Correspondence
Cancer of the Ovary
N Engl J Med 1994; 330:1012-1014April 7, 1994
- Article
To the Editor:
Dr. Cannistra stated in his review article on cancer of the ovary (Nov. 18 issue)1 that “the regimen of cisplatin plus cyclophosphamide is just as effective as more complicated and toxic regimens, such as those containing altretamine or doxorubicin hydrochloride.” It appears that the author did not review the literature critically. For example, Hainsworth et al. (Cannistra's reference 42) reported a response rate of 96 percent for the combination of altretamine (hexamethylmelamine), cyclophosphamide, doxorubicin, and cisplatin (H-CAP)2. More important, the median survival for the entire group of patients was 45 months, and it was 72 months for patients with limited residual disease before the start of chemotherapy. In a follow-up report from the same institution, the patients treated with H-CAP were compared with a subsequent cohort of patients treated with cyclophosphamide, doxorubicin, and cisplatin (CAP) in a regimen of comparable dose and schedule3. The median survival was 49 months with H-CAP, as compared with 21 months with CAP (P = 0.006). In patients with limited residual tumor ( ≤ 3 cm), the median survival was 101 months and 21 months, respectively (P = 0.002). A similar retrospective analysis by Bruckner et al.4 demonstrated an apparent benefit when altretamine was added to CAP. The overall response rate was 76 percent for patients receiving H-CAP, as compared with 69 percent for those receiving CAP alone. Most important, the median survival of 43 months for patients treated with H-CAP was significantly longer than the 25 months for similar patients receiving cisplatin plus cyclophosphamide (CP) at their institution. The benefit of altretamine was also suggested by the long-term follow-up data from a randomized, controlled trial reported by Edmonson et al.5 comparing H-CAP with CP. Forty-three percent of the patients receiving four drugs survived six years, as compared with 21 percent of those receiving two drugs.
In view of these data, altretamine is an underused agent. The addition of altretamine to the full-dose CAP regimen, as employed in these studies to treat patients with advanced ovarian cancer, resulted in prolonged survival with little additional toxicity.
5 ReferencesJohn Lurain, M.D.
Northwestern University Medical School, Chicago, IL 606111
Cannistra SA . Cancer of the ovary. N Engl J Med 1993;329:1550-1559
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Hainsworth JD ,Grosh WW ,Burnett LS ,Jones HW III ,Wolff SN ,Greco FA . Advanced ovarian cancer: long-term results of treatment with intensive cisplatin-based chemotherapy of brief duration. Ann Intern Med 1988;108:165-170
Web of Science | Medline3
Greco FA ,Johnson DH ,Hainsworth JD . A comparison of hexamethylmelamine (altretamine), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) vs. cyclophosphamide, doxorubicin, and cisplatin (CAP) in advanced ovarian cancer. Cancer Treat Rev 1991;18:Suppl A:47-55
CrossRef | Web of Science | Medline4
Bruckner HW ,Cohen C ,Mandeli J , et al. Hexamethylmelamine for the treatment of ovarian cancer -- the Mount Sinai experience. Cancer Treat Rev 1991;18:Suppl A:57-65
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Edmonson JH, McCormack GW, Wieand HS. Late emerging survival differences in a comparative study of HCAP vs. CP in stage III-IV ovarian carcinoma. In: Salmon SE, ed. Adjuvant therapy of cancer. 6. Proceedings of the 6th International Conference on the Adjuvant Therapy of Cancer, Tucson, Arizona, March 7-10, 1990. Philadelphia: W.B. Saunders, 1990.
To the Editor:
We were disappointed at the limited reference to radiation therapy in an otherwise comprehensive review of cancer of the ovary. Cannistra indicates that salvage radiotherapy after failed chemotherapy yields poor results. This, however, presupposes the routine use of postoperative chemotherapy rather than radiotherapy, a highly debatable presupposition. Neglected in the review, but much more important than a limited discussion of radiotherapy as salvage therapy, is the curative role of abdominopelvic irradiation in epithelial ovarian cancer.
