ONCOLOGY
  

Excerpted from a monograph on cancer therapies written to accompany release of the first recombinant human GM-CSF in the early-1990s. The text has been updated and shortened to accommodate this format.

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THE ENEMY WITHIN
Current and Future Strategies
In the War on Cancer

Introduction

      Some cancer cells are far more dangerous than others. Relatively few have the ability to leave the tumor mass, burrow into hematic or lymphatic circulation, travel to distant sites, find their way into and adhere to receptive tissue and proliferate into a metastatic clone. The differences between cancer cells able to successfully complete this arduous journey and those that cannot appear to be the crux of malignant disease. Thus, invading cells are the primary targets of anticancer drugs and the chemotherapy of cancer is, in effect, the prevention of metastases.
___________________Cancer cells on the move__________________

The primary tumor angiogenesis dispersion of metastatic cells arrival into receptive tissue adherence proliferation metastatic clone
___________________________________________________________

      Fortunately, researchers have solved one of the most basic mysteries of cancer biology: what controls malignant transformation? This information enables development of molecular strategies that interfere with tumor expansion at various steps during malignant differentiation.
      It's also known that metastasis to various sites is facilitated by similar receptors on the surface of the invading cells and those in target tissue. Identification of specific receptors on individual cancer cells can predict which organs are most likely to be colonized and target these areas selectively, minimizing bystander cell damage. [The sidebar below showing why bone is such a popular destination for metastasizing cancer cells illustrates how much has been learned in recent years.]

______________ Why bone is a preferred target _________________


      Metastasizing malignant cells have a predilection for bone. Thanks to the invention of gene arrays, proteomics and the availability of appropriate animal models, scientists now know why. Of course there are receptor site similarities, but additionally:
•Blood flow is high around red marrow, seeding more malignant cells into the area;
•Tumor cells secrete adhesive molecules that preferentially bind to marrow stromal cells and bone matrix;
•These adhesive molecules trigger tumor cell production of angiogenic and bone-resorbing factors enhancing tumor growth in bone;
•Bone itself is a large repository of immobilized growth factors (such as transforming growth factor , insulin-like growth factors I and II, fibroblast growth factors, platelet-derived growth factors, bone morphogenetic proteins and calcium):
oThe growth factors activated and released during cancer-cell induced bone resorption provide fertile ground for tumor clone proliferation.

The importance of this information becomes clear considering that:
•Bone becomes involved in up to 70% of patients with advanced breast or prostate cancer;
•Approximately 15 to 30% of people with lung, colon, stomach, bladder, uterus, rectal, thyroid or kidney cancer develop bone metastases;
•An estimated 350,000 people in the U.S. die with metastasized bone cancer each year:
oOnce tumor cells spread to bone a patient's chance of living another 5-year years is exception rather than the rule,
oThe consequences of bone metastases include severe pain, pathologic fractures, life-threatening hypercalcemia and spinal cord compression.
______________________________________________________________

Part 1
Chemotherapy

      Anticancer treatment has come a long way since World War II's secret chemicals weapons program serendipitously provided the first effective chemotherapy. The observation that sailors accidentally exposed to mustard gas sustained marrow and lymphoid hypoplasia led to the use of alkylating agents in patients with Hodgkin's disease and other lymphomas.
Unfortunately, initial excitement over the dramatic regression of advanced disease changed to disappointment when treatment ended and the tumors grew back. But the potential of these agents was established and the search was on for new anticancer drugs and more effective ways of using them.       By the early 1960s H.E. Skipper had devised what is still a guiding principle of cancer chemotherapy: the invariable inverse relationship between the number of cancer cells and curability. This explained why advanced cancers and large tumor mass respond less well to anticancer drugs than small, fast-growing, target-rich tumor burdens. Thus it is critical that an anticancer agent reach its target in efficient amounts for a sufficient length of time to affect a cure. Unfortunately, most anticancer chemotherapies cause considerable collateral damage which is a great impediment to optimal dosing.
      Acquired resistance to antineoplastic drugs also quickly emerged and became another barrier to cure. In 1979 Goldie and Coldman proposed that drug resistance in cancer cells is similar to that in bacteria: spontaneously developed resistance mutants are selected for survival and proliferation by continuous exposure. Expansion of the resistant clones helped explain why some cancers initially respond to treatment but reappear when the resistance clone(s) expand. Factoring in the genetic instability of cancer cells, Goldie and Coldman devised a mathematical model predicting the potential resistance of various tumors.
      However, the Goldie and Colman hypothesis, which presumed that drug resistance in cancer cells is a one-step process, turned out to be a major oversimplification. In fact, when malignant cell lines are exposed to a single agent in increasing amounts they often become resistant to a number of cytotoxic compounds and not all of them are structurally related.
      Nonetheless, clinical experience has shown that anticancer agents are best given in combination. Not only does combining chemotherapies with differing mechanisms of action help slow the emergence of resistance, it provides a wider range of cytotoxicity against a heterogeneous tumor population. Furthermore, combination therapy enables a maximum cancer cell kill within the range of toxicity tolerability for each of the drugs.

