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Options for Investigative Postsurgical Therapy for Gastric Cancer, and Case Report of Using the Option for Combined Immunotherapy and Chemotherapy

Gerhardt, Philipp, Ph.D.

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American Journal of Clinical Oncology: February 2001 - Volume 24 - Issue 1 - p 47-51
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Abstract

Cancer of the stomach occurs relatively infrequently in America. Cases of distal gastric cancer have been decreasing for 6 decades, whereas those of the cardia and gastroesophageal junction have been rising rapidly in the last 2 decades. Because its symptoms are so vague and mild, proximal gastric cancer has often become advanced before it is brought to medical attention and diagnosis. Radical surgery is still the single standard form of treatment for this malignancy, but the 5-year survival rate of those stricken can be only 10% to 15%. 1

CASE REPORT

Diagnosis

The patient (also the author of this article) sought medical care October 11, 1995 because of periodic symptoms during several weeks of stomach discomfort and hiccups after eating that were not relieved by antacid remedies. At the time of presentation, he was nearly 74 years of age, active physically and mentally, and in good health. His primary-care physician at the Michigan State University clinic promptly ordered double-contrast radiographic examination of the esophagus and upper gastrointestinal tract. The films indicated a moderate-sized hiatal hernia and associated ulceration at the gastroesophageal junction, which raised the possibility of neoplastic involvement. An ensuing endoscopy of the esophagus, stomach, pylorus, and duodenal bulb revealed the presence of a friable, inflamed area in the proximal gastric cardia. Microscopic examination of biopsy sections of this area by a pathologist revealed an infiltrating, moderately differentiated adenocarcinoma in the proximal gastric cardia but no specific pathologic changes in the pyloric antrum. Subsequent double-contrast computerized tomography scans of the thorax, abdomen, and pelvis confirmed the presence of an abnormal mass in the distal esophagus and proximal gastric cardia, but did not reveal any evidence of distant metastatic disease. The gastroesophageal adenocarcinoma was believed to be a primary tumor rather than a metastatic recurrence of the patient’s colonic adenocarcinoma that had been resected in 1985 without sequelae.

Surgical Procedure

Accordingly, on November 13, 1995, a team of four university oncologic surgeons using regional medical center hospital facilities successively performed a preliminary laparoscopy to rule out tumor metastases and implants, followed by a radical subtotal gastroesophagectomy. Frozen-section microscopic examination of the resected margins of the stomach and the esophagus were negative for indications of cancer. An end-to-side anastomosis of the esophagus to the stomach was done in the right pleural cavity (Ivor-Lewis procedure). The surgical procedure also included the resection of both vagus nerves, an anterior pyloroplasty, and the placement of a feeding jejunostomy catheter. The demanding surgical procedure was accomplished in 7.5 hours with remarkable effectiveness. No serious problems, at the time or since, have ensued in wound healing, in the gastroesophageal anastomosis, or in the functioning of the feeding jejunostomy catheter.

Surgical Pathology

The tumor area measured 4 cm × 5 cm and its thickness was 2 cm. Microscopic examination of frozen sections of the surgical sections revealed a moderately differentiated, infiltrating, intestinal variant of gastric adenocarcinoma at the gastroesophageal junction. The tumor infiltrated the entire thickness of the stomach wall but did not penetrate the serosal surface, although there were many areas of lymphatic invasion. Six of the nine resected lymph nodes showed metastatic adenocarcinoma. The tumor was classified 1 as stage IIIA, T3, N1, M0. Serologic tests were negative for Helicobacter pylori.

Adjunctive Treatments

The surgery and subsequent recovery were complicated by the patient’s history of valvular heart disease with mild mitral and aortic regurgitation, mild mitral stenosis, and mild congestion. Supportive cardiac and gastric medications were provided during hospitalization and continued since then by appropriate oral administration of furosemide, losartan, metoprolol tartrate, warfarin, and lansoprazole. Moderate obstructive/central sleep apnea was disclosed by polysomnography immediately after the surgery, requiring nightly administration of continuous positive airway pressure during hospitalization and continuing since then.

The patient’s physiologic state was and is monitored at appropriate intervals by electrocardiography and echocardiography; double-contrast computerized tomography scans of the thorax, abdomen, and pelvis; endoscopies of the esophagus, stomach, pylorus, and duodenal bulb; colonoscopies with biopsies of excised polyps; and blood analyses that include carcinoembryonic antigen, prostate-specific antigen, complete blood count, and blood chemistry profiles.

