Michael Höckel

Oxygenation status of malignant tumors: Pathogenesis of hypoxia and significance for tumor therapy

Hypoxic areas are a characteristic property of solid tumors. Hypoxia results from an imbalance between the supply and consumption of oxygen. Major pathogenetic mechanisms for the emergence of hypoxia are (1) structural and functional abnormalities in the tumor microvasculature; (2) an increase in diffusion distances; and (3) tumor- or therapy-associated anemia leading to a reduced O2 transport capacity of the blood. There is pronounced intertumor variability in the extent of hypoxia, which is independent of clinical size, stage, histopathologic type, and grade. Local recurrences have a higher hypoxic fraction than primary tumors. Tumor hypoxia is intensified in anemic patients, especially in tumors with low perfusion rates. Tumor hypoxia is a therapeutic problem, as it makes solid tumors resistant to sparsely ionizing radiation and some forms of chemotherapy. Hypoxia also may modulate the proliferation and cell cycle position of tumor cells and, in turn, the amount of cells destroyed following therapy. Recent clinical studies suggest that hypoxia can enhance malignant progression and increase aggressiveness through clonal selection and genome changes. As a result, loss of differentiation and apoptosis, chaotic angiogenesis, increased locoregional spread, and enhanced metastasis can further increase resistance to therapy and affect long-term prognosis. Hypoxia is a powerful, independent prognostic factor in cervix cancers, carcinomas of the head and neck, and in soft-tissue sarcomas.

Hypoxia and radiation response in human tumors

This study demonstrates by an updated analysis of an ongoing prospective study that tumor oxygenation, as measured with a validated standardized polarographic needle electrode method before treatment, powerfully predicts the prognosis of patients receiving radiotherapy for intermediate and advanced stage cancer of the uterine cervix. First evidence for a host component in tumor oxygenation based on a significant correlation between median pO(2) values determined in normal subcutaneous fatty tissue and in cervical cancer is also presented. Further investigations are necessary to clarify whether tumor hypoxia is just a marker of intrinsic tumor aggressiveness or whether the negative impact of tumor hypoxia on survival is related to radiobiological mechanisms caused by hypoxia per se, which may include (1) the reduced oxygen enhancement effect, (2) increased radioresistance due to expression of genes for cell cycle delay and stress proteins, and/or (3) accelerated tumor progression to more radioresistant and metastatic variants by increased genetic heterogeneity.

Five-year experience with combined operative and radiotherapeutic treatment of recurrent gynecologic tumors infiltrating the pelvic wall

Whereas 25 to 50% of selected patients with gynecologic tumors who relapse centrally in an irradiated pelvis can be salvaged by exenteration, postirradiation recurrence infiltrating the pelvic side wall generally has been fatal. We have designed the combined operative and radiotherapeutic treatment (CORT) procedure for the treatment of postirradiation recurrence infiltrating the pelvic wall and developed several new techniques for its realization. The aim of the surgery is as follows: (1) total resection of the tumor with only a microscopic margin (R1) at the pelvic wall, preserving the bony pelvis and the neurovascular support of the leg; (2) modulation of the therapeutic index for a second high‐dose irradiation of the pelvic wall by transferring autologous tissue from the abdomen or the thigh, and (3) reconstruction of pelvic organ functions lost due to tumor resection. The tumor bed is irradiated postoperatively with brachytherapy through transcutaneous guide tubes implanted at the pelvic wall.

Intratumoral PO2 Histography as Predictive Assay in Advanced Cancer of the Uterine Cervix

Experimental evidence suggests that the hypoxic fraction in a solid tumor may increase its malignant potential and reduce its sensitivity towards nonsurgical treatment modalities such as standard irradiation and certain anticancer agents1–5. However, the clinical importance of tumor hypoxia remains uncertain since valid methods for the routine measurement of intratumoral O2-tensions in patients have so far been lacking.

