- Email: [email protected]
Treatment of advanced bronchogenic carcinoma with adriamycin and 5-fluorouracil
Brit.
3. Dis.
Chest
(‘975)
6g,
199
TREATMENT OF ADVANCED BRONCHOGENIC CARCINOMA WITH ADRIAMYCIN AND 5-FLUOROURACIL G. J. G. REES, A. BUGAIGHIS St
Woolos Hospital,
AND G. ANDERSON
Newport,
Gwent
is a glycoside antibiotic; 5-fluorouracil is a pyrimidine derivative. Both are cytotoxic agents which inhibit DNA and RNA synthesis. This drug combination has been used to treat patients with advanced lung cancer.
ADRIAMYCIN
Patients
and Methods
Thirty patients with histologically confirmed bronchogenic carcinoma were admitted to the study. In all patients the disease was considered too advanced for treatment with surgery or radiotherapy. In 6 the disease had recurred after radiotherapy, in 2 after treatment with other cytotoxic drugs and in I after surgery. The patients were given 4 courses of cytotoxic treatment at 8-weekly intervals and 2 patients received a fifth course. Each treatment comprised adriamycin to a total dose of 80 mg/m2 of body surface area and 5-fluorouracil I. 2 g, both given into the tubing of an intravenous infusion of normal saline. Initially, each treatment was administered over 4 consecutive days; after 8 patients had been treated, the remainder were given the total dose of adriamycin on the first day with 600 mg of 5-fluorouracil on days I and 2. The shorter period of drug administration is claimed to reduce the incidence of toxic effects (Benjamin et al. 1974). The following investigations were made in all patients before treatment began and were repeated before each treatment cycle: postero-anterior chest radiograph with an appropriate lateral, haemoglobin concentration, platelet and differential white cell counts, levels of serum bilirubin and glutamic pyruvic transaminase and an electrocardiogram. Measurements were made of the sum of two diameters at right angles of the tumour shadow in the plain radiograph. Paratracheal nodes were measured in a horizontal diameter only. Skin metastases were measured in two diameters at right angles. Objective improvement was defined as a reduction of more than 50% in these measurements. (Receivedfor
publication
April
1975)
I.
RESbLTS
Cell trpe
0F
of more than 50% in tumour
Squamous Anaplastic Anaplastic Adenocarcinoma Squamous Adenocarcinoma Anaplastic Squamous Oat Adenocarcinoma Squamous Oat Oat Squamous Anaplastic Squamous Squamous Squamous Squamous squamous Squamous Squamous Adenocarcihoma Squamous Anaplastic Anaplastic squamous Anaplastic ’ Squamous Oat
SUMMARY
Orbit Mediastinum Mediastinum Lymph nodes Bones Brain Skin Local recurrence only Liver Pleura Local recurrence only Liver Lymph nodes, liver Brain Mediastinum Brain Ribs Skin Bones Mediastinum None Mediastinum Other lung Brain Skin Skin Liver Bones, skin Liver Liver
Site of m&-stases
* + Indicates reduction t Still alive.
23 24 25 26 27 28 29 30
20 21 22
16 ‘7 18 ‘9
‘3 ‘4 ‘5
I2
IO II
9
ii
2
:
I 2
Case NO.
TABLE
TREATMENT
diameter.