The Transformation of Clinical Oncology

      During the 1990s, information from the human genome project combined with advances in molecular biotechnology began to transform clinical oncology with predictive, targeted therapy replacing empirical treatment. For example, a new six-gene DNA microarray that predicts the response of diffuse large-B-cell lymphomas to standard therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) just became available. This PCR-based diagnostic tool is expected to fit easily into clinical practice and help individualize and optimize treatment. Eventually, molecular diagnostic tools -both DNA and RNA- will be created for all human cancers.
      Nuances in the mechanisms of anticancer drug activity are also being revealed. Some of the information is surprising; as for example, recent information about cisplatin, an agent that's been used to treat cancer patients for more than 30 years. This drug is remarkably potent against certain solid tumors but not others. The usual explanation for cisplatin's antitumor activity is formation of platinum-DNA adducts that, if not removed by DNA repair, block cell replication. It's recently been discovered that cisplatin's antitumor action also involves cell-to-cell communication. --the drug produces a death signal that is transferred from the damaged cell to its neighbors through connecting channels called gap junctions. The signal is produced by DNA-dependent protein kinase and may explain why tumors are variably sensitive to cisplatin --information that enables development of strategies to sensitize drug-resistant tumors.
      Thus the future holds considerable hope for patients with cancer. Nonetheless, it is still true that aggressive treatment when tumor burden is at a minimum increases a patient's chances for recovery. But the toxicity associated with anticancer drugs often makes people unwilling to undergo therapy when they consider themselves free of the disease. It is also difficult for physicians not to lower the dose or increase the intervals between treatment cycles in order to reduce suffering. Unfortunately, underdosing is probably the main reason for treatment failure in patients with drug-sensitive tumors receiving their first round of chemotherapy. Indeed, the most toxic effect of treatment may be premature death resulting from insufficient amounts of drug.

Part 2
Hematopoietic Risk

      Immunosuppresion is common in cancer patients and may be caused by the underlying malignancy or, as it is more often, a consequence of chemotherapy.
      But the life span of blood cells is relatively short and large numbers need to be replenished daily. However, because it proliferates so rapidly, bone marrow is the most sensitive normal tissue affected by cytotoxic drugs. Indeed, accommodation of bone marrow recovery led to the familiar 2-week treatment-free intervals between cycles of the most drug combinations (with a new cycle beginning on the 28th day after the first drug dose).
      Bone marrow has a storage compartment capable of warehousing an 8- to 10-day supply of mature blood cells for release into peripheral circulation. As a consequence, immune impairment usually lags at least a week behind damage to the stem cell pool. Leukopenia and thrombocytopenia tend to develop on the ninth or tenth day after initial dosing in patients given cytotoxic drugs for the first time. The lowest, or nadir, blood counts occur by days 14 to 18, recovery apparent by day 21, and the blood cell count back up by day 28.
      If prior treatment with chemotherapy or radiotherapy has already depleted the stem cell pool than the above sequence is altered, with the time to leukopenia and thrombocytopenia shortened and the recovery period prolonged.
      The nadir level of white cells and platelets is the cytotoxic effect of greatest clinical consequence. The highest risk of infection or bleeding occurs when the granulocyte count falls below 500/mg3 and there are fewer than 20,000/mg3 platelets.
      Patients treated with intensive myelosuppressive drugs or radiation therapy are at particular risk of becoming granulocytopenic with basophils, eosinophils, macrophages and neutrophils at risk. All are stimulated into differentiation and growth from multipotent stem cells in bone marrow by colony-stimulating cytokines such as GM-CSF and Interleukin-3.
      The incidence and severity of infection is inversely proportional to absolute granulocyte count. And because the compromised host generally spends considerable time in the hospital or clinic, he or she is prey to an array of opportunistic organisms likely to be resistant to virtually every available antibiotic. Furthermore, the organisms will probably be acquired in a manner particularly conductive to infection (intravenous catheters or respirators, for example). Effective cancer therapy is of little use if patients die from infections before immune recovery.

Part 3
Hematopoietic Rescue

      Breakthroughs in recombinant DNA technology during the early 1990s enabled the ready biosynthesis of hematopoietic growth factors (HGF) in sufficient amounts for clinical use.

___________________FDA approved HGFs___________________

      More than 20 different cytokines are known to effect blood cell development and function. Even though many have been clinically tested, so far only four - granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoeitin (EPO), granulocyte colony-stimulating factor (G-CSF), and interleukin-11 (IL-11) -have been approved by the U.S. Food and Drug Administration.
_________________________________________________________

      One of the earliest HGFs to be used in patients --rHuGM-CSF (molgramostin)-- is a fermentation product of the workhorse bacterium Escherichia coli with a human gene for GM-CSF inserted. rHuGM-CSF stimulates hematopoiesis to reconstitute a patient's neutrophils, eosinophils, macrophages and, sometimes, lymphocytes. This agent remains an important and widely used component of many cancer treatments to this day, resulting in safer and more tolerable therapy for many patients -particularly those undergoing high-dose chemotherapy and bone marrow transplantation.

