Hypoxia & Cervical Cancer

Sample of a clinical paper written in 2003 (considerably shortened and with client identifiers deleted).

Adjunctive Use of A New Hematopoietic Agent In Women Treated For Advanced Cervical Cancer

Authors and affiliations.

Purpose: To compare the disease-free survival (DFS) of women receiving sequential chemo-radiotherapy with and without stimulation of red blood cell production.

Patients and Methods: A total of 500 high-risk cervical cancer patients were recruited into this multicenter, randomized trial: Of these, almost half met all entry criteria and were assessable at interim evaluation. All patients were treated with ifosphamide, carboplatin and subsequent percutaneous radiotherapy. Patients in Arm A (n= 240) received transfusions only and served as the study control. Those in Arm B (n=260) were treated with 12,000 IUs of a newly cloned hematopoietic agent 3 times a week plus oral iron supplements sufficient to maintain a target hemoglobin of 13 g/dL (8 mmol/L).

Results: This first trial evaluating the addition a red-blood-cell stimulant to anticancer therapy for patients with advanced cervical cancer showed significant reductions in grades 1-2 anemias and transfusion requirements. Although significance was not reached, compared to control patients, those receiving the new immunotherapy had longer relapse-free survivals and fewer cancer recurrences.

Conclusion: The new hematopoietic agent proved a safe and effective preventative treatment for anemias in cancer patients. Stabilizing hemoglobin at normal levels reduced tumor hypoxia, thereby decreasing the malignant potential of the tumor as well as increase its sensitivity to anticancer treatments. Furthermore, the addition of this agent to existing treatment helped improve patients' well being, enabling treatment in accordance with protocol.

J Clin Oncol X: (pages). (year) by American Society of Clinical Oncology.

[Introduction]:
There is no longer any doubt that anemia, a common complication of both cancer and cancer therapy, has a negative effect on treatment success. Importantly, its impact reaches far beyond the more obvious quality of life concerns such as fatigue, chest pain, and a loss of mental acuity. Anemia is also a major contributor to tumor hypoxia which can enhance cancer progression and increase malignant aggressiveness. (Littlewood, 2001 pp. 49,50; Vaupel 2001, p. 29; Vaupel 2002, p. 336)

The negative effects of hypoxia on treatment were discovered decades ago. In the 1920s, molecular oxygen was reported to be the most important modifier of ionizing radiation and by the early 1950s it was shown that radiation therapy loses potency in an anaerobic environment.(Hellman 2001, p.274; Coleman 2001, p. 610). It soon became apparent why this happened: the antitumor activity of radiation is mediated by formation of free radicals which, in the presence of oxygen, kill cancer cells by disrupting their DNA and cell membranes. Free radicals are not "fixed" in an anaerobic environment, limiting radiation effect. (Colman 2001, p. 610; Littlewood 2001, p. 50)

A number of recent clinical trials demonstrate that hypoxic tumors are also more difficult to control with surgery and have proved resistant to some forms of chemotherapy as well (e.g., carboplatin, cyclophosphamide). (Coleman et al 2001 pp.610,611; Vaupel 2002, p. 337; Vaupel 2001, p. 32; Harrison 2002 abstract)

Why should anemia have such a negative impact on clinical outcome? Obviously, a poor quality of life can decrease the amount of treatment delivered. And, as noted above, the effects of radiation as well as some types of chemotherapy are impaired in oxygen-deficient environments. But hypoxia also appears to enhance tumor growth and spread on a molecular level.

Most, if not all, cancer cells share a common set of altered cell attributes known as "acquired capabilities;" physiologic changes enabling them to generate their own mitogenic signals, resist external growth-inhibitory signals, evade apotosis, become immortal, proliferate without limits and develop vasculature (angiogenesis). (Hahn 2002, pp.1595,1596)

Hypoxic environments increase genetic instability, facilitating the mutability necessary for malignant transformation and progression. Anaerobic conditions also interfere with apoptosis, curtailing elimination of cells carrying damaged DNA. Additionally, hypoxia induces genetic changes encoding expression of oxygen-dependent proteins such as vascular endothelial growth factor, thus increasing the rate of angiogenesis and a tumor's potential for expansion. (Littlewood 2001, p. 50; Hahn 2002, pp. 1595,1596)

Whatever the underlying causes, the relationship between hemoglobin levels and prognosis in patients with locally advanced cervical cancer has been amply demonstrated. Indeed, evidence that anemia plays a causative role in pelvic recurrences was first reported in 1978. In that small but pivotal randomized study from the Princess Margaret Hospital, patients maintained at hemoglobin levels of at least 12.5 gm% had a significantly lower locoregional recurrence rate than control patients with levels of 10 gm%. (Eifel 2001, p. 1534) The present investigation was undertaken in an attempt to further confirm these findings as well as to determine if a new immunologic regulator of red cell production is a more effective means of preventing anemia and it's ill effects than transfusion alone. Preliminary results are reported here.

