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A Unifying Vision of Cancer Therapy for the 21st Century

From the University of Arizona, College of Medicine,Arizona Cancer Center, Tucson, AZ.

Address reprint requests to David S. Alberts, MD, Arizona Cancer Center, 1515 N Campbell Ave, PO Box 245024, Tucson, AZ 85724-5024; email dalberts{at}azcc.arizona.edu

THE ONCOLOGIST OF the 21st century will be interested in the therapy of all stages of cancer, starting with the first initiated cell and continuing with mild, moderate, and severe dysplasia, not just therapy for invasive and metastatic cancer. It is time for us to understand that we are missing an opportunity to have a significant impact at all stages of cancer progression.

The dictionary's definition of therapy is "specific treatment, cure, something serving to cure or soothe." This definition certainly applies to the cancer problem, and whether we are targeting the mildly dysplastic cell, severe dysplasia, invasive cancer, or metastatic cancer, there are opportunities for intervention all along the carcinogenesis pathway. We seem to be focused only on the terminal portion of the pathway, wherein treatment consists of chemotherapy and radiation therapy with limited emphasis on chemopreventive interventions and lifestyle changes. However, we need to consider the possibility of earlier interventions in patients who have preneoplastic conditions and/or who are genetically predisposed to cancer development. There are tremendous opportunities to implement chemoprevention, dietary intervention, and lifestyle changes that could profoundly reduce the risk of cancer in these patients (Fig 1). Whether we are talking about the treatment of cancer or precancerous conditions, the likelihood of success would be increased by a cohesive interdisciplinary approach that uses the expertise of epidemiologists, biostatisticians, and behavioral scientists.

View larger version (26K): [in this window] [in a new window]   Fig 1. A unifying vision of cancer therapy.

The oncologist of the 21st century should be a constant caregiver and an enthusiastic educator who dares to discover. The desire for new discovery is the most important element for the oncologist. This is what gets our "juices" flowing and what gets us up in the morning and ready to go to work. We need to continuously focus on discovery because there are 560,000 cancer deaths each year in this country.¹ We cannot afford anything but constant discovery and improvement in what we do. We cannot become complacent.

The thirst for scientific discovery is what brought me to oncology. During my years in house staff training in the 1960s, I was absolutely fascinated that an anticancer drug could be injected intravenously and then find its way to the tumor bed while largely sparing normal tissue cells. And so, early on, I became interested in drug metabolism, drug targeting, drug disposition, and pharmacokinetics. At my first big presentation at the 1969 meeting of the American Association for Cancer Research, I had the opportunity to discuss initial human pharmacology studies of daunorubicin. Daunorubicin is still a major drug in the treatment of acute myelogenous leukemia. In fact, Dr Alan List, at the Arizona Cancer Center, recently reported that the addition of cyclosporin to a daunorubicin/cytarabine regimen is associated with an approximate doubling of survival time in older-age patients with acute myelogenous leukemia.² Thus, scientific discovery and clinical development must be dynamic processes.

TREATMENT FOR OVARIAN CANCER

The advances in the treatment of ovarian cancer and the prevention of colon cancer are examples of what an oncologist can do (at least in an academic setting) to improve the health of our patients. Ovarian cancer is the leading cause of death from gynecologic cancer in the United States. It is estimated that there will be 25,200 new diagnoses and 14,500 deaths from this cancer in 1999.¹ The vast majority of these cases present at an advanced stage. Ovarian cancer is now a curable disease, even in the advanced stage. We expect that in the first part of the 21st century, the median survival for patients with advanced disease will be well in excess of 5 years.

In the 1960s, the average survival time for ovarian cancer was less than 12 months. Melphalan was the drug of choice. I became interested in melphalan during the 1960s because I noticed that in the treatment of both multiple myeloma and ovarian cancer, there were patients who could receive doses of up to 2 mg/kg with no myelosuppression. We developed a high-power liquid chromatography assay at the National Cancer Institute and then at the University of California at San Francisco to measure melphalan levels in plasma after oral dosing versus intravenous dosing. This was one of the first high-power liquid chromatography assays to be used in cancer chemotherapy. We showed that after oral administration, some patients did not absorb the drug, absorption was enhanced after ingestion of a meal, and low stomach acidity hampered absorption. In fact, on average, only about 50% of this drug is absorbed after an oral dose.³ Poor oral absorption explained why some patients with multiple myeloma and ovarian cancer had no response to melphalan and did not experience bone marrow suppression.