Supplemental nightly feeding of an isotonic liquid nutrient with fiber (Jevity; Ross Laboratories, Columbus, OH, U.S.A.), via the jejunostomy catheter, was begun after the surgery and continues with a present amount of 711 ml (750 kcal) in compensation for limited amounts of orally ingested food, as needed to maintain body weight. The patient’s body weight decreased from 81 kg to 83 kg before surgery to a plateau of 72 kg to 74 kg during recovery and since. During the initial several years, the prolonged reliance on most of his nutritional needs via the jejunostomy catheter, which bypasses the main absorption sites in the duodenum and upper jejunum for iron and certain other essential nutrients, resulted in symptoms and belated diagnosis of iron-deficiency anemia. This disorder has now been corrected after iron stores were replenished by daily oral consumption for 24 months of polysaccharide-complexed iron (150 mg) fortified with vitamin B12 (25 μg) and folic acid (1 mg) (Niferex-150 Forte; Schwarz Pharma, Mequon, WI, U.S.A.), together with vitamin C (500 mg). Possible deficiencies in these and other essential nutrients were monitored by periodic blood counts to detect megaloblastic anemia. Vitamin B12 deficiency can occur after gastric resection 2 and in elderly patients. 3 A multivitamin/mineral chewable dietary supplement (Centrum Kids Conplete; ESI Lederle Generics, Philadelphia, PA, U.S.A.) is now consumed daily as a precautionary measure, together with a light but balanced ordinary diet.

In due course after the surgery, the patient resumed daily calisthenics, regular walking, and mentally stimulating work. He still maintains participation in microbiology research and in writing biomedical articles (such as this one) at his university office.

Exercised Therapy Options

In the absence of codified postsurgical therapy and in reaction to the poor statistical probability for 5-year survival without further treatment, the patient initiated a search for investigative therapies that had undergone substantial clinical trials based on sound scientific rationales. He was advantaged in this effort by career-long experience in biomedical research, familiarity with clinical colleagues in the two medical colleges of the university and in several other American medical schools, access to a network of biomedical scientists around the world, and an inquisitive and assertive personality. He was also aided by a longtime association with a small biopharmaceutical company (Ribi ImmunoChem Research, Inc.) which produced immunostimulants (immunomodulators, immunoadjuvants, immunopotentiators) that were being used in a number of malignant and infectious-disease vaccines under investigation by the Ribi company and licensees.

Option 1

The first exercised option for postsurgical therapy of the patient’s gastric cancer was to be the administration of a vaccine that included an adenocarcinoma-specific synthetic carbohydrate hapten of mucin conjugated to a carrier protein as the antigen and a Ribi immunostimulant as the adjuvant. The vaccine was being tested by a licensee in clinical trials for therapy for human breast cancer. 4 However, the patient’s efforts to obtain an appended individual trial for therapy for his gastric cancer were turned aside.

Option 2

The patient’s next exercised therapy option was to be the use of cisplatin-conjugated monoclonal antibodies that block growth-factor surface receptors produced by the neu (erbB-2 or Her2) oncogene, which are overexpressed in adenocarcinomas. 5 Such immunochemotherapy was being tested by another biotechnology company in breast-cancer therapy clinical trials. Again, the patient’s efforts to obtain an appended individual trial for therapy of his gastric cancer were turned aside.

Option 3

The third and successfully exercised therapy option was the combined use of immunotherapy and chemotherapy, which was based on extensive clinical trials in South Korea, where gastric cancer is the most frequent and deadly malignancy. A 1992 seminal report by Kim et al. 6 had indicated that postsurgical immunotherapy using a Streptococcus pyogenes immunostimulant preparation (OK-432) combined with chemotherapy using 5-fluorouracil and mitomycin C substantially increased the 5-year survival rate of advanced-disease patients who had received both radical surgery and chemotherapy and even more so of patients who had received the surgery alone. The immunotherapy alone had been shown to be only rarely effective.

