Oncology 32: 53-57 (1975)
Three Primary Cancers in Different Organs' Frederick F. Holmes and Paul A. Cole, jr. Cancer Information Service, University of Kansas Medical Center, Kansas City, Kans.
Key Words. Multiple primary tumors • Host defenses Abstract. In a registry of 24,105 cancers, 15 patients were found to have three primary cancers in different organs. Decreasing time intervals between sequential diagnoses and then death were noted. Occurrence and sequence of cancer sites appeared to be random. Stage of second and third cancers tended, on the average, to be more advanced than those of the first cancers. This study strengthened the hypothesis that patients with primary cancers in differ ent organs are victims of compromised host defenses against cancer.
Introduction Patients who develop two or more cancers are not uncommon. Whether they represent a failure of host defense mechanisms against cancer, or a suscep tibility to cancer-inciting factors, or both is not yet known. There is considerable evidence to indicate a depressed immune status in advanced cancer (2—4) as well as substantial evidence showing that patients with compromised immunity have a greater risk of developing cancer (5, 6). Patients with three primary cancers arising in distinctly different organs would seem to be an ideal population for study of the phenomenon. From published data, it is well established that patients developing cancers in two or more organs constitute less than 5 % of the cancer patient population (1, 7 -9 ). Moertel (7) demonstrated that 2.8% of patients with one cancer developed a second and that 5 % of these double primary patients developed a third cancer and 5.8 % of these a fourth cancer.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/16/2018 4:07:45 PM
This study was supported in part by the Mid-America Cancer Center Program.
Table I. Diagnostic and death data for patients with three primary cancers in different organs Second cancer
Third cancer
Holmes/Cole, jr.
First cancer
Living
age
site
stage
age
site
stage
age
site
stage
age
50 54 67
testes endometrium soft tissue of leg
local local local
75 69 67
prostate breast breast
regional local regional
75 71 69
colon bladder ovary
local local local
77 72 73
79 65 69 74 70 67 63 50 67 57 63 57
Hodgkin’s CLL pancreas bladder colon endometrium CLL CLL prostate cranial nerve lip salivary gland
not staged generalized generalized local generalized regional generalized generalized local local local local
79 72 70 74 70 71 68 70 70 61 65 72
gallbladder lung lung prostate ovary breast lung parotid pancreas lymphoma lung prostate
regional unknown generalized local regional unknown generalized regional generalized generalized regional regional
79 73 70 77 70 76 68 73 70 61 66 77
meninges unknown prostate tongue meninges colon prostate lung pituitary kidney pancreas lung
local generalized generalized regional local unknown regional generalized local local generalized generalized
age
cause
79 74 70 78 70 78 68 73 70 61 66 77
Hodgkin’s not cancer lung all three colon not cancer lung lung pancreas lymphoma pancreas lung
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/16/2018 4:07:45 PM
Dead
55
Three Primary Cancers in Different Organs
Beyond occasional case reports, relatively little has been written about triple primary cancers. Study of multiple primary cancers is useful in attempting to understand host defenses in purely clinical and natural history terms.
Methods During the period 1944-1973, the Tumor Registry of the University of Kansas Medi cal Center registered 24,105 cancers. This represents 23,481 patients, 624 of whom had more than one primary cancer (non-melanoma skin cancers excluded). Of this group, 15 patients were identified who had three primary tumors in three different organs. Over the years, only 49 of the 23,481 patients have been lost to follow-up. Thus, 99.8% of all patients registered were accounted for at the time of this study, including all of the 15 patients with triple primary tumors.
