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Will Harvard Cure Cancer?

By Philip Weiss

Down in Mexico they squeeze peach pits and apricot kernels to get laetrile--active ingredient: amygdallin--and they smuggle it across the U.S. border to patients in the States. A man named Ernest T. Krebs Sr., M.D., first administered the drug in the twenties and Dr. Krebs junior followed his father in 1951, and claimed he could effectively inject the stuff. Trouble is, laetrile breaks down into cyanide, and the Food and Drug Administration has never approved its use. The FDA also says that it can't allow the marketing of quack medicines.

What makes laetrile so in demand is what the Krebs claimed was its "antineoplastic" activity. That means it's supposed to shrink tumor growth, or as they say in medicine, cure cancer. People who are convinced laetrile will arrest their cancers sometimes manage to get around the FDA, and one particularly desperate man in Oklahoma City who won a case last month was granted a six-month supply of laetrile. The FDA is fighting the verdict.

Dr.M. Judah Folkman doesn't like to see his name associated in print with cures for cancer. No matter how obscure the reference, Folkman says, he is "deluged, absolutely deluged" with abject pleas for treatment, and the publicity is not worth the suffering it causes.

Folkman, Andrus Professor of Pediatric Surgery, is involved in cancer research at the Boston Children's Hospital that has been heavily publicized since the Monsanto Corporation invested $23 million for the right to patent any product of Folkman's research over the next 12 years. Harvard University and Monsanto negotiated the contract after Folkman sought to use the St. Louis firm's extensive tissue-culture equipment for work on his study of a large protein that, he hypothesizes, allows cancers to grow: Tumor Angiogenesis Factor (TAF).

Folkman published his findings slightly over one year ago, concluding that TAF is a protein that malignant tissue releases, instructing neighboring tissue to supply the budding tumor with a blood supply. Other pathologic conditions, as well as cancers, depend on the obedience of the victim in setting up an arterial supply to the lesion, or disease focus. What doctors speculate Monsanto is investing in is an agent or antibody that could block the action of the TAF protein. Such a pharmaceutical could be administered systematically upon diagnosis of a primary tumor, and the presence of the anti-TAF might insure that secondary and hidden tumor formations in other parts of the body would never gain the nourishment they need but die before reaching a half-inch in length.

Dr. Bert L. Vallee, Cabot Professor of Biological Chemistry, is included in Folkman's investigations because he is expert at research on molecular biology.

Those involved with cancer research at Harvard, however, note that much more than Folkman's heavily bankrolled investigation of TAF is proceeding well in the Medical area. Increasingly, basic scientists--those not concerned with the clinical aspects of medicine--have responded to the flood of federal funding for study of the disease since the National Cancer Act of 1971. Anatomists, cell biologists, microbiologists, pathologists, biochemists, biophysicists, and immunologists are basic scientists who have come to the field only lately, as it earned respect beyond its clinical aspect as a horrible, and usually incurable, rotting disease.

The artist's conception of the Dana Building that Dr. Emil Frei III has on his office wall closely resembles the actual building, which you can see out the window near the Children's Hospital, between Francis and Binney Streets in Boston. Frei is director of the Sidney Farber Center for the study of cancer, which will take up the new and angular black building that is a grim but gleaming testament to the gravity of the disease it was built for.

The new Dana building is funded largely by the National Cancer Institute, which just last week extended another $5 million to the Farber center for completion of the facilities. It is a Harvard teaching hospital and will have 100 beds for patients. The center is operating now on an outpatient basis, accepting about 25,000 visits a year from cancer patients.

Frei, professor of medicine, says that plans for the new center are proceeding "smashingly," and he gives equally glowing accounts of the progress cancer treatment is making and of the bold new field of "medical oncology." Frei is a lanky man with wisps of reddish hair and a sweeping white coat that somehow properly identifies him as a modern crusader, the image one senses he enjoys.

