Uveal melanoma: therapeutic consequences of doubling times and irradiation results; a review

Abstract

Thirty-six of 39 published calculated doubling times (Td's) of uveal melanomas appeared to be longer than 60 days. Metastatic death occurs 35-40 Td's after dissemination. The shortest interval between dissemination and metastatic death in individual patients may, therefore, be calculated as 35 x 60days = 6 years; the interval may extend to 80 years. This suggests, that local therapy cannot influence the survival data within the first 7 post-therapeutic years, because almost all metastatic deaths within these 7 years are due to pretreatment dissemination. For that reason, the published comparative survival analyses after various therapies have within this period failed to show statistically significant death rates differences.Microscopically viable melanoma tissue has been noted in 215 of 231 histopathologically studied irradiated uveal melanomas. Observed mitotic figures 4-6 years after irradiation indicate retained reproductive integrity. This constitutes a -by enucleation avoidable -incremental risk for post-irradiation exponential growth and dissemination. The risk cannot become statistically manifest before a -> 10-year follow-up period. Retained, generally poor, visual acuity in a small percentage of patients cannot balance the incremental risk/benefit ratio of irradiation. A few, at present justifiable, indications for radiotherapy on uveal melanomas are enumerated.

Histopathologic and MR Imaging Appearance of Spontaneous and Radiation-Induced Necrosis in Uveal Melanomas: Initial Results

“…However, although radiotherapy has a noticeable effect on the viability of malignant cells and is able to produce considerable tumor regression, it rarely manages to destroy all neoplastic cells in uveal melanomas. In their review analyzing several reports published from 1977 to 1990, dealing with irradiated choroidal melanomas, Manschot et al found that whilst tumor necrosis was present in 61% of microscopic examinations (a result very similar to our), viable tumor cells were still observable in 93% of cases [ 46 ]. The Collaborative Ocular Melanoma Study (COMS) subsequently confirmed that external beam radiotherapy significantly decreases, but does not eradicate mitotic activity [ 47 ].…”

“…Therefore, irradiation is not always able to destroy the reproductive capability of all malignant stem cells. Different reasons can explain the relative radioresistance of uveal melanomas: (1) the ability to repair sublethal radiation-induced damage because of a particularly efficient repair system; (2) a usually considerable amount of poorly oxygenated cells needing high radiation dose [ 46 ].…”

Histopathologic and MR Imaging Appearance of Spontaneous and Radiation-Induced Necrosis in Uveal Melanomas: Initial Results

“…However, although radiotherapy has a noticeable effect on the viability of malignant cells and is able to produce considerable tumor regression, it rarely manages to destroy all neoplastic cells in uveal melanomas. In their review analyzing several reports published from 1977 to 1990, dealing with irradiated choroidal melanomas, Manschot et al found that whilst tumor necrosis was present in 61% of microscopic examinations (a result very similar to our), viable tumor cells were still observable in 93% of cases [ 46 ]. The Collaborative Ocular Melanoma Study (COMS) subsequently confirmed that external beam radiotherapy significantly decreases, but does not eradicate mitotic activity [ 47 ].…”

“…Therefore, irradiation is not always able to destroy the reproductive capability of all malignant stem cells. Different reasons can explain the relative radioresistance of uveal melanomas: (1) the ability to repair sublethal radiation-induced damage because of a particularly efficient repair system; (2) a usually considerable amount of poorly oxygenated cells needing high radiation dose [ 46 ].…”

Modelling uveal melanoma

“…This model shares features in common with the Manschot–Van Peperzeel hypothesis,5 6 which states that seeding occurs early in the disease process. This model agrees that seeding can occur early.…”

Circulating melanoma cells in peripheral blood of patients with uveal melanoma before and after different therapies and association with prognostic parameters: a pilot study