0
0 0 -0 0 0 0 0 . 0 + + + 0 0
4
: 0 0 0 0 0 0
+ + + .o
Results*
0F
0 0
0 0 0 0 0 0
0
0
Dyspnoea Bone pain Dyspnoea
Stridzr
0
Bone :ain
Stridor
0
Bone pain
Bone pain
Subjective relief only
WITH
I
I
s
got
I$
f
4 4 4
1st 2ot
i I I I
I I I 2 2 2 2
5 I 3
2 I 2
4
it
I
Comment
Brain metastases responded to radiotherapy. Died pneumonia Developed cerebral metastases
No relief cerebral metastases Died pneumonia No relief cerebral metastases
Developed cerebral metastases Developed cerebral metastases Died of pneumonia Developed cerebral metastases No effect on cerebral metastases See case report See case report
~-PLU~ROURA~IL
.No. of courses
AND
I2
7
: 2
ii! I IO
i
I2 2 2 2
I
f 42 A
3i
39 40
2
Survival (weeks)
ADRIAMYCIN
t
E m 01 M H
$
TREATMENT
OF
ADVANCED
BRONCHOGENIC
CARCINOMA
201
Results The results are summarized in Table I. Eight patients showed a reduction in diameter of tumour or metastases which exceeded 50%. Of the remaining 22 patients, 2 experienced permanent disappearance of stridor and in 2 dyspnoea was improved, while 4 experienced useful relief of bone pain. Ten patients died within 2 weeks of starting treatment, death occurring before a response might have been expected. The relationship between response to treatment and the histological type of tumour is shown in Table 2. The best response was with anaplastic tumours when 6 of 7 patients achieved an objective response. Squamous tumours responded least well and only I patient showed an objective response, although useful symptomatic relief occurred in 7. The numbers of patients in the adenocarcinoma and oat cell groups were too small for adequate assessment. TABLE
2. RELATION
.Number treated
Cell tyke ___
OF RESPONSE TO CELL TYPE Objective response
Subjective relief or+
-
Anaplastic Squamous Oat-cell Adenocarcinoma
TA'BLE -
7 ‘5 4 = 4
3.< TOXIC Toxic
EFFECTS
effect
Alo&cia Nausea or vomiting Stomatitis Nasal stuffiness Leucopenia Thrombocytopenia Proctitis and balanitis Abnormal electrocardiograph
6 I 0 I
; 0 0
IN 30 PATIENTS Jvo. o~cases . . i
13 :* 3 2 I I I
' w;r.
Toxic efects The toxic effects are listed in Table 3. All patients surviving 2 treatments experienced virtually total alopecia, although hair regrew after the final treatment cycle. Transient leucopenia occurred in I patient but in another patient, who had previously received other antimitotic drugs, the leucopenia was probably the cause of a fatal pneumonia. Stomatitis was manifested as a sore tongue or throat which, however, usually appeared normal on clinical examination. Three patients complained of nasal stuffiness. In a single patient the electrocardiograph showed T-wave flattening after a total of 412 mg/ms of adriamycin. This was not accompanied by any clinical signs of heart disease.
REES
202
Case
ET
AL.
Reports
Case 3 This male patient aged 55 years presented with a superior vena caval obstruction. There was a right hilar opacity 5 x g cm on the chest radiograph with a right paratracheal opacity 3 *o cm in width (Fig. I). Two days after starting treatment, the vena caval obstruction resolved. By the second treatment, the hilar opacity was smaller and at bronchoscopic examination stenosis of the right upper lobe orifice was seen and bronchial secretions contained anaplastic malignant cells. By the fourth treatment, the patient was able to resume work
FIG.
I. Case
3. Right
hilar
and
paratracheal
opacity
and the chest radiograph showed only residual mottling at the site of the tumour (Fig. 2). Twenty-five weeks after starting treatment, he was re-admitted with a r-week history of confusion and was found to have papilloedema and signs of a left-sided pyramidal lesion. A brain scan suggested a right-sided
TREATMENT
OF
ADVANCED
BRONCHOGENIC
CARCINOMA
203
cerebral metastasis which was treated with dexamethasone and brain radiotherapy to a dose of 800 rads. At this time he was given a fifth course of chemotherapy. Over the next 2 weeks his confusion disappeared and he was able to work in his garden. He died of pneumonia 40 weeks after his first treatment. Case 7 This female patient aged 56 years, diagnosed as having anaplastic carcinoma of bronchus in 1969, had been previously treated with radiotherapy
FIG.
