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The current causes of death in patients with malignant melanoma
Europ. j . Cancer Vol. 14, pp. 327 330. Pergamon Press 1978. Printed ill Great Britain
The Current Causes of Death in Patients with Malignant Melanoma DANIEL R. BUDMAN, ELBER CAMACHO and ROBERT E. WITTES Department of Medicine, Memorial Slaon-Kettering Cancer Center, New York, New ~brk 10021, U.S.A. A b s t r a c t - - T h e immediate cause of death was determined for all patients dying at Memorial Hospital from 1973 to 1976 with biopsy-proven malignant melanoma. One-third of patients died of a central nervous system involvement. Pulmonary involvement and infections were the next most common causes of death. The addition of chemotherapy or chemoimmunotherapy to surgery did not change the causes of death. The incidence of postmortem, documented CNS metastases has also increasedsince prior studies 10 yr ago.
INTRODUCTION
hemorrhage, herniation and/or progressive metastatic disease with irreversible neurologic signs leading to death were included under this category. Infectious causes required cultures and/or evidence of an infection such as fever with leukocytosis and/or a pulmonary infiltrate which led to respiratory and/or vasomotor collapse not explainable by other causes. Respiratory causes of death only included pulmonary insufficiency directly caused by the metastatic process and not by superimposed infection. A hemorrhagic cause of death was defined as uncontrollable bleeding leading to vaso-motor collapse and/or leading to irreversible damage of a vital organ. Supportive autopsy evidence was available in 73 patients. When the immediate cause of death was clinically or pathologically uncertain the patient was scored as having "other" cause of death. The age at time of death, sex and stage of disease at first diagnosis were determined. Final laboratory values, if within two days of death, were noted. The patients were then placed into one of three groups (Table 1) according to the type of treatment they received: (1) Surgery and/or irradiation. (2) Chemotherapy in addition to surgery and/or radiation therapy. Chemotherapy usually involved treatment with nitrosurea and D T I C initially, followed by multiple other experimental agents. (3) Immunotherapy, in addition to surgery and/or radiation therapy plus chemotherapy. Thirty-five patients received only BCG, 10 C. parvum, 5 mixed bacterial vaccine (a variant of Coley's toxins), 3 allogeneic tumor vaccine and 2 transfer factor.
MALIGNANT melanoma is a tumor of interest as its incidence is increasing at a rate greater than any other tumor except lung cancer [1, 2]. Recent studies have suggested that both chemotherapy and chemoimmunotherapy have at most limited effects in this neoplasm [3-5]. As the immediate cause of death in melanoma patients has not been carefully examined since the advent of chemotherapy and chemoimmunotherapy, this study examined the effect of current therapeutic modalities on the cause of death in these patients.
MATERIAL A N D M E T H O D S The immediate cause of death in all patients with biopsy-proven malignant melanoma dying at Memorial Hospital between 1973 and 1976 were examined. Patients treated at Memorial but dying elsewhere were excluded from study to ensure uniformity of both medical care and pathologic findings during the final admission. Approximately 50% of patients followed for malignant melanoma at Memorial Hospital were included in this study. A total of 139 patients were evaluated. The clinical cause of death was determined by using the criteria of a previous study on the causes of death in cancer patients [6]. A CNS catastrophe was defined as a primary neurologic event due to tumor leading directly to the patient's demise. Intracranial Accepted 30June 1977. Please direct requests tor reprints to Dr. Wittes, 1275 York Avenue, New York, New York. 327
Daniel R. Budma~ Elber Camacho and Robert E. Wittes
328
Table 1.
Number of patients Male/female Medain age (range) Stage, at time of diagnosis of melanoma Localized (skin ___nodes) Number of patients Disseminated Not determined Second malignancies in patients
Characteristicsof patients studied
Group 1 (surgery)
3 ( + chemotherapy)
3 ( + immunotherapy )
Total group
24 18/6 63 (32-92)
69 38/31 48 (20 76)
46 29/17 50 (16 73)
139 85/54 52 (16-92)
19 5
51 14 4
41 4 1
111 23 5
4 1. Breast cancer 2. Cervical carcinoma 3. Adenocarcinoma of the sigmoid colon 4. Adenocarcinoma of the sigmoid colon, lymphoma
2 1. Breast cancer 2. Adenocarcinoma of the sigmoid colon
The causes of death were then examined as indicated above and statistical analysis was done by chi square analysis with Yates' correction. RESULTS Table 1 indicates the composition of the patients studied. No significant differences among the three groups were found. Males predominated in all groups. Approximately 80% of patients in each group had localized skin or localized skin with proximal node metastases at the time of initial presentation. Table 2 indicates the final hematologic values at time of death. Patients treated with either chemotherapy or chemoimmunotherapy tended to be more anemic, have a higher B U N and lower platelet count than patients treated solely with surgery and/or radiation. These differences were not of statistical significance. Hypercalcemia, defined as a serum calcium greater than 11.0 mg per deciliter, was noted in three of the chemotherapy and three of the chemoimmunotherapy patients. Table 2.
