Lung Cancer: Adenocarcinoma of the Lung with Multiple Brain Metastases

February 25, 2010 by admin  
Filed under Immunotheraphy

Lung Cancer
Adenocarcinoma of the Lung with Multiple Brain Metastases

Metastatic spread to brain is a major problem in patients with cancer of lung origin. Primary tumor resection is contraindicated in patients with carcinoma of the lung who present with concurrent cerebral metastases, as there is virtually no chance for cure in such a setting (1-3). Opinions concerning optimal therapy vary widely.

Literature reports of fully active survivorship of more than two years in non-small cell lung cancer (NSCLC) with unresected brain metastasis have not been found. While some authors have reported patients who were alive, well, and working after resection of both primary and a solitary brain metastasis (4,5), multiple brain metastases at presentation is widely felt to be a contraindication to therapy.

Protracted cancer survival with immunotherapy was interpreted as establishing a “proof of principle” (6,7). The applicability of such methodology to lung cancer is not established by randomized prospective trial.

CASE REPORT

A 47-year-old male with a one week history of right sided weakness, gait instability, and headache was hospitalized after a grand mal seizure caused post ictal right hemiplegia and aphasia. One week before presentation he was treated for deep venous thrombosis.

CT scan demonstrated multiple brain lesions (picture below). Chest CT scan revealed a small peripheral lung mass and multiple cavitary mediastinal nodes none of which exceeded 2 cm in diameter. Nodal biopsy at mediastinoscopy confirmed adenocarcinoma. Initial CEA was 111.2 ng / mL (nl < 3.0).

lung-cancer_brain1

Unusual aspects of this patient’s presentation favoring BRM intervention included small volume primary tumor, small volume regional adenopathy, and asymptomatic locoregional tumor. Aside from the central nervous system, there were no systemic manifestations of metastatic spread. The patient was young and physically active. To assess efficacy of BRM intervention, CEA was a potentially useful clinical marker.

Initial brain radiotherapy with 180 cGy x 25 = 4500 cGy in five weeks was intended to cause bulk reduction in the brain. As post radiotherapy immunotherapy with GH secretagogue methodology was planned, the hypophysis and immediately overlying hypothalamus was excluded from the bilateral treatment fields.

The mediastinum was initially left unirradiated because it was hoped that BRM therapy might restore growth hormone (GH) secretion and result in improved thymus gland function. Initial BRM therapy begun during radiotherapy consisted of equine conjugated estrogen 1.25 mg twice daily, methyl testosterone 10 mg twice daily, ascorbate 1000 mg daily, alpha-tocopherol acetate 400 IU three times daily, cimetidine 400 mg three times daily, and a troche containing coenzyme Q-10 200 mg / ergaloid mesylates 10 mg daily.

During the therapy, neurological signs and symptoms eventually returned to normal. After radiotherapy BRM was continued by the addition of medroxyprogesterone acetate 10 mg twice daily after 14 day cycles of equine conjugated estrogen, bromocriptine1.25 mg twice daily, tetraiodothyronine 100 mcg daily, coumadin 2.5 mg daily, melatonin 50 mg daily, and interleukin-2 (IL-2), 5.5 million units subcutaneously at bed time.

IL-2 was associated with a progressive decline in CEA ending five weeks later in Jan. 1996, when a small rise led to the conclusion that the mediastinal tumor was probably progressing. Irradiation of the primary tumor and node containing mediastinum with a total dose of 180 cGy x 28 = 5040 cGy was carried out. After chest radiotherapy was completed, IL-2 was restarted, and another CEA decline was documented for five months during continued IL-2 therapy. A very gradual rise was noted.

Natural killer cell and CEA response to Immunotherapy

lung-cancer_graph

Treatment caused 13 interval reductions in CEA. The first started after brain radiotherapy. The second began at the time of chest radiotherapy. Over these two intervals, 5,5 million units of IL-2 was injected nightly. A fall in CEA from 111.2 to 5.7 (fig. 1) was observed. Natural killer cells (NKH-1) during this period rose from 14% (nl 3-15%) on Dec. 14, 1994 to 62% on 5/1/95.

After serial CEA determinations showed declines had ceased, the patient had become weak and despondent from the long course of immunotherapy, and he elected to stop the IL-2.

Note the rapid subsequent rise in CEA from 5.9 to 20.7 over just four weeks. Graph segments showing CEA decline usually occurred during eight day cycles of IL-2. It was noted that the end cycle CEA levels (nadirs) were gradually rising, and the magnitude of the CEA drop associated with the IL-2 cycles was decreasing. Development of tumor resistant to IL-2 was feared. Granulocyte-monocyte colony stimulating factor (GM-CSF) injections were added to the IL-2 injections at this time. Cycles of IL-2 / GM-CSF were begun on 7/1/96. Both GM-CSF and IL-2 were injected in the same place and at bedtime. The magnitude of CEA decline associated with the two combination IL-2 / GM-CSF cycles was relatively large compared to the two which proceeded them. A CEA decline from 20.0 to 12.1 was noted during the cycle of IL-2 / GM-CSF.