During the 1970s, I became very interested in cooperative group activities and I have chaired the Southwest Oncology Group (SWOG) Gynecologic Cancer Committee since 1997. Our first phase III ovarian cancer study compared a combination of doxorubicin and cyclophosphamide with the same combination plus cisplatin with or without Bacille bilié de Calmette-Guérin in suboptimal stage III or IV disease. We determined that the addition of cisplatin resulted in a 10-month improvement in survival, which represented a doubling of the survival duration.⁴ Platinum is still the most important agent in the treatment of ovarian cancer.

In the 1980s, we struggled to develop new agents during the Reagan/Bush era, when cancer research was underfunded. During a sabbatical leave, I worked with Dr Hilary Calvert at the Institute of Cancer Research and the Royal Marsden Hospital, who was studying an interesting new agent, carboplatin. When I returned to the United States, I performed the first combination phase I study of carboplatin with cyclophosphamide.⁵ Shortly thereafter, SWOG initiated a phase III study of carboplatin versus cisplatin in combination with cyclophosphamide in patients with stage III and IV suboptimal disease.⁶ The results of this study were presented at the Plenary Session of the 1989 ASCO Annual Meeting. During the presentation, a member of the audience commented that all we had done was to replace Coca-Cola with Pepsi Cola. I have a different opinion. I think carboplatin is much better tolerated, and its development has been very beneficial to ovarian cancer patients. Indeed, the clinical complete response rates, pathologic complete response rates, and survival were similar in the two arms of the study, but there was significantly less toxicity associated with the use of carboplatin (Table 1).⁶ Interestingly, a pharmacoeconomic analysis showed that carboplatin was actually less expensive because there were fewer hospitalizations and less long-term toxicity.⁷

In the 1990s, several of us, including Dr Steven Howell and Dr Maurie Markman, have devoted our lives to developing intraperitoneal therapy for ovarian cancer. Howell has shown that after intraperitoneal (IP) administration of cisplatin at 90 mg/m², there is excellent distribution within the IP space and a high area under the interperitoneal disappearance curve (AUC) of approximately 75 µg·h/ml cisplatin is achieved (Fig 2).⁸ On the basis of these findings, in 1986, SWOG and the Gynecologic Oncology Group (GOG) initiated a study to compare intravenous (IV) administration of cisplatin with cisplatin administered intraperitoneally in combination with cyclophosphamide for six courses in patients with stage III optimal disease. I presented the study results at the 1995 ASCO Plenary Session. The median survival on the IV arm was 41 months, compared with 49 months on the IP arm, and the IP to IV death hazard ratio was .76 (ie, there was a 24% reduction in mortality related to simply changing the route of therapy) (Table 2). Interestingly, there was far less neurotoxicity, peripheral neuropathy, ototoxicity, and myelosuppression associated with IP therapy.⁹ Thus, IP drug delivery was tremendously superior. Obviously, this is a controversial study, but there is no question that at the end of the trial more women were alive and in better condition on the IP treatment arm.

View larger version (27K): [in this window] [in a new window]   Fig 2. Intravenous versus intraperitoneal administration of cisplatin (data from Howell et al8).

This study was followed by GOG-114/SWOG-9227, which was an intergroup trial designed by Dr Steven Williams, Markman, and me. We compared the standard McGuire regimen of IV cisplatin plus IV paclitaxel¹⁰ with a regimen of two cycles of high-dose IV carboplatin followed by IP cisplatin plus IV paclitaxel. Markman presented the study results at the 1998 ASCO Annual Meeting in Los Angeles, CA. Median survival on the IV arm was 47.6 months, compared with 52.9 months on the IP arm. The reduction in risk of death was 22% (Table 2).¹¹ Thus, this was the second large trial (523 patients) to show evidence of improved survival. Dr Mace Rothenberg, who served as the discussant after the presentation of GOG-114/SWOG-9227, asked, "Would we be excited by the development of an IV drug which increases disease-free and overall survival by 20% to 25% and at the same time reduces oto-, neuro-, and myelotoxicity?" Obviously, the answer is yes.

