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.