Accordingly, the postsurgical immunochemotherapy protocol of Kim et al. was adapted for use by this patient. However, the S. pyogenes preparation was replaced by a newer, purified, nonspecific immunostimulant (DetoxPC). It is comprised of a detoxified derivative of the active component of lipopolysaccharide endotoxin from Salmonella minnesota (monophosphoryl lipid A, MPL) 7 and of a residue of cell walls from Mycobacterium phlei. 8

Before starting the combined immunochemotherapy, a single-patient, sponsor-investigator Investigational New Drug application and a request for waiver of the 30-day review period were submitted to and allowed by the U.S. Food and Drug Administration.

DetoxPC was injected subcutaneously at various sites in amounts and at intervals shown in Table 1, depending on the disappearance of mild cutaneous reactions, e.g., granulomas. The immunotherapy was finally discontinued after 10 injections during 105 weeks because of a slow-healing, sterile ulceration at the last injection site.

Table 1
Table 1:
Time intervals of postsurgical treatments

The chemotherapy was essentially that reported by Kim et al. in the second of their clinical trials. 6 5-Fluorouracil and mitomycin C were given intravenously as shown in Table 1 but were discontinued after 22 days because of the usual adverse reactions to the toxicity of 5-fluorouracil.

Sixteen weeks after the patient’s last immunostimulant injection and with negative findings from all physiologic monitoring, his postsurgical therapy was terminated. At the date of writing, he remains in good health, has no signs or symptoms of malignant disease, and enjoys a greatly increased statistical probability of extended survival. 1

Unexercised Therapy Options

Option 4

A fourth but unexercised option considered for postsurgical therapy was based on the ingestion of any of several edible mushrooms that had long been used as a traditional medical treatment for gastric cancer in Asia. From one of these (Lentinan edodes) there had been extracted and purified a soluble β-glucan (Lentinan), which in combination with chemotherapy had been shown in Japanese clinical trials to be usefully therapeutic in patients with gastric cancer. 9

Option 5

Another such option was based on the ingestion of extracts from mistletoe (Viscum album), which had been clinically tested and used extensively throughout Europe as an alternative treatment for various types of solid tumors and which apparently owe their effectiveness to nonspecific immunostimulation and cytotoxicity. One such extract is Iscador, which had been tested as a single drug in postoperative treatment of gastric carcinoma. 10

Option 6

A frequent site of distant metastasis from gastric cancer is the liver. Intrahepatic artery infusion with cisplatin, which is preferentially absorbed in the liver, offered last-resort chemotherapy should such metastasis subsequently have occurred or does occur in the future. 11

DISCUSSION

After successful postsurgical therapy of his regionally metastasized gastric cancer, this patient’s perspective includes wonderment at why the principle of combining immunotherapy with chemotherapy apparently has not been clinically tested for the disease in the United States. 1 Extensive trials of the combination therapies have been conducted not only in South Korea using a streptococcal immunostimulant 6 (option 3), but also in Japan using a purified fungal immunostimulant 10 (option 4). The principle seems similarly applicable to the purified mistletoe immunostimulants tested as a single drug in Europe 9 (option 5). Furthermore, the combination principle seems applicable not only to these nonspecific immunotherapies in which the antigenic stimulus arises from in vivo tumor cells, but also to specific immunotherapies in which the antigenic stimulus arises from cultured tumor cells or their derivatives in a vaccine. Indeed, the principle should also apply to malignancies other than gastric cancer, and might even apply to last-resort chemotherapy treatment of certain distant metastases 11 (option 6).

This patient’s selective confidence in the use of Detox was based on its incorporation in a new vaccine for the therapy for stage IV malignant melanoma, which resulted from the clinical breakthrough research of Mitchell et al. 12 The melanoma “theraccine” (Melacine) was produced by the Ribi company (now Corixa Corporation) after a decade of development. The theraccine was awarded a Notice of Compliance on November 4, 1999 by the Canadian Health Protection Branch for distribution and sale in Canada. 13,14 Melacine acts by generating both cellular and humoral immune responses to melanoma antigens unique to tumors, which include delayed-type hypersensitivity, cytotoxic T lymphocytes, and melanoma-reactive antibody. Melacine is arguably the world’s first therapeutic cancer vaccine approved by a national regulatory agency for commercial distribution!