The combined operative and radiotherapeutic treatment (CORT) of recurrent tumors infiltrating the pelvic wall: First experience with 18 patients

CORT is a new radiosurgical treatment concept for patients with recurrent gynecologic malignancies infiltrating the pelvic wall. The operative part consists of (i) staging laparotomy; (ii) maximum debulking of the tumor from the pelvic wall and exenteration of infiltrated central pelvic organs; (iii) implantation of brachytherapy guiding tubes on the residual tumor/tumor bed at the pelvic wall; (iv) pelvic wall plasty with muscle and omentum flaps to create a protective distance between the tubes and the pelvic hollow organs and to induce therapeutic angiogenesis; and (v) surgical reconstruction of bowel, bladder, and vulvoperineovaginal functions. Radiation is given postoperatively as fractionated HDR brachytherapy via the implanted tubes. Patients without prior pelvic radiation also receive preoperative whole pelvis teletherapy. Eighteen patients with recurrent malignancies infiltrating one pelvic wall have been treated with CORT in a prospective phase I/II trial at the University of Mainz. Fourteen patients had a history of radiation therapy with midpelvic doses of 40-100 Gy (median, 65 Gy) as primary treatment. Eleven patients (61%) are without evidence of disease at 6-32 months (median, 15 months) follow-up. Four patients have died from pelvic progression and distant metastases, and two patients are alive with disease after 12 months. There was no operative mortality; however, one patient succumbed from fatal thromboembolism 6 months after therapy. Three patients with prior radiation of greater than 75 Gy had to be treated for intestinal fistulas. We conclude that CORT is feasible with encouraging preliminary results.

Are pelvic side-wall recurrences of cervical cancer biologically different from central relapses?

Background. By using the Combined Operative and Radiotherapeutic Treatment (CORT) procedure, pelvic side‐wall recurrences of gynecologic malignancies arising in a previously irradiated pelvis may be locally controlled. Local control of central relapses may be achieved by exenteration alone. If, in cervical cancer, both relapse patterns are biologically different (as hypothesized by some investigators), distinct disease courses after local treatment may be expected.

A new perineal template assembly for high-dose-rate interstitial brachytherapy of gynecologic malignancies

This technical note introduces a modified Syed-Neblett type perineal template for high-dose-rate interstitial brachytherapy of gynecologic malignancies. The template can easily be disassembled after the insertion of the central needles into the pelvis allowing the cystoscopic and rectoscopic control of the needle positions. Thus needles penetrating the bladder or the rectum are recognized and can be repositioned before reassembling the template. Elimination of hot irradiation zones in tumor-free bladder and rectum walls might lead to reduction of severe late complications without compromising the therapeutic efficacy.

Tumor Vascularity, Hypoxia, and Malignant Progression in Solid Neoplasms

Malignant progression designates the biologic process which transforms a phenotypically normal cell fixed and cooperating within a tissue into a disseminated therapy-resistant lethal disease. In clinical terms this process consists of three major steps (Fig. 1): () the transition from regulated to deregulated cell proliferation, () the emerging ability of the neoplastic cell collectives to induce angiogenesis and to invade other tissues, () the development of metastases and of resistance towards anti-tumor therapies.

Tumor Oxygenation and Tumor Vascularity: Evidence for Their Clinical Relevance in Cancer of the Uterine Cervix and Considerations on Their Potential Biological Role in Tumor Progression

Most solid malignancies are thought to be derived from a single neoplastic precursor cell having lost proliferation control and gained the ability to penetrate basement membranes and to invade into the stroma. During the disease course tumors increase their overall cell number by local expansion and the development of regional and distant metastases. Along with the increase in cell number the tumors loose hormonal or other external signal dependencies and acquire resistances towards radio— and chemotherapy. The progressing disease causes symptoms through impaired tissue/organ functions and complications, and finally kills the individual (unless other causes leading to death become manifest earlier).

Therapeutic Angiogenesis in Surgery and Oncology

The aim of this presentation is to demonstrate the pathological importance of microenvironmental tissue hypoxia and to elucidate a general treatment concept for this situation which we have termed therapeutic angiogenesis 1. Hypoxia not only represents an insufficient oxygen supply for the cells of a given tissue area but is also regarded as an indicator for their metabolic deprivation and the concomitant accumulation of waste products. Therapeutic angiogenesis applied either with clinically established methods or using novel ways, which are the objectives of laboratory research and clinical trials at present, or in so far hypothetical forms, should lead to an expansion of the functional microvascular space resulting in an increased nutritive blood flow. Thus microregional oxygen availability should be elevated and directly counteract local tissue hypoxia. The problems of nutritional deprivation and waste product accumulation are also treated by therapeutic angiogenesis.