Practicing Clinical Oncologists to the Rescue

Cancer patients and their physicians can find themselves at the wrong end of many scientific discoveries. For example, the drug capecitabine, sold commercially as Xeloda, was originally marketed at a daily dose of 2500 mg/m2 given for two weeks.

This schedule developed by the pharmaceutical investigators, is known as the maximum tolerated dose (MTD) and it performed well against other regimens for breast and colon cancer. With an FDA approval in hand, oncologists began administering the drug on the recommended schedule.

MTD2It did not take long before physicians and their patients realized that 2500 mg/m2/day was more than many patients could tolerate. Hand-foot Syndrome (an inflammation of the skin of palms and soles), mucositis (oral ulcers) myelosuppression (lowered blood counts) and diarrhea were all observed. Immediately clinical physicians began to dose de-escalate. Soon these astute practitioners established more appropriate dose schedules and the drug found its rightful place as a useful therapeutic in many diseases.

What was interesting was that activity continued to be observed. It appeared that the high dose schedule was simply toxic and that lower doses worked fine, with fewer side effects.

Modern targeted agents have been introduced over recent years with dose schedules reminiscent of capecitabine. The drug sunitinib, approved for the treatment of renal cell carcinoma, is given at 50 mg daily for four weeks in a row, followed by a two week rest. Despite good activity, toxicities like mucositis and skin rash often set in by the third week. What remained unclear was whether these schedules were warranted. A recent report in the Annals of Oncology examined this very question. In a retrospective analysis of patients with kidney cancer the physicians found that lowering the dose of sunitinib preserved activity but reduced toxicity.

As a practitioner, I have long reduced my patient’s schedule of sunitinib to two weeks on, one week off or even 11 days on, 10 days off. In one patient that I treated for a gastrointestinal stromal tumor (GIST), I achieved a durable complete remission with just 25 mg/day, given seven days each month, a remission that persists to this day, seven years on.

We are in a new world of targeted therapy, one in which very few people understand the kinetics, pharmacodynamics and response profiles of patients for novel drugs. In our laboratory, favorable dose response curves often suggest that many agents could be administered at lower doses. More interestingly, some patients who do not carry the “targets” for these drugs nonetheless respond. This has broad implications for multi-targeted inhibitors like sunitinib that can influence multiple targets simultaneously.

As so often happens, it is the nimble clinical physicians with their feet on the ground, confronting the very real needs of their patients who can outmaneuver and outthink their academic colleagues. The trend toward consolidation in medicine and the absorption of clinical practices into hospital groups all using standardized algorithms has the risk of stifling the very independence and creativity of practicing oncologists that has proven both effective and cost-effective for our patients and our medical system at large.

Gastric Cancer: A Call for Patient Selection

Gastric cancer is the fourth most common cancer worldwide with more than 930,000 diagnoses and 800,000 deaths attributed to this disease each year. Although relatively uncommon in the U.S., constituting only 2 percent of new cancers, in countries like Korea it makes up 20 percent of all new malignancies.

Among the causes are Helicobacter pylori infection, diets rich in smoked food, a high intake of nitrates and nitrites and cigarette smoking. A rare but aggressive form of the disease is associated with a gene mutation known as CDH1. The high frequency of metastatic disease at the time of initial diagnosis often precludes surgery, leaving systemic chemotherapy as the principal treatment option.

Annals of Oncology coverA recent report in The Annals of Oncology (No improvement in median survival for patients with metastatic gastric cancer despite increased use of chemotherapy: Bernards N. et al, Annals of Oncology. November, 2013) describes a retrospective analysis by Dutch investigators who examined the use of chemotherapy in patients with inoperable gastric cancer.

In total, 4,797 cases were examined from 1990 to 2011. Over this time, the proportion of patients presenting with metastatic disease increased from 24 percent in 1990 to 44 percent in 2011. At the same time, palliative chemotherapy use increased from 5 percent to 36 percent. Younger patients and those of higher socioeconomic status had the largest increase in chemotherapy use, while older patients, those with linitis plastica and those with multiple metastases had lower chemotherapy use. Despite the significant increase in the use of chemotherapy, the median survival for patients was unchanged at 15 weeks in 1990 and 17 weeks in 2011 (P = 0.1).

Over this period, early treatment regimens like 5-fluorouracil (5FU) and FAM were largely replaced by combinations like Docetaxel/Cisplatin/5-FU (DCF), Cisplatin/Irinotecan, Epirubicin/Oxaliplatin/Capecitabine (EOX) and Carboplatin/Taxol. While response rates and palliative benefits have continued to improve, this has not translated into improved overall survival. This reflects a dilemma that has confronted medical oncologists for decades.

For many years, clinical trialists have held that one cannot assess the benefit of a treatment by comparing responders to non-responders. That is, time to progression and survival must compare all patients on a given treatment arm to those on the control arm. Their rationale was that “one must treat all patients to obtain the benefit seen in some.”  Put differently you cannot “cherry pick” your winners and losers. It was said that this proscription was needed to avoid selection bias. But as any medical or nonmedical person would recognize, people who respond to treatment do better than those who do not. Lacking the ability to identify responders upfront, these trialists have insisted upon a one-size-fits-all approach to the detriment of clinical therapeutics and drug development.

With the dawn of the molecular era we see chinks in the armor of these trial designs as investigators now question why everyone should receive a treatment if only a small percentage will benefit. In gastric cancer, HER2 over-expression, found in 20-25 percent of patients, is now routinely used to identify patients who will respond to trastuzumab. But what of the other 75-80 percent of patients who do not carry HER2 and for whom there are no widely used determinants of clinical response? Do the results of Bernard article suggest that these patients should not receive therapy?

The Bernard article offers an interesting insight into what may be the future of medical oncology. As cancer therapy is increasingly scrutinized, not only for response or palliation but also for overall survival, patients may soon be denied treatments unless the results of the therapy rise to this, the highest level of evidence, for the entire population of treated patients.

Would it not be preferable to use laboratory analyses, like the EVA-PCD®, to select among treatment candidates before subjecting all patients to the risk and expense of toxic chemotherapy? In this regard, the author’s comments are poignant: “Identification of the subgroup of patients which benefit from palliative chemotherapy is of the utmost importance to avoid unnecessary treatment.” As a laboratory investigator engaged in the field of drug selection science (functional profiling), I couldn’t agree more.