- Email: [email protected]
Second primary malignancies following the treatment of early stage ovarian cancer: Update of a study by the National Cancer Institute of Canada—Clinical Trials Group (NCIC—CTG)
Annals of Oncology 11: 65-68. 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Second primary malignancies following the treatment of early stage ovarian cancer: Update of a study by the National Cancer Institute of Canada-Clinical Trials Group (NCIC-CTG) S. F. Dent,1 D. Klaassen,2 J. L. Pater,3 B. Zee3 & M. Whitehead3
50% in the whole abdominal radiotherapy arm, 62% in the melphalan arm and 51% in the chromic phosphate arm Background: Ovarian cancer is the leading cause of death from (P = 0.147). Long term follow-up has not demonstrated a gynecological malignancies and the fourth most frequent fatal significant difference between treatment arms. Second primary malignancy in women. Despite improved surgical techniques malignancies developed in 29 women (11%) after 2,229 person as many as 20% of women with early stage disease will years of follow-up. This compares to 18.7 second primary eventually relapse and die from their disease. The post-opera- malignancies which would have been expected in this group tive management of these women remains controversial. Here of age-matched controls and was statistically significant we present the long term follow-up data of our previously (P = 0.018). There was no significant difference in the total published study, as well as the incidence of second primary number of second primary malignancies between treatment arms. Melphalan appeared to be associated with an increased malignancies in these women. Patients and methods; Two hundredfifty-seveneligible pa- risk of developing leukemia/myelodysplastic syndrome comtients with stage I, IIA 'high risk' ovarian carcinoma and IIB, pared to the whole abdominal radiotherapy arm (P = 0.06). IIIO (disease confined to pelvis) were randomized to either Conclusions: Long-term follow-up has not demonstrated a whole abdominal radiotherapy 2,250 rads in ten fractions (107 significant difference in overall or disease free survival between patients), melphalan 8 mg/m2/d x 4 weeks x 18 courses (106 treatment arms. An excess of second primary malignancies patients) or intraperitoneal chromic phosphate 10-20 mCi (44 (35%) was observed suggesting that lifelong surveillance is patients). All patients were initially treated with pelvic radio- required in this population. Further research with newer treattherapy. ment programs are needed to improve the cure rates in this Results: Overall survival estimates at 10 years were: 45% in population. the whole abdominal radiotherapy arm; 49% in the melphalan arm and 50% in the intraperitoneal chromic phosphate arm (P - 0.30). Relapse-free survival estimates at 10 years were: Key words: ovarian cancer, second primary malignancies Summary
Introduction
Epithelial ovarian carcinoma is the leading cause of death from gynecological malignancies and the fourth most frequent fatal malignancy in women [1]. While the majority of women present with advanced ovarian cancer, those who present with disease confined to the pelvis are potentially curable. Improved surgical staging and treatment of early stage disease has led to long term survival rates of 80%-95% [2, 3]. Unfortunately as many as 20%-30% of women with early stage I disease will eventually relapse and die from their disease [4]. Clearly there is a subgroup of women with early stage disease who potentially may benefit from adjuvant treatment. The post-operative management for this group of women remains controversial [5]. Several treatment options in the literature have been explored including: abdominopelvic radiotherapy, intraperitoneal radioactive chromic phosphate and systemic chemotherapy [3, 6-12].
No clear consensus exists [13]. Recommendations for these women is hampered by the potential long-term complications of adjuvant therapy in a cancer where the prognosis is already reasonable. There is limited data in the literature on the longterm follow-up of women treated for early stage ovarian cancer. Long-term data is needed to identify women who have relapsed as well as to assess long-term toxicities such as second primary malignancies. This information might influence future treatment options for women with early stage disease. In November 1985 the National Cancer Institute of Canada - Clinical Trials Group reported the results of a randomized control trial of whole abdominal radiotherapy, melphalan or intraperitoneal chromic phosphate for patients with poor prognosis early stage ovarian cancer [9]. We present an update of our previous analysis including overall and disease-free survival as well as the incidence of second primary malignancies.
Downloaded from https://academic.oup.com/annonc/article-abstract/11/1/65/276292 by guest on 15 September 2019
'Northwestern Ontario Regional Cancer Center, Thunder Bay, Ontario; 2British Columbia Cancer Agency, Vancouver, British Columbia; National Cancer Institute of Canada - Clinical Trials Group, Kingston, Ontario, Canada
3
66 Patients and methods
80%
|3
60%
c o
a
40% 20% 0%
2
4
6
10
Time (years) • Pelvic & abdominal radiation Pelvic radiation & melphalan Pelvic radiation & chronic phosphate Figure 1 Overall survival.
