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Kaplan-Meier survival curves for death from metastatic melanoma according to parity and sex.

Kaplan-Meier survival curves for death from metastatic melanoma according to parity and sex.

Table 1. 
Survival and Follow-up Statistics by Sex and Parity
Survival and Follow-up Statistics by Sex and Parity
Table 2. 
Actuarial Tumor-Specific Survival Rates After Irradiation by Sex and Parity*
Actuarial Tumor-Specific Survival Rates After Irradiation by Sex and Parity*
Table 3. 
Prognostic Factors for Melanoma-Related Death According to Sex and Parity
Prognostic Factors for Melanoma-Related Death According to Sex and Parity
Table 4. 
Cox Regression for Influence of Sex and Parity on Melanoma-Related Survival After Irradiation*
Cox Regression for Influence of Sex and Parity on Melanoma-Related Survival After Irradiation*
Table 5. 
Cox Regression for Influence of Parity Factors on Melanoma-Related Survival Rates After Proton Irradiation*
Cox Regression for Influence of Parity Factors on Melanoma-Related Survival Rates After Proton Irradiation*
1.
Mooy  CMDeJong  PTVM Prognostic parameters in uveal melanoma: a review. Surv Ophthalmol. 1996;41215- 228Article
2.
Stidham  KRJohnson  JLSeigler  HF Survival superiority of females with melanoma: a multivariate analysis of 6383 patients exploring the significance of gender in prognostic outcome. Arch Surg. 1994;129316- 324Article
3.
Karakousis  CPDriscoll  DL Prognostic parameters in localised melanoma: gender versus anatomical location. Eur J Cancer. 1995;31A320- 324Article
4.
Ries  LGPollack  ESYoung  JL Cancer patient survival: surveillance, epidemiology and end results program 1973-79. J Natl Cancer Inst. 1983;70693- 707
5.
Thorn  MAdami  HORingborg  UBergstrom  RKrusemo  U Long-term survival in malignant melanoma with special reference to age and sex as prognostic factors. J Natl Cancer Inst. 1987;79969- 974
6.
Garbe  CButtner  PBertz  J  et al.  Primary cutaneous melanoma: prognostic classification of anatomic location. Cancer. 1995;752484- 2491Article
7.
Blois  MSSagebiel  RWAbarbanel  RMCaldwell  TMTuttle  MS Malignant melanoma of the skin, I: the association of tumor depth and type, and patient sex, age, and site with survival. Cancer. 1983;521330- 1341Article
8.
Hersey  PMorgan  GStone  DEMcCarthy  WHMilton  GW Previous pregnancy as a protective factor against death from melanoma. Lancet. 1977;1451- 452Article
9.
Bork  KBrauninger  W Prior pregnancy and melanoma survival. Arch Dermatol. 1986;1221097Article
10.
Shaw  HMMilton  GWFarago  GMcCarthy  WH Endocrine influences on survival from malignant melanoma. Cancer. 1978;42669- 677Article
11.
Gradoudas  ESGoitein  MKoehler  A  et al.  Proton irradiation of choroidal melanomas: preliminary results. Arch Ophthalmol. 1978;961583- 1591Article
12.
Gragoudas  ESSeddon  JMGoitein  M  et al.  Current results of proton irradiation of uveal melanomas. Ophthalmology. 1985;92284- 291Article
13.
Kaplan  ELMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53457- 481Article
14.
Cox  DR Regression models and life tables. J R Stat Soc Series B. 1972;34187- 220
15.
Gragoudas  ESSeddon  JMEgan  KMGlynn  RJGoitein  MMunzenrider  J Metastasis from uveal melanoma after proton beam irradiation. Ophthalmology. 1988;95992- 999Article
16.
Cox  DROakes  D Analysis of Survival Data.  New York, NY Chapman & Hall1984;
17.
Peto  RPeto  J Asymptotically efficient rank invariant procedures. J R Stat Soc Series A. 1972;135185- 207Article
18.
Kjems  EKrag  C Melanoma and pregnancy: a review. Acta Oncol. 1993;32371- 378Article
19.
Janerich  DT The fetal antigen hypothesis for breast cancer revisited. Med Hypotheses. 1994;43105- 110Article
20.
Lambe  MHsieh  CTrichopoulos  DEkbom  APavia  MAdami  HO Transient increase in the risk of breast cancer after giving birth. N Engl J Med. 1994;3315- 9Article
21.
Shiu  MHSchottenfeld  DMacLean  MBFortner  JG Adverse effect of pregnancy on melanoma: a reappraisal. Cancer. 1976;37181- 187Article
22.
Grin  CMDriscol  MSGrant-Kels  JM Pregnancy and the prognosis of malignant melanoma. Semin Oncol. 1996;23734- 736
23.
Egan  KMWalsh  SMSeddon  JMGragoudas  ES An evaluation of the influence of reproductive factors on the risk of metastases from uveal melanoma. Ophthalmology. 1993;1001160- 1166Article
Epidemiology and Biostatistics
July 1999

