be tried clinically. While new trials using adjuvant chemotherapy are being started, there is a need to examine the results of earlier work in this area. This study reviews retrospectively the records of 38 patients who received a short course of nitrogen mustard as an adjuvant to radical mastectomy. These patients have been followed up for an average of 10 years. We can find only one other series in the English literature in which nitrogen mustard was used as the sole adjunctive chemotherapeutic agent in patients with breast carcinoma.
Patients and methods The 38 fm-de patients in this study had ‘surgically curable’ breast carcinoma as there were no cases with skin ulceration, chest wall fixation, fixed axillary nodes, distant metastases or inflammatory carcinoma. The ages of the patients ranged from 30 to 72 years, the average being 5 5 years. None of these patients had a serious associated medical illness. The size of the primary tumour ranged from 1 to 10 cm in greatest dimension, the average being 3 cm. All the tumours were adenocarcinoma of ductal origin. Thirteen of the 38 patients had one or more positive axillary lymph nodes. All the patients were subjected to a standard radical mastectomy’ The wounds were washed with a 50 per cent sodium hypochlorite @akin’s) Solution Prior to Skin c l o s ~ ~in r ean effort to reduce local recurrence. Nitrogen mustard was given 36*
intravenously during the operation and on the first 2 postoperative days. The total dose was 0.4 mg/kg and each patient received an average of 7 m g a day for 3 days. Leucocyte and platelet counts were taken daily in 34 of the 38 patients. Patients with positive nodes received postoperative irradiation to the axillary, internal mammary and supraclavicular areas, the average total dose being about 7000 rad. Five patients, all premenopausal, were subjected to prophylactic oophorectomy shortly after mastectomy. The postoperative follow-up was from 7 to 15 years. the average being 10 years. One patient was lost to follow-up after 50 months, but all of the others have been traced. WBC
3000
I000
1
,
,
,
6
,
,
,
,
9
,
,
,
,
,
,
,
15 Postoperative day 12
,
,
I
18
Fig. 1. Serial leucocyte counts in patients receiving NH, following mastectomy. Each dot represents the lowest count of a patient and the postoperative day that it was recorded.
Results None of the patients in this series developed complications directly attributable to the chemotherapy. There were no deaths or serious postoperative morbidity. Wound problems occurred in 12 of the 38 patients (32 per cent). These were fluid collection in 6 patients, heavy crusting of the skin edges with slow healing in 3 patients, necrosis of skin requiring grafting in 2 patients and scar formation requiring plastic correction in 1 patient. These complications are similar in type and degree to those found in most series of patients with radical mastectomy with chemotherapy (Cohn et al., 1968). No significant depression of platelet counts was noted. Leucocyte depression was common, the lowest count being 900/ml. The lowest white blood cell counts were from the twelfth to the
* Department of Surgery, Northwestern University Medical School, Chicago, Illinois. 497
James R. Hines and John S. Williams Table I: HISTOLOGY OF THE TUMOURS No. of Tumour tYDe patients Poorly differentiated scirrhous carcinoma Poorly differentiated adenocarcinorna Well-differentiated scirrhous carcinoma Well-differentiated adenocarcinoma Poorly differentiated mucinous carcinoma Well-differentiated medullary carcinoma Well-differentiated mucinous carcinoma Well-differentiated intraductal carcinoma Undifferentiated carcinoma
No. died
4
16 5 4
3 0
3 2
0
2
0
1 1
0
I
1
1
1
Table II: NODAL STATUS OF THE PATIENTS No. of No. No. of oositive nodes patients died X survived 0 1-3 4 or more
24
3
2 9
1
50
6
32
87.5
eighteenth day and the average count on the fifteenth postoperative day was 2030/ml (Fig. 1 ) . After this time a gradual rise toward normal was seen and the counts had returned to normal by the thirtieth day. Reverse isolation was used when the white cell count went below 2000/mI. One patient was lost to follow-up at 50 months. At that time she was clinically free of her tumour. Two patients died of unrelated diseases, one at 34 months and one at 50months; both patients wereclinically free of breast carcinoma at the time of their death. Thus, 35 patients were available for long term follow-up. Two patients developed carcinoma in the opposite breast, one at 6 years and one at 7 years. Both are still alive 5 and 7 years later, following a second mastectomy. Local skin recurrences were detected in 2 patients, one at I year and one at 4 years. The first patient is still alive 7 years later, but the second died of disseminated disease. Two patients developed isolated bone lesions presumed to be metastases, one in a pelvic bone 4 years after mastectomy and one in a rib 4 years after mastectomy. Both were treated by irradiation and are alive 6 and 7 years later respectively. Four of the 5 patients subjected to prophylactic or adjunctive oophorectomy are alive and well. Two of these patients had the isolated bone lesions. Ten of the 35 patients followed up died of breast carcinoma. The other 25 patients (71 per cent) are alive and clinically free of breast cancer at this time. Of the deaths, 9 patients died within 5 years and one died 10 years following mastectomy: The average time from mastectomy to death was 42 months. The patients with the more undifferentiated tumours had a somewhat lower rate of survival (Table I ) . The patients with positive lymph nodes had a markedly reduced survival rate (Table ZI). The crude 5-year survival rate was 68 per cent and the adjusted 5-year survival rate was 74 per cent. The crude 10-year survival rate was 65 per cent and the adjusted 10-year survival rate was 71 per cent.