2. Case
3. Thirteen
weeks
after
start tumour
of chemotherapy size
showing
reduction
in
and cyclophosphamide. The tumour recurred with a right-sided pleural effusion, phrenic nerve palsy and subcutaneous metastases in the right axilla with lymphatic obstruction producing marked swelling of the arm. There was a good response to the first treatment with considerable relief of lymphatic obstruction and a complete clinical disappearance of the subcutaneous metastases. This patient died suddenly from a massive pulmonary embolus. At post mortem there was no macroscopic evidence of lung tumour or metastases.
REES
204
ET
AL.
At microscopic examination, the nodes at the hilum of the right lung contained sheets of anaplastic malignant cells interspersed amongst a fibrous stroma. There was no other histological evidence of malignancy. Case 8 This male patient aged 5g years was admitted to hospital with a Q-day history of increasing breathlessness of such severity that he was unable to walk and was frightened to to go to sleep. Six months previously he had received radiotherapy to a dose of 2800 rads for a squamous carcinoma of the right upper lobe. On examination there was severe stridor and signs of collapse of the right lung. A chest radiograph confirmed the collapse of the right lung. Three days after the first course of combination therapy, the stridor resolved and did not recur. He was given a total of 5 courses and was able to walk a few miles. Thirty-five weeks after starting chemotherapy, he developed a left hemiplegia and a brain scan confirmed a right parietal metastasis. This was treated with radiotherapy to a dose of.800 rads and when last seen seven weeks later (42 weeks after the first treatment) he felt well and symptom free.
Discussion Adriamycin has been used in the treatment of lung cancer but when given as a single cytotoxic agent, it seems, like other cytotoxic drugs, to be only moderately effective. Praga (1971) c1aimed objective improvement in 7 of 41 patients with advanced lung dancer. Reductions in tumour diameter exceeding 50% were found in 8 of 56 /,patients by O’Bryan et al. 11973) and in 7 of 27 patients by Kenis and Michel ( 1972). In the present series a combination of adriamycin and 5-fluorouracil-yielded reductions in tumour diameter ofpore than 50% in 8 of 30 patients, iuggesting that the 2 drugs may have a synergistic effect. In spherical turnour!& reductions in diameter of this order ‘correspond to larger reductions in t’umour volume, since volume is proportional to the cube of the radius. Where’iumour diameter was reduced, this effect was accompanied by weight gain and sense of well-being enabling 3 of the group to return to work. It is difficult to prove that this chemotherapy prolongs life, but for example, Case 8 could not possibly have survived for more than a few weeks untreated, and we felt that life had undoubtedly been prolonged in some patients. It was clear that in other patients valuable symptomatic relief had been achieved even where tumour shrinkage was not demonstrated. The best response occurred in the rapidly growing anaplastic tumours and the least in the squamous carcinomas, although useful subjective benefits did occur in 8 patients of this group. In the literature there is conflicting experience regarding the relative susceptibilities of different cell types to adriamycin therapy. Blum and Carter (I 974) refer to epidermoid carcinoma as being the most susceptible lung cancer type, claiming adenocarcinoma and small cell types to be less responsive. Others (O’Bryan et al. 1973; Cortes et al. 1974) claim that oat-cell tumours gave the highest response rate, with adenocarcinoma next, followed by squamous or epidermoid types. Yet others (Takita et al. 1973) found a 43% response rate in oat-cell carcinoma of lung, appearing to confirm
TREATMENT
OF
ADVANCED
BRONCHOGENIC
CARCINOMA
205