In the year 2000, we will have the next derivation of intraperitoneal therapy. SWOG has conducted SWOG-9619, a phase II study of IV paclitaxel on day 1, IP cisplatin on day 2, and IP paclitaxel on day 8 in stage III, optimal-disease ovarian cancer (Fig 3). This study completed accrual in 1998. Analysis of the data will begin in July 2000. It was a safe, relatively well-tolerated combination, and it has become the experimental arm on a large GOG study (GOG-172). I am certain that this arm will be associated with a major survival advantage.

View larger version (23K): [in this window] [in a new window]   Fig 3. Schema for SWOG-9619 and SWOG-9912. The schema for SWOG-9912 is identical to that for SWOG-9619 except for the addition of intravenous liposomal encapsulated doxorubicin (Doxil) on day 8.

In the very near future, hopefully before the year 2000, the SWOG will activate SWOG-9912. This trial adds IV liposomal encapsulated doxorubicin (Doxil; Alza Pharmaceuticals, Mountain View, CA) on day 8 to the SWOG-9619 regimen (IV paclitaxel on day 1, IP cisplatin on day 2, and IP paclitaxel on day 8) (Fig 3). It is our first attempt to add a third drug to a previously studied regimen.

Because ovarian cancer is a highly chemosensitive tumor, new agents are often tested against this disease. Currently, a dozen different drugs are approved for the treatment of ovarian cancer. The most recently approved are topotecan and amifostine. We need to find ways to introduce new drugs into first-line treatment for ovarian cancer, including drugs such as gemcitabine, vinorelbine, and liposomal doxorubicin. In fact, at this meeting, a group of us from the SWOG, the GOG, the European Organization for Research and Treatment of Cancer, and the National Cancer Institute of Canada met and designed the next worldwide study. The proposed five-arm study will examine the most promising new agents and will compare four cycles of gemcitabine/carboplatin followed by four cycles of paclitaxel/carboplatin versus four cycles of liposomal doxorubicin/carboplatin followed by four cycles of paclitaxel/carboplatin versus four cycles of topotecan/carboplatin followed by four cycles of paclitaxel/carboplatin versus eight cycles of gemcitabine/paclitaxel/carboplatin versus eight cycles of paclitaxel/carboplatin (control arm). The accrual goal for this study will be approximately 3,000 patients.

I want to briefly comment on one other drug, amifostine. I passionately believe that we must be concerned about the supportive care of our patients and do everything we can to prevent the debilitating side effects of chemotherapy, including neurotoxicity, ototoxicity, and cumulative myelosuppression. Amifostine is an extremely exciting chemomodulating agent. It is a prodrug that produces an active metabolite, WR-1065, and then WR-33278.¹² WR-1065 is identical in structure to spermine polyamines and is trophic for deep progenitor cells in the bone marrow.¹³ Additionally, it may have activity as a nerve growth factor.¹⁴

PREVENTION OF COLON CANCER

My experience running a colon cancer clinic starting in the early 1970s at the University of California at San Francisco and throughout the ‘70s, ‘80s, and ‘90s at the University of Arizona has given me the conviction that the most effective means of treating colon cancer is to prevent it. Starting in the 1980s, potential dietary risk factors related to colon cancer causation began to be studied in earnest. In 1994, Edward Giovannucci reported that a diet with a high intake of beef, pork, and lamb was associated with a greater than three-fold increase in risk of colon cancer in the Harvard Health Professionals Follow-Up Study.¹⁵ Other epidemiologic studies have shown that diets low in dietary fiber and calcium are also associated with an increased risk of colorectal cancer.^16,17

