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Adjuvant chemotherapy for stage D1 adenocarcinoma of prostate
ADJUVANT
CHEMOTHERAPY
ADENOCARCINOMA DEVERE WHITE,
RALPH
RICHARD JOHN
OF PROSTATE
M.D.
K. BABAYAN, M.D.
KRIKORIAN,
ROBERT
FOR STAGE Dl
J. KRANE,
CARL A. OLSSON.
M.D. M.D. M.D.
From the Departments of Urology and Medicine, School of Medicine, Boston, Massachusetts
Boston University
ABSTRACT--In a series of 112 patients undergoing pelvic lymphadenectomy for clinically localized prostate cancer, 37 were found to have pelvic lymph node metastases. After prostatic irradiation, these 37 patients were divided into groups receiving adjunctive chemotherapy versus no additional treatment. The patients werefollowedfor a period rangingfrom twelve to sixty-five months for evidence of disease progression. Of the 12 patients administered chemotherapy, disease progression was documented in 4 (average time to progression was fifteen months). In contrast, of the 25 patients receiving no additional treatment, 12 exhibited evidence of gross metastatic disease within an average interval of 11.6 months. One death has been recorded in the chemotherapy group at twenty-nine months after diagnosis; 4 deaths have occurred in patients receiving no systemic therapy (average time to death was eighteen months).
The presence of pelvic lymph node metastases as determined by surgical staging of clinically localized adenocarcinoma of the prostate confers an ominous impact on patient’s survival. l 5 This study was undertaken to see if an adjuvant chemotherapy protocol could retard the progression of disease that is predictable in these patients. Material
and Methods
Of 112 patients undergoing pelvic lymph node dissection for clinically localized prostatic carcinoma, 37 were found to have lymph node involvement. After completing prostatic irradiation (interstitial Iodine-125 plus/or 4 cm x 4 cm external beam therapy,), patients were divided into those receiving no additional treatment versus those administered adjunctive chemotherapy. Chemotherapy consisted of cyclophosphamide 750 mg/M2 and doxorubicin hydrochloride (Adriamycin) 50 mg/M2 ad-
ministered intravenously once every three weeks on an ambulatory basis. Total doxorubitin hydrochloride administered was 450 mg/M2 in each patient; cyclophosphamide (Cytoxan) usually was given for a period of six months, although 2 early cases received the agent for a period of eighteen months. Also, in the initial cases, methotrexate 50 mg/M2 was administered orally on days 9, 12, 16, and 19 of each three-week cycle. Because of prominent stomatitis and other complications occurring with this added agent, patients seldom received the intended dosage, and thus the chemotherapy protocol was restricted to cyclophosphamide and doxorubicin hyrochloride alone. Patients were followed for periods of up to sixty-five months after pelvic lymphadenectomy for evidence of disease progression. No patient was followed for less than twelve months. Disease progression was defined as documented appearance of soft tissue or bony metastases.
Documentation usually was established by skeletal bone survey or radioisotope bone scan. Serum acid phosphatase elevation often accompanied the progression of disease. In no instance were we required to depend solely on an elevated serum acid phosphatase to determine disease progression.
Progression of disease in patients with Stage Dl prostatic cancer (25 no chemotherapy and 12 with chemotherapy) TABLE I.
Condition Progressed Died Stable
Results
To ju,stify a program of adjuvant chemotherapy, 3 conditions should be fulfilled. First, the untreated disease should carry a poor prognosis. Second, the agents utilized should have demonstrated anti-tumor activity. Finally, the list of complications arising from adjuvant treatment should be low compared with its potential benefits. These 3 conditions were considered in the design of this treatment study.
MARCH
1983
! VOLUME
XXI. NUMBER
Chemotherapy* (Mos.)