the activity of adriamycin against this tumour, while Bonadonna et al. (1973) found consistent responses only in the undifferentiated carcinomas of lung (both oat-cell and large cell). Adriamycin may have some activity against all cell types of lung cancer and the differences in the various trials possibly reflect variations between the patients or statistical fluctuations due to the small numbers of patients in most reported treatment groups. The method by which the drug was administered in this study allows hospital admission for I night every 3 weeks, and in a few instances treatment was given on a day-patient basis. Six patents survived 20 or more weeks and it is noteworthy that 4 of these developed cerebral metastases which were not accompanied by extracerebral secondaries, nor by radiological or clinical evidence that the primary tumour had recurred. Neither adriamycin nor fluorouracil crosses the blood-brain barrier and it appears likely that tumour spread to the brain had taken place before chemotherapy had been started, so that the cerebral metastases continued to grow and eventually caused symptoms even with adequate control of extracerebral tumour. Where this happened useful symptomatic relief could sometimes be obtained with brian irradiation (Cases 3 and 8). The main toxic effects were alopecia and stomatitis. In those patients surviving the last treatment cycle, the hair started to grow again about I month later and the stomatitis always resolved within I week of treatment. The nasal stuffiness noted by 3 of our patients was not accompanied by any visible abnormality in the nose and has not previously been described. Leucopenia led to death in a single patient who had previously received other chemotherapeutic agents, but this combination seems relatively non-toxic to the bone marrow. Although a cardiomyopathy does occur with adriamycin, the only possible manifestation was in a single patient with a slightly abnormal electrocardiograph and it seems uncommon where the total adriamycin dose is less than 550 mg/m2 of body surface area (Lancet 1974). The combination of adriamycin and 5-fluorouracil was found to be helpful, and the relative non-toxicity to the bone marrow may allow addition of other cytotoxic agents in future trials. Summary Thirty patients with an advanced bronchogenic carcinoma were treated with a combination of adriamycin and 5-fluorouracil; in eight the size of the tumour or its metastases was reduced by over 50%, and eight further patients experienced useful relief of symptoms. This drug combination is useful in the management of lung cancer. REFERENCES
BENJAMIN, R. S., WIERNICK, P. H. & BACH~R, N. R. (1974) Adriamycin chemotherapy: Efficacy, safety and pharmacological ba$is of an intermittent single high-dosage schedule. BLUM,
cancer, NJ., 33, 19. R. H. & CARTER, clinical activity. Ann.
S. K. (1974) intern.
Med.,
Adriamycin, 80, 249.
a new anticancer
drug with significant
206
REES
ET
AL.
BONADONNA, G., TANCINI, G. & BAJETTA, E. (1973) Chemotherapy of lung cancer: The experience of the national cancer institute of Milan. Cancer Chemother. Refi., 4, 23 I. CORTES, E. P., TAKITA, H. & HOLLAND, J. F. (1974) Adriamycin in Advanced Bronchogenic Carcinoma Cancer, N. r., 34, 5 18. EDITORIAL (I 974) Adriamycin and the heart, Lancet, I, I 325. KENIS, Y. & MICHEL, J. (1971) Preliminary results of a clinical trial with intermittent doses 01 adriamycin in lung cancer. In International Symposium on Adrian-v&, ed. Carter, S. K., Dimarco, A., Ghione, M., Krakoff, I. H. & Mathe, G. pp. 161-4. Berlin, Heidelberg and New York: Springer Verlag. O’BRYAN, R. M., LUCE, J. K., TALLEY, R. W., GOTTLIEB, J. A., BAKER, L. H. & BONADONNA, G. (1973) Phase II Evaluation of Adriamycin in Human Neoplasia. Cancer, N.N.T., 32, I. PRAGA, C., (1972) Co-operative clinical study on adriamycin in advanced lung tumors. In International Symposium on Adriamycin, ed. Carter, S. K., Dimarco, A., Ghione, M., Krakoff, I. H. & Mathe, G., pp. 173-g. Berlin, Heidelberg and New York: Springer Verlag. TAKITA, H., BRUGAROLAS, A., MARABELLA, P. & VINCENT, R. G. (1975) Small-cell carcinoma of the lung; clinicopathological studies. 3. thorac. cardiovasc. Surg., 66, 472.
