Stand Up to Cancer Research! The Downside to Clinical Trials.

As the practice of medicine has moved from a profession to an industrial undertaking, this most human of experiences has fallen prey to the dictates of the American business model. Patients are no longer the purchasers of medical care and services, but instead, the consumers of those goods and services that meet the needs of the purveyors. Whether this is a governmental entity, academic institution, or pharmaceutical company, individuals have become cogs in the wheel of the medical-industrial complex.

This has become glaringly apparent in the field of cancer research. Cancer patients were once, for better or worse, in charge of their own destinies. They could choose their surgeon, oncologist, and institution, even to some degree the treatments that they wished to undergo. As the HMO model came into play, patients were increasingly told what doctor, what treatment, and what hospital. The capacity of individuals to make decisions was eliminated in favor of standardized care, cost guidelines and treatment protocols. While much of the academic community described this as progress with adherence to standardized protocols, these protocols have not provided superior outcomes in most settings. Instead, they offer hospital administrators the opportunity to anticipate costs, allocate resources, codify drug administration and regulate care delivery.

Recent experience has brought several disturbing examples to the fore. Working in the laboratory, we have been able to select candidates for new combinations, sometimes years before these regimens became broadly available. We then identify centers with access to these drugs under protocol. Many of the drugs have well-established safety records from prior phase 1 and 2 clinical trials, but have not achieved full FDA approval. When several of our patients with lung cancer revealed sensitivity to a regimen that we had identified years earlier (Kollin, C et al Abs 2170, Proc AACR, 2005) we immediately explored sites offering this combination of an oral agent with an IV antibody. The closest we could find was in Colorado. The injection, a widely established monoclonal antibody, FDA approved for gastrointestinal cancer, was not yet approved for lung cancer while the pill had been administered safely in hundreds of patients. Indeed, the combination had also been safely administered to dozens of patients by the time we inquired. Nonetheless, to participate in this potentially life-saving treatment my patients were forced to commute from LA to Colorado every other week.

It would have been quite easy, once the patients were formally accrued, for them to return to California and receive the same drugs under our care. After all, we were the ones who identified them as candidates in the first place and we were very familiar with the trial. Despite this, the rigidity of the protocol forced these lung cancer patients to become frequent fliers. The good news was that the treatments worked.

More recently a patient, who had failed experimental therapy for advanced uterine carcinoma at a large academic center in Texas, returned to LA five years ago to seek my assistance. A lymph node biopsy at the time revealed exquisite sensitivity to a drug combination developed and published by our group and she achieved a prompt complete remission. She has since relapsed and required additional chemotherapy. My concern for her long-term bone marrow tolerance, with repeated exposure to cytotoxic drugs, led me to seek alternatives. Her EVA-PCD functional profile had revealed excellent activity for PARP inhibitors. Here, I thought, would be the solution to her problem. After all, the PARP inhibitors had been in development for years. Several had revealed compelling activity in clinical trials and they are well tolerated. Despite this, no PARP inhibitor has been FDA approved.

When we pursued opportunities to accrue the patient to one of the PARP inhibitor trials, however, she did not qualify. Having received low dose Carboplatin several months earlier she ran afoul of an exclusion criterion in the protocol that dictated no platinum exposure for six months. “Six months?” I exclaimed. Few cancer patients can wait six months to start treatment and virtually no cancer patients can wait six months once they have relapsed. I was flabbergasted.

What exactly were the protocol designers thinking when they demanded a six-month wash out, fully four, five or six times longer than any protocol I’d ever encountered?  The absurdity of this demand virtually eliminated patients-in-need from consideration. As I considered the dilemma it became increasingly clear. When one examines the thinking behind clinical protocols it becomes evident that they are not designed to help patients or cure cancer. Instead, they are created to answer specific questions. In so doing they further the careers of investigators, expand medical center market share, standardize treatments and simplify the activities of clinical research organizations. Patient outcomes, well-being and convenience are far down the ladder of expectations.

As I pondered the inconvenience, hardship and lost opportunities associated with clinical trial participation for many patients around the United States, I began to wonder whether patients should throw off the yoke of this oppressive system. After all, it is not the academic centers that own the process, it is the patients. It is those brave individuals willing to participate in these studies. It is the patients whose tax dollars support these institutions. It is the patients who purchase either directly or indirectly the drugs they receive and it is the patients that are necessary for the process to succeed.