12 (11.6)
4 (15)
.I (29)
4 (18)
13 (36)
8 (37) and
doxorubicin
50 mg/M’
Patients with pelvic lymph node metastases from clinically localized prostate cancer experience an ominous prognosis indeed. At five years, in 85 per cent of such patients overt metastases develop. l This observation has been confirmed by other reports showing 60 per cent disease progression in such patients at thirtytwo months.2 Even at two years of follow-up, disease progression can be seen in 50 per cent of patients.3 We have reported previously a similar progression rate at twenty-four months,4 whereas, in 75 patients with negative lymph nodes, only 5 experienced overt metastatic disease in the same period of time.5 In earlier reports, Whitmore suggested that minimal microscopic involvement of pelvic lymph nodes might not adversely affect patient prognosis.’ However, this opinion recently has been revised, and it now has been shown that the potential for disease progression is high in any patient with pelvic lymph node metastases from prostatic cancer. 6 Indeed, it should come as no surprise that patients with Stage Dl prostate cancer fare poorly, since this is in keeping with observations made in many other malignancies. For example, women with breast cancer that has metastasized to axillary lymph nodes experience a much higher relapse rate compared with negative axillary nod.e dissection.7 Having decided that patients with Stage Dl prostate cancer experience a prognosis sufficiently severe to justify adjuvant treatment, one is then faced with the need to define a course of treatment that will be useful in altering prognosis. Various single-agent chemotherapy trials have been tested in patients with widely metastatic prostate cancer, and response rates have been recorded in the form of either partial remission or stabilization of disease.8.g Rased on these studies and our experience with a combination of cyclophosphamide and doxorubicin in Stage D3 adenocarcinoma of the
Comment
/
(Mos.)
*Cyclophosphamide 750 mg/M2 every three weeks for six months.
Of the 25 patients who received no additional treatment, 12 experienced disease progression, with an average time to progression of 11.6 months. Four of these 12 patients have died, at an average interval of eighteen months from the time of lymphadenectomy. Thirteen patients remain stable with an average follow-up period of thirty-six months. The total disease-free, patient-months in the untreated 25 patients was 24.3. In contrast, of the 12 patients who received adjunctive cyclophosphamide and doxorubicin hydrochloride, 4 experienced disease progression (average time to progression fifteen months); 1 patient died twenty-nine months after pelvic lymphadenectomy. The remaining 8 patients undergoing adjunctive treatment continue to show no disease progression (average follow-up of thirty-seven months). Over-all, the 12 patients treated with cyclophosphamide and doxorubicin hydrochloride have experienced 29.7 patient-months free of disease (Table I). There were few complications that could be related to the administration of cyclophosphamide and doxorubicin hydrochloride. In 1 patient a transient change in EKG pattern developed after reaching a dosage level of 450 mg/ M2 doxorubicin hydrochloride. A year later, this patient underwent surgery for an unrelated problem; at that time his EKG pattern showed nonspecific changes only. The initial patients subjected to adjunctive chemotherapy received oral methotrexate with resultant stomatitis. In 1 patient methotrexate pneumonia developed which necessitated a week of hospitalization.