Unfortunately, no randomized trials directly comparing abdominopelvic radiotherapy with chemotherapy after adequate cytoreductive therapy have been successfully completed. It is recognized that the volume of postoperative residual disease is more critical to a favorable outcome with radiotherapy than with chemotherapy. However, in patients with stage II or III disease in whom the volume of postoperative residual disease has been carefully documented and found to be minimal (as is commonly achieved with current surgical techniques), long-term (>10 year) disease-free and overall survival is on the order of 40 to 60 percent1,2. Unlike some other tumors,3 ovarian tumors extremely rarely relapse after eight years1. Therefore, these data provide compelling evidence that radiotherapy has a role in the management of ovarian cancer.
3 ReferencesMichael J. McKay, M.D.
Colin A. Bull, M.D.
University of Sydney, Westmead 2145, Sydney, Australia1
Dembo AJ . Epithelial ovarian cancer: the role of radiotherapy. Int J Radiat Oncol Biol Phys 1992;22:835-845
CrossRef | Web of Science | Medline2
Thomas GM ,Dembo AJ . Integrating radiation therapy into the management of ovarian cancer. Cancer 1993;71:Suppl:1710-1718
CrossRef | Web of Science | Medline3
McKay MJ ,Langlands AO . Prognostic factors in breast cancer. N Engl J Med 1992;327:1317-1317
Full Text | Web of Science | Medline
To the Editor:
Cannistra discusses the value of the tumor marker CA-125 in the diagnosis and follow-up of patients with ovarian cancer and also states that elevated levels of CA-125 can be observed in nonmalignant conditions. However, he does not mention a cause of abnormal serum CA-125 levels -- ascites.
Serous effusions, especially ascites, are a well-known cause of abnormal CA-125 values1,2. On the other hand, ascites frequently develops in patients with ovarian cancer, especially in advanced stages, although it can also be detected in disease limited to the ovaries.
We studied CA-125 in 159 patients with nonmalignant liver diseases with and without ascites2. CA-125 was found to be an excellent marker for ascites (sensitivity, 98.4 percent; specificity, 95.9 percent; efficiency, 96.9 percent). It was also very sensitive to the presence of minimal ascites. Moreover, CA-125 showed a correlation with the amount of ascites (P<0.001), with some patients reaching levels higher than 3000 U per milliliter.
2 ReferencesJulio Collazos, M.D.
Hospital de Galdakao, 48960 Vizcaya, Spain1
Bergmann JF ,Bidart JM ,George M ,Beaugrand M ,Levy VG ,Bohuon C . Elevation of CA 125 in patients with benign and malignant ascites. Cancer 1987;59:213-217
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Collazos J ,Genolla J ,Ruibal A . CA 125 serum levels in patients with non-neoplastic liver diseases: a clinical and laboratory study. Scand J Clin Lab Invest 1992;52:201-206
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To the Editor:
The review article on cancer of the ovary revisits the controversy surrounding the name given to paraumbilical lymphadenopathy. The umbilicus is in the path of the superficial and deep lymphatic drainage of the intraabdominal and pelvic structures as well as numerous venous communications1. Metastatic extension of intraabdominal neoplasms may directly affect the umbilicus. Legend has it that Sir Hamilton Bailey suggested naming the paraumbilical nodule “Sister Joseph's node” in honor of Sister Joseph2. In the early days of the Mayo Clinic, Sister Joseph was Dr. William Mayo's first assistant and the superintendent of St. Mary's Hospital. She observed that patients with paraumbilical lymphadenopathy were often afflicted with intraabdominal or pelvic cancers1,3. It is not clear whether the “Mary” of Sister Mary Joseph's node, as this nodule is often called, was due to Sister Joseph's involvement with St. Mary's Hospital or to the custom of Catholic nuns to acquire the name “Mary”3. Thus, if tradition is to prevail, paraumbilical lymphadenopathy should be referred to as Sister Joseph's node instead of Sister Mary Joseph's node.