Results Ten of the 15 patients studied were males. Three are living. Table I shows the patients’ age at diagnosis, and the site and stage for each of their three cancers. Present age, if living, or age at death and cause of death are also in cluded. The average age at diagnosis of the first cancer was 63.5 years (range 5 0 79), second cancer was 70.2 years (range 61—79), and for the third cancer, 72.4 years (range 61—79). Table II shows these figures with the average interim peri ods between diagnoses and then from diagnosis of the third cancer until death or last follow-up if alive. The decrease in time of the intervals from 6.7 to 1.5 years to 0.7 years was notable. Only 5 of the patients had a sequence of cancers with diagnoses separated by more than 1 year between the first and second, and the second and third. In 8 patients, two of the cancers were diagnosed concurrently, and in another 2, all three cancers were diagnosed at the same time. Excluding the 2 patients with three cancers diagnosed simultaneously, the first cancers were local in extent in the remaining 13 patients with tire exception
Event
Age
Interval
First cancer Second cancer Third cancer Death
63.5 70.2 71.1 72.4
6.7 1.5 0.7 Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/16/2018 4:07:45 PM
Table II. Average ages at diagnoses and death and average intervals between these events expressed in years
Holmes/Cole, jr.
56
of a regionally spread endometrial carcinoma and 3 cases of chronic lymphocytic leukemia. Only 1 of these 13 patients died of the first primary cancer. Chronic lymphocytic leukemia was not diagnosed as a second or third cancer in any patient. Of the dead patients (excluding the 2 patients with concurrent diagnosis of all three cancers) it may be noted that 2 patients did not die of their cancer at all; 4 died of their second cancer; 3 died of their third cancer; and in 1 patient, death was attributed to all three cancers.
Discussion The data presented in this study strengthen the impression that patients with cancers in several different organs are victims of a failure of their host defenses against cancer. Three patients whose first cancer was chronic lympho cytic leukemia, which is known to predispose to subsequent malignancies (1, 5, 6) seemed to reinforce this hypothesis. Further support for the concept of a failing host defense against cancer was offered by the decreasing time interval between subsequent cancers and death. The average time from diagnosis of the second cancer to the diagnosis of the third cancer was less than one-fourth of that noted between the diagnosis of the first cancer to that of the second. The average time between diagnosis of the third cancer and death was less than one-eighth of the first interval. A common inciting cause for all three cancers was not demonstrated in any of the patients. There was no common pattern of progression detected from the first to third cancer and the selection and sequence of cancer sites appeared quite random. Given the fact that the risk of future new cancers increases in some geomet ric progression as a patient’s number of primary cancers increases (7) it appeared that second and third primary cancers are diagnosed, in most cases, at a later stage than first primaries. Though the nature of this study excluded consideration of new primary cancers in the same organ as the first, it would nonetheless seem that whatever heightened suspicion of subsequent new cancers a doctor or patient may have, it is rare that either manages to capitalize on this by diagnosing a second or third cancer at a stage as early as the first cancer. References Berg, J.W.: The incidence of multiple primary cancers. 1. Development of further cancers in patients with lymphomas, leukemias, and myeloma. J. natn. Cancer Inst. 38: 741-752 (1967). Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/16/2018 4:07:45 PM
1
Three Primary Cancers in Different Organs
3 4 5 6 7 8 9
Catalona, W.J.; Sample, W.F., and Chretien, P.B.: Lymphocyte reactivity in cancer patients: correlation with tumor histology and clinical stage. Cancer 31: 65-71 (1972). Glasgow, A.H. et al.: Association of anergy with an immunosuppressive peptide frac tion in the serum of patients with cancer. New Engl. J. Med. 291: 1263-1267 (1974). Gross, L.: Immunological defect in aged population and its relationship to cancer. Cancer 18: 201-204 (1965). Gunz, F.W. and Angus, H.B.: Leukemia and cancer in the same patient. Cancer 18: 145-152 (1965). Manusow, D. and Weinerman, B.H.: Subsequent neoplasia in chronic lymphocytic leukemia. J. Am. med. Ass. 232: 267-269 (1975). Moertel, C.G.: Multiple primary malignant neoplasms. Recent results in cancer re search, vol. 7 (Springer, New York 1966). Warren, S. and Ehrenreich, T.: Multiple primary malignant tumors and susceptibility to cancer. Cancer Res. 4: 554-570 (1944). Warren, S. and Gates, O.: Multiple primary malignant tumors: a survey of the literature and a statistical study. Am. J. Cancer 16: 1358-1414 (1932).
F.F. Holmes, MD, Cancer Information Service, University of Kansas Medical Center, Kansas City, KS 66103 (USA)
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/16/2018 4:07:45 PM
2
57
Three Primary Cancers in Different Organs' Frederick F. Holmes and Paul A. Cole, jr. Cancer Information Service, University of Kansas Medical Center, Kansas City, Kans.