Childbearing History Associated With Improved Survival in Choroidal Melanoma

Author Affiliations

From the Retina Service, Massachusetts Eye and Ear Infirmary (Drs Egan and Gragoudas and Ms Quinn), and the Department of Epidemiology, Harvard School of Public Health (Dr Egan), Boston, Mass.

Arch Ophthalmol. 1999;117(7):939-942. doi:10.1001/archopht.117.7.939
Abstract

Background  Research in cutaneous melanoma suggests that women may experience better tumor-dependent survival than men, and some studies have shown that the advantange is specific to childbearing.

Objective  To examine whether childbearing may be a favorable prognostic factor in melanoma of the uveal tract.

Design  Prospective follow-up study.

Setting  Hospital.

Main Outcome Measure  Death from metastatic choroidal melanoma.

Methods  We evaluated a consecutive series of 1818 patients with choroidal melanoma, 748 parous and 165 nulliparous women and 905 men, after treatment with proton irradiation. Three hundred fifty-two deaths from metastasis were documented in follow-up.

Results  Overall multivariate-adjusted death rates from metastasis were approximately 25% higher in nulliparous women (relative risk [RR], 1.23; 95% confidence interval [CI], 0.83-1.82) and men (RR, 1.25; 95% CI, 1.00-1.56) than in women who had given birth. The protective influence of parity was strongest in the early period following diagnosis and treatment (RR, 1.58; 95% CI, 0.88-2.86, and RR, 1.51; 95% CI, 1.04-2.19, in nulliparous women and men, respectively, during the first 36 months of follow-up). The level of protection increased with the number of live births (P for trend, .04).

Conclusion  These data provide support for the hypothesis that a history of childbearing confers protection from death in choroidal melanoma.

INTRAOCULAR MELANOMA is the only potentially fatal eye tumor in adults. Established prognostic factors include tumor size, patient age, and histologic cell type, among others.1 The current investigation was motivated by studies in which cutaneous melanoma showed women to have a better prognosis than men.28 In a few studies810 the advantage was limited to women who had given birth. To investigate the possible role of childbearing in melanoma of the uveal tract, we prospectively evaluated a large cohort of individuals with these tumors after a detailed reproductive history had been collected from the women during baseline examination.

SUBJECTS AND METHODS

The analysis was based on a cohort of 1843 patients with a diagnosis of unilateral choroidal and/or ciliary body melanoma who had undergone proton irradiation for the tumor at the Harvard cyclotron, Cambridge, Mass, between July 1975 and December 1995.11,12 The patients were all US or Canadian citizens who had not previously been treated for the tumor and showed no evidence of metastatic disease at pretreatment workup. All were treated with a total dose of 70 cGy under the care of one of us (E.S.G.). A detailed parity history was available for all but 13 eligible women.

Patients were evaluated at regular intervals after irradiation. Most returned to our institution for routine follow-up care. The remaining patients were followed up through the referring ophthalmologist or local primary care physicians. In 1991 and in 1995, all surviving patients were mailed a follow-up questionnaire to collect interim data on reproductive history and current menstrual status; these surveys were returned by an estimated 85% of surviving patients. We excluded the 12 women who gave birth after irradiation treatment for the tumor, bringing the total for analysis to 1818 subjects.

