Treating Stage IV Lung Cancer: “You can’t get there from here.”
There is a joke about a traveling salesman who finds himself lost in the countryside and stops a farmer to ask directions to the highway. The farmer first suggests one route and then reconsiders and suggests a different one. He then reconsiders again and suggests yet another route. Finally, the farmer explains apologetically “You can’t get there from here”. I was reminded of this after meeting a very nice woman with advanced lung cancer in February of 2019. Originally diagnosed in 2016, she was found to have an EGFR-mutation and started treatment with Erlotinib (Tarceva) later changed to Osimertinib (Tagrisso). Small brain metastases were well controlled with cyber-knife radiation and the patient did very well for almost 2 years. In June of 2018, with evidence of progression, chemotherapy was initiated but toxicity led her travel to Chicago where chrono-modulated therapy provided better tolerance. In December of 2018, with rapid growth of the disease, the patient requested an opinion.
Surprise Finding – A New Diagnosis The CT scan showed extremely rapid growth and I referred her to our surgeon to conduct a biopsy. The results were unexpected and revealed that this was no longer non-small cell lung cancer (NSCLC) but instead had converted to small-cell lung cancer, an entirely different form of lung malignancy. With our laboratory results confirming activity for Carboplatin plus Etoposide, we initiated treatment for small cell cancer with dramatic improvement. The patient began maintenance therapy but a rise in her CEA tumor marker and increased shortness of breath showed that she was progressing. I conducted a thoracentesis (needle aspiration of lung fluid) that revealed not one, but two distinct lung cancers: One, the original adenocarcinoma and the second, recurrence of her small cell lung cancer. Her Functional Profiling Results With our laboratory platform, we could distinguish each different type of tumor under the microscope to identify drug activity by cell type. The adenocarcinoma remained sensitive to the previously prescribed Tagrisso and this was re-started immediately. However, the small cell cancer had now become Carboplatin plus Etoposide resistant and would require an entirely new treatment combination. Cytoxan plus Topotecan was clearly the most active doublet for the small cell cancer component. Interestingly, neither Topotecan or Cytoxan alone showed much activity as single agents. It was only in combination that we found activity and synergy. The patient who resides in LA had been traveling between Los Angeles and our office in Long Beach for therapy but her LA-based physician was a good ally and was fully prepared to use what was best for the patient. Everything Looked Good Until… After reviewing the findings, I recommended the Cytoxan plus Topotecan doublet. This was where the story took a strange turn. Her LA-based physician reported that she would not be allowed to give the combination. The pharmacy committee had denied the 2 drugs together as they were not part of the “formulary” drug combinations used in small cell lung cancer at that institution. I was dumbfounded. What is the Problem? Both drugs are FDA approved. Both drugs are widely used in small cell lung cancer. This very same doublet had been published for use in small cell lung cancer by investigators at Yale University and related doublets are widely used in ovarian cancer and sarcoma. I re-doubled my efforts and provided literature references, including one of my own publications from the British Journal of Cancer that confirmed the described synergy. All of this was to no avail and by now the patient felt too ill to travel to our hospital. Begrudgingly, the patient began single agent Topotecan administered 5 days in a row. A Turn for the Worse Within a week her blood counts fell as she suffered a low white count and low platelets requiring hospitalization for transfusions and IV antibiotics. Despite the bone marrow toxicity, her disease progressed rapidly and she became oxygen dependent. Working closely with our group, I was able get both drugs for the combined treatment. The Right Treatment Begins The patient arrived, gasping for air on supplemental O2 as we began her first cycle. As her blood counts fell again, we adjusted the schedule to day 1 and day 8 for her second cycle. By cycle 2 the patient no longer required oxygen. She was breathing easily and looked good. With cycle 3 she was well enough to travel alone from LA to our office unassisted. She was clearly responding. What is wrong with this picture? A Closer Look at The Problem
First, the two drugs that we recommended are widely used and well-established chemotherapy drugs that have a long history of use in the treatment of small cell lung cancer. Second, the combination is synergistic, such that neither of the drugs alone carries the activity that the patient required. She needed both drugs together, just as we described in our earlier paper on Topotecan synergy. Finally, the drugs are not only safe and effective, they’re inexpensive. Why would the Pharmacy Committee deny this treatment despite ample scientific and literature support? The answer is that medicine is no longer practiced by doctors. The Bottom Line Medicine has become a Byzantine bureaucracy managed by bean counters. The Pharmacy Committee looked only at their established norms. Lacking the depth of experience and the pharmacologic knowledge to judge the merits of the recommendation they simply denied the combination outright. When I saw the patient in clinic and examined her chest, she had no re-accumulation of fluid. It was obvious that our drug selection had been correct. My Advice and Final Thoughts It has become abundantly clear that patients more than ever need to take charge of their disease and counter generic guideline-driven therapies that are preventing them from receiving the treatments they need. Cancer medicine is not a pharmacy guideline or an institutional algorithm. It is a human experience and every patient deserves the right to be treated correctly. The question is, do their physicians have the capacity and the fortitude to do the right thing?