Discussion The principle of adjuvant chemotherapy is based on two experimental observations. In animals, cure of 498
implanted carcinoma has been achieved following subtotal tumour resection and simultaneous administration of chemotherapeutic agents. In addition, chemotherapeutic agents were effective in preventing the ‘take’ of injected tumour cells (Cruz et al., 1956; McDonald et al., 1956, 1957). Circulating tumour cells have been demonstrated in the bloodstream of patients with various forms of malignancy. The number of these tumour cells increases during periods of surgical manipulation (Roberts et al., 1961; Evans and Scott, 1969). The objective of adjuvant chemotherapy is both the prevention of implantation of circulating tumour cells and the possible eradication of early metastases. During the mid-1950s many investigators began clinical trials of adjuvant chemotherapy in the surgical treatment for breast carcinoma (Shimkin and Moore, 1958; Holland, 1961; Roberts et al., 1961; Noer, 1963; Fisher et al., 1968; Donegan, 1970; Mrazek and McDonald, 1970; Nissen-Meyer, 1970; Finney, 1971; Fisher, 1971; Nissen-Meyer et al., 1971; Donegan, 1974). Results varied from markedly optimistic, especially during the early phases of the studies (Mrazek and McDonald, 1970), to those showing decreased survival and increased recurrence compared with control groups (Finney, 1971). In most of the studies single agent, short-term, postmastectomy chemotherapy did little to alter the longterm survival in breast carcinoma. The major investigation, undertaken by the National Institutes of Health National Surgical Adjuvant Breast Project (NSABP) involving 23 separate institutions over a 10-year period, was reported by Fisher et al. in 1968. A total of 1341 patients in the project received thiotepa, 5-fluorouracil or a placebo. They found that a 3-day course of postoperative thiotepa to be of benefit only to premenopausal women with four or more histologically positive axillary lymph nodes. The 5year survival rate in this group was 58 per cent, and was 25 per cent in the controls. They also found that thiotepa seemed to have the same inhibitory effect on local recurrence that is seen with postoperative radiotherapy. Tormey and Geelhoed (1975) quoted a Russian study reporting a lowered recurrence rate following 2 weeks of postoperative thiotepa. They also reported that a German study using oral cyclophosphamide for 2 months effectively reduced recurrence, and a study from a Scandinavian group using cyclophosphamide also gave good early results. Mrazek and McDonald (1970) gave nitrogen mustard at the time of operation and every 3 months for several courses of treatment. They found a reduced recurrence rate, especially in premenopausal patients with negative axillary nodes. This is the only study we have found in which nitrogen mustard was used as the sole adjuvant drug in the primary treatment of breast carcinoma. The long term use of adjuvant chemotherapy with thiotepa has been reported by Long et al. (1969) and Donegan (1970,1974). They gave weekly injections and have reported a trend towards improved survival in patients with negative axillary nodes. The NSABP is
Nitrogen mustard and breast carcinoma organizing a trial of long term chemotherapy with phenylalanine nitrogen mustard as an adjuvant to radical mastectomy in patients with four o r more positive axillary nodes (Fisher, 1972). Combination chemotherapy has had encouraging results in patients with metastatic breast carcinoma (Carter, 1972). Protocols for adjuvant chemotherapy with a combination of drugs are being developed by several groups including the Eastern Oncology Group, Acute Leukemia Group B, the Mayo Clinic and Berto Verici in Milan. Another intriguing possibility that has been suggested is the combination of chemotherapy and immunotherapy. Chemotherapy would serve to decrease the number of tumour cells prior to the initiation of immunotherapy (Fisher, 1972). The current study of 38 patients is too small to provide evidence for o r against adjuvant chemotherapy in breast carcinoma. The 71 per cent survival rate with an average follow-up of 10 years is above the average 5- or 10-year survival rates (Butcher, 1961; Goldenberg et al., 1961). This survival rate may have been favourably influenced by aggressive postoperative follow-up care. The incidence of complications in this series was no greater than that seen in patients having radical mastectomy without chemotherapy, and