Patients were followed up until April 30, 1997. Five hundred ninety-two deaths were documented, 352 caused by metastatic melanoma (primarily to the liver), 78 caused by another primary tumor, and 159 caused by noncancer causes; in 3 additional cancer deaths, the site of the primary tumor could not be determined, and these were classified as non–tumor-related causes. For most patients, cause of death was confirmed with medical records, including biopsy reports and results of liver scans, hospital discharge summaries, and autopsy reports (83% overall [90% of metastatic deaths]) and/or death certificates (total with documentation, 90% overall [95% of metastatic deaths]). The remaining deaths were classified based on information given by next of kin.

For analysis, we evaluated survival as a function of sex and parity using Kaplan-Meier procedures13 to estimate cumulative survival rates after irradiation and Cox regression14 to estimate multivariate-adjusted relative risk (RR) ratios for melanoma-related death, the end point in all analyses (10 patients were alive with metastasis at the time of analysis). Multivariate models included terms for known prognostic factors,15 including largest tumor diameter and patient age as continuous variables, location of the anterior margin of the tumor (ciliary body, anterior to the equator without ciliary body involvement, or posterior to the equator), presence or absence of extrascleral extension, and symptoms vs screen-detected tumor diagnosis. The RR ratios were estimated for tumor-related death in nulliparous women and men relative to parous women. To test formally for uniformity of RR ratios over time (eg, the proportional hazards assumption), we constructed separate models that included product terms for sex and parity multiplied by the logarithm of the survival time, such that: h0exp[B1Z1+B2Z2(t)], where Z1 is an indicator variable denoting group membership, and Z2(t)=Z1 (logarithmic survival time). If the ratio of the hazard functions for the 2 groups (parous women vs the remaining patients) is nearly constant for any value of survival time, then B2 should be close to 0.16 Equality of survival curves was evaluated using the Wilcoxon rank sum test.17

RESULTS

Of the 1818 patients evaluated, 905 were men and 913 were women; among the women, 748 (82%) were parous. Patients ranged in age from 14 to 93 years (median, 61 years); 10% of women were under the age of 40 years at presentation. Table 1 shows follow-up statistics by parity and sex. Approximately 20% of patients died from metastasis an average of 3.6 years after irradiation (range, 3 months to 16 years). Median follow-up in the 1226 surviving patients was 8.5 years (12 years or more in 25% of patients). Most survivors had recent follow-up; survival status was known within 10 months of study closeout (April 30, 1997) in 90% of the surviving patients.

Overall 10-year survival rates were 61%, 59%, and 66% for men, nulliparous women, and parous women, respectively. Tumor-specific survival curves are displayed in Figure 1 according to parity and sex, and corresponding survival estimates are given in Table 2. Parous women had modestly though significantly better survival rates than men (P=.02) throughout follow-up; death rates were also reduced among women with a prior birth compared with the nulliparous women, although the difference was not significant (P=.29). Tumor-specific survival at 10 years was 77% in parous women compared with 75% in the other groups.

Table 3 shows a comparison of baseline prognostic factors according to sex and parity. Groups were comparable on most factors. However, nulliparous women were younger than the other patients. In addition, men were more likely to present with ocular symptoms (eg, vision loss, photophobia). We used Cox regression to examine relative death rates as a function of sex and parity while accounting for these baseline differences (Table 4). Tumor-associated death rates were approximately 25% higher in men (RR, 1.25; 95% CI, 1.00-1.56) and nulliparous women (RR, 1.23; 95% CI, 0.83-1.82) than in women who had ever given birth.

The protective influence of parity was largely confined to the early period following diagnosis and treatment (Table 4); partitioning follow-up into intervals (0-36, >36 to 72, and >72 months), multivariate-adjusted death rates were elevated by 50% and 60% in men and nulliparous women, respectively, during the first 3 years after treatment. Relative risk ratios were not materially elevated in the next interval (>36 to 72 months), and beyond 6 years, the protective influence for parity disappeared. Results of a test for nonuniformity in RRs across time intervals (comparing parous women with remaining patients) were of borderline statistical significance (P=.07)

Results according to number of liveborn children and time since most recent birth are given in Table 5. There was a significant inverse relationship between number of children and degree of protection associated with childbearing. This trend was most evident in the first 3 years after treatment; death rates in women who had more than 4 children were approximately one third those of nulliparous women and men (multivariate RR, 0.35; 95% CI, 0.10-1.12). Each live birth reduced death rates by 6% overall (RR, 0.94), and by 14% for deaths in the first 36 months (RR, 0.86) (data not shown). No consistent patterns were observed according to years since last completed pregnancy; for early deaths (≤36 months), the greatest protection was afforded for childbirth ending 11 to 30 years prior to treatment (RR, 0.33; 95% CI, 0.16-0.70). Relative risk ratios were nonsignificantly elevated (RR, 1.7; 95% CI, 0.50-5.62) in association with recent childbirth (within 10 years of treatment).