3. Dis.
Chest
(‘975)
6g,
199
TREATMENT OF ADVANCED BRONCHOGENIC CARCINOMA WITH ADRIAMYCIN AND 5-FLUOROURACIL G. J. G. REES, A. BUGAIGHIS St
Woolos Hospital,
AND G. ANDERSON
Newport,
Gwent
is a glycoside antibiotic; 5-fluorouracil is a pyrimidine derivative. Both are cytotoxic agents which inhibit DNA and RNA synthesis. This drug combination has been used to treat patients with advanced lung cancer.
ADRIAMYCIN
Patients
and Methods
Thirty patients with histologically confirmed bronchogenic carcinoma were admitted to the study. In all patients the disease was considered too advanced for treatment with surgery or radiotherapy. In 6 the disease had recurred after radiotherapy, in 2 after treatment with other cytotoxic drugs and in I after surgery. The patients were given 4 courses of cytotoxic treatment at 8-weekly intervals and 2 patients received a fifth course. Each treatment comprised adriamycin to a total dose of 80 mg/m2 of body surface area and 5-fluorouracil I. 2 g, both given into the tubing of an intravenous infusion of normal saline. Initially, each treatment was administered over 4 consecutive days; after 8 patients had been treated, the remainder were given the total dose of adriamycin on the first day with 600 mg of 5-fluorouracil on days I and 2. The shorter period of drug administration is claimed to reduce the incidence of toxic effects (Benjamin et al. 1974). The following investigations were made in all patients before treatment began and were repeated before each treatment cycle: postero-anterior chest radiograph with an appropriate lateral, haemoglobin concentration, platelet and differential white cell counts, levels of serum bilirubin and glutamic pyruvic transaminase and an electrocardiogram. Measurements were made of the sum of two diameters at right angles of the tumour shadow in the plain radiograph. Paratracheal nodes were measured in a horizontal diameter only. Skin metastases were measured in two diameters at right angles. Objective improvement was defined as a reduction of more than 50% in these measurements. (Receivedfor
publication
April
1975)
I.
RESbLTS
Cell trpe
0F
of more than 50% in tumour
Squamous Anaplastic Anaplastic Adenocarcinoma Squamous Adenocarcinoma Anaplastic Squamous Oat Adenocarcinoma Squamous Oat Oat Squamous Anaplastic Squamous Squamous Squamous Squamous squamous Squamous Squamous Adenocarcihoma Squamous Anaplastic Anaplastic squamous Anaplastic ’ Squamous Oat
SUMMARY
Orbit Mediastinum Mediastinum Lymph nodes Bones Brain Skin Local recurrence only Liver Pleura Local recurrence only Liver Lymph nodes, liver Brain Mediastinum Brain Ribs Skin Bones Mediastinum None Mediastinum Other lung Brain Skin Skin Liver Bones, skin Liver Liver
Site of m&-stases
* + Indicates reduction t Still alive.
23 24 25 26 27 28 29 30
20 21 22
16 ‘7 18 ‘9
‘3 ‘4 ‘5
I2
IO II
9
ii
2
:
I 2
Case NO.
TABLE
TREATMENT
diameter.
