Treatment of Ovarian Cancer at the Crossroads: 50 Years After Single-Agent Melphalan Chemotherapy

"Although the majority of patients with advanced ovarian cancer will die of the disease, optimism is justified in view of the improved results of surgery followed by cisplatin and carboplatin based chemotherapy."[1]

Over 2 decades ago I shared that optimistic outlook reported by Neijt, as evidenced by the title of a paper I authored in 1984: "Ovarian Carcinoma. A Decade of Progress."[2] Although great strides were made in the 1970s and 1980s, my sense is that the progress in the past decade and a half represents more nuance and fine points and that ovarian cancer treatment is truly at a crossroads. More on that later.

The 1950s and 1960s

Let's start at the beginning. Before 1950 there were only two options for treating ovarian cancer—surgery and radiotherapy. Chemotherapy had not been discovered. Just before the first of today's baby boomers were born (1952), researchers investigating palliation (not cure) of advanced ovarian cancer started using a relative of nitrogen mustard, the alkylating agent hemisulfide mustard, which controlled ascites in 7 of 10 patients.[3] In 1956, researchers at M. D. Anderson Hospital started treating patients with another relative of nitrogen mustard, the alkylating agent melphalan (phenylaline mustard [Alkeran]), which resulted in "shrinkage" (not cure) of tumors in six of seven patients with advanced ovarian cancer.[4]

Fast forward to 1966: Other researchers from M. D. Anderson Hospital reported that melphalan could actually be potentially curative, an amazing concept at that time. They reported that 13 patients "had such an unusual good response that laparotomy was performed . . . to evaluate if an inoperable tumor had become removable [and] to evaluate the need for additional therapy. In each of the 13 patients,

no tumor was found

and chemotherapy was discontinued" (emphasis mine). At a subsequent follow-up, only two patients had developed recurrence.[5] It is now 40 years later, and we are still searching for the elusive cure for the vast majority of women with advanced ovarian cancer.

The 1970s

For patients treated with melphalan or similar drugs during the 60s and early 70s, no effective treatment was available if melphalan was not successful. However, a 1976 report from the United Kingdom demonstrated that one of every four patients treated had a "response" to (but were not cured by) a totally new class of drugs, represented by cisplatin.[6] Thus was born the modern era of chemotherapy for ovarian cancer. That was thirty years ago!

Radical debulking surgery for ovarian cancer has been advocated for more than 70 years. In 1934, Peham and Amreich stated, "in an ovarian tumor which has been recognized as malignant the chief mass of the tumor which is considered inoperable should be removed."[7] That this was not the standard of care was illustrated in a 1976 report, in which 33 of 100 consecutive patients with advanced ovarian cancer had only an omental biopsy as their surgical procedure.[8]

In 1978, the most compelling results for advocating debulking surgery were reported by Griffiths and Fuller.[9] They reported that the 40-month survival was best for patients who underwent debulking surgery that resulted in residual disease less than 1.6 cm in diameter. In contrast, no patient with residual disease larger than 1.5 cm survived 40 months! Some 30 years later, most oncologists currently agree that optimal residual disease in advanced ovarian cancer is defined as tumor masses less than 1 cm in greatest diameter.

With regard to early-stage ovarian cancer, Bagley et al reported in 1972 that the mean 5-year survival rate in patients with stage IA disease (limited to one ovary) was only 63%. Conversely, they found that approximately 40% of these patients would be dead from the disease in less than 5 years—this from the earliest-stage ovarian cancer.[10] Therapy for early-stage ovarian cancer at that time consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without pelvic or abdominal radiation.

In a 1978 collective review, we learned that most of the women thought previously to have early-stage disease, actually had stage III (abdominal) disease with unrecognized microscopic disease in the undersurface of the diaphragm, omentum, and pelvic and para-aortic lymph nodes to explain this high mortality.[11] This retrospective analysis was confirmed in 1982 by the first prospective study of surgical staging in clinically localized ovarian cancer reported by the Ovarian Cancer Study Group.[12]

Among researchers using cisplatin when it was a new agent, Vogl et al in 1979 reported results that had previously not even been envisioned in advanced ovarian cancer—a 90.4% clinical response rate with a 47.6% complete response rate.[13]

The 1980s and 1990s

Thirteen years after the report of the effectiveness of cisplatin as second-line therapy, McGuire et al in 1989 added another nuance to the treatment of ovarian cancer in their report, "Taxol: A Unique Anti-neoplastic Agent With Significant Activity in Advanced Ovarian Epithelial Neoplasms."[14] But it was the 1996 report on a randomized phase III trial of cisplatin plus paclitaxel compared to cisplatin and cyclophosphamide that resulted in near unanimity that paclitaxel and a platinum compound was the best available therapy for advanced ovarian cancer.[15] Of concern, however, was the fact that women who received paclitaxel/cisplatin had a median progression-free survival that was only 4.5 months longer than those receiving cisplatin and cyclophosphamide. None of the women in this trial had what would be considered optimal surgery prior to starting chemotherapy—that is, they all had residual implants greater than 1 cm.