3 1. Thyroid papillary adenocarcinoma 2. Adenocarcinoma of the colon 3. Lymphoma, Basal cell carcinoma of the skin
The most common causes of death (Fig. 1) were (1) central nervous system involvement by tumor ( P < 0 . 0 3 compared to pulmonary involvement), (2) metastatic pulmonary involvement with respiratory insufficiency and (3) infections. One-half of the infectious processes in each group were pneumonias. Therapy did not change the relative frequency of the various causes of death in any of the groups (Fig. 1 ). The extent of metastatic disease found on autopsy is shown in Table 3. Patients dying without evidence of melanoma (2 patients) or in the immediate postoperative period (3 patients) were excluded from analysis. Except tbr central ~UIlJl~a|TromtlllUmt
3O L/ 20
E~Bowelobstructionorperforationrri Liverfailure • Cardiac: CHF.MI, arrhymthia ~ Otherneoplasm E~CNS [ ] Othercause [] Heenorrhage ~ Pulmonarymetastaticdisease [] Inlection • Pulmonarye~nboli
9 S u r g i c a l mid C h e m o t h e r a p y T r e a t m e n t
29 10 0 $U~IcM a M
Laboratoryvalues of study patients
Che~Mmmu~llmerapy
o
Percentage of abnormal values at time of death
Hemoglobin < 10.0 White blood cell count < 2.0 Platelets < 100,000 BUN > 25
Group 1
Group 2
Group 3
35
45
54
5 15 29
6 21 49
5 25 54
,°
A l l P a U e n l s Studied 1973 - 1976
2d-
Fig. 1.
Causes o/ death in melanoma patienls.
Cause~ oJ Death in Melanoma Patients
329
Table 3. Extentof diseaseproven by autopsy Percentage of involvementby organ system
Number of patients Median age
Bladder and ureter Bone CNS Kidney Heart Liver Lung Stomach and intestines
Group 1
Group2
8 58
35 47
Group3
Total
24 67 45 Site of metastasis Percentage of involvementby organ system
Historical control Memorial Hospital [7] 125
0 25 88* 63 50 63 88
23 57 69* 34 51 71 77
29 71 75* 50 54 71 75
22 58 73* 45 52 70 78
18 Not stated 39 45 49 68 70
50
66
75
67
58
*Differentfrom historical control, P < 0.05. nervous system (CNS) involvement, the sites of involvement at time of death has not changed compared to historical controls at Memorial Hospital [7]. Approximately three-quarters of all study patients had CNS involvement at time of death (Table 3) which is almost twice the frequency previously reported from this Institution. CNS involvement usually demonstrated multiple mass lesions in the brain. The total percentage of second malignant tumors in the patients studied was 6%. Four patients in the Group 1, two in Group 2, and three in Group 3 had at least one other malignancy (Table 1). No predominance of specific pathologic type of neoplasm was noted.
DISCUSSION Several recent reviews have stressed the importance of-infection in causing the demise of patients with cancer [6, 8]. However, these studies contained a heterogenous group of malignancies. Based upon these findings we have examined the immediate cause of death in one specific neoplasm and have noted that infection is not the major cause of death. Approximately one-third of all patients with malignant melanoma die of CNS involvement independent of the modalities of treatment used. A previous report has emphasized that all patients with pathologic evidence of CNS involvement at autopsy died of CNS involvement [3]. This study did not confirm this finding as 73~}~ of patients had pathologic proof of CNS metastases (Table 3), but slightly less than onehalf that number died as a result. Since the last
review of autopsy material from this Institution, however, the incidence of CNS involvement seems to have markedly increased. Patients in the current study had almost twice the frequency of involvement as did patients examined a decade ago at Memorial Hospital (Table 3). The reasons for this apparent increase are obscure, but may reflect more aggresive supportive care of other organ system involvement thus allowing a longer survival time to make neurologic disease evident. There is no change in the method of pathologic examination of the central nervous system since the last study to account for this finding. Pulmonary insufficiencycaused by metastatic disease in the lungs was the second most common cause of death in the total group of patients. This cause of death has not been previously stressed. Infection was the third most common cause of death. As pneumonia accounted for one-half of infectious causes of death, a pulmonary demise whether secondary to metastatic disease or infection was very frequent. Heightened awareness of possible infectious complications and early use of antibiotics may account for the lowered incidence of infections seen in this study compared to previous reports~ In addition, we did not find the severe neutropenia seen in a previous study [8]. Whether this difference represents less aggresive cytotoxic therapy or heightened supportive care to maintain the. patient over his leukopenic episode remains uncertain.