there was no significant patient discomfort o r increased hospital stay associated with the treatment. While the use of nitrogen mustard did not prevent the use of other forms of adjuvant therapy-irradiation and oophorectomy-it has the potential for causing serious untoward effects. Nitrogen mustard (mustargen hydrochloride, NH,) is the parent compound of all the alkylating agents and one of the first chemotherapeutic agents found to be effective against tumour cells. Alkylating agents affect tumour cells (and to a lesser extent normal cells) by disturbing D N A synthesis during cell division through a process of misreplication of the D N A chains (Finney, 1971). HN, has the disadvantage of requiring intravenous administration because of its vesicant properties, but this caused no problem in the present series as all the patients were hospitalized and were given a short course of treatment. N H 2 has been shown to be effective in the treatment of metastatic breast carcinoma (Holland, 1961 ; Carter, 1972). Immediate undesirable reactions of NH, include anorexia, nausea and vomiting. Long term untoward effects include leucopenia, thrombocytopenia, allergic rash, infection with herpes zoster and menstrual irregularities. Phlebitis, skin slough and severe brawny induration have been seen following local infiltration of the drug. Nitrogen mustard can cause serious problems. A patient in our institution died of leucopenia and thrombocytopenia following its administration as adjuvant chemotherapy. In a nearby hospital a subcutaneous extravasation of NH, caused a skin slough that required extensive skin grafting. While the untoward effects of nitrogen mustard have limited its use as an adjuvant agent, the studies using this drug are so few that we feel even this small series should be reported.
The value of adjuvant chemotherapy in breast carcinoma is not known. Bernard Fisher, one of the principal investigators in the NSABP study, feels that the trials to date d o not repudiate the value of adjuvant chemotherapy, but simply provide ‘no test’ (Fisher, 1972). Because of increased understanding of tumour pathology, tumour-host relationships, the mechanism of chemotherapeutic agents and the development of new drugs, new trials should be undertaken. While renewed interest appears warranted, it is still an experimental procedure. Only by well-planned, cooperative, prospective clinical trials can the value of this treatment be obtained in a reasonable period of time. Surgeons should join these trials if there is a possibility of long term benefit to the patients and the treatment has a low incidence of toxicity. D r Douglas C . Tormey, Chief of the National Cancer Institute’s Medical Breast Cancer Service, said in March 1974: ‘Current estimates suggest that micrometastases are present with a breast mass’ and that animal studies strongly suggest ‘it is much easier to eradicate early micrometastases than it is for them to become clinically manifest’. References jun. (1961) Effectiveness Of radical mastectomy for mammary cancer: an analysis of mortality by the method of probits. Ann. Surg. 154, 383-396. CARTER s. jun. (1972) Single and combined nonhormonal chemotherapy in breast cancer. Cancer 30, 1543-1555. COHN I . , SLACK N . and FISHER B. (1968) Comp~ications and toxic manifestations of surgical adjuvant chemotherapy for breast cancer. Surg. Cynecol. Obsret. 127, 1201-1209. CRUZ E, MCDONALD A . and COLE w. (1956) Prophylactic treatment of cancer, the use of chemotherapeutic agents to prevent tumor metastases. Suvgery 40, 29 1-296. DONEGAN w. L. (1970) Prolonged surgical adjuvant chemotherapy with Thio-TEPA for mammary carcinoma. Tenth Int. Cancer Congr. (Abstr.), p. 500. DONEGAN w. L. (1974) Extended adjuvant chemotherapy for mammary carcinoma. Central Surgical Assoc., 2lst Annual Meeting, Cincinnati, Ohio, March 1974. EVANS H . J. and SCOTT D. (1969) The induction of chromosome aberrations by nitrogen mustard and its dependence on D N A synthesis. Proc. R. SOC.Lond. (Biol.) 173, 491-512. FINNEY R . (1971) Adjuvant chemotherapy in the radical treatment of carcinoma of the breast-a clinical trial. Am. J . Roentgenol. 111, 137-141. FISHER B. (1971) Status of adjuvant therapy: results of the national surgical adjuvant breast project studies on oophorectomy, post-operative radiation therapy and chemotherapy. Cancer, 28 1654-1658. FISHER B. ( I 972) Surgical adjuvant therapy for breast cancer. Cancer 30, 1556-1 564. BUTCHER H. R .