The influence of parity on survival was generally absent among younger patients (data not shown). In those patients over age 50 years (278 deaths), adjusted overall RR ratios were 1.37 (95% CI, 0.88-2.12) and 1.38 (95% CI, 1.07-1.79) for nulliparous women and men, respectively; in younger patients (74 deaths), these estimates were 0.67 (95% CI, 0.25-1.80) and 0.88 (95% CI, 0.54-1.44), respectively. Relative risk ratios in the older group according to numbers of births were 0.85, 0.73, 0.75, and 0.62 for 1, 2, 3 or 4, and 5 or more births, respectively (RR per birth, 0.92; P for trend, .02). There was no similar trend among the younger patients (RR per birth, 1.03; P=.74).

COMMENT

This study provides evidence that a history of childbearing affords protection from metastatic death in intraocular melanoma. Our results support a role specific to childbearing; death rates were higher in nulliparous women than in those who had ever given birth, in a similar magnitude to the excess observed in men relative to parous women. In addition, there was an apparent dose response for parity, with death rates inversely proportional to the number of children delivered. These results were unconfounded by stage at diagnosis and other established clinical prognostic factors in this disease. Given the high level of surveillance in this population, the results are unlikely to reflect differential follow-up by sex or according to parity. Our data provide support for studies in cutaneous melanoma810 suggesting that the survival advantage for women noted in many studies is likely to be secondary to childbearing.

These results suggest that the benefit associated with childbearing may be transitory, in effect only during the early years following diagnosis and treatment. However, since the preponderance of deaths occur in this early period (K.M.E., J.L.Q., E.S.G., unpublished data), the advantage in parous women extends for a decade or more following treatment in terms of cumulative death rates. This temporary nature of parity-associated immunity is further supported by the analysis of time since most recent childbirth; the lowest death rates occurred in women who had given birth within 11 to 30 years. Considering only the parous women, overall age-adjusted death rates were significantly lower (by 40%; RR, 0.58; P=.03) in the women who had given birth within 11 to 30 years compared with 30 or more years before the tumor was diagnosed.

Several potential mechanisms have been advanced to explain how pregnancy and childbearing might affect the pathogenesis of cancer.18 Exposure to fetal tissue could provide immunity to cancerous cells that theoretically present similar antigens.19 The theory was put forth to explain the phenomenon in breast cancer of pregnancy causing a short-term increase in breast cancer incidence, followed within several years by a gradually declining incidence relative to nulliparity.20 This short-term promotional effect is attributed to maternal immune tolerance during pregnancy. The theory is intriguing in light of the literature on cutaneous melanoma concerning the possibly aggravating effect of concurrent pregnancy21,22 and our findings suggesting a possible increase in death rates for recent childbearing. In a previous analysis23 we found nonsignificantly higher death rates in women of reproductive age (<45 years) than in men (RR, 1.28), which may be in line with a risk-enhancing influence of concurrent or recent pregnancy.

CONCLUSIONS

These results constitute the first evidence that a remote history of childbearing may improve survival rates in uveal melanoma, albeit temporarily. These findings, if confirmed, offer new potential insights into the mechanisms by which metastatic cells may lie dormant in the liver for extended periods and provide further rationale for seeking immune or vaccine therapies as a means of extending survival in patients with melanocytic tumors.

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Article Information

Accepted for publication January 22, 1999.

This study was supported in part by the Melanoma Research Fund, Massachusetts Eye and Ear Infirmary, Boston, Mass, and by the Retina Research Foundation, Houston, Tex (Dr Gragoudas). Dr Gragoudas is a Research to Prevent Blindness Senior Scientific Investigator, Research to Prevent Blindness Inc, New York, NY.