One means of preventing colon cancer is early detection and removal of colonic adenomatous polyps. These precancerous lesions occur in about 10% of people over the age of 40 and up to 50% of people over the age of 70.¹⁸ Approximately 50% of adenoma patients will experience recurrence within 1 or more years after initial polypectomy.^19,20 The current management includes polypectomy and follow-up colonoscopy. There is a phenomenal opportunity to significantly reduce deaths from colon cancer simply by following the current American Cancer Society guidelines for screening. If we consistently performed fecal occult blood testing at age 50, sigmoidoscopy every 3 to 4 years starting at age 50, and colonoscopy for high-risk subjects, we would see a 50% reduction in colon cancer mortality within a decade.²¹

The National Polyp Study by Winawer et al,²² published in the New England Journal of Medicine in 1993, clearly showed that periodic colonoscopy with polypectomy reduced the incidence of colorectal cancer. The rate of colon cancer incidence in the National Polyp Study was 0.6 per 1,000, compared with rates of 5.2 and 5.8 per 1,000 in the St Marks and Mayo Clinical observational studies, wherein polyps were not removed.^23,24 According to Surveillance, Epidemiology, and End-Results data, the incidence rate for colorectal cancer in the general population is 2.5 per 1,000.²⁵ Thus, after adjusting for age and sex distribution in the National Polyp Study, routine surveillance and polyp removal resulted in a 76% to 90% reduction in colorectal cancer incidence.

During the 1990s, we began to understand the molecular events that are associated with the progression of colon cancer. Six to seven genetic mutations must occur over a lifetime to convert a normal epithelium to an invasive colon cancer.^26,27 There are multiple opportunities to intervene before the development of invasive or metastatic cancer during the progression from an abnormal epithelium to small, intermediate, and large adenomas (Fig 4).

View larger version (20K): [in this window] [in a new window]   Fig 4. Continuum of colon cancer "treatment." Asterisk indicates healthy diet (eg, less red meat), increase physical exercise, discontinue tobacco, and decrease alcohol intake.

There are a number of phase III clinical studies looking at chemoprevention of dietary interventions for the prevention of colorectal cancer (Table 3). In 1994, Greenberg et al,²⁸ at Dartmouth College, published the results of a multicenter study of vitamin C plus vitamin E, plus beta-carotene, using a factorial design. Unfortunately, there was no effect. Clark et al,²⁹ at the University of Arizona, performed a multicenter study of selenium in patients with nonmelanoma skin cancer. The study was designed to evaluate prostate, colon, and lung cancer incidence as secondary end points. There was a 60% reduction in colorectal cancer incidence in subjects who were randomized to receive selenium 200 µg/d in the form of brewer’s yeast. This positive result obviously bears further follow-up in a polyp population. John Baron's group from Dartmouth evaluated an intervention with calcium carbonate versus placebo in slightly more than 900 subjects with a previous history of colonic polyps.³⁰ Results showed that there was a 19% reduction in polyp recurrence at 3 years in the treatment group.

There are other ongoing, phase III studies that should be analyzed in the near future. Baron et al are conducting a study of high- versus low-dose aspirin with or without folic acid in 1,100 subjects. Accrual has been completed and the study will undergo end point analysis in 2 to 3 years. Giovannucci, at the Harvard School of Public Health, is conducting an ongoing study of folic acid versus placebo in 1,000 male health professionals. The results from the National Cancer Institute's National Polyp Study of a low-fat, high-fruit and -vegetable diet versus a regular diet in 2,079 subjects with resected polyps should be available soon. The primary end point of this study was the polyp recurrence rate.