Patients should demand more user-friendly, convenient, patient-centric therapy programs. Perhaps patients should simply refuse to participate. A ground swell of patient advocacy could re-orient the discussion away from the convenience and ease of the treating physicians and toward the good outcome and ease of the treated patient. While we applaud the investigators for their brilliance and prowess, we forget that no clinical investigator would receive accolades were it not for the hundreds or thousands of patients who martyr themselves at the altar of clinical research. Patients, not their doctors, are the heroes.  Perhaps it is time for cancer patients to stand up to cancer research.

Breast Cancer and Avastin, the Ongoing Saga

As many are now aware, in November of 2011, the United States FDA withdrew approval for bevacizumab (Avastin) for the treatment of breast cancer. Medicare and the National Comprehensive Cancer Network  (NCCN) are now re-examining their guidelines. In the interim, reimbursement for Avastin is a patchwork of approvals and denials across the country.

Into this mix comes an interesting concept apparently floated by Roche’s European affiliates. Described in a brief press release was the suggestion that Roche might be prepared to attach Avastin reimbursement to its efficacy. That is – Roche would only demand payment from patients and third party payers if the treated patient revealed objective evidence of response. This is an interesting idea!

The concept of conditional reimbursement is extremely intriguing. Contrary to contemporary reimbursement policy, the purveyors of therapy would only receive compensation if they could prove benefit, not mind you, benefit in the broad brush Phase III tiny statistically significant result (e.g. the FDA approval of erlotinib plus gemcitabine in pancreatic cancer for a median survival advantage of 10.6 days!), but instead very real benefit on a patient-by-patient basis.

We use erlotinib plus gemcitabine, as well as Avastin combinations, to great benefit for many of our patients and applaud the availability of these drugs and combinations. But we never, just give them. Were the federal government, major payers or HMOs to be prepared to reimburse novel therapies predicated on their efficacy, we might envisage a meaningful advance in cancer therapeutics.

Today, few small laboratories, start-up companies and early stage biotech firms have the resources to marshal multi-million dollar clinical trials to test new therapies. This may in part be why advances in cancer therapy are moving so slowly forward.  The barriers to entry are insurmountable, causing many good ideas to fall by the wayside for lack of the hundreds of millions of dollars required to achieve FDA approval and Medicare reimbursement. But what if on an individual basis, reimbursement policies reflected the most meaningful of all endpoints – individual patient response and survival. Even the largest pharmaceutical companies are now coming to realize that despite their clout they too are suffering under the guidelines forced upon drug developers in this era of ever increasing regulation.

This is a concept worth pursuing. Let’s see where it goes.

The Avastin Saga Continues

We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patient’s response durability. It was hoped and believed that time to progression would be an early measure of survival.

Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastin’s indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs).

There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval — statistically significant survival — was not met.

The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), “I am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.”

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma.

The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 — providing her an additional five years of life — it wasn’t until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication.

We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test.

Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward.

The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma.

We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies.

We stand at the ready for the challenge.

What’s Wrong with Avastin?

Nothing really. It’s a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman, MD, at Harvard University. Dr. Folkman reasoned that:

1. Cancers require oxygen and nutrients
2. These would need to be delivered by a blood supply
3. Tumors would avidly seek their own blood supply via humoral factors.

His groundbreaking work ultimately lead to the discovery of VEGF, as well as the FDA approval of Avastin, the monoclonal antibody that binds and inactivates circulating VEGF in patients. The problem isn’t with Avastin, it’s with the practice of oncology – the clinical trial process and the muddied waters that surround clinical utility of any drug, new or old.

There are no perfect drugs. There are simply drugs that work for certain patients. VEGF down-regulation is an attractive and highly appropriate therapy for a subset of cancer patients with many different diagnoses whose tumors use the VEGF pathway to their advantage. Avastin combined with carboplatin and taxol has improved the survival of lung cancer patients. Avastin plus folfox has improved survival for colon cancer patients. Avastin plus chemotherapy improves the survival of some breast cancer patients. The problem is that it doesn’t improve the survival of all breast cancer patients.

When the FDA rules on the clinical utility of a drug, they use a broad-brush approach that looks at the global outcomes of all patients, determining whether these glacial trends reflect a true climate change. The problem is that while Bethesda, Maryland may not be noticing significant changes in ocean levels, people who live on the Maldives are having a very different experience. As these scientists ponder the significance of Avastin, some breast cancer patients are missing out on a treatment that could quite possibly save their lives.

One breast cancer patient’s life saving therapy is another’s pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another. Our solution to this problem has been to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s outcome. Our results to date in patients with non-small cell lung cancer, colorectal cancer and even rare tumors (like medullary carcinoma of the thyroid) suggest this to be a highly productive direction for future development.