Modification of tumor response to cyclophosphamide and irradiation by preirradiation of the tumor bed: Prolonged growth delay but reduced curability

Ito, Hisao; Barkley, Thomas; Peters, Lester J.; Milas, Luka

doi:10.1016/0360-3016(85)90186-5

Cited by 26 publications

(8 citation statements)

References 11 publications

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“…For growth delay to be determined solely by cell survival, the tumor growth rate must be independent of the radiation dose. However, irradiation of the tumor bed can alter the growth of a tumor implanted after irradiation [103][104][105][106][107], and there are tumor systems in which the post-irradiation tumor growth rate has been shown to vary with the radiation dose [108][109].…”

Section: Assumptions Made Only In Growth Delay Hypoxic Fraction Assaysmentioning

confidence: 99%

Tumor hypoxia: its impact on cancer therapy

1987

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The presence of radiation resistant cells in solid human tumors is believed to be a major reason why radiotherapy fails to eradicate some such neoplasms. The presence of unperfused regions containing hypoxic cells may also contribute to resistance to some chemotherapeutic agents. This paper reviews the evidence that radiation resistant hypoxic cells exist in solid tumors, the assumptions and results of the methods used to detect hypoxic cells, and the causes and nature of tumor hypoxia. Evidence that radiation resistant hypoxic cells exist in the vast majority of transplanted rodent tumors and xenografted human tumors is direct and convincing, but problems with the current methodology make quantitative statements about the magnitude of the hypoxic fractions problematic. Evidence that radiation resistant hypoxic cells exist in human tumors is considerably more indirect than the evidence for their existence in transplanted tumors, but it is convincing. However, evidence that hypoxic cells are a significant cause of local failure after optimal clinical radiotherapy or chemotherapy regimens is limited and less definitive. The nature and causes of tumor hypoxia are not definitively known. In particular, it is not certain whether hypoxia is a chronic or a transient state, whether hypoxic cells are proliferating or quiescent, or whether hypoxic cells have the same repair capacity as aerobic cells. A number of new methods for assessing hypoxia are reviewed. While there are still problems with all of the new techniques, some of them have the potential of allowing the assessment of hypoxia in individual human tumors.

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Section: Assumptions Made Only In Growth Delay Hypoxic Fraction Assaysmentioning

confidence: 99%

Tumor hypoxia: its impact on cancer therapy

1987

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“…Radiationinduced injury to the host vasculature and connective tissue, resulting in impaired neovascularization, is considered the major cause of the tumor bed effect (14,15). Compared with control tumors in unirradiated beds, tumors in preirradiated beds commonly show a hostile microenvironment characterized by reduced blood perfusion (16), low extracellular pH (16), and low oxygen tension (17), resulting in extensive necrosis (9,11,14,15), elevated hypoxic fractions (18)(19)(20)(21)(22), and impaired curability after treatment with ionizing radiation (18,20,22) and cytotoxic agents (8,23).…”

Section: Introductionmentioning

confidence: 99%

The Tumor Bed Effect: Increased Metastatic Dissemination from Hypoxia-Induced Up-regulation of Metastasis-Promoting Gene Products

et al. 2005

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Cancer patients with recurrent local disease after radiation therapy have increased probability of developing regional and distant metastases. The mechanisms behind this observation were studied in the present work by using D-12 and R-18 human melanoma xenografts growing in preirradiated beds in BALB/c-nu/nu mice as preclinical models of recurrent primary tumors in humans. D-12 tumors metastasize to the lungs, whereas R-18 tumors develop lymph node metastases. Based on earlier studies, we hypothesized that metastasis was governed primarily by the proangiogenic factor interleukin-8 (IL-8) in D-12 tumors and by the invasive growth-promoting receptor urokinase-type plasminogen activator receptor (uPAR) in R-18 tumors. Pimonidazole was used as a hypoxia marker, and hypoxia, microvascular hotspots, and the expression of IL-8 and uPAR were studied by immunohistochemistry. The metastatic frequency was significantly higher in tumors in preirradiated beds than in control tumors in unirradiated beds, and it increased with the preirradiation dose. D-12 tumors showed increased fraction of hypoxic cells, increased fraction of IL-8-positive cells, and increased density of microvascular hotspots in preirradiated beds, and R-18 tumors showed increased fraction of hypoxic cells and increased fraction of uPAR-positive cells in preirradiated beds. Strong correlations were found between these parameters and metastatic frequency. IL-8 was up-regulated in hypoxic regions of D-12 tumors, and uPAR was up-regulated in hypoxic regions of R-18 tumors. Daily treatment with anti-IL-8 antibody (D-12) or anti-uPAR antibody (R-18) suppressed metastasis significantly. Our preclinical study suggests that primary tumors recurring after inadequate radiation therapy may show increased metastatic propensity because of increased fraction of hypoxic cells and hypoxia-induced up-regulation of metastasis-promoting gene products. Two possible mechanisms were identified: hypoxia may enhance metastasis by inducing neoangiogenesis facilitating hematogenous spread and by promoting invasive growth facilitating lymphogenous spread. The aggressive behavior of postirradiation local recurrences suggests that they should be subjected to curative treatment as early as possible to prevent further metastatic dissemination. Moreover, the possibility that patients with a high probability of developing local recurrences after radiation therapy may benefit from postirradiation treatment with antiangiogenic and/or anti-invasive agents merits clinical investigation. (Cancer Res 2005; 65(6): 2387-96)