UROLOGY
No Chemotherapy
3
271
prostate, we intiated the adjuvant program. As methotrexate was inipreviously mentioned, tially intended to complete the adjuvant protocol. However, this drug was omitted after the number of complications interfered with patient compliance. Regarding complications of therapy, there were few that could be related to the adjunctive program selected. After omitting methotrexate, a single electrocardiographic abnormality was recorded in 1 patient receiving the maximum 450 mg/M2 of doxorubicin. Despite our concerns about possible radiomimetic actions of doxorubicin, there was no difference in incidence of proctitis in patients receiving chemotherapy versus those receiving radiation alone. As can be seen from our results, the rate of disease progression appears to have been slowed by the adjuvant chemotherapy program, although the results do not reach statistical significance. There is a slightly improved average duration of disease-free survival in patients undergoing chemotherapy (29.7 versus 24.3 months). More importantly, there is a distinct difference in reduction of mortality (1 death in the treated group versus 4 in the untreated group). In patients with Stage Dl adenocarcinoma of the prostate, time to progression in the control population is short, so that one can determine the value of an adjunctive chemotherapy pro-
gram in a relatively limited period of time. Although the figures obtained in this initial report do not justify any firm conclusions, they are sufficiently encouraging to suggest further trials of adjuvant chemotherapy in this group of patients. Columbia University College of Physicians and Surgeons 630 West 168th Street New York, New York 10032 (DR. DEVERE WHITE) References 1. Barzell W, Bean MA, Hilaris BS, and Whitmore WF Jr: Prostatic adenocarcinoma: relationship of grade and local extent to the pattern of metastases, J Urol 118: 278 (1977). 2. Prout GR Jr, et al: Nodal involvement as a prognostic indicator in patients with prostatic carcinoma, ibid. 124: 226 (1980). 3. Kramer SA, et al: Experience with Gleason’s histopathologic grading in prostate cancer, ibid. 124: 223 (1980). 4. Babayan RK, et al: Benefits and complications of staying pelvic lymph node dissection in prostatic adenocarcinoma, Prostate 1: 315 (1980). 5. deVere White R. Babayan RK. Feldman M, and Olsson CA: Adjunctive therapy with interstitial irradiation for prostate cancer: progression and late complications, Urology 19: 395 (1982). 6. Grossman BH, and Whitmore WF Jr: 1rz5 Implantation of the prostate: prediction of treatment results (Abstr. 126). presented at 76th Annual Meeting of American Urological Association, Boston, Map 11, 1981. 7. Fisher B, et al: Cancer of the breast: size of neoplasm and prognosis, Cancer 24: 1071 (1969). 8. DeWys WD, and Begg CB: Comparison of Adriamycin and 5-fluorouracil in advanced prostatic cancer, Proc Am Assoc Cancer Res 19: 330 (1978). 9. Scott WW, et al: Chemotherapy of advanced prostatic carcinoma with cyclophosphamide or 5-fluorouracil, results of first national randomized study, J Urol 114: 909 (1975).
UROLOGY
: MARCH
1983
/ VOLUME
XXI, NUMBER
3
CHEMOTHERAPY
ADENOCARCINOMA DEVERE WHITE,
RALPH
RICHARD JOHN
OF PROSTATE
M.D.
K. BABAYAN, M.D.
KRIKORIAN,
ROBERT
FOR STAGE Dl
J. KRANE,
CARL A. OLSSON.
M.D. M.D. M.D.
From the Departments of Urology and Medicine, School of Medicine, Boston, Massachusetts
Boston University
ABSTRACT--In a series of 112 patients undergoing pelvic lymphadenectomy for clinically localized prostate cancer, 37 were found to have pelvic lymph node metastases. After prostatic irradiation, these 37 patients were divided into groups receiving adjunctive chemotherapy versus no additional treatment. The patients werefollowedfor a period rangingfrom twelve to sixty-five months for evidence of disease progression. Of the 12 patients administered chemotherapy, disease progression was documented in 4 (average time to progression was fifteen months). In contrast, of the 25 patients receiving no additional treatment, 12 exhibited evidence of gross metastatic disease within an average interval of 11.6 months. One death has been recorded in the chemotherapy group at twenty-nine months after diagnosis; 4 deaths have occurred in patients receiving no systemic therapy (average time to death was eighteen months).