Key Words. Multiple primary tumors • Host defenses Abstract. In a registry of 24,105 cancers, 15 patients were found to have three primary cancers in different organs. Decreasing time intervals between sequential diagnoses and then death were noted. Occurrence and sequence of cancer sites appeared to be random. Stage of second and third cancers tended, on the average, to be more advanced than those of the first cancers. This study strengthened the hypothesis that patients with primary cancers in differ ent organs are victims of compromised host defenses against cancer.
Introduction Patients who develop two or more cancers are not uncommon. Whether they represent a failure of host defense mechanisms against cancer, or a suscep tibility to cancer-inciting factors, or both is not yet known. There is considerable evidence to indicate a depressed immune status in advanced cancer (2—4) as well as substantial evidence showing that patients with compromised immunity have a greater risk of developing cancer (5, 6). Patients with three primary cancers arising in distinctly different organs would seem to be an ideal population for study of the phenomenon. From published data, it is well established that patients developing cancers in two or more organs constitute less than 5 % of the cancer patient population (1, 7 -9 ). Moertel (7) demonstrated that 2.8% of patients with one cancer developed a second and that 5 % of these double primary patients developed a third cancer and 5.8 % of these a fourth cancer.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/16/2018 4:07:45 PM
This study was supported in part by the Mid-America Cancer Center Program.
Table I. Diagnostic and death data for patients with three primary cancers in different organs Second cancer
Third cancer
Holmes/Cole, jr.
First cancer
Living
age
site
stage
age
site
stage
age
site
stage
age
50 54 67
testes endometrium soft tissue of leg
local local local
75 69 67
prostate breast breast
regional local regional
75 71 69
colon bladder ovary
local local local
77 72 73
79 65 69 74 70 67 63 50 67 57 63 57
Hodgkin’s CLL pancreas bladder colon endometrium CLL CLL prostate cranial nerve lip salivary gland
not staged generalized generalized local generalized regional generalized generalized local local local local
79 72 70 74 70 71 68 70 70 61 65 72
gallbladder lung lung prostate ovary breast lung parotid pancreas lymphoma lung prostate
regional unknown generalized local regional unknown generalized regional generalized generalized regional regional
79 73 70 77 70 76 68 73 70 61 66 77
meninges unknown prostate tongue meninges colon prostate lung pituitary kidney pancreas lung
local generalized generalized regional local unknown regional generalized local local generalized generalized
age
cause
79 74 70 78 70 78 68 73 70 61 66 77
Hodgkin’s not cancer lung all three colon not cancer lung lung pancreas lymphoma pancreas lung
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/16/2018 4:07:45 PM
Dead
55
Three Primary Cancers in Different Organs
Beyond occasional case reports, relatively little has been written about triple primary cancers. Study of multiple primary cancers is useful in attempting to understand host defenses in purely clinical and natural history terms.
Methods During the period 1944-1973, the Tumor Registry of the University of Kansas Medi cal Center registered 24,105 cancers. This represents 23,481 patients, 624 of whom had more than one primary cancer (non-melanoma skin cancers excluded). Of this group, 15 patients were identified who had three primary tumors in three different organs. Over the years, only 49 of the 23,481 patients have been lost to follow-up. Thus, 99.8% of all patients registered were accounted for at the time of this study, including all of the 15 patients with triple primary tumors.
Results Ten of the 15 patients studied were males. Three are living. Table I shows the patients’ age at diagnosis, and the site and stage for each of their three cancers. Present age, if living, or age at death and cause of death are also in cluded. The average age at diagnosis of the first cancer was 63.5 years (range 5 0 79), second cancer was 70.2 years (range 61—79), and for the third cancer, 72.4 years (range 61—79). Table II shows these figures with the average interim peri ods between diagnoses and then from diagnosis of the third cancer until death or last follow-up if alive. The decrease in time of the intervals from 6.7 to 1.5 years to 0.7 years was notable. Only 5 of the patients had a sequence of cancers with diagnoses separated by more than 1 year between the first and second, and the second and third. In 8 patients, two of the cancers were diagnosed concurrently, and in another 2, all three cancers were diagnosed at the same time. Excluding the 2 patients with three cancers diagnosed simultaneously, the first cancers were local in extent in the remaining 13 patients with tire exception
Event
Age
Interval
First cancer Second cancer Third cancer Death
63.5 70.2 71.1 72.4
6.7 1.5 0.7 Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/16/2018 4:07:45 PM
Table II. Average ages at diagnoses and death and average intervals between these events expressed in years
Holmes/Cole, jr.
