UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

Novel applications of growth factors in solid tumors

Westermann, A.

Link to publication

Citation for published version (APA):Westermann, A. (1999). Novel applications of growth factors in solid tumors.

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).

Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.

Download date: 26 Aug 2019

n

• o

Background and outline of the thesis [summary]

Background and outline of the thesis [summary]

Background In this century, chemotherapy has attained increasing importance in the treatment of advanced

cancer, fostered by the rapidly expanding insights into the origins and behavior of malignant

disease. Since the clinical observation that the sulfur mustard gas used in World War I caused

lymphoid aplasia, and its subsequent evaluation as an antitumor agent in the 1930s and 1940s ' ,

a range of natural and synthetic compounds have made their way into the clinic. In the 1960s

and 1970s, the dramatically improved outcome for patients with previously incurable tumors

such as lymphomas, leukemias and advanced germ cell tumors through the use of newly

discovered anticancer agents further enhanced the interest in chemotherapy. However, many of

the more common tumors either did not respond to chemotherapy, or rapidly relapsed after the

induction of remission.

Skipper et al2 observed that in certain laboratory tumors the growth fraction and cell loss

fraction were highly stable, independent of the size of the cell population. Further study showed

that when treated with cytotoxic drugs, a certain dose killed a certain constant fraction of these

tumor cells, regardless of the number of cells present, an observation often referred to as the

log kill phenomenon 3. In the absence of regrowth, repeated doses of the same drug will,

therefore, lead to an exponential decrease in the number of surviving tumor cells. This is the

theoretical basis for the common practice of chemotherapy administration in repeated cycles of

fixed duration.

Since the log kill fraction in the murine tumors used by Skipper often increases as the dose

increases, and each drug in combination treatment contributes its own log kill, combination

chemotherapy, with enough cycles in high enough doses of each individual agent, should eradicate

more, or even all tumor cells. This hypothesis led to the evaluation of increased doses of

chemotherapy in the 1980s, a concept called dose escalation. This evolution was greatly aided

by improvements in supportive care to overcome toxicity in normal tissues, such as anti-emetics

for nausea and vomiting, growth factors for bone marrow suppression, and novel antibiotics for

both prophylaxis and treatment of infectious complications.

The application of dose escalation to cancer treatment culminated in the use of very high,

myelo-ablative doses of chemotherapy with alkylating agents, supported by autologous bone

marrow transplants at first, and stem cell transplants from the 1990s onwards. While a very

hazardous venture in the 1980s, with high mortality and morbidity rates, the risk of high dose

chemotherapy with autologous stem cell transplant in the 1990s has decreased formidably

through the aforementioned supportive measures. In the 1990s, multiple high dose chemotherapy

Chapter 1

courses with stem cell support became feasible 4. The reduction in morbidity and mortality

eased the way for transfer of most of the treatment to the home setting rather than the prolonged

4 to 6-week hospital stays common in the 1980s 5. High dose chemotherapy has improved the

outcome for hematologic malignancies, childhood tumors and germ cell tumors. However,

although the likelihood of tumor response and complete remission has increased for most cancers,

no survival benefit has been proven for a range of more common malignancies.

In the 1980s, the recognition that many of the more common tumors in the advanced stages

could not be cured by even very high dose chemotherapy, led to a change in the direction of

anticancer research. The study of tumor cell kinetics and the way it is affected by anticancer

agents further focused research on drug scheduling rather than dose alone. Clinical experience,

such as the observation that larger tumors are not always more sensitive to treatment than

smaller tumors, did not seem to support the murine tumor model-derived concept of Skipper,

with assumed exponential proliferation, or constant doubling times, as the only kinetic paradigm

in human tumor cell growth. The sigmoid-shaped curve based on the 1825 Gompertz' equation

(the 'law of mortality') as a model for tumor cell kinetics does not presuppose a constant doubling

time, but shows increasing doubling time with increasing tumor size, with a maximum growth

fraction at about 37% of the maximum tumor size. Although the likelihood of a response of a

tumor to cytotoxic drugs is independent of the size of that tumor, the relative magnitude of that

response will depend on where the tumor is in its Gompertzian growth curve, because smaller

tumors will have a larger growth fraction than larger tumors. It then follows that the more

tumor cells are killed by chemotherapy, the faster the regrowth of the surviving cells, thus

severely restricting the ability to cure tumors6. Norton showed that Gompertzian sigmoid-curve

kinetics are consistent with the shape of survival curves of untreated breast cancer patients, and

with the curves of freedom of progression after mastectomy 7.