His own clinical research has been most successful recently with a program for the treatment of bone cancer, osteogenic sarcoma, by chemotherapy, or the administration of chemicals. The field that Frei extols--medical oncology--is the study of tumors, and it is neither clinical nor pure research by his definition. Rather, Frei explains, it is a field only now "coming to fruition," involving scientist from almost all disciplines, and concerned especially with the effects of radiation therapy and chemotherapy on malignancies. In the Farber Center, Frei boasts, "No man can be an island; optimal evaluation and treatment for cancer involves the multiple occupation of a number of clinicians."

While Frei brims with oliched pronouncements on the history of cancer treatment over the last ten years, he also recognizes the intense controversy in the medical community surrounding the glorification of the medical oncologist amid the wash of federal spending. "Progress and controversy," Frei wrote recently, "are handmaidens."

Problems arise, first of all, over the techniques of treatment. Both radiation therapy and chemotherapy are methods for the destruction of malignant growths in a live human being, and both can have extremely toxic side effects on the patients. Frei says that he feels limited by the federal laws that required detailed informed consent of the patients he would treat by these methods, and that it is hard to innovate with new drugs when the Food and Drug Administrations is very conservative about authorizing their administration to human beings.

"All patients tested with new drugs," Frei says, "are patients with incurable cancer and have received all known acceptable treatment." Testing new and unknown drugs on these individuals, he says, may be worthwhile if only for the hope it gives the patient. "Hope," he says, "is an extremely important factor." What's more, Frei explains, failure to innovate in the National Cancer Institute hospitals may only lead desperate patients to seek new and glorious treatments from quacks. Laetrile, Frei points out, only becomes more attractive in the absence of innovative drug programs.

The FDA requires extensive tests of a drug on animals before it will approve the chemical for human administration. Even that approval, however, is for very limited use until investigations prove the drug's effectiveness. Wayne Pines, a spokesman for the federal agency, says the FDA has approved 25 drugs for commerical distribution in the treatment of cancer, and has granted licenses for the experimental investigation of another 175 chemicals.

Frei says that academic boards of authorities should be allowed to decide what chemicals can be administered to terminal cancer cases. As he said on the telephone to a colleague two weeks ago, "Many (cancer) centers have much more sophisticated people sitting around a table than the FDA has." Frei's image of a self-contained cancer center where researchers determine the limits on experimentation suggests the type of facility where heady and expert investigators can experiment on human beings with impunity, but he emphasizes the ethical obligation to serve the patient first, above any commitment to research. But Frei adds, "For patients with disseminated cancer where there is no cure, therapeutic treatment is treatment.... The important dividend to appreciate is that even if that drug does not work, in a patient, the door of hope has been held open."

The cancer research boom of the last decade may, as Frei and others come close to admitting, reflect only the concern of legislators for a visible disease, second only to heart disease in its annual toll. Dr. Kurt J. Isselbacher, Mallinckrodt Professor of Medicine at Mass General Hospital, has an official interest in the academic acceptance of the field. He is chairman of Harvard's cancer committee and says, as does Frei, that the basic biology of the cancer tumor, and the subtle distinctions that make its cells malignant, are valid concerns for the basic scientist/pure academic.

Five years ago, the Medical School gave academic approbation to the once-clinical field of radiation therapy by creating a department of that name. Isselbacher and his committee are now considering whether to create another such department in medical oncology.

Dr. Samuel Hellman, Fuller American Cancer Society Professor of Radiation Therapy and chairman of the radiation therapy department, explains that the field is oriented more towards research than towards purely clinical considerations of dosages. "There's a tremendous amount of work being done on basic biology of tumor cells to make treatment more specific," he says. Radiation's effects on the DNA, or chemical genetic messenger system, of both malignant and normal cells, for instance, is an important area of basic cancer research, Hellman adds.

Hellman acknowledges the problems of performing clinical research on living cancer victims, noting that "perfectly ethical" experimentation is "difficult but possible." It depends, he says, on frank discussion with the patient of the malady and possible cures.