The patient noted clinically positive one cm nodes in the lower neck, progressive cough and anorexia. Chest CT demonstrated a right hilar mass and growth at the original site of the primary tumor. Nodules noted in the lower half of the neck on both sides were irradiated ending 9/20/96.

Patient continued to take courses of IL-2 therapy, and HGH and DHEA were added to lessen side effects. These agents resulted in a qualitative change in patient tolerance, the patient feeling robust and vigorous throughout the last cycle of treatment. The improved tolerance seemed attributable to the concurrent use of HGH.

Follow up CT scan of the brain 04/02/97 revealed a very much reduced density at the site of the previous large mass, and no evidence of recurrence (picture below). There has never been any evidence of central nervous system recurrence.

lung-cancer_brain2

DISCUSSION

Radiotherapy for brain metastases is widely accepted, but survival is short. Recurrences of NSCLC in the brain, the “sanctuary effect”, have been common in systemically treated lung cancer patients, and, adenocarcinoma of the lung, in particular, seems to exhibit a predisposition for CNS relapse in patients previously treated with chemotherapy (8). We did not choose chemotherapy as initial therapy.

Perceiving CEA elevation as a clinical tool with which to monitor success or failure of immunotherapy, we decided to explore the use of combination BRM. We have had a long interest in BRM therapy of lung adenocarcinoma (9-11).

Proof for BRM efficacy in metastatic cancer arises from use of IL-2 for renal cell carcinoma and melanoma (12-14). Recent evidence suggest low dose subcutaneous IL-2 is efficacious in carcinomas (15-16). This case suggests IL-2 may be combined with other agents resulting in increased efficacy, and with a combination of low dose HGH and IL-2 deserving special attention.

Both the lymphocyte lineage and the monocyte / macrophage lineage arise from the same primitive stem cell. IL-2 is a growth factor exclusively stimulating the entire lymphocyte lineage, including B cells and NK, and lymphokine activated killer (LAK) cells (17). GM-CSF stimulates the macrophages, also capable of contact cytotoxicity. There is cooperation or “crosstalk” between these two systems in cancer recognition and contact cytotoxicity; GM-CSF has been shown to enhance the cytotoxicity of IL-2 stimulated LAK cells in the peripheral blood (18). If both lineages are influenced by age related loss, restoring one lineage without restoring the other could greatly limit overall efficacy.

We studied the effect of IL-2 and GM-CSF administered subcutaneously. We noted that the two agents markedly increased the IL-2 injection site indurations if the two agents were injected at the same site. We hypothesized that monoclonal proliferation of immunocytes taking place in the injection site indurations, which reached 6 – 8 cm across, could give rise to circulating systemically active killer cells.

This IL-2 / GM-CSF combination caused more side effects. The confluent injection site induration was painful, and fever and other flu-like side effects of the treatment were pronounced.

Melatonin as a potentiator of IL-2 efficacy has been reviewed by Rozencwaig (19). Many studies support the concept that antioxidant vitamins have immune stimulating effects (20-23). Dietary intake vitamins C and E may not only play a role in defense against oxidative damage, but may increase the intensity of immune resistance to cancer once cancer is present. Added dietary selenium induces the endogenous production of glutathione peroxidase, a powerful selenoenzyme antioxidant (24-25).

Sinecommitant immunity is recognizable in this case by the ability of the immune system to repeatedly cause decline in CEA, such decline being generally accepted as an accurate indication for tumor response. The cancer condition is a dynamic state, much like warring forces across a battle front. In this case the forces of neoplasia and the forces of defense were relatively equally balanced for many months.

Recombinant proteins, including HGH, GM-CSF, beta interferon, and IL-2, are sufficiently new to the arsenal of the oncologists, and the clinical efficacy of combination treatments is relatively unexplored. In a single protracted case history we observe several combinations which appear to cause not only an objective anticancer effect but a treatment tolerable by quality of life standards. In this case we maintained a regimen of oral BRM’s essentially unchanged throughout treatment, and CEA variations were caused at the margin by recombinant protein injections.

In conclusion, multimodality treatment with radiotherapy and BRM including IL-2 and GM-CSF may was consistent with an excellent quality of life, allowing continued gainful employment for 30 months. This unusual case suggests similar treatment and monitoring methodology may have a wider application.

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