The presence of pelvic lymph node metastases as determined by surgical staging of clinically localized adenocarcinoma of the prostate confers an ominous impact on patient’s survival. l 5 This study was undertaken to see if an adjuvant chemotherapy protocol could retard the progression of disease that is predictable in these patients. Material
and Methods
Of 112 patients undergoing pelvic lymph node dissection for clinically localized prostatic carcinoma, 37 were found to have lymph node involvement. After completing prostatic irradiation (interstitial Iodine-125 plus/or 4 cm x 4 cm external beam therapy,), patients were divided into those receiving no additional treatment versus those administered adjunctive chemotherapy. Chemotherapy consisted of cyclophosphamide 750 mg/M2 and doxorubicin hydrochloride (Adriamycin) 50 mg/M2 ad-
ministered intravenously once every three weeks on an ambulatory basis. Total doxorubitin hydrochloride administered was 450 mg/M2 in each patient; cyclophosphamide (Cytoxan) usually was given for a period of six months, although 2 early cases received the agent for a period of eighteen months. Also, in the initial cases, methotrexate 50 mg/M2 was administered orally on days 9, 12, 16, and 19 of each three-week cycle. Because of prominent stomatitis and other complications occurring with this added agent, patients seldom received the intended dosage, and thus the chemotherapy protocol was restricted to cyclophosphamide and doxorubicin hyrochloride alone. Patients were followed for periods of up to sixty-five months after pelvic lymphadenectomy for evidence of disease progression. No patient was followed for less than twelve months. Disease progression was defined as documented appearance of soft tissue or bony metastases.
Documentation usually was established by skeletal bone survey or radioisotope bone scan. Serum acid phosphatase elevation often accompanied the progression of disease. In no instance were we required to depend solely on an elevated serum acid phosphatase to determine disease progression.
Progression of disease in patients with Stage Dl prostatic cancer (25 no chemotherapy and 12 with chemotherapy) TABLE I.
Condition Progressed Died Stable
Results
To ju,stify a program of adjuvant chemotherapy, 3 conditions should be fulfilled. First, the untreated disease should carry a poor prognosis. Second, the agents utilized should have demonstrated anti-tumor activity. Finally, the list of complications arising from adjuvant treatment should be low compared with its potential benefits. These 3 conditions were considered in the design of this treatment study.
MARCH
1983
! VOLUME
XXI. NUMBER
Chemotherapy* (Mos.)
12 (11.6)
4 (15)
.I (29)
4 (18)
13 (36)
8 (37) and
doxorubicin
50 mg/M’
Patients with pelvic lymph node metastases from clinically localized prostate cancer experience an ominous prognosis indeed. At five years, in 85 per cent of such patients overt metastases develop. l This observation has been confirmed by other reports showing 60 per cent disease progression in such patients at thirtytwo months.2 Even at two years of follow-up, disease progression can be seen in 50 per cent of patients.3 We have reported previously a similar progression rate at twenty-four months,4 whereas, in 75 patients with negative lymph nodes, only 5 experienced overt metastatic disease in the same period of time.5 In earlier reports, Whitmore suggested that minimal microscopic involvement of pelvic lymph nodes might not adversely affect patient prognosis.’ However, this opinion recently has been revised, and it now has been shown that the potential for disease progression is high in any patient with pelvic lymph node metastases from prostatic cancer. 6 Indeed, it should come as no surprise that patients with Stage Dl prostate cancer fare poorly, since this is in keeping with observations made in many other malignancies. For example, women with breast cancer that has metastasized to axillary lymph nodes experience a much higher relapse rate compared with negative axillary nod.e dissection.7 Having decided that patients with Stage Dl prostate cancer experience a prognosis sufficiently severe to justify adjuvant treatment, one is then faced with the need to define a course of treatment that will be useful in altering prognosis. Various single-agent chemotherapy trials have been tested in patients with widely metastatic prostate cancer, and response rates have been recorded in the form of either partial remission or stabilization of disease.8.g Rased on these studies and our experience with a combination of cyclophosphamide and doxorubicin in Stage D3 adenocarcinoma of the
Comment
/
(Mos.)
*Cyclophosphamide 750 mg/M2 every three weeks for six months.