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“…In part, these changes result from changes in the normal tissue stroma surrounding malignant tumors, and the stroma–tumor interaction has been implicated as a determinant of tumor biology and response to cytotoxic treatments [10–14]. Ionizing radiation causing disruption of the physical and the functional integrity of the tumor bed stroma has been suggested to result in alteration of tumor response to radiation and chemotherapy [12]. Early studies using tumor models have also suggested that radiation-induced stromal injury can be conducive to tumor initiation and distance metastasis (DM) [13].…”

Section: Introductionmentioning

confidence: 99%

Among women who experience a recurrence after postmastectomy radiation therapy irradiation is not associated with more aggressive local recurrence or reduced survival

Woodward

Truong

et al. 2010

Breast Cancer Res Treat

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Recent pre-clinical models suggest that radiation can promote tumor aggressiveness. We hypothesized that if this were occurring clinically, locoregional recurrences (LRRs) after postmastectomy radiation therapy (PMRT) would lead to lower survival than LRR after mastectomy alone. This study used two independent data-sets to compare survival after LRR in women treated with versus without PMRT. Data from 229 LRR cases among 1,500 patients enrolled on prospective trials at the MD Anderson Cancer Center (MDA), and 66 LRR cases among 318 patients enrolled in the British Columbia Cancer Agency (BCCA) PMRT randomized trial were analyzed. In the MDA non-randomized dataset, 189/1031 had LRR after mastectomy alone and 40/469 had LRR after PMRT. In the randomized BC trial dataset, 52/158 had LRR after mastectomy alone and 14/160 had LRR after PMRT. In both datasets, survival was calculated from the time of LRR to death. Analysis of MDA data shows that in all LRR cases regardless of distant metastasis (DM), 5/10-year OS were 50/34% without PMRT and 27/19% after PMRT (P = 0.006). However, PMRT-treated patients had increased risk factors for DM (advanced T and N stages) and more PMRT-treated patients developed DM prior to LRR (63 vs. 34%, P = 0.005). Analyzing only patients will an isolated LRR (without previous or simultaneous DM), there was no OS difference between groups (P = 0.33). Analysis of BCCA data shows that distributions of T and N stages were similar in patients with LRR after mastectomy alone versus after PMRT. DM free survival after any LRR and after isolated LRR were similar in mastectomy alone versus PMRT-treated patients (P = 0.75, P = 0.26, respectively). Overall survival after any LRR and after isolated LRR were also similar in the two groups (P = 0.93, P = 0.28, respectively). Patients who develop LRR after mastectomy alone have high rates of DM and poor OS but these rates are not affected by the use of PMRT at the time of primary treatment. These data do not support the hypothesis that irradiation promotes biologically aggressive local recurrences.

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Modification of tumor response to cyclophosphamide and irradiation by preirradiation of the tumor bed: Prolonged growth delay but reduced curability

Cited by 26 publications

References 11 publications

Tumor hypoxia: its impact on cancer therapy

Tumor hypoxia: its impact on cancer therapy

The Tumor Bed Effect: Increased Metastatic Dissemination from Hypoxia-Induced Up-regulation of Metastasis-Promoting Gene Products

Among women who experience a recurrence after postmastectomy radiation therapy irradiation is not associated with more aggressive local recurrence or reduced survival

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