This patient’s opinion also includes ideas on patients coping with a malignancy when the prognosis for postsurgical 5-year survival is poor. His immediate reflex, as a biomedical academic but recommended also for physician referral to selected patients, was to become informed and conversant about the problem. Five references were found especially useful: (1 and 2), PDQ Treatment Summary for Patients: Gastric Cancer15 and the same-titled one for health professionals, 1 which are available on request from the National Cancer Institute; (3) American Cancer Society Textbook of Clinical Oncology,16 which is available at nominal cost from regional or national offices of the Society; (4) Cancer: Principles and Practiceof Oncology17; and (5) a paperback medical dictionary for nonmedical persons. 18

The second reflex of this patient, as an activist, was to inquire from all available resources about possible postsurgical therapies and then to select and prioritize six that had undergone substantial clinical testing and had a sound scientific rationale. This effort too can be undertaken by some other patients, even those who may not be as advantaged as this one.

His next step, after inability to exercise the first or second therapy options, was to learn the necessity of and the procedure for obtaining single-patient, fast-track Investigational New Drug approval from the U.S. Food and Drug Administration, in cooperation with the attending oncologist and the commercial source of the immunostimulant, and then get on with it as soon as possible.

This patient’s use of the third therapy option (and his prioritization of the six options) reflected his confidence in and knowledge of the immunotherapy for cancer. The successful use of it, in combination with conventional chemotherapy, appears to justify his confidence. Were such combined therapy to be used in the future, however, it would be better administered sooner after surgery, possibly after pretreatment with low-dose cyclophosphamide, which has been shown to enhance immunogenicity in specific and nonspecific cancer therapy. 17

Monitoring of the stimulation of cellular immunity by flow cytometry 19 should be used in the future. However, it should be started before immunotherapy so as to obtain a reference titer, and then should be used before and after each injection of immunostimulant when the marker(s) has been determined to have peaked. This method provides a promising way to quantify the immune response.

Nutritional needs seem often to be overlooked by attending physicians, as happened with this patient. His postoperative iron-deficiency anemia, although predictable because the jejunostomy feeding catheter bypassed the main iron-absorption sites, was left undiagnosed until he pointed out the occurrence during 28 months in five successive laboratory tests of moderately low values for hemoglobin, erythrocytes, and hematocrit volume, any one of which values was not alarming in itself. Similarly, the possibility of vitamin B12 and folate deficiencies, although predictable because of their prevalence after gastric resection 2 and in elderly patients, 3 was also overlooked until the patient undertook appropriate measures.

Another important component of this patient’s postsurgical therapy is thought to be his positive, assertive, believing faith in biomedical science. The consequences of such a “faith factor” have been evidenced in the familiar placebo effect, which can apply to a significant percentage of patients even in vaccine clinical trials where psychogenic influence seemingly should be absent. Affirmation of this factor is contained in popular books by Norman Cousins (Anatomy of an Illness as Perceived by the Patient20), and by Herbert Benson (Timeless Healing. The Power and Biology of Belief21), which are recommended for physicians’ as well as patients’ reading.

Acknowledgment: The author thanks the many individuals who helped him: clinical colleagues at the University, particularly Dr. Rafael de los Santos for oncological surgery, Dr. Nikolay Dimitrov for oncological therapy, Dr. John Jones for primary and heart care, and Dr. James Mayle for gastric therapy; associates at the Ribi company, particularly founder Dr. Edgar Ribi (deceased) for discovery of the immunostimulant and Dr. Kenneth Von Eschen for advising on clinical use of it; correspondents, particularly Dr. Kendall Sauter (deceased) for alerting the author to the South Korean clinical trials of postsurgical immunochemotherapy for gastric cancer, and Dr. Mark Greene for immunotherapy advice; several colleagues for critical copyediting of the manuscript; Ellen Gerhardt Brown for nutritional advice; and devoted caregivers, particularly clinical nurses and especially Vera Gerhardt.

REFERENCES

1. PDQ treatment summary for health professionals. Gastric cancer. Washington, DC:National Cancer Institute, 2000: 1–10. (Telephone 800–4CANCER, or access website http://www.cancernet.nih.gov).
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3. Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr 1999; 19: 357–77.
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16. Murphy GP, Lawrence W, Lenhard RE. American Cancer Society textbook of clinical oncology, 2nd ed. Atlanta: American Cancer Society, 1995.
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Keywords:

Gastric cancer; Cancer, immunochemotherapy; Cancer, investigative postsurgical therapy; Cancer, postsurgical therapy; Proximal gastric cancer

© 2001 Lippincott Williams & Wilkins, Inc.