Maurie Markman, MD
It was my exposure to patients with cancer during my time as an internal medicine trainee in the 1970s that led me to pursue a career in medical oncology. Perhaps the most impactful part of this experience was the opportunity to observe firsthand how patients with ovarian cancer were affected by an experimental drug just entering the clinical trials arena at that time. The agent was cisplatin, a drug requiring hospital admission, extensive monitoring, and intensive medical care for potentially debilitating adverse effects. More than one commentator has noted that cisplatin is responsible for providing the single greatest strikingly negative image of chemotherapy among patients, their families, and society at large.
I vividly remember being asked to place a routine order for a nephrology consultation on admission due to the anticipated serious potential for a major decline in renal function. Another detail that stands out is that it was necessary to have multiple very large basins at the patient’s bedside for the anticipated severe emesis, which was experienced by essentially all patients given the drug. I remember asking one of the treating physicians why we were doing this to patients with ovarian cancer. The answer was simple and direct: “Because the drug works.”
Fast forward several decades and the platinum story has largely been told; it’s a truly magnificent example of how clinical investigation has improved the welfare of patients with cancer. Although the potential for renal toxicity associated with cisplatin remains a concern, it has long been possible to deliver the drug safely in the outpatient setting, and several generations of antinausea drugs have made the emesis associated with cisplatin generally tolerable for 3 to 6 administered cycles.
Today, in the management of ovarian cancer, carboplatin has essentially replaced cisplatin due to its more favorable toxicity profile, with equivalent efficacy, making the treatment experience for most patients, although difficult, far more acceptable. However, since the introduction of platinum agents in this malignancy, it is reasonable to suggest there have been only limited changes in the basic paradigm of ovarian cancer management over the past several decades.
Yes, paclitaxel replaced cyclophosphamide, or doxorubicin, in frontline therapy due to strong evidence of superior outcomes; both improved progression-free and overall survival. Several single-agent and combination chemotherapy strategies also have been approved by the FDA over the years for the treatment of both recurrent potentially platinum-sensitive disease, which is progression more than 6 months after the completion of a frontline platinum strategy to which the patient responded, and platinum-resistant disease, which is progression less than 6 months after the completion of a frontline platinum strategy.
But, to be blunt, what we have now in ovarian cancer management is largely a simple list of reasonable therapeutic options that might be employed in patients and that will likely, at least hopefully, be paid for by third-party payers. However, there are preciously limited data as to which specific therapies should be used and in what sequence to provide optimal management for an individual patient with ovarian cancer.
In the era highlighted at the beginning of this commentary, ovarian cancer treatment was appropriately focused on the rapid control of cancer-related symptoms (eg, increasing ascites, abdominal pain, progressive weakness and debility). In most patients, this included an attempt at aggressive cytoreductive surgery followed rather quickly with combination cytotoxic chemotherapy. This “acute care” model was unquestionably successful in alleviating cancer symptoms in most patients with ovarian cancer and in prolonging survival.
Today, it is understood that for as many as 20% of patients presenting with advanced disease, there will be no further clinical evidence of disease during the remaining years of their life following the completion of the primary treatment program, which typically comprises surgery plus chemotherapy. However, for the remaining approximately 80% of patients, the disease will either not respond in a meaningful manner to cytotoxic chemotherapy (20% of those treated overall) or there will be documented evidence of recurrence following an initial response.
Our existing classification schema simply divides this large group of patients into the above-noted disease categories of potentially platinum-sensitive and platinum-resistant. This terminology and view of disease management was quite rational at a time when there were very few available therapeutic options and no reason, other than patient choice and drug toxicity, to select one strategy over another. Plus, with the available therapeutic armamentarium we had during this era, the anticipated ultimate survival for an individual patient, even with potentially platinum-sensitive recurrent disease, was limited.