Acknowledgement--The authors thank Dr. Robert Golbey for his critical review of the manuscript.
330
Daniel R. Budman, Elber Camacho and Robert E. Wittes REFERENCES 1. J. M. F~LWOODand J. A. LEE, Recent data on the epidemiology of malignant melanoma. Semin. Oncol. 2, 149 (1975). 2. .]. A. LEE and A. P. CARTER,Secular trends in mortality from malignant melanoma. j . nat. Cancerlnst. 45, 91 (1970). 3. L.H. EINHORN, M. A. BURGESS,C. VALLEGOS,G. P. BODEY,J. GUTTERMAN,G. MAVLIGIT, E. M. HERSH, J. K. LUCE, E. FEI (IlI), E. J. FREIREICH and J. A. GOTTLIEB,Prognostic correlation and response to treatment in advanced metastatic malignant melanoma. CancerRes. 34, 1995 (1974). 4. R . D . CARTER, E. T. KREMENTZ, G. J. HILL II, et al., D T I C and combination therapy ot melanoma. I. Studies with I)TIC, BCNU, CCNU, Vincristine and hydroxyurea. Cancer Treat. Rep. fall, 601 (1976). 5. J.U. GUTTIe'RMAN,G. MAVLIC;I'I',R. REFD, el al., Immunology and immunotherapy of human-malignant melanoma: Historic review and perspectives |br tile future. Semin. Oncol. 2, 155 (1975). 6. J. KLASTERSKY,D. DANEAU and A. VERHEST, Causes of death in patients with cancer. Europ. J. Cancer2, 149 (1972). 7. T. DAS GUPTA and R. BRASFIELD,Metastatic melanoma. Cancer (Philad.) 17, 1323 (1964). 8. J. INAC,AKI, V. RODRIGUEZand (3. BODEY,Causes of death in cancer patients. Cancer (Philad.) 33, 568 (1974).
The Current Causes of Death in Patients with Malignant Melanoma DANIEL R. BUDMAN, ELBER CAMACHO and ROBERT E. WITTES Department of Medicine, Memorial Slaon-Kettering Cancer Center, New York, New ~brk 10021, U.S.A. A b s t r a c t - - T h e immediate cause of death was determined for all patients dying at Memorial Hospital from 1973 to 1976 with biopsy-proven malignant melanoma. One-third of patients died of a central nervous system involvement. Pulmonary involvement and infections were the next most common causes of death. The addition of chemotherapy or chemoimmunotherapy to surgery did not change the causes of death. The incidence of postmortem, documented CNS metastases has also increasedsince prior studies 10 yr ago.
INTRODUCTION
hemorrhage, herniation and/or progressive metastatic disease with irreversible neurologic signs leading to death were included under this category. Infectious causes required cultures and/or evidence of an infection such as fever with leukocytosis and/or a pulmonary infiltrate which led to respiratory and/or vasomotor collapse not explainable by other causes. Respiratory causes of death only included pulmonary insufficiency directly caused by the metastatic process and not by superimposed infection. A hemorrhagic cause of death was defined as uncontrollable bleeding leading to vaso-motor collapse and/or leading to irreversible damage of a vital organ. Supportive autopsy evidence was available in 73 patients. When the immediate cause of death was clinically or pathologically uncertain the patient was scored as having "other" cause of death. The age at time of death, sex and stage of disease at first diagnosis were determined. Final laboratory values, if within two days of death, were noted. The patients were then placed into one of three groups (Table 1) according to the type of treatment they received: (1) Surgery and/or irradiation. (2) Chemotherapy in addition to surgery and/or radiation therapy. Chemotherapy usually involved treatment with nitrosurea and D T I C initially, followed by multiple other experimental agents. (3) Immunotherapy, in addition to surgery and/or radiation therapy plus chemotherapy. Thirty-five patients received only BCG, 10 C. parvum, 5 mixed bacterial vaccine (a variant of Coley's toxins), 3 allogeneic tumor vaccine and 2 transfer factor.
