Pedro Bilbao

The role of re-irradiation of secondary and recurrent head and neck carcinomas. Is it a potentially curative treatment? A practical approach

Despite aggressive efforts to cure head and neck cancer patients, including altered fractionation and the addition of chemotherapy to radiation, locoregional recurrence remains a serious issue to face in clinical practice. Indeed, recurrent and second primary tumors occurring in previously irradiated area are common clinical challenge. Whenever possible, patients are advised to undergo salvage surgery. Nevertheless, few patients are suitable candidates for curative resection. In such cases, chemotherapy alone has traditionally been considered, with a poor response rate. It has been questioned whether re-irradiation toxicity outweighs the potential benefits, considering that the median survival of re-irradiated patients marginally exceeds the benefits observed with chemotherapy alone. However, full-dose re-irradiation is a viable treatment option, offering long-term survival for selected patients. Moreover, several prognostic factors should be considered for patients undergoing re-irradiation, such as basic patient characteristics, performance status, the location and extension of recurrent disease, patient co-morbidities, current speech and swallowing function, the interval from the initial radiation therapy to recurrence, previously received doses by critical structures and prior treatment toxicity. Nevertheless, several questions remain unanswered. The purpose of this review is to evaluate the major issues in the field of re-irradiation regarding the current evidence. Therefore, the major selection criteria and new treatment strategies are discussed to define the ideal candidates to undergo re-irradiation and describe a practical approach to these patients. Given the limited evidence in this field, the optimal treatment of recurrent and second primary cancers remains to be defined. Future prospective study of this approach is warranted.

Interleukin-2 increases intracellular glutathione levels and reverses the growth inhibiting effects of cyclophosphamide on B16 melanoma cells

Glutathione (GSH) plays an essential role in the metabolism of melanoma. As changes in intracellular GSH content can modify the processes of cell proliferation and detoxification, this could determine the therapeutic response to some cancer treatment strategies. The purpose of this study was to test the effects of treatment with interleukin-2 (IL-2), alone and in combination with cyclophosphamide (CY), on survival of mice bearing B16 melanoma liver metastases, and to determine the influence of these therapeutic agents on the GSH metabolism of B16 cells. In the in vivo test system, B16 melanoma liver metastases were induced in C57BL/6 mice which were subsequently treated with IL-2, CY and CY plus IL-2. Survival time was used to determine the response to treatment. In the in vitro system, we evaluated the effects of IL-2, acrolein (an active metabolite of CY responsible for GSH depletion) and acrolein plus IL-2 on GSH levels and proliferation of B16 melanoma cells. Results indicated that, in vivo, all treatments increased mouse survival times with respect to control mice. However, the addition of IL-2 to CY therapy decreased survival time compared with treatment with CY alone. In vitro, whereas acrolein produced a GSH depletion and inhibited B16 cell proliferation, IL-2 increased GSH content and cell proliferation rate compared with untreated cells. Moreover, addition of IL-2 to cells preincubated with acrolein increased GSH levels and proliferation with respect to acrolein alone. In summary, the data suggest that GSH plays a critical role in the growth-promoting effects of IL-2 on B16F10 melanoma cells and in the antagonistic effect of IL-2 on CY inhibitory activity on these tumor cells.

Effects of L-2-oxothiazolidine-4-carboxylate on the cytotoxic activity and toxicity of cyclophosphamide in mice bearing B16F10 melanoma liver metastases.

&NA; Glutathione (GSH) is the major non‐protein thiol in cells that plays a critical role against damage from electrophilic agents such as alkylating drugs. Selective therapeutic GSH elevation in normal but not in tumour cells has been suggested as a means of protecting host tissues against more intense doses of chemotherapy. The present study investigated the response of B16 melanoma to treatment with the cysteine pro‐drug L‐2‐oxothiazolidine‐4‐carboxylate (OTZ), alone and in combination with cyclophosphamide (CY). We found that OTZ decreased the GSH levels and proliferation rate of B16 melanoma cells in vitro, sensitizing them to the cytotoxic action of the activated metabolite of CY, acrolein (AC). In contrast to OTZ, the cysteine deliverer N‐acetylcysteine (NAC) enhanced B16 melanoma cell proliferation by increasing GSH levels, and markedly decreased the sensitivity of these tumour cells to AC. In vivo studies showed the antitumoral activity of OTZ in B16 melanoma liver meta‐stasis‐induced mice, increasing their life span. We also observed that, whereas with CY treatment the GSH levels in peripheral blood mononuclear cells (PBMCs) were reduced and a dose‐dependent leukopenia was produced, OTZ significantly increased PBMC GSH content, reducing toxicity and enhancing the survival of mice bearing established melanoma liver metastases treated with lethal dose CY. These results suggest a critical role for OTZ in protecting against alkylator agent‐induced immunosuppression, which may allow the dose escalation of these cytostatic drugs to improve their therapeutic benefit in the treatment of malignant melanoma.