0
0 0 -0 0 0 0 0 . 0 + + + 0 0
4
: 0 0 0 0 0 0
+ + + .o
Results*
0F
0 0
0 0 0 0 0 0
0
0
Dyspnoea Bone pain Dyspnoea
Stridzr
0
Bone :ain
Stridor
0
Bone pain
Bone pain
Subjective relief only
WITH
I
I
s
got
I$
f
4 4 4
1st 2ot
i I I I
I I I 2 2 2 2
5 I 3
2 I 2
4
it
I
Comment
Brain metastases responded to radiotherapy. Died pneumonia Developed cerebral metastases
No relief cerebral metastases Died pneumonia No relief cerebral metastases
Developed cerebral metastases Developed cerebral metastases Died of pneumonia Developed cerebral metastases No effect on cerebral metastases See case report See case report
~-PLU~ROURA~IL
.No. of courses
AND
I2
7
: 2
ii! I IO
i
I2 2 2 2
I
f 42 A
3i
39 40
2
Survival (weeks)
ADRIAMYCIN
t
E m 01 M H
$
TREATMENT
OF
ADVANCED
BRONCHOGENIC
CARCINOMA
201
Results The results are summarized in Table I. Eight patients showed a reduction in diameter of tumour or metastases which exceeded 50%. Of the remaining 22 patients, 2 experienced permanent disappearance of stridor and in 2 dyspnoea was improved, while 4 experienced useful relief of bone pain. Ten patients died within 2 weeks of starting treatment, death occurring before a response might have been expected. The relationship between response to treatment and the histological type of tumour is shown in Table 2. The best response was with anaplastic tumours when 6 of 7 patients achieved an objective response. Squamous tumours responded least well and only I patient showed an objective response, although useful symptomatic relief occurred in 7. The numbers of patients in the adenocarcinoma and oat cell groups were too small for adequate assessment. TABLE
2. RELATION
.Number treated
Cell tyke ___
OF RESPONSE TO CELL TYPE Objective response
Subjective relief or+
-
Anaplastic Squamous Oat-cell Adenocarcinoma
TA'BLE -
7 ‘5 4 = 4
3.< TOXIC Toxic
EFFECTS
effect
Alo&cia Nausea or vomiting Stomatitis Nasal stuffiness Leucopenia Thrombocytopenia Proctitis and balanitis Abnormal electrocardiograph
6 I 0 I
; 0 0
IN 30 PATIENTS Jvo. o~cases . . i
13 :* 3 2 I I I
' w;r.
Toxic efects The toxic effects are listed in Table 3. All patients surviving 2 treatments experienced virtually total alopecia, although hair regrew after the final treatment cycle. Transient leucopenia occurred in I patient but in another patient, who had previously received other antimitotic drugs, the leucopenia was probably the cause of a fatal pneumonia. Stomatitis was manifested as a sore tongue or throat which, however, usually appeared normal on clinical examination. Three patients complained of nasal stuffiness. In a single patient the electrocardiograph showed T-wave flattening after a total of 412 mg/ms of adriamycin. This was not accompanied by any clinical signs of heart disease.
REES
202
Case
ET
AL.
Reports
Case 3 This male patient aged 55 years presented with a superior vena caval obstruction. There was a right hilar opacity 5 x g cm on the chest radiograph with a right paratracheal opacity 3 *o cm in width (Fig. I). Two days after starting treatment, the vena caval obstruction resolved. By the second treatment, the hilar opacity was smaller and at bronchoscopic examination stenosis of the right upper lobe orifice was seen and bronchial secretions contained anaplastic malignant cells. By the fourth treatment, the patient was able to resume work
FIG.
I. Case
3. Right
hilar
and
paratracheal
opacity
and the chest radiograph showed only residual mottling at the site of the tumour (Fig. 2). Twenty-five weeks after starting treatment, he was re-admitted with a r-week history of confusion and was found to have papilloedema and signs of a left-sided pyramidal lesion. A brain scan suggested a right-sided
TREATMENT
OF
ADVANCED
BRONCHOGENIC
CARCINOMA
203
cerebral metastasis which was treated with dexamethasone and brain radiotherapy to a dose of 800 rads. At this time he was given a fifth course of chemotherapy. Over the next 2 weeks his confusion disappeared and he was able to work in his garden. He died of pneumonia 40 weeks after his first treatment. Case 7 This female patient aged 56 years, diagnosed as having anaplastic carcinoma of bronchus in 1969, had been previously treated with radiotherapy
FIG.