Of the 25 patients who received no additional treatment, 12 experienced disease progression, with an average time to progression of 11.6 months. Four of these 12 patients have died, at an average interval of eighteen months from the time of lymphadenectomy. Thirteen patients remain stable with an average follow-up period of thirty-six months. The total disease-free, patient-months in the untreated 25 patients was 24.3. In contrast, of the 12 patients who received adjunctive cyclophosphamide and doxorubicin hydrochloride, 4 experienced disease progression (average time to progression fifteen months); 1 patient died twenty-nine months after pelvic lymphadenectomy. The remaining 8 patients undergoing adjunctive treatment continue to show no disease progression (average follow-up of thirty-seven months). Over-all, the 12 patients treated with cyclophosphamide and doxorubicin hydrochloride have experienced 29.7 patient-months free of disease (Table I). There were few complications that could be related to the administration of cyclophosphamide and doxorubicin hydrochloride. In 1 patient a transient change in EKG pattern developed after reaching a dosage level of 450 mg/ M2 doxorubicin hydrochloride. A year later, this patient underwent surgery for an unrelated problem; at that time his EKG pattern showed nonspecific changes only. The initial patients subjected to adjunctive chemotherapy received oral methotrexate with resultant stomatitis. In 1 patient methotrexate pneumonia developed which necessitated a week of hospitalization.
UROLOGY
No Chemotherapy
3
271
prostate, we intiated the adjuvant program. As methotrexate was inipreviously mentioned, tially intended to complete the adjuvant protocol. However, this drug was omitted after the number of complications interfered with patient compliance. Regarding complications of therapy, there were few that could be related to the adjunctive program selected. After omitting methotrexate, a single electrocardiographic abnormality was recorded in 1 patient receiving the maximum 450 mg/M2 of doxorubicin. Despite our concerns about possible radiomimetic actions of doxorubicin, there was no difference in incidence of proctitis in patients receiving chemotherapy versus those receiving radiation alone. As can be seen from our results, the rate of disease progression appears to have been slowed by the adjuvant chemotherapy program, although the results do not reach statistical significance. There is a slightly improved average duration of disease-free survival in patients undergoing chemotherapy (29.7 versus 24.3 months). More importantly, there is a distinct difference in reduction of mortality (1 death in the treated group versus 4 in the untreated group). In patients with Stage Dl adenocarcinoma of the prostate, time to progression in the control population is short, so that one can determine the value of an adjunctive chemotherapy pro-
gram in a relatively limited period of time. Although the figures obtained in this initial report do not justify any firm conclusions, they are sufficiently encouraging to suggest further trials of adjuvant chemotherapy in this group of patients. Columbia University College of Physicians and Surgeons 630 West 168th Street New York, New York 10032 (DR. DEVERE WHITE) References 1. Barzell W, Bean MA, Hilaris BS, and Whitmore WF Jr: Prostatic adenocarcinoma: relationship of grade and local extent to the pattern of metastases, J Urol 118: 278 (1977). 2. Prout GR Jr, et al: Nodal involvement as a prognostic indicator in patients with prostatic carcinoma, ibid. 124: 226 (1980). 3. Kramer SA, et al: Experience with Gleason’s histopathologic grading in prostate cancer, ibid. 124: 223 (1980). 4. Babayan RK, et al: Benefits and complications of staying pelvic lymph node dissection in prostatic adenocarcinoma, Prostate 1: 315 (1980). 5. deVere White R. Babayan RK. Feldman M, and Olsson CA: Adjunctive therapy with interstitial irradiation for prostate cancer: progression and late complications, Urology 19: 395 (1982). 6. Grossman BH, and Whitmore WF Jr: 1rz5 Implantation of the prostate: prediction of treatment results (Abstr. 126). presented at 76th Annual Meeting of American Urological Association, Boston, Map 11, 1981. 7. Fisher B, et al: Cancer of the breast: size of neoplasm and prognosis, Cancer 24: 1071 (1969). 8. DeWys WD, and Begg CB: Comparison of Adriamycin and 5-fluorouracil in advanced prostatic cancer, Proc Am Assoc Cancer Res 19: 330 (1978). 9. Scott WW, et al: Chemotherapy of advanced prostatic carcinoma with cyclophosphamide or 5-fluorouracil, results of first national randomized study, J Urol 114: 909 (1975).
UROLOGY
: MARCH
1983
/ VOLUME
XXI, NUMBER
3