“…Have these cells the same affinity to settle down and to build up metastases? Some authors could show that micrometastases have already developed long before the detection of the tumour (Manschot & van Strik 1992;Eskelin et al 2000;Eskelin & Kivela¨2001;Singh 2001). Consequently, cells that are set free during manipulation of the eye or the tumour would settle down later and would grow up to a clinically detectable metastasis much later than those cells that were released spontaneously by the tumour.…”

Histopathologic and MR Imaging Appearance of Spontaneous and Radiation-Induced Necrosis in Uveal Melanomas: Initial Results

“…However, although radiotherapy has a noticeable effect on the viability of malignant cells and is able to produce considerable tumor regression, it rarely manages to destroy all neoplastic cells in uveal melanomas. In their review analyzing several reports published from 1977 to 1990, dealing with irradiated choroidal melanomas, Manschot et al found that whilst tumor necrosis was present in 61% of microscopic examinations (a result very similar to our), viable tumor cells were still observable in 93% of cases [ 46 ]. The Collaborative Ocular Melanoma Study (COMS) subsequently confirmed that external beam radiotherapy significantly decreases, but does not eradicate mitotic activity [ 47 ].…”

“…Therefore, irradiation is not always able to destroy the reproductive capability of all malignant stem cells. Different reasons can explain the relative radioresistance of uveal melanomas: (1) the ability to repair sublethal radiation-induced damage because of a particularly efficient repair system; (2) a usually considerable amount of poorly oxygenated cells needing high radiation dose [ 46 ].…”

Modelling uveal melanoma

“…This model shares features in common with the Manschot–Van Peperzeel hypothesis,5 6 which states that seeding occurs early in the disease process. This model agrees that seeding can occur early.…”

Circulating melanoma cells in peripheral blood of patients with uveal melanoma before and after different therapies and association with prognostic parameters: a pilot study

“…Have these cells the same affinity to settle down and to build up metastases? Some authors could show that micrometastases have already developed long before the detection of the tumour (Manschot & van Strik 1992;Eskelin et al 2000;Eskelin & Kivela¨2001;Singh 2001). Consequently, cells that are set free during manipulation of the eye or the tumour would settle down later and would grow up to a clinically detectable metastasis much later than those cells that were released spontaneously by the tumour.…”

Histopathologic and MR Imaging Appearance of Spontaneous and Radiation-Induced Necrosis in Uveal Melanomas: Initial Results

“…However, although radiotherapy has a noticeable effect on the viability of malignant cells and is able to produce considerable tumor regression, it rarely manages to destroy all neoplastic cells in uveal melanomas. In their review analyzing several reports published from 1977 to 1990, dealing with irradiated choroidal melanomas, Manschot et al found that whilst tumor necrosis was present in 61% of microscopic examinations (a result very similar to our), viable tumor cells were still observable in 93% of cases [ 46 ]. The Collaborative Ocular Melanoma Study (COMS) subsequently confirmed that external beam radiotherapy significantly decreases, but does not eradicate mitotic activity [ 47 ].…”

“…Therefore, irradiation is not always able to destroy the reproductive capability of all malignant stem cells. Different reasons can explain the relative radioresistance of uveal melanomas: (1) the ability to repair sublethal radiation-induced damage because of a particularly efficient repair system; (2) a usually considerable amount of poorly oxygenated cells needing high radiation dose [ 46 ].…”

Modelling uveal melanoma

“…This model shares features in common with the Manschot–Van Peperzeel hypothesis,5 6 which states that seeding occurs early in the disease process. This model agrees that seeding can occur early.…”

Circulating melanoma cells in peripheral blood of patients with uveal melanoma before and after different therapies and association with prognostic parameters: a pilot study

“…Have these cells the same affinity to settle down and to build up metastases? Some authors could show that micrometastases have already developed long before the detection of the tumour (Manschot & van Strik 1992;Eskelin et al 2000;Eskelin & Kivela¨2001;Singh 2001). Consequently, cells that are set free during manipulation of the eye or the tumour would settle down later and would grow up to a clinically detectable metastasis much later than those cells that were released spontaneously by the tumour.…”