Lung Cancer: Disseminated Adenocarcinoma of the Lung
Immunotherapy Keeping Cancer at Bay
Earl Daniels’ Successful Offense Against Disseminated Adenocarcinoma of the Lung: A Case History
Introduction: Expanding options in cancer treatment and unprecedented access to objective tests for tumor progression and host immune activation are available. These provide new evidence of immune system participation in prolonged cancer control.
Summary: A case history is presented of a lung cancer victim treated with immunotherapeutic intent who became an extraordinary cancer survivor. Objective evidence accumulated during the course of this treatment supports the operation of a host-mediated immune response
believed central to this patient’s cancer remission status.
Basic Tenets in Our Immuntherapeutic Paradigm:
Natural immune resistance to cancer reduces the risk of cancer during reproductive adulthood (age 15-40).
Cancer risk rises rapidly after “the change” at approx age 40.
The integrity of host immune system surveillance against cancer determines whether or not small volume cancers are able to proliferate in the hoist environment.
Small volume cancers consist of two categories; (a) de novo cancers that are sub-clinical and (b) cancers reduced to small volume by treatment.
Cancer immune surveillance is linked teleologically and physiologically to reproductive function, and hormones related to reproduction also influence immunity. Hormones produced by the ovaries and testicles – estrogen, testosterone, progesterone, etc – undergo life cycle decline deleterious to immune system integrity. These hormones have a useful role in immune restoration as cancer treatment.
Immunity may be restored to reproductive era integrity, and then further stimulated to supra-youthful levels by appropriate management.
Immunotherapy may produce protracted cancer remissions with high quality of life. The global quality of life in cancer survivors is far better than what the patient typically experiences during protracted chemotherapy.
Previous conventional chemotherapy does not prohibit successful immunotherapy if the method employed is adequate. Alternative medicine advocates who assert chemotherapy precludes subsequent biological approaches are wrong in their assertion.
Sequential determinations of cancer markers (CEA, PSA, BR27.29, CA125, alpha fetoprotein, etc), typically accurately reflect individual patient body burden of cancer. If CEA is initially elevated, serial CEA determinations and assessment of interval change will be quite useful in assessing treatment efficacy during therapeutic trials of different regimens.
Natural killer lymphocytes (NK) are instrumental in immunologically driven cancer remissions.
NK% in peripheral blood is more valuable than absolute NK numbers or NK functional studies as a practical clinical assessment of immune activation.
Most, but not all, patients with immunologically driven cancer remissions will have protracted intervals of NK% elevation well above the normal range.
Large cancers suppress immunity. Tumor antigen released by the death fraction in large cancers escapes into the blood stream to complex with antibodies on killer cells targeting the cancer. The immune system’s killer cells are blinded by this excess cancer antigen.
Most patients present with a sufficient mass of cancer (“body burden”) to render the immune system poorly operable by tumor bulk alone.
A threshold level of body burden of cancer exists below which an activated immune system may regain its ability to effectively attack the cancer. We term the body burden threshold above which the immune system is incompetent the “immune incompetency threshold” (IIT). The clinical goal of clinical immunotherapy is to concurrently bulk reduce the cancer to below the IIT, while building up immunity to youthful or supra-youthful.
Degree of Immune activation in an individual patient may be estimated by NK% determinations or measurements of size of the IL-2 belly plaque.
Immune system stimulation to reproductive adulthood status or to hyperimmune status typically takes several weeks.
PET scanning is quite useful in inventorying larger metastases.
Radiotherapy and/or surgery and/or chemotherapy may be used for tumor bulk reduction in disseminated disease to achieve body burdens allowing the immune system to regain its capacity to control. The use of focal radiotherapy to bulk reduce an asymptomatic adrenal metastasis associated with rising CEA exemplifies this concept nicely.
Adenocarcinoma of lung origin is a favorable tumor type for successful Immunotherapy
There is ample and rapidly increasing justification to go beyond “standard of care” as this term is employed in Medicare regulations or other third party payers language. Standard of care is a phrase often employed by third party payers in efforts to limit third party liability reimbursement for pharmaceutical usage. Many payers strive to limit their indemnification liability to drug applications where success has been proven in drug company sponsored, FDA approved, randomized, prospective clinical trials.
There is ample and rapidly increasing justification to go beyond “indicated use” of pharmaceuticals, as this term is employed in the FDA drug approval process. “Indicated use” and “standard of care” are both a “phrase of art” implying other uses are “not standard” or “not indicated”. Applications “not indicated” in the government regulatory sense may constitute life-saving, evidence based, applications of scientific medical care.
It is essential for the cancer victim to realize that physicians face unprecedented pressure to ration medical care.
Due diligence, rational decision-making for cancer care in a universe of diverse treatment options requires both knowledge and judgement in weighing both scientific and political factors. The cancer victim and his or her advisors should decide which approaches are justified by science and economic realities. The internet is an indispensable aid in exploring options rationally.
Evidence Particular to This Case
1. Earl presented with bulky mediastinal (between the lungs) tumor containing adenocarcinoma at biopsy. This mass was sufficiently large to cause superior vena cava syndrome, a syndrome resulting from a blockage of venous return to the heart from the upper half of the body.
