After the FDA’s decision, Shively put together his records and notes into his book, self-published it, and distributed copies free of charge to medical libraries around the world.² In 2021, according to WorldCat, only six libraries have a copy. And while a previous historical overview of practitioners who have utilized enzymes in the treatment of cancer included interesting information about Shively’s career and struggles with the FDA, the case reports included in Shively’s book were not discussed.² I have one of the few remaining copies of Shively’s book; here, I will review his case reports. His efforts deserve a wider audience, even if his specific approach is not currently possible to replicate in the United States.

In the late 1940s, Shively discovered the work of John Beard, the British embryologist who theorized that pancreatic enzymes might be useful in the treatment of cancer. Beard observed that the early stage of the placenta, the trophoblast, looked and acted much like cancer, and that the trophoblast matured into the placenta around the time the fetus began to make pancreatic enzymes. Beard speculated that pancreatic enzymes influenced this change in the character of the trophoblast, and might also work against cancer. The initial sections of Shively’s book review in ponderous detail the mechanisms that Beard, or Shively, postulated could explain the enzymes’ actions.

Shively administered trypsin, chymotrypsin, ribonuclease, desoxyribonuclease and pepsinogen intravenously, along with oral amylase, providing explanations of his dosing decisions as his therapy evolved. He reported that for intravenous use, he needed enzymes that “had been crystallized, recrystallized two times and lypholized [sic],” then reconstituted in Ringer’s solution.¹ Based on the technology described and available at the time, the products would have contained additional proteins besides what was on the label.³  Later authors have suggested that the precursor form of pancreatic enzymes is effective against cancer, not the activated form.^4-6 The product Shively used could well have contained both active and precursor enzymes.

The history of medicine is rife with elaborate theoretical rationales for ineffective therapies, so to see if there might be substance to the theory, I am more interested in the specifics of the patient outcomes he describes. Shively stated that he treated 193 patients, but I counted only 24 case reports, so by no means all patients that Shively treated are included. And not all of those included were successfully treated; the book reads more like research notes, with details provided so that someone attempting to follow in his footsteps would be able to learn from both successes and failures. At the end of the book, he includes supportive letters from former patients, presumably solicited from them in his efforts to keep the FDA from shutting down his work. Some of those patients had surgical resections before seeing Shively, with a high likelihood of recurrence but no definite active disease. For these patients, Shively’s treatment had been adjuvant in nature and so a case report would not be relevant. This may account for some of the undescribed patients in his total count of 193.

Many of the cases in the book are difficult to assess because of complicated treatment courses that included other modalities such as radiation. Almost always, the follow-up period is quite short, not surprising for a private practitioner in an era when long-distance phone calls could be expensive. Shively included patients’ names, but not their dates of birth, so it is difficult to find information about survival via public records with confidence. And in Shively’s era, diagnostic imaging was limited, so assessment of treatment effect was done by physical examination. In a few cases, Shively reported that ulcerated lesions had resolved and provided photographic evidence, but the images in the book are of such poor quality that I did not feel confident about the cases and so did not include them.

Here, I will provide details about the case histories in Shively’s work that I found to be interesting.

Breast cancer. In 1953, the patient had a mastectomy for breast cancer. In 1955, she developed biopsy-proven metastatic nodules on the chest wall. She underwent a course of enzymes, and the lesions went away, a straightforward clinical response. A year later, the chest wall lesions came back; the patient received radiation, then resumed the enzyme treatment. The lesions responded, but the patient’s condition was described as poor, and she died.

Uterine cancer. The patient had a hysterectomy for uterine cancer in November 1946. In July 1948, a pelvic mass was removed and found to be recurrent cancer. In 1951 another recurrent mass was resected. In October 1953, she developed a discharge from the cervical stump, which was found to contain cancer cells. She then had 16 radiation treatments, which caused a severe deterioration in her clinical status, including a rectovaginal fistula. She started intravenous enzymes November 1953, and immediately the rectovaginal fistula began to heal. The fistula remained closed for the rest of her life, but in August 1955 she had a recurrence accompanied by mesenteric thrombosis, and she died.

Abdominal carcinomatosis. After surgery for breast cancer, one year later, the patient had a recurrence in the scar. She received radiation to the scar and to her ovaries “for sterilization.” In December 1953 an ovarian mass was noted on pelvic exam, and by February 1954 she was found to have abdominal carcinomatosis. In October 1954, she began intravenous enzymes, and underwent three paracenteses. By the end of October 1954, the fluid had resolved, and she completed a series of treatments with the enzymes.

In June 1955, she developed fluid around her lungs and received another round of enzymes. The fluid resolved. She had another series of enzymes in January 1956. She then discontinued the treatment; to quote Shively, “further treatments with our present efficiency were considered unwise”—which I interpret to mean that other practitioners involved in her care did not approve of his methods. She died six months after treatment was stopped.

Liver metastases. Because of severe, prolonged abdominal pain and vomiting, this patient underwent an exploratory laparotomy in December 1953 and was found to have extensive liver metastases, with pathology showing an anaplastic cancer thought to be renal in origin. Two weeks after his operation, he began enzyme treatment with Shively. Over the next few months, his symptoms gradually resolved, and by October 1954 he had regained 35 pounds and returned to work. He did well for many years, but then developed severe edema and died in early 1960. On autopsy, he was found to have carcinoid tumor, with valvular heart disease (which can be caused by hormones secreted by carcinoid tumors). While it is possible that the original diagnosis of anaplastic cancer was incorrect and that he had carcinoid tumor (an indolent cancer) all along, what makes this case interesting to me is the improvement in his performance status. He went from tumor burden causing abdominal pain and vomiting, to several asymptomatic and productive years before his death.