We continue to conduct multiple colon cancer prevention studies at the University of Arizona. Our first studies used a wheat bran fiber intervention. In the 4th century B.C., Hypocrites stated that, "To the human body it makes a great difference whether the bread be made of fine flour or coarse, whether the wheat with bran or the wheat without bran." Later, Dennis Burkitt suggested that wheat bran fiber could prevent hemorrhoids, phlebitis, diverticulitis, coronary artery disease, and colon cancer. In the mid-1980s, we performed our first phase I dose-finding trial of wheat bran fiber in Green Valley, AZ, a retirement community just south of Tucson. We found that about two thirds of a cup of wheat bran fiber was a very tolerable intervention for a period of up to 1 year.³¹ Next, we conducted phase II studies in Sun City and Phoenix, AZ, and then a large phase III trial was launched in 1991 in patients with resected polyps in the Phoenix metropolitan area.^32,33

In one of our phase II trials, patients with resected colorectal adenomas underwent a 3-month run-in period on low-dose fiber and low-dose calcium. They were then randomized using a factorial design to low-dose cereal fiber (2 g/d) versus high-dose cereal fiber (13.5 g/d) and low-dose calcium carbonate (250 mg/d) versus high-dose calcium carbonate (1,500 mg/d) for 9 months (Fig 5). A secondary study end point was deoxycholic acid levels in the stool. Deoxycholic acid, a secondary bile acid, is a potent cancer promoter that causes damage to cellular DNA, promotes mutagenesis in in vitro assays, and causes dysplasia in tissue culture. Fecal concentrations of deoxycholic acid are positively correlated with colon cancer risk and are increased by dietary fat and decreased by cereal fiber and calcium.³⁴ In our study, there was a 48% reduction in deoxycholic acid in the solid phase of stool from patients who were on the study arm with high fiber and high calcium supplement intake for 9 months.³²

View larger version (29K): [in this window] [in a new window]   Fig 5. Phase II randomized, double-blind study of wheat bran fiber versus calcium versus combination in participants with resected colorectal adenomas.

This positive clinical result encouraged us to initiate our first phase III trial. Study subjects with a recent history of colorectal adenoma resection underwent a placebo run-in, and then were randomized to a low dose of fiber (2 g/d) versus a high dose of fiber (13.5 mg/d) for a period of up to 5 years, with end point colonoscopy being the primary end point (Fig 6). Secondary end points included an analysis of associations between polyp recurrence and blood bile acid levels at final colonoscopy with diet, exercise, and the intervention. Tertiary end points included possible associations between polyp recurrence and proliferating cell nuclear antigen–labeling index, history of previous polyps, dietary factors, and characteristics of the baseline adenoma. Final analysis of this study is underway, and results will be presented at next year's meeting of the American Society of Clinical Oncology.

View larger version (23K): [in this window] [in a new window]   Fig 6. Schema for phase III prevention study of wheat bran fiber.

We also have an ongoing studies of ursodeoxycholic acid at the University of Arizona. Ursodeoxycholic acid is a bile acid that is normally present in trace amounts in humans and is commercially available under the trade name of Actigall (ursodiol; Novartis Pharmaceuticals Corp, East Hanover, NJ) for the dissolution of cholesterol gall stones. It is a conversion product from chenodeoxycholic acid and prevents the bacterial metabolism of cholic acid to deoxycholic acid.³⁵ In a preclinical trial in an azoxymethane rat model, we showed that ursodeoxycholic acid completely inhibited cancer formation in the colon, piroxicam was partially preventive, and cholic acid increased colon cancer formation (Fig 7).³⁶ There was also a nine-fold reduction in the concentration of deoxycholic acid in the stool associated with the ursodeoxycholic acid treatment.³⁷ We conducted a phase I clinical trial and observed similar reductions in fecal water concentrations of deoxycholic acid. We are currently conducting a phase III study of ursodeoxycholic acid in subjects with a history of resected colonic adenomas, and we have accrued 1,100 of the 1,200 patients required for this study. The 3-year end point colonoscopies will be completed in the year 2002 or 2003.

View larger version (16K): [in this window] [in a new window]   Fig 7. Azoxymethane-induced malignant tumors (data from Earnest et al36).