Patterns of Care for Brachytherapy in Europe: Facilities and resources in brachytherapy in the European area

PURPOSE The objective of the survey was to obtain detailed information on the use of brachytherapy through a web-based questionnaire. The present article describes the resources available in 2002. METHODS AND MATERIALS The European area was divided into three groups: Group I included the 15 original member countries of the European Union plus 4 others according to economic wealth; Group II included the 10 most recent members of the European Union; and Group III included 14 other European countries. A national coordinator was designated for each country with a general coordinator to oversee the project to encourage the participation of every radiotherapy center. RESULTS Three hundred forty-eight (47.2%) of the responding centers provided brachytherapy services and, compared to data from 1997, most showed a significant increase in the mean number of brachytherapy patients per center. The average number of radiation oncologists involved in brachytherapy was similar in the three groups. The average workload estimated in hours per week at the cancer centers was, however, higher in Groups II and III. Most centers had at least one treatment planning system, although in Group I 7.7% of the centers had three or more treatment planning systems. CONCLUSIONS Notable differences in brachytherapy treatment were observed, especially in the workload of radiation oncologists and physicists in Groups II and III, the two groups with largest number of patients. New surveys can provide a detailed analysis of changes over time, a potentially useful tool to eliminate the differences observed.

Tunicamycin Treatment Reduces Intracellular Glutathione Levels: Effect on the Metastatic Potential of the Rhabdomyosarcoma Cell Line S4MH

Highly metastatic cells are known to overexpress certain Asn-linked oligosaccharides in the plasmatic membrane. Another phenotypic characteristic of malignant cells consists in the expression of high levels of intracellular glutathione (GSH). The aim of the present work was to demonstrate that the inhibition of N-glycosylation induces changes in intracellular GSH levels, and in turn participates in the inhibition of the metastatic potential of tumor cells by tunicamycin treatment. Firstly, we demonstrated that in comparison to the poorly metastatic cell line F21, the highly metastatic cells S4MH express a higher number of Asn-linked β1–6 branched oligosaccharides and sialic acid (SA) and/or chitobiose oligosaccharides in glycoproteins involved in the regulation of the adhesion efficiency of tumor cells on endothelial cells and extracellular matrix. Our results showed that the decrease in S4MH cell adhesion efficiency on endothelial cells and extracellular matrix after the inhibition of N-glycan processing by tunicamycin treatment was caused by: (1) inhibition of the expression of N-glycan structures recognized by endothelial endogenous lectins, including β1–6 branched oligosaccharides and SA and/or chitobiose oligosaccharides, and (2) redistribution of cell surface glycoproteins with β1–6 branched oligosaccharides and/or SA and/or chitobiose oligosaccharides in their structures, caused by the depletion of intracellular GSH levels. The latter condition prevents the organization of these glycoproteins in the plasmatic membrane of S4MH cells necessary for anchoring to the substratum.