56
of a regionally spread endometrial carcinoma and 3 cases of chronic lymphocytic leukemia. Only 1 of these 13 patients died of the first primary cancer. Chronic lymphocytic leukemia was not diagnosed as a second or third cancer in any patient. Of the dead patients (excluding the 2 patients with concurrent diagnosis of all three cancers) it may be noted that 2 patients did not die of their cancer at all; 4 died of their second cancer; 3 died of their third cancer; and in 1 patient, death was attributed to all three cancers.
Discussion The data presented in this study strengthen the impression that patients with cancers in several different organs are victims of a failure of their host defenses against cancer. Three patients whose first cancer was chronic lympho cytic leukemia, which is known to predispose to subsequent malignancies (1, 5, 6) seemed to reinforce this hypothesis. Further support for the concept of a failing host defense against cancer was offered by the decreasing time interval between subsequent cancers and death. The average time from diagnosis of the second cancer to the diagnosis of the third cancer was less than one-fourth of that noted between the diagnosis of the first cancer to that of the second. The average time between diagnosis of the third cancer and death was less than one-eighth of the first interval. A common inciting cause for all three cancers was not demonstrated in any of the patients. There was no common pattern of progression detected from the first to third cancer and the selection and sequence of cancer sites appeared quite random. Given the fact that the risk of future new cancers increases in some geomet ric progression as a patient’s number of primary cancers increases (7) it appeared that second and third primary cancers are diagnosed, in most cases, at a later stage than first primaries. Though the nature of this study excluded consideration of new primary cancers in the same organ as the first, it would nonetheless seem that whatever heightened suspicion of subsequent new cancers a doctor or patient may have, it is rare that either manages to capitalize on this by diagnosing a second or third cancer at a stage as early as the first cancer. References Berg, J.W.: The incidence of multiple primary cancers. 1. Development of further cancers in patients with lymphomas, leukemias, and myeloma. J. natn. Cancer Inst. 38: 741-752 (1967). Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/16/2018 4:07:45 PM
1
Three Primary Cancers in Different Organs
3 4 5 6 7 8 9
Catalona, W.J.; Sample, W.F., and Chretien, P.B.: Lymphocyte reactivity in cancer patients: correlation with tumor histology and clinical stage. Cancer 31: 65-71 (1972). Glasgow, A.H. et al.: Association of anergy with an immunosuppressive peptide frac tion in the serum of patients with cancer. New Engl. J. Med. 291: 1263-1267 (1974). Gross, L.: Immunological defect in aged population and its relationship to cancer. Cancer 18: 201-204 (1965). Gunz, F.W. and Angus, H.B.: Leukemia and cancer in the same patient. Cancer 18: 145-152 (1965). Manusow, D. and Weinerman, B.H.: Subsequent neoplasia in chronic lymphocytic leukemia. J. Am. med. Ass. 232: 267-269 (1975). Moertel, C.G.: Multiple primary malignant neoplasms. Recent results in cancer re search, vol. 7 (Springer, New York 1966). Warren, S. and Ehrenreich, T.: Multiple primary malignant tumors and susceptibility to cancer. Cancer Res. 4: 554-570 (1944). Warren, S. and Gates, O.: Multiple primary malignant tumors: a survey of the literature and a statistical study. Am. J. Cancer 16: 1358-1414 (1932).
F.F. Holmes, MD, Cancer Information Service, University of Kansas Medical Center, Kansas City, KS 66103 (USA)
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/16/2018 4:07:45 PM
2
57
![The extreme variety of genotoxic response to benzo[a]pyrene in three different human cell lines from three different organs.](/assets/img/hold.png)