2. The cancer was secreting CEA at a high level. This degree of CEA elevation is found in lung cancer almost exclusively with adenocarcinoma.
3. Under initial, conventional, combined concurrent radiotherapy and chemotherapy the markedly elevated CEA returned to normal. (see graph)
4. Taxotere “consolidation” chemotherapy was poorly tolerated (“like to killed me”), not an unusual experience for chemotherapy recipients after repeated cytotoxic cycles. This patient, like many others, declined further chemotherapy as his independent decision. We respect this decision was prudent.
5. After further chemotherapy was declined, the conventional treatment would have been “watchful waiting”. This is a euphemism for doing nothing. In this case multiagent immunotherapy including IL-2 immunotherapy was discussed with the patient and begun in earnest with his informed consent.
6. Five months later after completing chest radiation therapy, at least 5 brain metastases were discovered on CT. Several of these exhibited central necrosis (dark centers on CT scan – see scan images), a common finding in lung adenocarcinomas and much less commonly seen in other lung cancer subtypes. These metastases required treatment with radiotherapy.
7. The brain metastases shrank markedly after radiotherapy.
8. Radiotherapy to the brain consisted of 4500 cGy in 5 weeks, a regimen far more protective of higher cognitive function than the often used 3000 cGy in two weeks.
9. Immunotherapy with IL-2 belly plaque and other agents was continued before and after the brain irradiation.
10. After brain radiotherapy was complete the CEA cancer marker began a disappointing steady rise (see graph).
11. In May 2003, PET scan and repeat CT scan revealed an active mass in the left adrenal which had developed since a CT scan taken at presentation. There were no other active sites outside the irradiated chest. It was hypothesized that this adrenal mass was metastatic cancer largely responsible for the progressive rise in CEA.
12. The adrenal gland is the source of cortisone and hydrocortisone, known immunosuppressive hormones. These hormones cause lysis (death) of lymphocytes. Brain and adrenal gland are well documented as preferred metastatic recurrence sites for adenocarcinoma of the lung. The brain is a common site for recurrences as chemotherapy does not penetrate the blood-brain barrier in sufficient quantities to have anticancer effects. The adrenal acts as “fertile soil” for recurrences likely due to the immunosuppressive micro environment hostile to natural killer lymphocyte mediated immunotherapy.
13. The same CT demonstrating the adrenal mass also memorializes a prominent IL-2 generated belly plaque (see scans). Blood determinations at around this time revealed substantial elevation of natural killer (NK) lymphocyte blood levels (see graph). This elevation supports our theory that the belly plaque is a factory for NK cells. NK cells escape the plaque to the general circulation.
14. Most medical oncologists would have recommended more chemotherapy at discovery of the adrenal metastasis, the indication being systemic recurrence or relapse. This was a critical decision fork.
15. The adrenal recurrence was treated with local radiotherapy, hopefully reducing the body burden below the IIT and blocking corticosteroid production be the adrenal. The tumor was radiosensitized with Iressa.
16. IL-2 belly plaque was continued, but was later stopped.
17. The CEA fell rapidly during adrenal irradiation to normal, and CEA has remained normal for 15 months.
18. The patient has remained physically and mentally active with an excellent quality of life.
19. The 14 month, no chemotherapy remission currently enjoyed by Mr. Daniels after two manifestations of distant spread (brain and adrenal) is an anomalous occurrence under the prevailing chemotherapy centric paradigm of cancer treatment. In our opinion, this protracted delay to recurrence in association with other evidence of immune activity makes our case that our immunotherapy efforts are successfully arresting tumor regrowth.
20. The residual mass in the mediastinum (see CT) may be a fibrous tissue scar left behind after the cellular part of a tumor is destroyed leaving behind only a contracted fibrous tissue scar from the connective tissue scaffolding of the previous cancer. Such masses are often seen after local control in bulky Hodgkin’s disease masses.
21. Based on the well established radiobiology of bulky adenocarcinomas, combined radiotherapy and chemotherapy, the treatment Mr. Daniels initially received, rarely create local control of 8 cm masses like the one in Mr. Daniels chest at presentation.
22. Another interpretation of this case, one that we favor for management purposes, is that immunotherapy has induced growth arrest of residual tumor in a greatly shrunken tumor rather than total tumor eradication or cure.
23. We believe the presumption should be that cancer clonagens are incorporated in residual masses, if likely existing at one or more distant sites, and these clonagens will proliferate if immune surveillance is lowered.
24. It has been our experience over the years that patients who decrease or terminate their immunotherapy based on duration of remission often relapse. Relapses after known systemic spread have been universally fatal. These considerations lead us to the conclusion that disciplined immunotherapy carried out by the patient for years under physician supervision is worthwhile for years after initial treatment so long as elevated serologic marker remain normal and no evidence of disease (NED) is the clinical condition of the patient.
25. This patient’s quality of life during immunotherapy has been as good as it was prior to his developing cancer. This high quality survival would not likely have been the case if, at the first sign of dissemination, chemotherapy had been elected by the patient as further treatment.