Further mathematical computations by Norton and Day 8 suggested a model, that predicted

that a schedule of sequential chemotherapy would lead to higher cell kill rates than the alternating

schedules that had been the cornerstone of especially hematological and childhood malignancies

for some time. Although the first results of such a sequential regimen in breast cancer showed an

advantage for this approach over alternating schedules 9, and promising results in small cell lung

cancer were obtained10, these results have not been confirmed by other studies11_13. Thus, sequential

regimens have not found a place in common practice so far.

High-dose chemotherapy in itself is not very likely to overcome the obstacle of regrowth in

the Gompertzian model, since even a very small remaining tumor burden at the end of treatment

10

Background and outline of the thesis [summary]

will rapidly proliferate. However, reducing the dose interval for standard dose combination

chemotherapy (a method of dose intensification known as increasing dose-density), could

minimize regrowth between chemotherapy cycles, and thus increase cell kill u . Theoretically,

this implies that if dose-dense combination chemotherapy at standard doses cannot be achieved,

single-agent therapy at standard doses might be preferred over low-dose combination

chemotherapy. This concept of dose-dense, frequent administration of single-agent chemotherapy

in standard doses has gained recognition in the dose-dense weekly cisplatin regimens in the

treatment of ovarian cancer15, head and neck cancer16, melanoma 17, and non-small cell lung

Although the efficacy of chemotherapy may be gradually increasing, partly due to the

implementation of dose-intensification and improved supportive care, long-term results in the

advanced stages of the most common tumors such as breast cancer, lung cancer and colorectal

cancer have remained modest. One explanation could lie in the survival of a small but consistent,

significant number of tumor cells irrespective of the amount of cytoreductive therapy, as was

suggested by the results of a phase III study of high-dose chemotherapy in patients with stage

IV breast cancer achieving complete remission on standard chemotherapy. Patients randomized

to immediate high-dose treatment had longer relapse-free survival, but shorter overall survival

than the patients randomized to undergo high dose chemotherapy only at relapse 20. After

high-dose chemotherapy, relapse-free and overall survival were identical, suggesting that there

is a limit to the amount of cytoreduction that can be achieved through high-dose chemotherapy.

If this is the case, no amount of chemotherapy can be expected to further minimize tumor

burden, after a certain maximum cytoreduction has been reached. This does not make sense,

however, since some patients are cured by chemotherapy. More likely, regrowth based on

Gompertzian kinetics may counteract chemotherapy as its efficacy increases, and a method to

inhibit regrowth by non-myelosuppressive means between high-dose courses could eliminate

this mechanism. Therefore a strategy directed at inhibition of regrowth of residual disease could

be very important.

In recent years, an array of novel targets for restriction of tumor cell proliferation without impairment

of chemotherapy effect has been recognized and has led to clinical studies. Examples are ras-

farnesylation inhibition, thought to suppress the growth of ras-transformed cancer cells21,22, vaccines

against cancer antigens 2324 and inhibition of angiogenesis, essential for tumor proliferation and

metastasis 25. The recent identification of growth factors and their receptors, in addition to the

elucidation of signal transduction pathways, suggests yet another treatment modality that can be

integrated into systemic therapy. Peptide growth factors and their receptors, such as the epidermal

11

Chapter 1

growth factor receptor (EGFR)-superfamily, the platelet-derived growth factor (PDGF) family,

basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), transforming

growth factor ß (TGFß), the insulin-like growth factors (IGF), and the interleukins are often

overexpressed in human tumors. In addition to these bioactive peptides, the recent recognition

of the unique phospholipid, lysophosphatidic acid (LPA), as a growth factor for ovarian cancer

and possibly other cancers has further expanded our knowledge and possibilities for treatment 26'27. Growth factors induce cell proliferation through stimulation of specific tyrosine kinase

receptors. Specific patterns of growth factor activity and growth factor receptor expression may

explain the behavior of particular tumor types, e.g. a role of LPA that has been suggested in

ovarian cancer2S.

Inhibition of growth factor receptor loops is one of the novel strategies for therapy that has

spawned a large research interest, and the number of growth factor receptor-inhibitors in

development has boomed. Clinical trials of such, generally non-toxic agents include the use of

anti-p185HER2 monoclonal antibody (of the EGFR-family) in phase III studies in breast cancer,

after promising preclinical and phase II results29'30. For instance, an anti-EGFR monoclonal antibody

is currently being tested in phase II trials in combination with topotecan, with encouraging

preclinical results 31'32. We have chosen to exploit the blocking of growth factor-receptor

interactions by suramine, specifically aiming at the inhibition of the bioactive LPA-like lipid growth

factors33. In addition, myriad inhibitors of growth factors and their receptors are expected to

enter clinical trials soon, after completion of preclinical testing.