The Pivotal Clinical Study
Of rHuGM-CSF

      The initial clinical testing of rHuGM-CSF was done in patients with small cell lung cancers (SCLC), an aggressive malignancy that demands an equally aggressive chemotherapeutic response. However, the myelotoxicity of the most active agents limited the dose intensity of treatment, compromising cure. These studies proved rHuGM-CSF significantly effective. When used concomitantly with chemotherapy, patients were able to tolerate their entire projected anticancer dosage far more often that those in the control group.
      Patients were randomly assigned to receive a combination of cyclosphamide, doxorubicin and etoposide either alone or with rHuGM-CSF 10 or 20 mcg/kg/day. The chemotherapeutic cocktail was administered intravenously (IV) for the first three days and rHuGM-CSF added subcutaneously (SC) on the next 10 days of consecutive 21 day cycles.
      One hundred and sixty-two (162) patients were initially enrolled in the trial. Of these, 148 were ultimately evaluable for both efficacy and safety.

Efficacy. The addition of rHuGM-CSF to therapy resulted in a significant and dose-dependent rise in median granulocyte count (P 0.01) and a reduced duration of severe neutropenia in cycles 1 and 2 (see table below).
Chemotherapy Schedule Treatment group Nadir granulocyte levels
(cells/mm3)		 Duration of severe granulocytopenia
(days*)
ANC 500/mm3 ANC 1000/mm3
Cycle 1 Observation

rHuGM-CSF 10 mcg/kg/day
rHuGM-CSF 20 mcg/kg/day 		120 (N=45)

275+ (N=51)
264 (N=47)
6

2
1		 9

5
6
Cycle 2 Observation

rHuGM-CSF 10 mcg/kg/day
rHuGM-CSF 20 mcg/kg/day 		666 (N=44)

933 (N=40)
1539+ (N=32)
0

0
0		 5

0
0
*Number of days that the treatment group median granulocyte count was 500/mm3 or 1000/mm3.
+ P<0.05 versus the nadir levels of the observation group.
N= number of patients

Note: Only cycles 1 and 2 were analyzed for significance because the protocol permitted adjustments of rHuGM-CSF doing on an individual patient basis during the remaining cycles.

      The median white blood count (WBC) was increased in all patients receiving rHuGM-CSF in addition to chemotherapy. Additionally, the WBC was significantly higher than the corresponding observation group values during cycles 1 (P<0.05) and 2 (P<0.01).
      The nadir platelet levels were similar among all patients during the first chemotherapy cycle. And while the number of platelets dropped significantly lower in the rHuGM-CSF group vs observation patients during cycle 2, levels were subsequently restored. Platelet recovery to >1000/mm3 was similar for patients in all three groups by the end of the first 2 cycles. Median hemoglobin levels in rHuGM-CSF patients were also similar to those of the observation group during the first two chemotherapy cycles.
      Importantly, greater numbers of patients treated with rHuGM-CSF were able to tolerate full doses of chemotherapy during all chemotherapy cycles (1-4). And more of the patient treated with 10 mcg/kg/day of rHuGM-CSF began cycles 2 and 3 on schedule.

Safety. rHuGM-CSF was well tolerated at both dosage levels. Apart from fever, myalgia, puritius and injection site reactions, adverse experiences were more probably related to underlying disease than rHuGM-CSF.
      Except for platelet counts, clinically significant changes in maximum World Health Organization (WHO) grades for laboratory values occurred with similar frequency in all patients. In cycles 3 and 6, severe thrombocytopenia (platelet counts <20,000/mm3) was reported in >10% of patients receiving rHuGM-CSF but not in those getting chemotherapy alone. However, although a numerically higher number of platelet transfusions were required for individuals getting rHuGM-CSF, the number did not reach clinical significance.

Summary

      The availability of the first purified recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) more than a decade ago launched a new phase in the war on cancer -one where myelosuppression ceased to be an invariable dose-limiting factor in anticancer treatment Today GM-CSF and other HGFs represent a significant advance in the supportive care available to cancer patients, enabling more aggressive chemotherapy and maximizing the chance for remission in patients with previously invulnerable tumors.


References used include:
  1. Cancer, Principles and Practices of Oncology. 6 ed, Philadelphia, J.B. Lippincott Company 2001. (DeVita VT, Hellman S, Rosenberg SA, eds.)
  2. Jensen R, Glazer PM. Cell-interdependent cisplatin killing by Ku/DNA-dependent protein kinase signaling transduced through gap junctions. Proc Natl Acad Sci U.S.A. 2004 Apr 20; 101(16):6134-9.
  3. Lossos, IS, Czerwinski DK, Alizadeh AA et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 2004; 350:1828-37.
  4. Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350:1655-64.
 @2004

Many thanks to my friend and colleague Barbara Strauss Spitzer for her very valuable review of this manuscript