499
James R. Hines and John S. Williams rISHER B., RAVDIN R. G., AUSMAN R. K., SLACK M. H., MORE G. E. and NOHR R. J. (1968) Surgical adju-
vant chemotherapy in cancer of the breast. Ann. Surg. 168, 337-356. GOLDENBERG I. s., BAILAR J. c., HAYES M. A. and LOWERY R. (1961) Female breast cancer: a reevaluation. Ann. Surg. 154, 397-407. HOLLAND J. F. (1961) Chemotherapy and chemopraxis of cancer, 1951. Cancer Res. 21, 1036-1099. LONG R. T., DONEGAN w. L. and EVANS A. M. (1969) Extended surgical chemotherapy for breast carcinoma. Am. J . Surg. 117, 701-704. MCDONALD G. o., CRUZ E. P. and COLE w. H. (1956) The effect of cancer inhibitor drugs on the “take” of Walker carcinosarcoma 256 in rats. Surg. Forum 7 , 486-489. MCDONALD G . o., LIVINSTON c., BOYLE c. R. and COLE w. H. (1957) The prophylactic treatment of malignant disease with nitrogen mustard and triethylenethiophosphromide (Thio-TEPA). Ann. Surg. 145, 624-629. MRAZEK R. G. and MCDONALD G. 0. (1970) Surgery and adjuvant chemotherapy in treatment of Breast carcinoma. Tenth Int. Cancer Congr. (Abstr.), p. 501.
500
( I 970) Preliminary report from the Scandinavian adjuvant study group. Tenth Int. Cancer Congr. (Abstr.), p. 499. NISSEN-MEYER R., KJELLGREN K., and MANSSON B. (1971) Preliminary report from the Scandinavian adjuvant chemotherapy study group. Cancer Chemother. Rep. 55, 561-566. NOER R. J. (1963) Adjuvant chemotherapy. ThioTEPA with radical mastectomy in the treatment of breast Cancer. Am. J. Surg. 106, 405412. NISSEN-MEYER R.
ROBERTS S., JONASSON O., MCCREW E. and COLE
LONG
L.,
M C G R A T H R.,
w. (1961) Clinical significance of cancer cells in the circulating blood. Ann. Surg. 154, 362-371. SHIMKIN M. B. and MOORE c. E. (1958) Adjuvant use of chemotherapy in the surgical treatment of cancer: plan of cooperative study. J A M A 167, 17 10-1 7 14. TORMEY D. c. (1974) Cancer therapy: how you can gauge adequacy of treatment. Med. Wld News, 17 May, pp. 38-44. TORMEY D. c. and GEELHOED G . w. (1975) Current concepts in the management of breast carcinoma. Contemporary Surg. 5, 9.
Nitrogen mustard as adjunctive chemotherapy for breast carcinoma J A M E S R . H I N E S A N D J O H N S. W I L L I A M S SUMMARY
A retrospective study is reported of 38 patients with breast carcinoma treated by radical mastectomy and a short course of nitrogen mustard. They were followed up j o r an average of 10 years. There were no serious untoward reactions to the drug, The 5- and 10-year corrected survival rates were 74 and 71 per cent respectively. There would appear to be a renewal of interest in adjuvant chemotherapy Jor patients with breast carcinoma.