It may well be that the future of systemic anti-cancer therapy in advanced tumors lies in the

combination of dose-dense chemotherapy with the non-toxic biologic agents mentioned above.

The novel targeted interventions are expected to have the greatest impact in situations of minimal

residual disease, such as after intensive chemotherapy, between courses of chemotherapy, and

in the adjuvant setting.

Outline of the thesis The research described in this thesis focuses on the global strategies outlined above. We have

developed intensive, repetitive high-dose chemotherapy with peripheral blood stem-cell

transplantation (Chapter 6) and we have adapted its practical application to the requirements of

cancer patients by removing part of the treatment from the hospital setting (Chapter 7). Although

this approach leads to a high proportion of complete remissions in solid tumors, eradication of

12

Background and outline of the thesis [summary]

all tumor cells is achieved in only a minority of patients, and either inhibition of regrowth between

chemotherapy cycles, or effective treatment of minimal residual disease (or both) are required

to realize cure.

Regrowth inhibition between chemotherapy cycles might be reached through the use of

appropriate growth factor receptor-inhibitors, that are not myelosuppressive. We have studied a

novel lipid growth factor, LPA, and its role in peritoneal malignancies such as ovarian cancer and

mesothelioma (Chapter 2). LPA may be important as a growth-promoting factor in ovarian cancer

(Chapter 3), and we have attempted to inactivate it using intraperitoneal suramin (Chapter 4).

Intraperitoneal administration is feasible, and has a distinct pharmacokinetic advantage over

systemic administration. Its effect as an antitumor agent remains to be established, but we have

observed an encouraging response in a single patient with peritoneal meothelioma (Chapter 5).

The integration of LPA-inhibition as a regrowth-inhibitor between cycles of high-dose

chemotherapy is envisaged, but is, at present, no more than a challenging prospect.

13

Chapter 1

References 1 Adair CPJ, Bagg HJ. Experimental and clinical studies on the treatment of cancer by dichloroethyl-

sulphide (mustard gas). Ann Surg 1931;93:190

2 Skipper HE. Kinetics of mammary tumor cell growth and implications for therapy Cancer 1971;28:1479-99

3 Skipper HE, Schabel FM Jr, Wilcox WS. Experimental evaluation of potential anticancer agents xiii: On the criteria and kinetics associated with 'curability' of experimental leukemia. Cancer Chemother Rep 1964;35:1

4 Rodenhuis S, Westermann AM, Holtkamp MJ, Nooijen WJ, Baars JW, van der Wall E et al. Feasibility of multiple courses of high-dose cyclophosphamide, thiotepa, and carboplatin for breast cancer or germ cell cancer. J Clin Oncol 1996;14:1473-83

5 Westermann AM, Holtkamp MMJ, Linthorst GAM, Van Leeuwen L, Willemse EJM, Van Dijk WC et al. At home management of aplastic phase following high-dose chemotherapy with stem-cell rescue for hematological and non-hematological malignancies. Ann Oncol 1999;10:511-17

6 Norton L. Adjuvant breast cancer therapy: Current status and future strategies - growth kinetics and the improved drug therapy of breast cancer. Semin Oncol 1999;26(suppl 3): 1-4

7 Norton L. A Gompertzian model of human breast cancer. Cancer Res 1988;48:7067-71 8 Norton L, Day R. Potential innovations in scheduling of cancer chemotherapy. Important Adv

Oncol 1991:57-72

9 Bonadonna G, Zambette M, Valagusa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. JAMA 1995;273:542-7

10 Twelves CJ, Goldman J, Ash CM, Souhami RL, Harper PG, Spiro SG et al. Sequential chemotherapy in good-prognosis patients with small-cell lung cancer. Cancer Chemother Pharmacol 1991;28:139-41

11 Laurie JA, Hahn RG, Therneau TM, Patel SR, Mailliard JA, Windschitl HE et al. Chemotherapy for hormonally refractory advanced prostate carcinoma. A comparison of combined versus sequential treatment with mitomycin C, doxorubicin, and 5-fluorouracil. Cancer 1992;69:1440-4

12 Haioun C, Lepage E, Gisselbrecht C, Bastion Y, Coiffier B, Brice P et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 1997;151131-7