MALIGNANT melanoma is a tumor of interest as its incidence is increasing at a rate greater than any other tumor except lung cancer [1, 2]. Recent studies have suggested that both chemotherapy and chemoimmunotherapy have at most limited effects in this neoplasm [3-5]. As the immediate cause of death in melanoma patients has not been carefully examined since the advent of chemotherapy and chemoimmunotherapy, this study examined the effect of current therapeutic modalities on the cause of death in these patients.
MATERIAL A N D M E T H O D S The immediate cause of death in all patients with biopsy-proven malignant melanoma dying at Memorial Hospital between 1973 and 1976 were examined. Patients treated at Memorial but dying elsewhere were excluded from study to ensure uniformity of both medical care and pathologic findings during the final admission. Approximately 50% of patients followed for malignant melanoma at Memorial Hospital were included in this study. A total of 139 patients were evaluated. The clinical cause of death was determined by using the criteria of a previous study on the causes of death in cancer patients [6]. A CNS catastrophe was defined as a primary neurologic event due to tumor leading directly to the patient's demise. Intracranial Accepted 30June 1977. Please direct requests tor reprints to Dr. Wittes, 1275 York Avenue, New York, New York. 327
Daniel R. Budma~ Elber Camacho and Robert E. Wittes
328
Table 1.
Number of patients Male/female Medain age (range) Stage, at time of diagnosis of melanoma Localized (skin ___nodes) Number of patients Disseminated Not determined Second malignancies in patients
Characteristicsof patients studied
Group 1 (surgery)
3 ( + chemotherapy)
3 ( + immunotherapy )
Total group
24 18/6 63 (32-92)
69 38/31 48 (20 76)
46 29/17 50 (16 73)
139 85/54 52 (16-92)
19 5
51 14 4
41 4 1
111 23 5
4 1. Breast cancer 2. Cervical carcinoma 3. Adenocarcinoma of the sigmoid colon 4. Adenocarcinoma of the sigmoid colon, lymphoma
2 1. Breast cancer 2. Adenocarcinoma of the sigmoid colon
The causes of death were then examined as indicated above and statistical analysis was done by chi square analysis with Yates' correction. RESULTS Table 1 indicates the composition of the patients studied. No significant differences among the three groups were found. Males predominated in all groups. Approximately 80% of patients in each group had localized skin or localized skin with proximal node metastases at the time of initial presentation. Table 2 indicates the final hematologic values at time of death. Patients treated with either chemotherapy or chemoimmunotherapy tended to be more anemic, have a higher B U N and lower platelet count than patients treated solely with surgery and/or radiation. These differences were not of statistical significance. Hypercalcemia, defined as a serum calcium greater than 11.0 mg per deciliter, was noted in three of the chemotherapy and three of the chemoimmunotherapy patients. Table 2.
3 1. Thyroid papillary adenocarcinoma 2. Adenocarcinoma of the colon 3. Lymphoma, Basal cell carcinoma of the skin
The most common causes of death (Fig. 1) were (1) central nervous system involvement by tumor ( P < 0 . 0 3 compared to pulmonary involvement), (2) metastatic pulmonary involvement with respiratory insufficiency and (3) infections. One-half of the infectious processes in each group were pneumonias. Therapy did not change the relative frequency of the various causes of death in any of the groups (Fig. 1 ). The extent of metastatic disease found on autopsy is shown in Table 3. Patients dying without evidence of melanoma (2 patients) or in the immediate postoperative period (3 patients) were excluded from analysis. Except tbr central ~UIlJl~a|TromtlllUmt
3O L/ 20
E~Bowelobstructionorperforationrri Liverfailure • Cardiac: CHF.MI, arrhymthia ~ Otherneoplasm E~CNS [ ] Othercause [] Heenorrhage ~ Pulmonarymetastaticdisease [] Inlection • Pulmonarye~nboli
9 S u r g i c a l mid C h e m o t h e r a p y T r e a t m e n t
29 10 0 $U~IcM a M
Laboratoryvalues of study patients
Che~Mmmu~llmerapy
o
Percentage of abnormal values at time of death
Hemoglobin < 10.0 White blood cell count < 2.0 Platelets < 100,000 BUN > 25
Group 1
Group 2
Group 3
35
45
54
5 15 29
6 21 49
5 25 54
,°
A l l P a U e n l s Studied 1973 - 1976
2d-
Fig. 1.
Causes o/ death in melanoma patienls.