POSTOPERATIVE adjunctive chemotherapy for patients with breast carcinoma is being reappraised. There have been at least 32 different studies using single drugs or combinations of drugs as adjuvant treatment in patients with ‘surgically resectable’ breast cancer and many new studies are in progress (Tormey and Geelhoed, 1975). Impetus for improved primary treatment of breast carcinoma comes from disappointment in the results of extended operations, pre- and postoperative irradiation, prophylactic oophorectomy and exogenous hormones. Immunotherapy has not yet had a significant impact as it is just beginning to be tried clinically. While new trials using adjuvant chemotherapy are being started, there is a need to examine the results of earlier work in this area. This study reviews retrospectively the records of 38 patients who received a short course of nitrogen mustard as an adjuvant to radical mastectomy. These patients have been followed up for an average of 10 years. We can find only one other series in the English literature in which nitrogen mustard was used as the sole adjunctive chemotherapeutic agent in patients with breast carcinoma.
Patients and methods The 38 fm-de patients in this study had ‘surgically curable’ breast carcinoma as there were no cases with skin ulceration, chest wall fixation, fixed axillary nodes, distant metastases or inflammatory carcinoma. The ages of the patients ranged from 30 to 72 years, the average being 5 5 years. None of these patients had a serious associated medical illness. The size of the primary tumour ranged from 1 to 10 cm in greatest dimension, the average being 3 cm. All the tumours were adenocarcinoma of ductal origin. Thirteen of the 38 patients had one or more positive axillary lymph nodes. All the patients were subjected to a standard radical mastectomy’ The wounds were washed with a 50 per cent sodium hypochlorite @akin’s) Solution Prior to Skin c l o s ~ ~in r ean effort to reduce local recurrence. Nitrogen mustard was given 36*
intravenously during the operation and on the first 2 postoperative days. The total dose was 0.4 mg/kg and each patient received an average of 7 m g a day for 3 days. Leucocyte and platelet counts were taken daily in 34 of the 38 patients. Patients with positive nodes received postoperative irradiation to the axillary, internal mammary and supraclavicular areas, the average total dose being about 7000 rad. Five patients, all premenopausal, were subjected to prophylactic oophorectomy shortly after mastectomy. The postoperative follow-up was from 7 to 15 years. the average being 10 years. One patient was lost to follow-up after 50 months, but all of the others have been traced. WBC
3000
I000
1
,
,
,
6
,
,
,
,
9
,
,
,
,
,
,
,
15 Postoperative day 12
,
,
I
18
Fig. 1. Serial leucocyte counts in patients receiving NH, following mastectomy. Each dot represents the lowest count of a patient and the postoperative day that it was recorded.
Results None of the patients in this series developed complications directly attributable to the chemotherapy. There were no deaths or serious postoperative morbidity. Wound problems occurred in 12 of the 38 patients (32 per cent). These were fluid collection in 6 patients, heavy crusting of the skin edges with slow healing in 3 patients, necrosis of skin requiring grafting in 2 patients and scar formation requiring plastic correction in 1 patient. These complications are similar in type and degree to those found in most series of patients with radical mastectomy with chemotherapy (Cohn et al., 1968). No significant depression of platelet counts was noted. Leucocyte depression was common, the lowest count being 900/ml. The lowest white blood cell counts were from the twelfth to the
* Department of Surgery, Northwestern University Medical School, Chicago, Illinois. 497
James R. Hines and John S. Williams Table I: HISTOLOGY OF THE TUMOURS No. of Tumour tYDe patients Poorly differentiated scirrhous carcinoma Poorly differentiated adenocarcinorna Well-differentiated scirrhous carcinoma Well-differentiated adenocarcinoma Poorly differentiated mucinous carcinoma Well-differentiated medullary carcinoma Well-differentiated mucinous carcinoma Well-differentiated intraductal carcinoma Undifferentiated carcinoma