The 21st Century

In the latest refinement, researchers demonstrated that carboplatin plus paclitaxel was as effective as cisplatin plus paclitaxel and less toxic in women with stage III optimally resected (less than 1 cm residual) ovarian cancer. However, they rightly pointed out that "more than 70% of the patients have experienced disease recurrence with a median time to progression of less than two years" and that "the results also emphasize the need for more effective therapy."[16] I could not agree more.

Ovarian cancer remains the number 1 killer from gynecologic malignancies. Given that every woman with ovarian cancer deserves and should have excellent surgery, I consider the landmark dates in lowering mortality in this setting to be 1956 (melphalan), 1976 (cisplatin), and 1996 (cisplatin/paclitaxel). We cannot wait another 20 years (ie, 2016) for another small incremental step in lowering that mortality.

Is the treatment of ovarian cancer at a crossroads? In the 2006 American Society of Clinical Oncology (ASCO) proceedings, there were 95 abstracts on gynecologic malignancies, 60% of which were on ovarian cancer. As I wrote in the April 2006 issue of ONCOLOGY, I do not believe "that more (three drugs vs two drugs) is better." This is supported by two important studies (abstracts 5002 and 5003 from ASCO 2006), in which the addition of a third drug to standard therapy did not improve progression-free survival. I also wrote that "what we need are novel agents to act against molecular targets." Regrettably, three important ASCO abstracts (5006, 5018, 5019) on one of the most promising new agents, bevacizumab (Avastin), revealed a high rate of life-threatening intestinal perforations that preclude the drug's use at this time.

Ovarian cancer therapy is indeed at a crossroads. It is time for a sea change in our approach to treating this disease.

—M. Steven Piver, MD, LLD (HC)

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Neijt JP: Treatment of advanced ovarian cancer: 10 years of experience. Ann Oncol 3:17-27, 1992.

2. Piver MS: Ovarian carcinoma. A decade of progress. Cancer 54:2706-2715, 1984.

3. Seligman AM, Ruttenburg AM, Persky L, et al: Effectiveness of 2-chloro-2´-hydroxy-diethyl sulfide (hemisulfide mustard) on carcinomatosis with ascites. Cancer 5:354-363, 1952.

4. Samuels ML, Howe CD, McDonald EJ: Alkylating agents in the treatment of patients with advanced cancer of the ovary, in Cumley RW et al (eds): Carcinoma of the Uterine Cervix, Endometrium and Ovary, pp 329-338. Chicago, Yearbook of Medical Publishers, 1962.

5. Rutledge F, Burns DC: Chemotherapy for advanced ovarian cancer. Am J Obstet Gynecol 96:761-772, 1966.

6. Wiltshaw E, Kroner T. Phase II study of cis-dichloro-diammine platinum (II) (NSC-119875) in advanced adenocarcinoma of the ovary. Cancer Treat Rep 60:55-60, 1976.

7. Peham HV, Amreich J: Malignant tumors: 50 years ago, in Peham HV, Amreich J (eds): Operative Gynecology. Philadelphia, Lippin-cott, 1934.

8. Piver MS, Barlow JJ: Preoperative and intraoperative evaluation in ovarian malignancy. Obstet Gynecol 48:312-315, 1976.

9. Griffiths CT, Fuller AF: Intensive surgical and chemotherapeutic management of advanced ovarian cancer. Surg Clin North Am 58:131-142, 1978.

10. Bagley CM Jr, Young RC, Canellos GP, et al: Treatment of ovarian carcinoma. Possibilities for progress. N Engl J Med 288:856-862, 1972.

11. Piver MS, Barlow JJ, Lele SB: Incidence of subclinical metastasis in stage I and II ovarian carcinoma. Obstet Gynecol 52:100-104, 1978.

12. Young RC, Decker DJ, Warden JT, et al: Staging laparotomy in early ovarian cancer. JAMA 250:3072-3076, 1983.

13. Vogl SE, Berenzweig M, Kaplan BH, et al: The CHAD and HAD regimens in advanced ovarian cancer: Combination chemotherapy including cyclophosphamide, hexamethyl-melamine, adriamycin and cis-dichloro-diammine platinum (II). Cancer Treat Rep 63:311-317, 1979.

14. McGuire WP, Rowinsky EK, Rosenhein MV, et al: Taxol: A unique anti-neoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 11:273-279, 1989.

15. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996.

16. Ozols RF, Bundy BN, Greer BE, et al: Phase III trial of carboplatin and paclitaxel with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer. A GOG study. J Clin Oncol 21:3194-3200, 2003.