100%
Survival was measured from the date of randomization until death or last follow-up. Relapse free-survival was calculated from the date of randomization to the first documented evidence of treatment failure. The Kaplan-Meier method was adopted to estimate survival. A Fisher's exact test was performed to compare the incidence of hematological malignancies in the melphalan and whole abdominal radiotherapy arms. A chi-square analysis was performed to compare observed versus expected malignancy rates in this population. Cancer incidence rates in age matched Canadian women were multiplied by person years at risk to determine the expected number of malignancies in this population. The median follow-up at the time of the current analysis (January 1996) was 13.5 years.
80%
60%
40%
20%
0%
2
4
6
10
Time (years)
Results From May 1975 to March 1984, a total of 284 patients were enrolled from 12 participating Canadian centers. Twenty-seven patients (10%) were considered initially ineligible; ten due to extrapelvic stage III or stage IV disease; nine because of incomplete surgery; three because on review of the pathology the disease was not felt to be due to ovarian cancer; two because of prior radiotherapy; two because the attending physician was not a study participant; and one because of a threemonth delay between surgery and radiation. There were 257 eligible patients included in this analysis. Overall survival and relapse-free survival In our 1986 analysis we found no significant difference in overall survival between the treatment arms: 62% in the whole abdominal radiotherapy arm; 61% in the melphalan arm and 66% in the chromic phosphate arm (P - 0.49). At the time of this analysis 44% of patients were still alive. The overall survival estimates at 10 years were similar in the 3 cohorts: 45% in the whole abdominal radiotherapy arm; 49% in the melphalan arm and 50% in the intraperitoneal arm (P = 0.301) (Figure 1). There was no significant difference in relapse-free
Pelvic & abdominal radiation Pelvic radiation & melphalan Pelvic radiation & chronic phosphate Figure 2. Relapse-free survival.
survival between treatment arms in our 1986 analysis. In that analysis we reported that melphalan appeared to have a marginal but not statistically significant benefit compared to the whole abdominal radiotherapy arm (P - 0.06). This trend was again demonstrated in our updated analysis with an estimated relapse-free survival at 10 years of 50% in the whole abdominal radiotherapy arm and 62% in the melphalan arm (P = 0.055, log-rank test). The relapse-free survival in the chromic phosphate arm was 51% (Figure 2). Second malignancies Second primary malignancies have developed in 29 women (11%) after 2229 person years of follow-up; 24 solid tumours and 5 hematological malignancies (Table 1). Second primary malignancies were seen in 11 women with stage IA disease: 2 women with stage IB disease; 4 women with stage IIA disease; 10 women with stage IIB disease and 2 women with stage III disease (Table 2).
Downloaded from https://academic.oup.com/annonc/article-abstract/11/1/65/276292 by guest on 15 September 2019
The methodology and eligibility criteria have been previously described [9]. Briefly, patients were eligible if they had FIGO (1971 classification) stage I or IIA ovarian cancer with either rupture of malignant ovarian cysts, poorly differentiated tumour, extracystic excrescences or positive cytology. Patients with stage IIB or III disease with disease confined to the pelvis were also included. Total abdominal hysterectomy and bilateral salpingo-oophrectomy must have been performed, but no prior chemotherapy or radiotherapy could have been administered. Patients were randomly assigned to one of three treatment arms: whole abdominal radiotherapy (2,250 rad in 20 fractions), oral melphalan (8 mg/m 2 /d x 4 days every 4 weeks x 18 courses), or intraperitoneal chromic phosphate (10-20 mCi, single dose). All patients received pelvic irradiation. In April 1980, accrual to the pelvic radiotherapy and intraperitoneal chromic phosphate arm was discontinued after 44 patients had been randomized, due to unacceptably high toxicity. Major complications including diarrhea and bowel obstructions were seen in 29% of patients [14]. Accrual to the other two arms was closed once the original accrual goal was met: 106 eligible patients on the melphalan arm and 107 patients on the whole abdominal radiation arm. The required follow-up examinations were every 2 months for the first 18 months, every 3 months up to 3 years, every 6 months up to 5 years, then yearly thereafter.