13 Ueoka H, Kiura K, Tabata M, Kamei H, Gemba K, Sakae K et al. A randomized trial of hybrid administration of cyclophosphamide, doxorubicin, and vincristine (CAV)/cisplatin and etoposide (PVP) versus sequential administration of CAV-PVP for the treatment of patients with small cell lung carcinoma: results of long term follow-up. Cancer 1998;83(2):283-90

14 Levein L, Hryniuk WM. Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 1987;756-67

1 5 Bolis G, Favalli G, Danese S, Zanaboni F, Mangili G, Scarabelli C et al. Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer. J Clin Oncol 1997;15:1938-44

16 Planting AS, de Mulder PH, de Graeff A, Verweij J. Phase II study of weekly high-dose cisplatin for six cycles in patients with locally advanced squamous cell carcinoma of the head and neck. Eur J Cancer 1997;33:61-5

17 Planting AS, van der Burg ME, Goey SH, Schellens JH, Vecht C, de Boer-Dennert M et al. Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in metastatic malignant melanoma. Eur J Cancer 1996;32A:2026-8

18 Planting A, Kho S, van der Burg M, Goey H, Schellens J, van den Bent M et al. A phase II study of weekly high-dose cisplatin combined with oral etoposide in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol 1997;40:347-52

14

Background and outline of the thesis [summary]

19 Planting AS, de Wit R, van der Burg ME, Stoter G, Verweij J. Phase II study of a closely spaced ifosfamide-cisplatin schedule with the addition of G-CSF in advanced non-small-cell lung cancer and malignant melanoma. Ann Oncol 1996;7:1080-2

20 Peters WP, Jones RB, Vredenberg J et al. A large, prospective , randomized trial of high-dose combination alkylating agents with autologous bone marrowsupport as consolidation for patients

-with metastastic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy. Proc Am Soc Clin Oncol 1996; 1 5:121 [abstr]

21 Gibbs JB, Oliff A, Kohl NE. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 1994;77:175-8

22 Zujewski J, Horak ID, Bol CJJG, Woestenborghs R, End D, Chiao J et al. A phase I and pharmacokinetic study of farnesyltransferase inhibitor, R11 5777, in advanced cancer. Proc Am Soc Clin Oncol 1999; 18:739 [abs]

23 Hsueh EC, Nathanson L, Foshag LJ, Essner R, Nizze JA, Stern SL et al. Active specific immunotherapy with polyvalent melanoma cell vaccine for patients with in-transit melanoma metastases Cancer 1999;85:2160-9

24 Vermorken JB, Claessen AM, van Tinteren H, Gall HE, Ezinga R, Meijer S et al. Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial Lancet 1999;353:345-50

25 Folkman J.Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis [Review] N Engl J Med 1995;333:1757-63

26 Xu Y, Mills GB. Activation of human ovarian cancer cells: role of lipid factors in ascitic fluid. In: Sharp F, Mason P, Blackett T, Berek J [eds.] Ovarian cancer 3, 1 st edition. London, Chapman and hall Medical, 1995;121-35

27 Westermann AM, Havik E, Postma FR, Beijnen JH, Dalesio O, Moolenaar WH, Rodenhuis S. Malignant effusions contain LPA-like activity. Annals Oncol 1998;437-42

28 Westermann AM, Beijnen JH, Moolenaar WH, Rodenhuis S. Growth factors in human ovarian cancer. Cancer Treatm Rev 1997;23:113-31

29 Baselga D, Tripathy D, Mendelsohn J et al. Phase II study of weekly intravenous humanized recombinant anti-p185 HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastaic breast cancer. J Clin Oncol 1996; 14:737-44 Proc Am Assoc Cancer Res 1999;40:155 [abs]

30 Norton L, Slamon D, Leyland-Jones B, Wolter J, Fleming T, Eirmann W et al. Overall survival advantage to simultaneous chemotherapy (CRx) plus the humanized anti-HER2 monoclonal antibody Herceptin in HER2-overexpressing metastatic breast cancer. Proc Am Soc Clin Oncol 1999;18:483 [abstr]

31 Baselga J, Norton L, Masui H et al. Anti-tumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibody. J Natl Cancer Inst 1993;85:1327-33

32 Ciardiello F, Bianco R, Damiano V, De Lorenzo S, Pepe S, De Placido S et al. Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Proc Am Ass Cancer Res 1999;40:1 55 [abstr]

33 Westermann AM, Dubbelman R, Moolenaar WH, Beijnen JH, Rodenhuis S. Successful intraperitoneal suramin tretament of peritoneal mesothelioma. Ann Oncol 1997;8:801-2