2. Case
3. Thirteen
weeks
after
start tumour
of chemotherapy size
showing
reduction
in
and cyclophosphamide. The tumour recurred with a right-sided pleural effusion, phrenic nerve palsy and subcutaneous metastases in the right axilla with lymphatic obstruction producing marked swelling of the arm. There was a good response to the first treatment with considerable relief of lymphatic obstruction and a complete clinical disappearance of the subcutaneous metastases. This patient died suddenly from a massive pulmonary embolus. At post mortem there was no macroscopic evidence of lung tumour or metastases.
REES
204
ET
AL.
At microscopic examination, the nodes at the hilum of the right lung contained sheets of anaplastic malignant cells interspersed amongst a fibrous stroma. There was no other histological evidence of malignancy. Case 8 This male patient aged 5g years was admitted to hospital with a Q-day history of increasing breathlessness of such severity that he was unable to walk and was frightened to to go to sleep. Six months previously he had received radiotherapy to a dose of 2800 rads for a squamous carcinoma of the right upper lobe. On examination there was severe stridor and signs of collapse of the right lung. A chest radiograph confirmed the collapse of the right lung. Three days after the first course of combination therapy, the stridor resolved and did not recur. He was given a total of 5 courses and was able to walk a few miles. Thirty-five weeks after starting chemotherapy, he developed a left hemiplegia and a brain scan confirmed a right parietal metastasis. This was treated with radiotherapy to a dose of.800 rads and when last seen seven weeks later (42 weeks after the first treatment) he felt well and symptom free.
Discussion Adriamycin has been used in the treatment of lung cancer but when given as a single cytotoxic agent, it seems, like other cytotoxic drugs, to be only moderately effective. Praga (1971) c1aimed objective improvement in 7 of 41 patients with advanced lung dancer. Reductions in tumour diameter exceeding 50% were found in 8 of 56 /,patients by O’Bryan et al. 11973) and in 7 of 27 patients by Kenis and Michel ( 1972). In the present series a combination of adriamycin and 5-fluorouracil-yielded reductions in tumour diameter ofpore than 50% in 8 of 30 patients, iuggesting that the 2 drugs may have a synergistic effect. In spherical turnour!& reductions in diameter of this order ‘correspond to larger reductions in t’umour volume, since volume is proportional to the cube of the radius. Where’iumour diameter was reduced, this effect was accompanied by weight gain and sense of well-being enabling 3 of the group to return to work. It is difficult to prove that this chemotherapy prolongs life, but for example, Case 8 could not possibly have survived for more than a few weeks untreated, and we felt that life had undoubtedly been prolonged in some patients. It was clear that in other patients valuable symptomatic relief had been achieved even where tumour shrinkage was not demonstrated. The best response occurred in the rapidly growing anaplastic tumours and the least in the squamous carcinomas, although useful subjective benefits did occur in 8 patients of this group. In the literature there is conflicting experience regarding the relative susceptibilities of different cell types to adriamycin therapy. Blum and Carter (I 974) refer to epidermoid carcinoma as being the most susceptible lung cancer type, claiming adenocarcinoma and small cell types to be less responsive. Others (O’Bryan et al. 1973; Cortes et al. 1974) claim that oat-cell tumours gave the highest response rate, with adenocarcinoma next, followed by squamous or epidermoid types. Yet others (Takita et al. 1973) found a 43% response rate in oat-cell carcinoma of lung, appearing to confirm
TREATMENT
OF
ADVANCED
BRONCHOGENIC
CARCINOMA
205