Presented at the annual meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Fla, May 1998.

Corresponding author: Kathleen M. Egan, ScD, Retina Service, Massachusetts Eye and Ear Infimary, 243 Charles St, Boston, MA 02114-3096 (e-mail: Kathleen.Egan@channing.harvard.edu).

References
1.
Mooy  CMDeJong  PTVM Prognostic parameters in uveal melanoma: a review. Surv Ophthalmol. 1996;41215- 228Article
2.
Stidham  KRJohnson  JLSeigler  HF Survival superiority of females with melanoma: a multivariate analysis of 6383 patients exploring the significance of gender in prognostic outcome. Arch Surg. 1994;129316- 324Article
3.
Karakousis  CPDriscoll  DL Prognostic parameters in localised melanoma: gender versus anatomical location. Eur J Cancer. 1995;31A320- 324Article
4.
Ries  LGPollack  ESYoung  JL Cancer patient survival: surveillance, epidemiology and end results program 1973-79. J Natl Cancer Inst. 1983;70693- 707
5.
Thorn  MAdami  HORingborg  UBergstrom  RKrusemo  U Long-term survival in malignant melanoma with special reference to age and sex as prognostic factors. J Natl Cancer Inst. 1987;79969- 974
6.
Garbe  CButtner  PBertz  J  et al.  Primary cutaneous melanoma: prognostic classification of anatomic location. Cancer. 1995;752484- 2491Article
7.
Blois  MSSagebiel  RWAbarbanel  RMCaldwell  TMTuttle  MS Malignant melanoma of the skin, I: the association of tumor depth and type, and patient sex, age, and site with survival. Cancer. 1983;521330- 1341Article
8.
Hersey  PMorgan  GStone  DEMcCarthy  WHMilton  GW Previous pregnancy as a protective factor against death from melanoma. Lancet. 1977;1451- 452Article
9.
Bork  KBrauninger  W Prior pregnancy and melanoma survival. Arch Dermatol. 1986;1221097Article
10.
Shaw  HMMilton  GWFarago  GMcCarthy  WH Endocrine influences on survival from malignant melanoma. Cancer. 1978;42669- 677Article
11.
Gradoudas  ESGoitein  MKoehler  A  et al.  Proton irradiation of choroidal melanomas: preliminary results. Arch Ophthalmol. 1978;961583- 1591Article
12.
Gragoudas  ESSeddon  JMGoitein  M  et al.  Current results of proton irradiation of uveal melanomas. Ophthalmology. 1985;92284- 291Article
13.
Kaplan  ELMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53457- 481Article
14.
Cox  DR Regression models and life tables. J R Stat Soc Series B. 1972;34187- 220
15.
Gragoudas  ESSeddon  JMEgan  KMGlynn  RJGoitein  MMunzenrider  J Metastasis from uveal melanoma after proton beam irradiation. Ophthalmology. 1988;95992- 999Article
16.
Cox  DROakes  D Analysis of Survival Data.  New York, NY Chapman & Hall1984;
17.
Peto  RPeto  J Asymptotically efficient rank invariant procedures. J R Stat Soc Series A. 1972;135185- 207Article
18.
Kjems  EKrag  C Melanoma and pregnancy: a review. Acta Oncol. 1993;32371- 378Article
19.
Janerich  DT The fetal antigen hypothesis for breast cancer revisited. Med Hypotheses. 1994;43105- 110Article
20.
Lambe  MHsieh  CTrichopoulos  DEkbom  APavia  MAdami  HO Transient increase in the risk of breast cancer after giving birth. N Engl J Med. 1994;3315- 9Article
21.
Shiu  MHSchottenfeld  DMacLean  MBFortner  JG Adverse effect of pregnancy on melanoma: a reappraisal. Cancer. 1976;37181- 187Article
22.
Grin  CMDriscol  MSGrant-Kels  JM Pregnancy and the prognosis of malignant melanoma. Semin Oncol. 1996;23734- 736
23.
Egan  KMWalsh  SMSeddon  JMGragoudas  ES An evaluation of the influence of reproductive factors on the risk of metastases from uveal melanoma. Ophthalmology. 1993;1001160- 1166Article
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