Cause~ oJ Death in Melanoma Patients
329
Table 3. Extentof diseaseproven by autopsy Percentage of involvementby organ system
Number of patients Median age
Bladder and ureter Bone CNS Kidney Heart Liver Lung Stomach and intestines
Group 1
Group2
8 58
35 47
Group3
Total
24 67 45 Site of metastasis Percentage of involvementby organ system
Historical control Memorial Hospital [7] 125
0 25 88* 63 50 63 88
23 57 69* 34 51 71 77
29 71 75* 50 54 71 75
22 58 73* 45 52 70 78
18 Not stated 39 45 49 68 70
50
66
75
67
58
*Differentfrom historical control, P < 0.05. nervous system (CNS) involvement, the sites of involvement at time of death has not changed compared to historical controls at Memorial Hospital [7]. Approximately three-quarters of all study patients had CNS involvement at time of death (Table 3) which is almost twice the frequency previously reported from this Institution. CNS involvement usually demonstrated multiple mass lesions in the brain. The total percentage of second malignant tumors in the patients studied was 6%. Four patients in the Group 1, two in Group 2, and three in Group 3 had at least one other malignancy (Table 1). No predominance of specific pathologic type of neoplasm was noted.
DISCUSSION Several recent reviews have stressed the importance of-infection in causing the demise of patients with cancer [6, 8]. However, these studies contained a heterogenous group of malignancies. Based upon these findings we have examined the immediate cause of death in one specific neoplasm and have noted that infection is not the major cause of death. Approximately one-third of all patients with malignant melanoma die of CNS involvement independent of the modalities of treatment used. A previous report has emphasized that all patients with pathologic evidence of CNS involvement at autopsy died of CNS involvement [3]. This study did not confirm this finding as 73~}~ of patients had pathologic proof of CNS metastases (Table 3), but slightly less than onehalf that number died as a result. Since the last
review of autopsy material from this Institution, however, the incidence of CNS involvement seems to have markedly increased. Patients in the current study had almost twice the frequency of involvement as did patients examined a decade ago at Memorial Hospital (Table 3). The reasons for this apparent increase are obscure, but may reflect more aggresive supportive care of other organ system involvement thus allowing a longer survival time to make neurologic disease evident. There is no change in the method of pathologic examination of the central nervous system since the last study to account for this finding. Pulmonary insufficiencycaused by metastatic disease in the lungs was the second most common cause of death in the total group of patients. This cause of death has not been previously stressed. Infection was the third most common cause of death. As pneumonia accounted for one-half of infectious causes of death, a pulmonary demise whether secondary to metastatic disease or infection was very frequent. Heightened awareness of possible infectious complications and early use of antibiotics may account for the lowered incidence of infections seen in this study compared to previous reports~ In addition, we did not find the severe neutropenia seen in a previous study [8]. Whether this difference represents less aggresive cytotoxic therapy or heightened supportive care to maintain the. patient over his leukopenic episode remains uncertain.
Acknowledgement--The authors thank Dr. Robert Golbey for his critical review of the manuscript.
330
Daniel R. Budman, Elber Camacho and Robert E. Wittes REFERENCES 1. J. M. F~LWOODand J. A. LEE, Recent data on the epidemiology of malignant melanoma. Semin. Oncol. 2, 149 (1975). 2. .]. A. LEE and A. P. CARTER,Secular trends in mortality from malignant melanoma. j . nat. Cancerlnst. 45, 91 (1970). 3. L.H. EINHORN, M. A. BURGESS,C. VALLEGOS,G. P. BODEY,J. GUTTERMAN,G. MAVLIGIT, E. M. HERSH, J. K. LUCE, E. FEI (IlI), E. J. FREIREICH and J. A. GOTTLIEB,Prognostic correlation and response to treatment in advanced metastatic malignant melanoma. CancerRes. 34, 1995 (1974). 4. R . D . CARTER, E. T. KREMENTZ, G. J. HILL II, et al., D T I C and combination therapy ot melanoma. I. Studies with I)TIC, BCNU, CCNU, Vincristine and hydroxyurea. Cancer Treat. Rep. fall, 601 (1976). 5. J.U. GUTTIe'RMAN,G. MAVLIC;I'I',R. REFD, el al., Immunology and immunotherapy of human-malignant melanoma: Historic review and perspectives |br tile future. Semin. Oncol. 2, 155 (1975). 6. J. KLASTERSKY,D. DANEAU and A. VERHEST, Causes of death in patients with cancer. Europ. J. Cancer2, 149 (1972). 7. T. DAS GUPTA and R. BRASFIELD,Metastatic melanoma. Cancer (Philad.) 17, 1323 (1964). 8. J. INAC,AKI, V. RODRIGUEZand (3. BODEY,Causes of death in cancer patients. Cancer (Philad.) 33, 568 (1974).