No. died
4
16 5 4
3 0
3 2
0
2
0
1 1
0
I
1
1
1
Table II: NODAL STATUS OF THE PATIENTS No. of No. No. of oositive nodes patients died X survived 0 1-3 4 or more
24
3
2 9
1
50
6
32
87.5
eighteenth day and the average count on the fifteenth postoperative day was 2030/ml (Fig. 1 ) . After this time a gradual rise toward normal was seen and the counts had returned to normal by the thirtieth day. Reverse isolation was used when the white cell count went below 2000/mI. One patient was lost to follow-up at 50 months. At that time she was clinically free of her tumour. Two patients died of unrelated diseases, one at 34 months and one at 50months; both patients wereclinically free of breast carcinoma at the time of their death. Thus, 35 patients were available for long term follow-up. Two patients developed carcinoma in the opposite breast, one at 6 years and one at 7 years. Both are still alive 5 and 7 years later, following a second mastectomy. Local skin recurrences were detected in 2 patients, one at I year and one at 4 years. The first patient is still alive 7 years later, but the second died of disseminated disease. Two patients developed isolated bone lesions presumed to be metastases, one in a pelvic bone 4 years after mastectomy and one in a rib 4 years after mastectomy. Both were treated by irradiation and are alive 6 and 7 years later respectively. Four of the 5 patients subjected to prophylactic or adjunctive oophorectomy are alive and well. Two of these patients had the isolated bone lesions. Ten of the 35 patients followed up died of breast carcinoma. The other 25 patients (71 per cent) are alive and clinically free of breast cancer at this time. Of the deaths, 9 patients died within 5 years and one died 10 years following mastectomy: The average time from mastectomy to death was 42 months. The patients with the more undifferentiated tumours had a somewhat lower rate of survival (Table I ) . The patients with positive lymph nodes had a markedly reduced survival rate (Table ZI). The crude 5-year survival rate was 68 per cent and the adjusted 5-year survival rate was 74 per cent. The crude 10-year survival rate was 65 per cent and the adjusted 10-year survival rate was 71 per cent.
Discussion The principle of adjuvant chemotherapy is based on two experimental observations. In animals, cure of 498
implanted carcinoma has been achieved following subtotal tumour resection and simultaneous administration of chemotherapeutic agents. In addition, chemotherapeutic agents were effective in preventing the ‘take’ of injected tumour cells (Cruz et al., 1956; McDonald et al., 1956, 1957). Circulating tumour cells have been demonstrated in the bloodstream of patients with various forms of malignancy. The number of these tumour cells increases during periods of surgical manipulation (Roberts et al., 1961; Evans and Scott, 1969). The objective of adjuvant chemotherapy is both the prevention of implantation of circulating tumour cells and the possible eradication of early metastases. During the mid-1950s many investigators began clinical trials of adjuvant chemotherapy in the surgical treatment for breast carcinoma (Shimkin and Moore, 1958; Holland, 1961; Roberts et al., 1961; Noer, 1963; Fisher et al., 1968; Donegan, 1970; Mrazek and McDonald, 1970; Nissen-Meyer, 1970; Finney, 1971; Fisher, 1971; Nissen-Meyer et al., 1971; Donegan, 1974). Results varied from markedly optimistic, especially during the early phases of the studies (Mrazek and McDonald, 1970), to those showing decreased survival and increased recurrence compared with control groups (Finney, 1971). In most of the studies single agent, short-term, postmastectomy chemotherapy did little to alter the longterm survival in breast carcinoma. The major investigation, undertaken by the National Institutes of Health National Surgical Adjuvant Breast Project (NSABP) involving 23 separate institutions over a 10-year period, was reported by Fisher et al. in 1968. A total of 1341 patients in the project received thiotepa, 5-fluorouracil or a placebo. They found that a 3-day course of postoperative thiotepa to be of benefit only to premenopausal women with four or more histologically positive axillary lymph nodes. The 5year survival rate in this group was 