Presumed linitus plastica. After early satiety causing massive weight loss, and an abnormal barium study, this patient underwent exploratory laparotomy in May 1956. The surgeon’s note described “widely infiltrating scirrhous carcinoma with adhesions … regional nodes were widely involved.” Since the disease could not be removed, no biopsy was done. Four months after the operation, the patient came to see Shively, reporting feeling stuffed after two bites of food, and a 140-pound weight loss. She was given two series of enzyme treatments, with some symptomatic improvement and weight gain. She lived another six months after the enzyme treatment was stopped.

Breast cancer. This patient underwent mastectomy in 1948. Ascites and pleural effusions developed in 1952, and she underwent paracentesis, radiation, and radioactive colloidal gold treatment, with a short-term improvement in fluid build-up. In March 1954, after a paracentesis, she was treated with a course of intravenous enzymes. The fluid resolved, her appetite and strength returned, and she gained weight. At the end of 1954, she developed chest nodules and possible rib metastases. She received more enzymes in late 1954 and early 1955, but then went elsewhere for more colloidal gold treatments. She died several months later.

Ovarian cancer. During surgery October 1960 for an acute abdominal emergency, her left ovary and Fallopian tube were removed due to adenocarcinoma. She received two doses of intraperitoneal thio-TEPA; but since she was pregnant, it was stopped and she had a C-section July 1961. At surgery, multiple tumor implants were seen and injected with thio-TEPA, and she received additional thio-TEPA both intraperitoneally and intravenously over the rest of 1961. In February 1962, an enlarging mass in the tumor bed was found on examination. She began enzyme treatment, and subsequently the mass became smaller. After a second series of enzymes, the mass was smaller but still present, and the patient felt symptomatically much improved by June of 1962. She then discontinued enzyme treatment. She did not live nearby, and she wrote to Shively with an update in early 1964. After completing her enzyme treatment, she had a persistent abdominal mass that did not grow, but she eventually developed a deep venous thrombosis and her doctors believed the mass had caused it. She opted for radiation treatment. While no further information about her is in Shively’s book, online I found that a woman of the same name and age died later that year.

Colon cancer. This patient had a colon cancer resected in 1951. In November 1955, a recurrent mass in the rectus sheath below the umbilicus was found, and the patient received enzyme treatment from Shively. In 1964, Shively received an update from the doctor who referred the patient, stating he was alive and well.

In these cases, there are examples of clinical improvement. Masses resolved, fluid collections went away, fistulas healed. I wish the FDA would have let him continue. But his approach did not fit into the orthodox medical viewpoint of his time, and in fact, the American Cancer Society listed him in their panoply of “unproven cancer therapies.”⁷

I think that Shively and his patients believed that there was no need for maintenance therapy. In many of the cases, after an initial success, when the disease recurred, the patient tried something else rather than resuming the enzyme treatment. But in the model shared by myself and my long-time colleague, the late Nicholas Gonzalez, MD, proteolytic pancreatic enzymes are part of the body’s surveillance mechanism for cancerous and precancerous cells, and short-term treatment is not going to correct the underlying deficiency. We looked at cancer as being similar to insulin-dependent diabetes, which requires long-term insulin and lasting dietary changes. In that era, the recent arrival of antibiotics to treat infectious disease may have meant that patients and physicians expected a lasting response from a short course of treatment and felt the treatment had failed if the response was not durable.

Of course, an intravenous treatment would be burdensome and expensive to continue as a maintenance therapy. Around the same time, William Donald Kelley, DDS, began using oral pancreatic enzymes to treat cancer; and Gonzalez and I utilized oral pancreas product as well.^8,9 I can’t help but wonder if a combination of intravenous and oral enzymes would be advantageous. Shively had some success with patients with ascites, which is difficult to treat with oral products since food intake is impaired. Oral pancreas would make a more manageable maintenance therapy.

Since intravenous proteolytic enzymes cannot be used in the United States because of FDA regulations, speculation about the possibilities is all that I can do. I write this in the same hope that Shively did when he self-published his notes and patient histories and distributed his book to medical libraries—perhaps someone, somewhere will see this and be able to follow up on it.

References

1.         Shively FL. Multiple Proteolytic Enzyme Therapy of Cancer. Dayton, OH: John-Watson Printing and Bookbinding Co.; 1969.

2.         Moss RW. Enzymes, trophoblasts, and cancer: the afterlife of an idea (1924-2008). Integr Cancer Ther. 2008;7(4):262-275.

3.         Titani K, et al. A simple and rapid purification of commercial trypsin and chymotrypsin by reverse-phase high-performance liquid chromatography. Anal Biochem. 1982;123(2):408-412.

4.         Novak JF, Trnka F. Proenzyme therapy of cancer. Anticancer Res. 2005;25(2A):1157-1177. Available at: https://ar.iiarjournals.org/content/anticanres/25/2A/1157.full.pdf.

5.         Gonzalez NJ, Isaacs LL. The Trophoblast and the Origins of Cancer: One solution to the medical enigma of our time. New York, NY: New Spring Press; 2009.

6.         González-Titos A, et al. Trypsinogen and chymotrypsinogen: potent anti-tumour agents. Expert Opin Biol Ther. 2021.

7.         Unproven methods of cancer treatment. CA Cancer J Clin. 1967;17(6):301-302. Available at: https://acsjournals.onlinelibrary.wiley.com/doi/epdf/10.3322/canjclin.17.6.301.

8.         Gonzalez NJ. One Man Alone; An Investigation of Nutrition, Cancer, and William Donald Kelley. New York, NY: New Spring Press; 2010.

9.         Gonzalez NJ, Isaacs LL. The Gonzalez therapy and cancer: a collection of case reports. Altern Ther Health Med. 2007;13(1):46-55.