100%
67 Table 1. Second primary malignancies. Total
Arm
Abdominal Chronic Melphalan radiation phosphate 3 2 1 0 1 1 1 0
1 0 2 0 0 0 0 0
3 1 1 1 1 2 3 5
7 3 4 1 2 3 4 5
Total
9
3
17
29
Table 2. Second primary malignancies by stage. Stage
Abdominal radiation IA IB IIA MB
Total
Arm
Chronic phosphate
Melphalan
mo
5 0 0 5 1
1 1 1 0 0
5 1 3 5 1
11 2 4 10 2
Total
11
3
15
29
In our 1986 analysis, we reported that four patients treated with melphalan (two patients were originally assigned to other treatment arms) developed either a myelodysplastic syndrome (one patient) or acute myelogenous leukemia (three patients). As of January 1996, one additional patient in the melphalan arm was reported to have developed acute myelogenous leukemia. The median time from diagnosis of ovarian cancer to diagnosis of leukemkia/myelodysplastic syndrome was five years (range 1-8 years). The median survival of patients from the time of diagnosis of their second primary malignancy was eight months (range 0-14). Three of the five women with hematological malignancies had stage IA/B disease. No cases were observed in women treated with intraperitoneal chromic phosphate or whole abdominal radiotherapy. Melphalan appeared to be associated with an increased risk of developing leukemia/myelodysplastic syndrome compared to the whole abdominal radiotherapy arm although this was not statistically significant (P - 0.06). Second solid primary malignancies have developed in 24 patients compared to 12 patients reported in our 1986 analysis. Patients treated with melphalan accounted for 12 second primary malignancies while 9 occurred in patients treated with whole abdominal radiotherapy and 3 occurred in the chromic phosphate arm. There was no statistically significant difference in the total number of second primary malignancies between treatment arms
Discussion In this updated analysis we found no significant difference in overall survival between the treatment arms. This is similar to our earlier analysis reported in 1986. Relapsefree survival was marginally superior in the melphalan arm in both analysis but did not reach statistical significance. In this study we report a 35% excess of second primary malignancies (29 observed vs. 18.5 expected) in women treated for ovarian cancer compared to agematched controls. Melphalan appeared to be associated with an increased risk of developing leukemia/myelodysplastic syndrome although this was not statistically significant. Previous studies have clearly demonstrated that patients who have received chemotherapy with alkylating agents for ovarian cancer have an increased risk of acute leukemia, particularly the myeloid type [1517]. The lack of statistical significance demonstrated in this study may be attributed to the small number of patients and consequently few events. Second primary malignancies following treatment for gynecological malignancies have been reported to occur in the breast, endometrium, colon, rectum, anus, vagina, bladder, kidney and lung [18, 19]. Few studies have addressed the long term complications associated with anti-cancer treatment in women with ovarian cancer. A retrospective analysis of 32,351 women diagnosed
Downloaded from https://academic.oup.com/annonc/article-abstract/11/1/65/276292 by guest on 15 September 2019
Breast carcinoma Colorectal carcinoma Lung carcinoma Pancreas Leiomyosarcoma Basal cell carcinoma Other solid tumours Leukemia/MDS
(P = 0.396). The median age at time of diagnosis of a second primary malignancy was 62 years (range 45-80) and the median time from diagnosis of ovarian cancer to the development of a second primary was 7.5 years (range 1-17). Median survival from the time of diagnosis of the second primary malignancy was 11 months (range 0-72). Fifteen patients were deceased at the time of this analysis. Breast cancer was the most common second primary malignancy occurring in seven patients followed by lung cancer (four patients); skin cancer (three patients) and colorectal cancer (three patients). Less common tumour types included: thryoid (one patient), pancreas (one patient), glioblastoma multiforme (one patient), mycosis fungoides (one patient) and multiple myeloma (one patient). Leiomyosarcoma developed in two patients: one patient with leiomyosarcoma of the abdominal wall was treated with whole abdominal radiotherapy. In this analysis 29 women developed second primary malignancies of which 24 were solid tumours. This compares to 18.7 second primary malignancies which would have been expected in this group of patients compared to age-matched controls. This was statistically significant (P = 0.018) and represented a relative risk of a developing a second primary malignancy of 1.55. Excess malignancies were reported in women aged 40-49 (2 observed vs. 0.78 expected), 50-59 (7 observed vs. 3.4 expected), 60-69 (10 observed vs. 7.1 expected) and in women aged 70-79 (8 observed vs. 6.0 expected).
68
Acknowledgements Supported by grants from the National Cancer Institute of Canada - Clinical Trials Group, Kingston, Canada. The authors wish to acknowledge the contributions of the original trial committee: W. Shelly, A. Starreveld, M. Kirk, D. Boyes, A. Gerulath, M. Levitt, R. Fraser, J. Carmichael.Y. Methot and A. Willan.