58 per cent, and was 25 per cent in the controls. They also found that thiotepa seemed to have the same inhibitory effect on local recurrence that is seen with postoperative radiotherapy. Tormey and Geelhoed (1975) quoted a Russian study reporting a lowered recurrence rate following 2 weeks of postoperative thiotepa. They also reported that a German study using oral cyclophosphamide for 2 months effectively reduced recurrence, and a study from a Scandinavian group using cyclophosphamide also gave good early results. Mrazek and McDonald (1970) gave nitrogen mustard at the time of operation and every 3 months for several courses of treatment. They found a reduced recurrence rate, especially in premenopausal patients with negative axillary nodes. This is the only study we have found in which nitrogen mustard was used as the sole adjuvant drug in the primary treatment of breast carcinoma. The long term use of adjuvant chemotherapy with thiotepa has been reported by Long et al. (1969) and Donegan (1970,1974). They gave weekly injections and have reported a trend towards improved survival in patients with negative axillary nodes. The NSABP is
Nitrogen mustard and breast carcinoma organizing a trial of long term chemotherapy with phenylalanine nitrogen mustard as an adjuvant to radical mastectomy in patients with four o r more positive axillary nodes (Fisher, 1972). Combination chemotherapy has had encouraging results in patients with metastatic breast carcinoma (Carter, 1972). Protocols for adjuvant chemotherapy with a combination of drugs are being developed by several groups including the Eastern Oncology Group, Acute Leukemia Group B, the Mayo Clinic and Berto Verici in Milan. Another intriguing possibility that has been suggested is the combination of chemotherapy and immunotherapy. Chemotherapy would serve to decrease the number of tumour cells prior to the initiation of immunotherapy (Fisher, 1972). The current study of 38 patients is too small to provide evidence for o r against adjuvant chemotherapy in breast carcinoma. The 71 per cent survival rate with an average follow-up of 10 years is above the average 5- or 10-year survival rates (Butcher, 1961; Goldenberg et al., 1961). This survival rate may have been favourably influenced by aggressive postoperative follow-up care. The incidence of complications in this series was no greater than that seen in patients having radical mastectomy without chemotherapy, and there was no significant patient discomfort o r increased hospital stay associated with the treatment. While the use of nitrogen mustard did not prevent the use of other forms of adjuvant therapy-irradiation and oophorectomy-it has the potential for causing serious untoward effects. Nitrogen mustard (mustargen hydrochloride, NH,) is the parent compound of all the alkylating agents and one of the first chemotherapeutic agents found to be effective against tumour cells. Alkylating agents affect tumour cells (and to a lesser extent normal cells) by disturbing D N A synthesis during cell division through a process of misreplication of the D N A chains (Finney, 1971). HN, has the disadvantage of requiring intravenous administration because of its vesicant properties, but this caused no problem in the present series as all the patients were hospitalized and were given a short course of treatment. N H 2 has been shown to be effective in the treatment of metastatic breast carcinoma (Holland, 1961 ; Carter, 1972). Immediate undesirable reactions of NH, include anorexia, nausea and vomiting. Long term untoward effects include leucopenia, thrombocytopenia, allergic rash, infection with herpes zoster and menstrual irregularities. Phlebitis, skin slough and severe brawny induration have been seen following local infiltration of the drug. Nitrogen mustard can cause serious problems. A patient in our institution died of leucopenia and thrombocytopenia following its administration as adjuvant chemotherapy. In a nearby hospital a subcutaneous extravasation of NH, caused a skin slough that required extensive skin grafting. While the untoward effects of nitrogen mustard have limited its use as an adjuvant agent, the studies using this drug are so few that we feel even this small series should be reported.