PATIENTS AND METHODS

Study Design
A multicenter Phase III study was initiated in 1999 to compare the DFS of patients with high-risk cervical cancer receiving adjuvant sequential chemo-radiotherapy with or without a red-cell stimulant. Secondary endpoints were 1) toxicity, 2) quality of life benefits and 3) number of transfusions needed. Patients were recruited from 42 clinics within 24 months. The protocol and informed consent form were approved by the appropriate institutional review board. Only patients who were able to understand the nature of the study and provide written informed consent were eligible.

Baseline information included patient demographics, weight, blood pressure, tumor type/histology, and current/previous chemotherapy. Hemoglobin and hematocrit levels were required clinical laboratory tests, preferably obtained before initiation of each cycle of chemo- and radiotherapy.

All patients received 4 cycles (q21d) of chemotherapy with ifosphamide (1.6 mg/m2, dL-3), carboplatin (AUC 3, dl) and subsequent percutaneous radiotherapy (5x1.8-2 Gy/week up to 50-50.5 Gy). Study Arm A patients received transfusions only. Arm B patients were given10,000 IUs of a red-cell stimulant 3 times a week plus oral iron supplements. Target hemoglobin for patients in the active drug study arm was 13 g/dL (8 mmol/l). Those who were transfused had average hemoglobins <9 g/dL (5.5 mmol/l).

Patients
Eligible patients were between 18 and 65 years old, had FIGO staging scores of IB, IIA, or IIB and radical hysterectomies according to Piver III. Mean patient age was 41.8 9.2 years (36% were under < 40 years); tumor size 35 mm; and number of excised lymph nodes 32. Exclusion criteria included uncontrolled hypertension, known hypersensitivity to mammalian cell-derived or human albumin products and a known history of anemia attributable to factors other than cancer or chemotherapy (i.e. iron or folate deficiencies, hemolysis, or gastrointestinal bleeding).

DISCUSSION

For many years physicians expected cancer patients to become anemic and were taught that no serious harm would occur until hemoglobin levels fell below 10.0 g/dL or even less than 8.0 g/dL. This has proved incorrect. Not only do hemoglobin levels below 12 g/dL have a major negative impact on quality of life, studies on a molecular level show that anemia-induced tumor hypoxia decreases a patient's chance of survival. (Littlewood 2001, pp. 51,52)

Cancer patients risk precipitously low hemoglobin levels for many reasons, some are related to the malignancy itself and others to the therapy they receive. Radiation to the pelvis or spine, as is the case in patients with cervical cancer, is particularly problematic because of the large volume of marrow within these bones. Indeed, the number of cancer patients suffering stem cell depletion is increasing as higher doses and repeated courses of chemotherapy and radiation become more common. (Griffin 2001, p. 2802)

Interim results of the first trial evaluating response to a new hematopoietic agent in high-risk cervical cancer receiving adjuvant, sequential radio-chemotherapy are reported here. One important early finding is that patients receiving active treatment had fewer recurrences of their cancers and longer relapse-free survivals than those receiving transfusions only. The short observation time precludes statistical evaluation of this endpoint; however, the strongly positive outcome at interim assessment is expected to reach significance as the trial progresses.

The events for which statistical analysis was possible revealed a number of significant results. Notably, anemia was significantly reduced in patients receiving immunotherapy. Correction of anemia is important in cancer patients, not only to improve their quality of lives but also to enhance chemo-radiosensitivity and thus increase cancer cure rates. (Vaupel 2002, p.342)

The new agent also significantly reduced the number of required transfusions. While blood transfusion is commonly used to correct anemia in cancer patients, it carries significant risks. For this reason, hemoglobin levels are allowed to fall below optimal levels before they are is given. Moreover, even when given, transfusion results in an immediate increase in hemoglobin level but this soon decreases without repeated transfusions or other interventions. (Littlewood 2001, p. 50) It was also shown that the new hematopoietic stimulant was well tolerated. Significant side effects were reported by neither by the patients or physicians participating in this trial.

In conclusion, a new red-blood-cell stimulating immunotherapy, given in conjunction with sequential adjuvant chemo-radiotherapy, is well-tolerated by patients with advanced cervical cancer. Importantly, women receiving this hematopoietic agent were significantly less anemic and needed fewer transfusions. There were also fewer cancer recurrences and longer relapse-free survivals among patients receiving the hematopoietic agent vs placebo patients.

References

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