References 1. Boring CC, Squires TS, Tong T. Cancer Statistics. Cancer 1992; 42:19-38. 2. Dembo AJ, Davey M, Stenwig AE et al. Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 1990; 75: 263-73. 3. Young RC, Walton LA, Ellenberg SS et al. Adjuvant therapy in stage I and II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med 1990; 322: 1021-7. 4. Cannistra SA. Cancer of the ovary. N Engl J Med 1993; 329: 1550-9. 5. Young R: Editorial. Gynecol Oncol 1991; 43: 193-4. 6. Bolis G, Colombo N, Pecorelh S et al. Adjuvant treatment for early epithelial ovarian cancer: Results of two randomized clinical trials comparing cisplatin to no further treatment or chromic phosphate (32 P). Ann Oncol 1995; 6: 886-93. 7. Dembo AJ, Bush RS, Beale FA et al. Ovarian carcinoma: Improved survival following abdominopelvic irradiation in patients with completed pelvic operation. Am J Obstet Gyecol 1979; 134: 793-800. 8. Hreshchyshyn MM, Park RC, Blessing JA et al. The role of adjuvant therapy in stage I ovarian cancer. Am J Obstet Gynecol 1980; 138: 139-45. 9. Klaassen D, Shelley W, Starreveld A et al. Early-stage ovarian cancer. A randomized clinical trial comparing whole abdominal radiotherapy, melphalan and intraperitoneal chromic phosphate: A NCIC CTG report. J Clin Oncol 1988; 6: 1254-63 10. Vergote JB, Vergote-De Vos LN, Abeler VM et al. Randomized trial comparing cisplatin with radioactive phsophorous or wholeabdomen irradiation as adjuvant treatment of ovarian cancer. Cancer 1992; 69: 741-9. 11. Smith JP, Rugledge FN, Delclos L. Postoperative treatment of early cancer of the ovary: A random trial between postoperative irradiation and chemotherapy. Natl Cancer Inst Monogr 1975; 42: 149-53. 12. Sell A, Bertelsen K, Andersen JE et al. Randomized study of whole-abdomen irradiaiton versus pelvic irradiation plus cyclophosphamide in treatment of early ovarian cancer. Gynecolog Oncol 1990; 37: 367-73. 13. NIH Consensus Conference. Ovarian cancer, screening, treatment and follow-up. JAMA 1995; 273 (6): 491-7. 14. Klaassen D. Starrveld A, Shelly W et al. External beam pelvic radiotherapy plus intraperitoneal radioactive chromic phosphate in early stage ovarian cancer: A toxic combination. Int J Radiat Oncol Biol Phys 1985; 11 (10): 1801-4. 15. Kaldor JM, Day NE, Pettersson F. Leukemia following chemotherapy for ovarian cancer. N Engl J Med 1990; 322 (1): 1-6. 16. De Gramont A, Remes P, Krulik M et al. Acute leukemia after treatment for ovarian cancer: Report of four cases and review of the literature. Oncology 1986; 43: 165-72. 17. Einhorn N. Acute leukemia after chemotherapy (melphalan). Cancer 1978; 41: 444-7. 18. Kaldor JM. Day NE, Band P et al. Second malignancies following testicular cancer, ovarian cancer and Hodgkins disease: An international collaborative study among cancer registries. Int J Cancer 1987; 39: 571-85. 19. Prior P, Pope DJ. Subsequent primary cancers in relation to treatment of ovarian cancer. Br J Cancer 1989; 59: 453-9. 20. Travis LB, Curtis RE, Boice JD et al. Second malignant neoplasms among long-term survivors of ovarian cancer. Cancer Res 1996: 56: 1564-70. Received 30 August 1999; accepted 2 December 1999. Correspondence to: S. F. Dent, MD Northwestern Ontario Regional Cancer Center 290 Munro Street Thunder Bay Ontario. P7A 7T1 Canada
Downloaded from https://academic.oup.com/annonc/article-abstract/11/1/65/276292 by guest on 15 September 2019
with ovarian cancer reported a significant elevated risk of developing solid tumours (RR 1.28) in women who had survived greater than 15 years. Based on this data the authors concluded that one in five women would be expected to develop a new malignancy within two decades of their diagnosis of ovarian cancer [20]. This is similar to our long term data which demonstrated an increased risk of developing a second primary tumour (RR 1.55) at a median of 13.5 years. This data would suggest that an increased awareness is necessary in this patient population as the risk of developing a second primary malignancy may exist for many years. Patients should be followed clinically and appropriate investigations initiated promptly based on reported symptoms. While one can suggest that anti-cancer therapy is likely responsible for the increased relative risk of developing a second primary malignancy in these women, it is also possible that these women may be predisposed to developing other cancers on the basis of a undefined genetic predisposition or co-carcinogenesis independent of the treatment effect. This would be difficult to separate from the long term risk associated with anticancer therapy and for the time being remains theoretical. The excess risk of developing a second primary malignancy may be acceptable with treatment of malignancies with a relatively poor prognosis. Anti-cancer treatment in malignancies with more favourable survival rates will have to consider the potential risk associated with such treatments. One might anticipate the emergence of solid tumour excesses in patients exposed to carcinogenic agents as both survival and long-term follow-up increases in this population. Further studies are needed to clarify the carcinogenic risks associated with modern therapies for ovarian cancer. Future trials should help clarify who we should be treating and what the ideal adjuvant therapy should be. A number of studies are currently addressing these issues. Gynecologic Oncology Group Protocol 157 is a randomized control trial of three versus six cycles of carboplatin and paclitaxel in women with early stage ovarian cancer. The International Collaborative Ovarian Neoplasm (ICON-1, EU-91002) study randomizes patients with fully resected early stage ovarian cancer to six cycles of cisplatin based adjuvant chemotherapy or observation. A similar European trial (EORTC-55904), randomizes women with early stage disease to observation or four to six cycles of cisplatin based chemotherapy. The results of these prospective trials should help clarify the role of adjuvant therapy in this population.