The value of adjuvant chemotherapy in breast carcinoma is not known. Bernard Fisher, one of the principal investigators in the NSABP study, feels that the trials to date d o not repudiate the value of adjuvant chemotherapy, but simply provide ‘no test’ (Fisher, 1972). Because of increased understanding of tumour pathology, tumour-host relationships, the mechanism of chemotherapeutic agents and the development of new drugs, new trials should be undertaken. While renewed interest appears warranted, it is still an experimental procedure. Only by well-planned, cooperative, prospective clinical trials can the value of this treatment be obtained in a reasonable period of time. Surgeons should join these trials if there is a possibility of long term benefit to the patients and the treatment has a low incidence of toxicity. D r Douglas C . Tormey, Chief of the National Cancer Institute’s Medical Breast Cancer Service, said in March 1974: ‘Current estimates suggest that micrometastases are present with a breast mass’ and that animal studies strongly suggest ‘it is much easier to eradicate early micrometastases than it is for them to become clinically manifest’. References jun. (1961) Effectiveness Of radical mastectomy for mammary cancer: an analysis of mortality by the method of probits. Ann. Surg. 154, 383-396. CARTER s. jun. (1972) Single and combined nonhormonal chemotherapy in breast cancer. Cancer 30, 1543-1555. COHN I . , SLACK N . and FISHER B. (1968) Comp~ications and toxic manifestations of surgical adjuvant chemotherapy for breast cancer. Surg. Cynecol. Obsret. 127, 1201-1209. CRUZ E, MCDONALD A . and COLE w. (1956) Prophylactic treatment of cancer, the use of chemotherapeutic agents to prevent tumor metastases. Suvgery 40, 29 1-296. DONEGAN w. L. (1970) Prolonged surgical adjuvant chemotherapy with Thio-TEPA for mammary carcinoma. Tenth Int. Cancer Congr. (Abstr.), p. 500. DONEGAN w. L. (1974) Extended adjuvant chemotherapy for mammary carcinoma. Central Surgical Assoc., 2lst Annual Meeting, Cincinnati, Ohio, March 1974. EVANS H . J. and SCOTT D. (1969) The induction of chromosome aberrations by nitrogen mustard and its dependence on D N A synthesis. Proc. R. SOC.Lond. (Biol.) 173, 491-512. FINNEY R . (1971) Adjuvant chemotherapy in the radical treatment of carcinoma of the breast-a clinical trial. Am. J . Roentgenol. 111, 137-141. FISHER B. (1971) Status of adjuvant therapy: results of the national surgical adjuvant breast project studies on oophorectomy, post-operative radiation therapy and chemotherapy. Cancer, 28 1654-1658. FISHER B. ( I 972) Surgical adjuvant therapy for breast cancer. Cancer 30, 1556-1 564. BUTCHER H. R .
499
James R. Hines and John S. Williams rISHER B., RAVDIN R. G., AUSMAN R. K., SLACK M. H., MORE G. E. and NOHR R. J. (1968) Surgical adju-
vant chemotherapy in cancer of the breast. Ann. Surg. 168, 337-356. GOLDENBERG I. s., BAILAR J. c., HAYES M. A. and LOWERY R. (1961) Female breast cancer: a reevaluation. Ann. Surg. 154, 397-407. HOLLAND J. F. (1961) Chemotherapy and chemopraxis of cancer, 1951. Cancer Res. 21, 1036-1099. LONG R. T., DONEGAN w. L. and EVANS A. M. (1969) Extended surgical chemotherapy for breast carcinoma. Am. J . Surg. 117, 701-704. MCDONALD G. o., CRUZ E. P. and COLE w. H. (1956) The effect of cancer inhibitor drugs on the “take” of Walker carcinosarcoma 256 in rats. Surg. Forum 7 , 486-489. MCDONALD G . o., LIVINSTON c., BOYLE c. R. and COLE w. H. (1957) The prophylactic treatment of malignant disease with nitrogen mustard and triethylenethiophosphromide (Thio-TEPA). Ann. Surg. 145, 624-629. MRAZEK R. G. and MCDONALD G. 0. (1970) Surgery and adjuvant chemotherapy in treatment of Breast carcinoma. Tenth Int. Cancer Congr. (Abstr.), p. 501.
500
( I 970) Preliminary report from the Scandinavian adjuvant study group. Tenth Int. Cancer Congr. (Abstr.), p. 499. NISSEN-MEYER R., KJELLGREN K., and MANSSON B. (1971) Preliminary report from the Scandinavian adjuvant chemotherapy study group. Cancer Chemother. Rep. 55, 561-566. NOER R. J. (1963) Adjuvant chemotherapy. ThioTEPA with radical mastectomy in the treatment of breast Cancer. Am. J. Surg. 106, 405412. NISSEN-MEYER R.
ROBERTS S., JONASSON O., MCCREW E. and COLE
LONG
L.,
M C G R A T H R.,
w. (1961) Clinical significance of cancer cells in the circulating blood. Ann. Surg. 154, 362-371. SHIMKIN M. B. and MOORE c. E. (1958) Adjuvant use of chemotherapy in the surgical treatment of cancer: plan of cooperative study. J A M A 167, 17 10-1 7 14. TORMEY D. c. (1974) Cancer therapy: how you can gauge adequacy of treatment. Med. Wld News, 17 May, pp. 38-44. TORMEY D. c. and GEELHOED G . w. (1975) Current concepts in the management of breast carcinoma. Contemporary Surg. 5, 9.