the activity of adriamycin against this tumour, while Bonadonna et al. (1973) found consistent responses only in the undifferentiated carcinomas of lung (both oat-cell and large cell). Adriamycin may have some activity against all cell types of lung cancer and the differences in the various trials possibly reflect variations between the patients or statistical fluctuations due to the small numbers of patients in most reported treatment groups. The method by which the drug was administered in this study allows hospital admission for I night every 3 weeks, and in a few instances treatment was given on a day-patient basis. Six patents survived 20 or more weeks and it is noteworthy that 4 of these developed cerebral metastases which were not accompanied by extracerebral secondaries, nor by radiological or clinical evidence that the primary tumour had recurred. Neither adriamycin nor fluorouracil crosses the blood-brain barrier and it appears likely that tumour spread to the brain had taken place before chemotherapy had been started, so that the cerebral metastases continued to grow and eventually caused symptoms even with adequate control of extracerebral tumour. Where this happened useful symptomatic relief could sometimes be obtained with brian irradiation (Cases 3 and 8). The main toxic effects were alopecia and stomatitis. In those patients surviving the last treatment cycle, the hair started to grow again about I month later and the stomatitis always resolved within I week of treatment. The nasal stuffiness noted by 3 of our patients was not accompanied by any visible abnormality in the nose and has not previously been described. Leucopenia led to death in a single patient who had previously received other chemotherapeutic agents, but this combination seems relatively non-toxic to the bone marrow. Although a cardiomyopathy does occur with adriamycin, the only possible manifestation was in a single patient with a slightly abnormal electrocardiograph and it seems uncommon where the total adriamycin dose is less than 550 mg/m2 of body surface area (Lancet 1974). The combination of adriamycin and 5-fluorouracil was found to be helpful, and the relative non-toxicity to the bone marrow may allow addition of other cytotoxic agents in future trials. Summary Thirty patients with an advanced bronchogenic carcinoma were treated with a combination of adriamycin and 5-fluorouracil; in eight the size of the tumour or its metastases was reduced by over 50%, and eight further patients experienced useful relief of symptoms. This drug combination is useful in the management of lung cancer. REFERENCES
BENJAMIN, R. S., WIERNICK, P. H. & BACH~R, N. R. (1974) Adriamycin chemotherapy: Efficacy, safety and pharmacological ba$is of an intermittent single high-dosage schedule. BLUM,
cancer, NJ., 33, 19. R. H. & CARTER, clinical activity. Ann.
S. K. (1974) intern.
Med.,
Adriamycin, 80, 249.
a new anticancer
drug with significant
206
REES
ET
AL.
BONADONNA, G., TANCINI, G. & BAJETTA, E. (1973) Chemotherapy of lung cancer: The experience of the national cancer institute of Milan. Cancer Chemother. Refi., 4, 23 I. CORTES, E. P., TAKITA, H. & HOLLAND, J. F. (1974) Adriamycin in Advanced Bronchogenic Carcinoma Cancer, N. r., 34, 5 18. EDITORIAL (I 974) Adriamycin and the heart, Lancet, I, I 325. KENIS, Y. & MICHEL, J. (1971) Preliminary results of a clinical trial with intermittent doses 01 adriamycin in lung cancer. In International Symposium on Adrian-v&, ed. Carter, S. K., Dimarco, A., Ghione, M., Krakoff, I. H. & Mathe, G. pp. 161-4. Berlin, Heidelberg and New York: Springer Verlag. O’BRYAN, R. M., LUCE, J. K., TALLEY, R. W., GOTTLIEB, J. A., BAKER, L. H. & BONADONNA, G. (1973) Phase II Evaluation of Adriamycin in Human Neoplasia. Cancer, N.N.T., 32, I. PRAGA, C., (1972) Co-operative clinical study on adriamycin in advanced lung tumors. In International Symposium on Adriamycin, ed. Carter, S. K., Dimarco, A., Ghione, M., Krakoff, I. H. & Mathe, G., pp. 173-g. Berlin, Heidelberg and New York: Springer Verlag. TAKITA, H., BRUGAROLAS, A., MARABELLA, P. & VINCENT, R. G. (1975) Small-cell carcinoma of the lung; clinicopathological studies. 3. thorac. cardiovasc. Surg., 66, 472.