Original article Second primary malignancies following the treatment of early stage ovarian cancer: Update of a study by the National Cancer Institute of Canada-Clinical Trials Group (NCIC-CTG) S. F. Dent,1 D. Klaassen,2 J. L. Pater,3 B. Zee3 & M. Whitehead3
50% in the whole abdominal radiotherapy arm, 62% in the melphalan arm and 51% in the chromic phosphate arm Background: Ovarian cancer is the leading cause of death from (P = 0.147). Long term follow-up has not demonstrated a gynecological malignancies and the fourth most frequent fatal significant difference between treatment arms. Second primary malignancy in women. Despite improved surgical techniques malignancies developed in 29 women (11%) after 2,229 person as many as 20% of women with early stage disease will years of follow-up. This compares to 18.7 second primary eventually relapse and die from their disease. The post-opera- malignancies which would have been expected in this group tive management of these women remains controversial. Here of age-matched controls and was statistically significant we present the long term follow-up data of our previously (P = 0.018). There was no significant difference in the total published study, as well as the incidence of second primary number of second primary malignancies between treatment arms. Melphalan appeared to be associated with an increased malignancies in these women. Patients and methods; Two hundredfifty-seveneligible pa- risk of developing leukemia/myelodysplastic syndrome comtients with stage I, IIA 'high risk' ovarian carcinoma and IIB, pared to the whole abdominal radiotherapy arm (P = 0.06). IIIO (disease confined to pelvis) were randomized to either Conclusions: Long-term follow-up has not demonstrated a whole abdominal radiotherapy 2,250 rads in ten fractions (107 significant difference in overall or disease free survival between patients), melphalan 8 mg/m2/d x 4 weeks x 18 courses (106 treatment arms. An excess of second primary malignancies patients) or intraperitoneal chromic phosphate 10-20 mCi (44 (35%) was observed suggesting that lifelong surveillance is patients). All patients were initially treated with pelvic radio- required in this population. Further research with newer treattherapy. ment programs are needed to improve the cure rates in this Results: Overall survival estimates at 10 years were: 45% in population. the whole abdominal radiotherapy arm; 49% in the melphalan arm and 50% in the intraperitoneal chromic phosphate arm (P - 0.30). Relapse-free survival estimates at 10 years were: Key words: ovarian cancer, second primary malignancies Summary
Introduction
Epithelial ovarian carcinoma is the leading cause of death from gynecological malignancies and the fourth most frequent fatal malignancy in women [1]. While the majority of women present with advanced ovarian cancer, those who present with disease confined to the pelvis are potentially curable. Improved surgical staging and treatment of early stage disease has led to long term survival rates of 80%-95% [2, 3]. Unfortunately as many as 20%-30% of women with early stage I disease will eventually relapse and die from their disease [4]. Clearly there is a subgroup of women with early stage disease who potentially may benefit from adjuvant treatment. The post-operative management for this group of women remains controversial [5]. Several treatment options in the literature have been explored including: abdominopelvic radiotherapy, intraperitoneal radioactive chromic phosphate and systemic chemotherapy [3, 6-12].
No clear consensus exists [13]. Recommendations for these women is hampered by the potential long-term complications of adjuvant therapy in a cancer where the prognosis is already reasonable. There is limited data in the literature on the longterm follow-up of women treated for early stage ovarian cancer. Long-term data is needed to identify women who have relapsed as well as to assess long-term toxicities such as second primary malignancies. This information might influence future treatment options for women with early stage disease. In November 1985 the National Cancer Institute of Canada - Clinical Trials Group reported the results of a randomized control trial of whole abdominal radiotherapy, melphalan or intraperitoneal chromic phosphate for patients with poor prognosis early stage ovarian cancer [9]. We present an update of our previous analysis including overall and disease-free survival as well as the incidence of second primary malignancies.
Downloaded from https://academic.oup.com/annonc/article-abstract/11/1/65/276292 by guest on 15 September 2019
'Northwestern Ontario Regional Cancer Center, Thunder Bay, Ontario; 2British Columbia Cancer Agency, Vancouver, British Columbia; National Cancer Institute of Canada - Clinical Trials Group, Kingston, Ontario, Canada
3
66 Patients and methods
80%
|3
60%
c o
a
40% 20% 0%
2
4
6
10
Time (years) • Pelvic & abdominal radiation Pelvic radiation & melphalan Pelvic radiation & chronic phosphate Figure 1 Overall survival.
100%
Survival was measured from the date of randomization until death or last follow-up. Relapse free-survival was calculated from the date of randomization to the first documented evidence of treatment failure. The Kaplan-Meier method was adopted to estimate survival. A Fisher's exact test was performed to compare the incidence of hematological malignancies in the melphalan and whole abdominal radiotherapy arms. A chi-square analysis was performed to compare observed versus expected malignancy rates in this population. Cancer incidence rates in age matched Canadian women were multiplied by person years at risk to determine the expected number of malignancies in this population. The median follow-up at the time of the current analysis (January 1996) was 13.5 years.