3 ReferencesJohn M. Embil, M.D.
University of Manitoba, Winnipeg, MB R2H 2A6, Canada1
Barrow MV . Metastatic tumors of the umbilicus. J Chronic Dis 1966;19:1113-1117
CrossRef | Medline2
Flynn VT ,Spurrett BR . Sister Joseph's nodule. Med J Aust 1969;1:728-730
Web of Science | Medline3
Sapira JD. The art and science of bedside diagnosis. Baltimore: Urban and Schwarzenberg, 1990:143.
Author/Editor Response
Dr. Cannistra replies:
To the Editor: I wish to assure Dr. Lurain that a critical appraisal of the literature was indeed conducted with regard to the role of agents such as altretamine in the first-line treatment of patients with ovarian cancer. His assertion that altretamine confers a survival advantage when added to platinum-based chemotherapy is based largely on single-group studies in which comparisons were made with historical controls, thus introducing the possibility of a selection bias. In contrast, a prospective study conducted by the Netherlands Joint Study Group randomly assigned 191 patients with advanced ovarian cancer to receive either a regimen containing altretamine (CHAP-5) or standard cyclophosphamide and cisplatin1,2. After a median follow-up of almost eight years, rates of response and survival were equivalent in both groups, although disabling neurotoxic effects were greater in the group receiving altretamine. Data such as these do not support the routine use of a potentially toxic drug such as altretamine in patients with newly diagnosed ovarian cancer.
Drs. McKay and Bull are correct in noting the curative role of whole-abdominal radiotherapy in the adjuvant setting. Nevertheless, platinum-based chemotherapy has largely replaced abdominal radiotherapy for several reasons. The use of platinum analogues has unequivocally resulted in improved median and overall survival in patients with advanced stages of disease2. This therapy can be administered by experienced community oncologists in a safe and reproducible fashion with acceptable levels of toxic effects. It is applicable to the majority of patients with advanced ovarian cancer, including those with bulky residual disease, which is not effectively treated by radiotherapy. Although abdominal radiotherapy and platinum-based chemotherapy have not been precisely compared in a randomized trial, the available data suggest that the addition of radiotherapy to chemotherapy does not result in improved survival3,4. Finally, it is often impossible to deliver full-dose chemotherapy to patients who have relapsed after radiotherapy because of compromise of pelvic bone marrow.
I agree with Dr. Collazos that CA-125 is a nonspecific marker that may be elevated in several nonmalignant conditions. Finally, although Dr. Embil points out that the term “Sister Mary Joseph's node” may be historically inaccurate, I suspect that it will be difficult to eradicate from the medical lexicon, and it is conceptually more pleasing to call Mary, rather than Joseph, a sister.
4 ReferencesStephen A. Cannistra, M.D.
Dana-Farber Cancer Institute, Boston, MA 021151
Neijt JP ,ten Bokkel Huinink WW ,van der Burg ME , et al. Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma. J Clin Oncol 1987;5:1157-1168
Web of Science | Medline2
Neijt JP ,ten Bokkel Huinink WW ,van der Burg ME , et al. Long-term survival in ovarian cancer: mature data from The Netherlands Joint Study Group for Ovarian Cancer. Eur J Cancer 1991;27:1367-1372
CrossRef | Web of Science | Medline3
Lambert HE ,Rustin GJ ,Gregory WM ,Nelstrop AE . A randomized trial comparing single-agent carboplatin with carboplatin followed by radiotherapy for advanced ovarian cancer: a North Thames Ovary Group Study. J Clin Oncol 1993;11:440-448
Web of Science | Medline4
Rothenberg ML ,Ozols RF ,Glatstein E ,Steinberg SM ,Reed E ,Young RC . Dose-intensive induction therapy with cyclophosphamide, cisplatin, and consolidative abdominal radiation in advanced-stage epithelial ovarian cancer. J Clin Oncol 1992;10:727-734
Web of Science | Medline