Both Hellman and Frei emphasize the modern and increasingly effective nature of "modality" treatment, involving several clinicians and even basic scientists in experimental cures. However, as Frei said in his phone conversation with a colleague, basic scientists are new to such clinical experimentation. He said that the same experimentation that a hospital's human studies committee approves may face opposition from basic scientists. "The trouble comes from the basic scientists," he said, "from the people who have never been involved in the treatment of anything more risky that poison ivy."

Isselbacher indicates that such "jurisdictional disputes" between clinicians, oncologists and basic scientists are inveitable, especially because the medical oncologist, like Frei, must have a special temperament just to work in a field where such a large percentage of one's patients die. "The dedication and commitment of treating cancer patients is not easy," Isselbacher explains. "I can appreciate that someone who does not live with cancer patients all the time might prove frustrating to Dr. Frei."

Figures compiled by Isselbacher's committee two years ago indicate that about one-quarter of the Med School's senior faculty was engaged in cancer study, although the percentage was lower for lower ranks in the medical faculty. Isselbacher acknowledges that the extent of federal funding has made cancer research glamorous, and that of reasonable concern is just what will happen to cancer-related, academic departments when the disease is cured or out of fashion.

Hellman says that the concern of basic scientists with the disease will persist because of the distinct nature of the cancer cell. Efforts to distinguish the malignant cell by what was presumed would be its faster rate of replication or by identification of foreign proteins on the cell have proved difficult, he says. Such studies involve virologists (studying viruses), pathologists, and molecular biologists. Other research in the last ten years has suggested that a cancer could be linked to a failure of the body's immune system; when asked about vogues in research, Hellman says, "My prejudice is, we're being over-immuned."

Tell that to Dr. Baruj Benacerraf, Fabyan Professor of Comparative Pathology, and he will shrug expansively. Benacerraf had been studying immunology, he says, "years before cancer became fashionable," and when the two fields overlapped, he had investigated the connection. Benacerraf's experiments with transplanting mouse tumors had indicated that tumor cells prompt immune defenses by the mouse. He says that some evidence suggests that the tumor might confuse the immune system's sense of what is self; that immune mechanisms begin to treat the malignant cells as "self" and then actually encourage growth of the tumor.

Other molecular biological research on tumor cells is aimed at identifying proteins on the surface of the cell, like Folkman's Angiogenesis Factor, which are foreign to the victim. Genetically, too, "the cancer cell is of a given differentiated type that loses control of its own growth," Benacerraf says. He is on the fourth floor of Building D at the stolid gray Med School quadrangle, and when he alludes to other investigations of cancer, it is usually by reference to the floor or building on the quadrange where the research is being conducted. His only apparent bias seems to be against the clinicians, whose "gross" methods of extinguishing cancer do not deal with the cause of the problems, but assume the pathologic presence of tumors in actual patients.

Kurt Isselbacher does not like the question, Will cancer be cured at Harvard? Cancer is many diseases and many scientists here are working on them. Certain methods that have been experimented with at Harvard, including Frei's protocol for osteogenic sarcom and Hellman's treatment for hematologic cancer, have been effective but apparently not conclusive.

Dr. David S. Rosenthal, assistant professor of medicine at the Peter Bent Brigham Hospital and a hematologist, says it is significant that three of Harvard's teaching hospitals--the Brigham, Beth-Israel, and the new Dana Center--have adopted the same protocol for treatment of Hodgkin's disease, a cancer of the lymph tissue. But this does not mean a definitive cure, Rosenthal says; only a high probability of cure at certain stages in the cancer.

Coordination of the multitude of Harvard clinicians at the Dana Center will be difficult, Isselbacher says, especially as there may be some disputes over who "gets" certain patients for study. Obsession with a cure, however, Isselbacher indicates, is delusory, as no doctor's individual research is likely to produce the answer. Such obsession, Isselbacher says, is not the proper attitude with which to view an academic field that is so broad-based. Besides, Isselbacher says, "The natural history of the disease is such that, it isn't like pneumonia, that in just two weeks you can find out whether Drug A is better than Drug B." Even the simplest clinical experiments may require a five-year waiting period.

Obsessions with cure, however, only encourage the creation of quack cures, Isselbacher says, and bootlegged nostrums from Mexico

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