80%
60%
40%
20%
0%
2
4
6
10
Time (years)
Results From May 1975 to March 1984, a total of 284 patients were enrolled from 12 participating Canadian centers. Twenty-seven patients (10%) were considered initially ineligible; ten due to extrapelvic stage III or stage IV disease; nine because of incomplete surgery; three because on review of the pathology the disease was not felt to be due to ovarian cancer; two because of prior radiotherapy; two because the attending physician was not a study participant; and one because of a threemonth delay between surgery and radiation. There were 257 eligible patients included in this analysis. Overall survival and relapse-free survival In our 1986 analysis we found no significant difference in overall survival between the treatment arms: 62% in the whole abdominal radiotherapy arm; 61% in the melphalan arm and 66% in the chromic phosphate arm (P - 0.49). At the time of this analysis 44% of patients were still alive. The overall survival estimates at 10 years were similar in the 3 cohorts: 45% in the whole abdominal radiotherapy arm; 49% in the melphalan arm and 50% in the intraperitoneal arm (P = 0.301) (Figure 1). There was no significant difference in relapse-free
Pelvic & abdominal radiation Pelvic radiation & melphalan Pelvic radiation & chronic phosphate Figure 2. Relapse-free survival.
survival between treatment arms in our 1986 analysis. In that analysis we reported that melphalan appeared to have a marginal but not statistically significant benefit compared to the whole abdominal radiotherapy arm (P - 0.06). This trend was again demonstrated in our updated analysis with an estimated relapse-free survival at 10 years of 50% in the whole abdominal radiotherapy arm and 62% in the melphalan arm (P = 0.055, log-rank test). The relapse-free survival in the chromic phosphate arm was 51% (Figure 2). Second malignancies Second primary malignancies have developed in 29 women (11%) after 2229 person years of follow-up; 24 solid tumours and 5 hematological malignancies (Table 1). Second primary malignancies were seen in 11 women with stage IA disease: 2 women with stage IB disease; 4 women with stage IIA disease; 10 women with stage IIB disease and 2 women with stage III disease (Table 2).
Downloaded from https://academic.oup.com/annonc/article-abstract/11/1/65/276292 by guest on 15 September 2019
The methodology and eligibility criteria have been previously described [9]. Briefly, patients were eligible if they had FIGO (1971 classification) stage I or IIA ovarian cancer with either rupture of malignant ovarian cysts, poorly differentiated tumour, extracystic excrescences or positive cytology. Patients with stage IIB or III disease with disease confined to the pelvis were also included. Total abdominal hysterectomy and bilateral salpingo-oophrectomy must have been performed, but no prior chemotherapy or radiotherapy could have been administered. Patients were randomly assigned to one of three treatment arms: whole abdominal radiotherapy (2,250 rad in 20 fractions), oral melphalan (8 mg/m 2 /d x 4 days every 4 weeks x 18 courses), or intraperitoneal chromic phosphate (10-20 mCi, single dose). All patients received pelvic irradiation. In April 1980, accrual to the pelvic radiotherapy and intraperitoneal chromic phosphate arm was discontinued after 44 patients had been randomized, due to unacceptably high toxicity. Major complications including diarrhea and bowel obstructions were seen in 29% of patients [14]. Accrual to the other two arms was closed once the original accrual goal was met: 106 eligible patients on the melphalan arm and 107 patients on the whole abdominal radiation arm. The required follow-up examinations were every 2 months for the first 18 months, every 3 months up to 3 years, every 6 months up to 5 years, then yearly thereafter.