The most exciting leads for future chemoprevention strategies, specifically targeted to prevent colorectal adenoma recurrence, include a general class of compounds described as nonsteroidal anti-inflammatory drugs (NSAIDs) and related drugs (Table 4). The results of epidemiologic studies, in vitro and in vivo preclinical models, and large prospective cohort studies have identified the NSAIDs as potential colon cancer prevention agents.^38,39 Furthermore, studies of sulindac, a relatively standard cyclo-oxygenase (COX)-1 and COX-2 inhibitor, have documented the ability of this NSAID to dissolve adenomatous colorectal polyps and inhibit the growth of new polyps in the colon and the rectum.^40-42

Of course, the biggest problem with sulindac and other standard NSAIDs that inhibit both COX-1 and COX-2 is patient intolerance related to upper gastrointestinal toxicity.⁴³ With this in mind, agents, such as celecoxib, that only inhibit COX-2 have been developed as chemopreventive agents. In a recent review at the American Association for Cancer Research Annual Meeting in May 1999, Dr Bandu Reddy stated that celecoxib is the most active single agent ever tested in the azoxymethane rat model of colon carcinogenesis, with a 95% inhibition of tumor formation.⁴⁴ Since celecoxib is a relatively pure inhibitor of COX-2, it causes very little upper gastrointestinal symptomatology.⁴⁵ Presently, it is being entered into phase III clinical trials in participants who carry the hereditary nonpolyposis colorectal cancer gene and in patients with a history of familial adenomatous polyposis.

Even more recently, a new class of compounds, represented by sulindac sulfone, a metabolite of sulindac, has proven active in in vitro and in vivo preclinical models of colorectal cancer.^46,47 Sulindac sulfone does not inhibit COX-1 or COX-2 enzymes and thus does not seem to affect the arachidonic acid pathway.⁴⁸ Because it does not inhibit COX-1, it has not been shown to cause any upper gastrointestinal symptomatology in phase I/II trials and seems to dissolve adenomatous polyps in patients with sporadic disease. Presently, it has been entered into phase III clinical trials to prove its effectiveness in inhibiting new adenomatous polyp growth.⁴⁹

All of us need to be serious about cancer prevention in the 21st century. As oncologists, we seem to be focused on chemotherapy and, hopefully, lifestyle changes for our patients, but we are at the end stage of the disease process. Instead, we need to aggressively pursue the treatment of patients with preneoplasia. There is an economic advantage for treating this much larger patient population. In the first part of the 21st century, we should focus on chemoprevention and lifestyle changes. If our patients improved their diet, ceased tobacco use, reduced alcohol intake, increased physical exercise, and underwent routine surveillance for colorectal cancer, we could observe a 70% reduction in mortality within 20 years.

Surgical, radiation, and medical oncologists can perform cancer prevention interventions in his or her practice on a daily basis (Table 5). The surgical oncologist has an opportunity to intervene with chemopreventive agents and dietary change in patients with dysplasias of the breast, bladder, colon, esophagus, head and neck, and prostate. The radiation oncologist can use cytoprotective and chemopreventive agents, in terms of the prevention of second primary cancers of the breast, cervix, head and neck, and lung. The medical oncologist has an opportunity to intervene with chemopreventive agents, dietary change, and lifestyle changes in terms of dysplasias of the bladder, breast, colon, esophagus, stomach, and prostate.

If cancer is to be conquered, we must develop parallel basic science and clinical research strategies for cancer prevention and cancer treatment. Clinical oncologists must receive training in both cancer prevention and cancer treatment. This is an essential part of medical training, and it is missing from most programs. Academic oncologists must view cancer treatment as a continuum from precancer to cancer. We need to find new structures in cancer centers to link basic scientists with epidemiologists, behaviorists, and oncologists in both prevention and treatment programs so we can really affect change and help our patients.

ACKNOWLEDGMENTS

The author thanks Dr Charles Coltman for the opportunity to serve as the Chair of the Gynecologic Cancer Committee in the Southwest Oncology Group since 1977. He also thanks Dr Ki Hong for nominating him to address the 1999 ASCO Annual Meeting and for their collegial relationship and collaboration in developing cancer prevention research in the United States during the past 25 years.

NOTES

Presented at the Thirty-Fifth Annual Meeting of the American Society ofClinical Oncology, May 15-18, 1999, Atlanta, GA.

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