100%
67 Table 1. Second primary malignancies. Total
Arm
Abdominal Chronic Melphalan radiation phosphate 3 2 1 0 1 1 1 0
1 0 2 0 0 0 0 0
3 1 1 1 1 2 3 5
7 3 4 1 2 3 4 5
Total
9
3
17
29
Table 2. Second primary malignancies by stage. Stage
Abdominal radiation IA IB IIA MB
Total
Arm
Chronic phosphate
Melphalan
mo
5 0 0 5 1
1 1 1 0 0
5 1 3 5 1
11 2 4 10 2
Total
11
3
15
29
In our 1986 analysis, we reported that four patients treated with melphalan (two patients were originally assigned to other treatment arms) developed either a myelodysplastic syndrome (one patient) or acute myelogenous leukemia (three patients). As of January 1996, one additional patient in the melphalan arm was reported to have developed acute myelogenous leukemia. The median time from diagnosis of ovarian cancer to diagnosis of leukemkia/myelodysplastic syndrome was five years (range 1-8 years). The median survival of patients from the time of diagnosis of their second primary malignancy was eight months (range 0-14). Three of the five women with hematological malignancies had stage IA/B disease. No cases were observed in women treated with intraperitoneal chromic phosphate or whole abdominal radiotherapy. Melphalan appeared to be associated with an increased risk of developing leukemia/myelodysplastic syndrome compared to the whole abdominal radiotherapy arm although this was not statistically significant (P - 0.06). Second solid primary malignancies have developed in 24 patients compared to 12 patients reported in our 1986 analysis. Patients treated with melphalan accounted for 12 second primary malignancies while 9 occurred in patients treated with whole abdominal radiotherapy and 3 occurred in the chromic phosphate arm. There was no statistically significant difference in the total number of second primary malignancies between treatment arms
Discussion In this updated analysis we found no significant difference in overall survival between the treatment arms. This is similar to our earlier analysis reported in 1986. Relapsefree survival was marginally superior in the melphalan arm in both analysis but did not reach statistical significance. In this study we report a 35% excess of second primary malignancies (29 observed vs. 18.5 expected) in women treated for ovarian cancer compared to agematched controls. Melphalan appeared to be associated with an increased risk of developing leukemia/myelodysplastic syndrome although this was not statistically significant. Previous studies have clearly demonstrated that patients who have received chemotherapy with alkylating agents for ovarian cancer have an increased risk of acute leukemia, particularly the myeloid type [1517]. The lack of statistical significance demonstrated in this study may be attributed to the small number of patients and consequently few events. Second primary malignancies following treatment for gynecological malignancies have been reported to occur in the breast, endometrium, colon, rectum, anus, vagina, bladder, kidney and lung [18, 19]. Few studies have addressed the long term complications associated with anti-cancer treatment in women with ovarian cancer. A retrospective analysis of 32,351 women diagnosed
Downloaded from https://academic.oup.com/annonc/article-abstract/11/1/65/276292 by guest on 15 September 2019
Breast carcinoma Colorectal carcinoma Lung carcinoma Pancreas Leiomyosarcoma Basal cell carcinoma Other solid tumours Leukemia/MDS
(P = 0.396). The median age at time of diagnosis of a second primary malignancy was 62 years (range 45-80) and the median time from diagnosis of ovarian cancer to the development of a second primary was 7.5 years (range 1-17). Median survival from the time of diagnosis of the second primary malignancy was 11 months (range 0-72). Fifteen patients were deceased at the time of this analysis. Breast cancer was the most common second primary malignancy occurring in seven patients followed by lung cancer (four patients); skin cancer (three patients) and colorectal cancer (three patients). Less common tumour types included: thryoid (one patient), pancreas (one patient), glioblastoma multiforme (one patient), mycosis fungoides (one patient) and multiple myeloma (one patient). Leiomyosarcoma developed in two patients: one patient with leiomyosarcoma of the abdominal wall was treated with whole abdominal radiotherapy. In this analysis 29 women developed second primary malignancies of which 24 were solid tumours. This compares to 18.7 second primary malignancies which would have been expected in this group of patients compared to age-matched controls. This was statistically significant (P = 0.018) and represented a relative risk of a developing a second primary malignancy of 1.55. Excess malignancies were reported in women aged 40-49 (2 observed vs. 0.78 expected), 50-59 (7 observed vs. 3.4 expected), 60-69 (10 observed vs. 7.1 expected) and in women aged 70-79 (8 observed vs. 6.0 expected).
68
Acknowledgements Supported by grants from the National Cancer Institute of Canada - Clinical Trials Group, Kingston, Canada. The authors wish to acknowledge the contributions of the original trial committee: W. Shelly, A. Starreveld, M. Kirk, D. Boyes, A. Gerulath, M. Levitt, R. Fraser, J. Carmichael.Y. Methot and A. Willan.
References 1. Boring CC, Squires TS, Tong T. Cancer Statistics. Cancer 1992; 42:19-38. 2. Dembo AJ, Davey M, Stenwig AE et al. Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 1990; 75: 263-73. 3. Young RC, Walton LA, Ellenberg SS et al. Adjuvant therapy in stage I and II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med 1990; 322: 1021-7. 4. Cannistra SA. Cancer of the ovary. N Engl J Med 1993; 329: 1550-9. 5. Young R: Editorial. Gynecol Oncol 1991; 43: 193-4. 6. Bolis G, Colombo N, Pecorelh S et al. Adjuvant treatment for early epithelial ovarian cancer: Results of two randomized clinical trials comparing cisplatin to no further treatment or chromic phosphate (32 P). Ann Oncol 1995; 6: 886-93. 7. Dembo AJ, Bush RS, Beale FA et al. Ovarian carcinoma: Improved survival following abdominopelvic irradiation in patients with completed pelvic operation. Am J Obstet Gyecol 1979; 134: 793-800. 8. Hreshchyshyn MM, Park RC, Blessing JA et al. The role of adjuvant therapy in stage I ovarian cancer. Am J Obstet Gynecol 1980; 138: 139-45. 9. Klaassen D, Shelley W, Starreveld A et al. Early-stage ovarian cancer. A randomized clinical trial comparing whole abdominal radiotherapy, melphalan and intraperitoneal chromic phosphate: A NCIC CTG report. J Clin Oncol 1988; 6: 1254-63 10. Vergote JB, Vergote-De Vos LN, Abeler VM et al. Randomized trial comparing cisplatin with radioactive phsophorous or wholeabdomen irradiation as adjuvant treatment of ovarian cancer. Cancer 1992; 69: 741-9. 11. Smith JP, Rugledge FN, Delclos L. Postoperative treatment of early cancer of the ovary: A random trial between postoperative irradiation and chemotherapy. Natl Cancer Inst Monogr 1975; 42: 149-53. 12. Sell A, Bertelsen K, Andersen JE et al. Randomized study of whole-abdomen irradiaiton versus pelvic irradiation plus cyclophosphamide in treatment of early ovarian cancer. Gynecolog Oncol 1990; 37: 367-73. 13. NIH Consensus Conference. Ovarian cancer, screening, treatment and follow-up. JAMA 1995; 273 (6): 491-7. 14. Klaassen D. Starrveld A, Shelly W et al. External beam pelvic radiotherapy plus intraperitoneal radioactive chromic phosphate in early stage ovarian cancer: A toxic combination. Int J Radiat Oncol Biol Phys 1985; 11 (10): 1801-4. 15. Kaldor JM, Day NE, Pettersson F. Leukemia following chemotherapy for ovarian cancer. N Engl J Med 1990; 322 (1): 1-6. 16. De Gramont A, Remes P, Krulik M et al. Acute leukemia after treatment for ovarian cancer: Report of four cases and review of the literature. Oncology 1986; 43: 165-72. 17. Einhorn N. Acute leukemia after chemotherapy (melphalan). Cancer 1978; 41: 444-7. 18. Kaldor JM. Day NE, Band P et al. Second malignancies following testicular cancer, ovarian cancer and Hodgkins disease: An international collaborative study among cancer registries. Int J Cancer 1987; 39: 571-85. 19. Prior P, Pope DJ. Subsequent primary cancers in relation to treatment of ovarian cancer. Br J Cancer 1989; 59: 453-9. 20. Travis LB, Curtis RE, Boice JD et al. Second malignant neoplasms among long-term survivors of ovarian cancer. Cancer Res 1996: 56: 1564-70. Received 30 August 1999; accepted 2 December 1999. Correspondence to: S. F. Dent, MD Northwestern Ontario Regional Cancer Center 290 Munro Street Thunder Bay Ontario. P7A 7T1 Canada
Downloaded from https://academic.oup.com/annonc/article-abstract/11/1/65/276292 by guest on 15 September 2019
with ovarian cancer reported a significant elevated risk of developing solid tumours (RR 1.28) in women who had survived greater than 15 years. Based on this data the authors concluded that one in five women would be expected to develop a new malignancy within two decades of their diagnosis of ovarian cancer [20]. This is similar to our long term data which demonstrated an increased risk of developing a second primary tumour (RR 1.55) at a median of 13.5 years. This data would suggest that an increased awareness is necessary in this patient population as the risk of developing a second primary malignancy may exist for many years. Patients should be followed clinically and appropriate investigations initiated promptly based on reported symptoms. While one can suggest that anti-cancer therapy is likely responsible for the increased relative risk of developing a second primary malignancy in these women, it is also possible that these women may be predisposed to developing other cancers on the basis of a undefined genetic predisposition or co-carcinogenesis independent of the treatment effect. This would be difficult to separate from the long term risk associated with anticancer therapy and for the time being remains theoretical. The excess risk of developing a second primary malignancy may be acceptable with treatment of malignancies with a relatively poor prognosis. Anti-cancer treatment in malignancies with more favourable survival rates will have to consider the potential risk associated with such treatments. One might anticipate the emergence of solid tumour excesses in patients exposed to carcinogenic agents as both survival and long-term follow-up increases in this population. Further studies are needed to clarify the carcinogenic risks associated with modern therapies for ovarian cancer. Future trials should help clarify who we should be treating and what the ideal adjuvant therapy should be. A number of studies are currently addressing these issues. Gynecologic Oncology Group Protocol 157 is a randomized control trial of three versus six cycles of carboplatin and paclitaxel in women with early stage ovarian cancer. The International Collaborative Ovarian Neoplasm (ICON-1, EU-91002) study randomizes patients with fully resected early stage ovarian cancer to six cycles of cisplatin based adjuvant chemotherapy or observation. A similar European trial (EORTC-55904), randomizes women with early stage disease to observation or four to six cycles of cisplatin based chemotherapy. The results of these prospective trials should help clarify the role of adjuvant therapy in this population.