A prospective analysis of factors that influence weight loss in patients undergoing radiotherapy

Malnutrition occurs frequently in patients with cancer. Indeed, a variety of nutritional and tumor-related factors must be taken into account in these patients. Recognizing this relationship, we aimed to prospectively evaluate the risk factors that influence weight loss in patients undergoing radiotherapy with oral nutritional supplementation and dietetic counseling. Weight loss of 74 patients during radiotherapy and 1 month after treatment was analyzed. Parameters such as age, gender, tumor location, tumor stage, Eastern Cooperative Oncology Group performance status (ECOG PS) score, and the use of chemotherapy were analyzed to evaluate their influence on weight loss. All patients underwent oral nutritional supplementation and dietetic counseling. Forty-six (65.7%) patients lost weight, with a mean weight loss of (4.73 ± 3.91) kg, during radiotherapy. At 1 month after treatment, 45 (66.2%) patients lost weight, presenting a mean weight loss of (4.96 ± 4.04) kg, corresponding to a (6.84 ± 5.24)% net reduction from their baseline weight. Head and neck cancer patients had a mean weight loss of (3.25 ± 5.30) kg, whereas the remaining patients had a mean weight loss of (0.64 ± 2.39) kg (P = 0.028) during radiotherapy. In the multivariate analysis, the head and neck tumor location (P = 0.005), use of chemotherapy (P = 0.011), and ECOG PS score of 2-3 (P = 0.026) were considered independent risk factors. Nutritional status and parameters, such as tumor location (especially the head and neck), the use of chemotherapy, and the ECOG PS score, should be evaluated before radiotherapy because these factors can influence weight loss during radiotherapy and 1 month after treatment.

Patterns of care for brachytherapy in Europe (PC BE) in Spain and Poland: Comparative results

Summary Background Cancer incidence and its mortality depend on a number of factors, including age, socio-economic status and geographic situation, and its incidence is growing around the world [1]. Cancer incidence in Europe is now about 4000 patients per million per year and due to the ageing population a yearly increase of 1–1.5% in cancer cases is estimated in the next two decades [2–4]. Most of the cancer treatments will include external beam radiotherapy or brachytherapy. Brachytherapy has increased its use as a radical or palliative treatment and become more sophisticated with the spread of pulsed dose rate and high dose rate afterloading machines, and the use of new planning systems has additionally improved quality of treatment [5–14] Aim The aim of the present study was to compare two countries (Poland and Spain) and to report the differences in the use of brachytherapy in these countries. For this reason, several characteristics related to brachytherapy were compared. Materials/Methods The data used were collected using a website questionnaire for the year 2002 where every centre that participated in the survey could introduce, change or update the information requested. Hospitals included in the study were those that provided data on brachytherapy, because our objective was to compare the brachytherapy facilities between Poland and Spain. Results Data were available for 22 centres in Poland and 39 centres in Spain that provided brachytherapy in 2002. Spain having more centres that applied brachytherapy (1.0 centre per 1,000,000 inhabitants in Spain vs. 0.6 centre per 1,000,000 inhabitants in Poland), the average number of brachytherapy patients per centre is lower in Spain than in Poland, 137 and 382 respectively. The 5 main tumour sites treated with brachytherapy in Poland were: gynaecological (73.7%), bronchus (13.0%), breast (2.8%), prostate (2.4%) and head and neck (1.6%). In Spain they were: gynaecological (59.7%), breast (15.4%), prostate (12.8%), head and neck (4.2%) and bronchus (1.5%). Statistically significant differences were found in the number of gynaecological, bronchial and breast brachytherapy patients between the countries. Conclusions Although both countries belong to the European Union, there were observed several differences in the use of brachytherapy. We also found some differences in the brachytherapy techniques used in prostate and head and neck cancers.

The addition of interleukin-2 to cyclophosphamide therapy can facilitate tumor growth of B16 melanoma

The role of interleukin-2 (IL-2) on tumor growth of B16F10 melanoma cells was assessed in two sets of mice with different immune status: normal (immunocompetent) mice and immunodeficient mice. The two sets of animals were treated with cyclophosphamide (CY) or IL-2 alone or with a combined therapy of CY+IL-2. On days 6 and 10 after tumor cell injection, we evaluated the incidence of hepatic B16 melanoma metastases and the percentage of hepatic volume occupied by metastatic tissue. We observed that the CY alone (300 mg/kg, days 3 and 8 post-tumoral inoculation) significantly reduced tumor growth in all treated mice; however, CY proved more effective in normal recipients than in immunodeficient hosts. On the other hand, whereas administration of IL-2 alone (105 IU daily, from day 3 to day 7) in immunocompetent mice significantly reduced tumor growth on days 6 and 10, in immunodeficient mice, no significant differences were observed in tumor growth either on the 6th or on the 10th day, in comparison to control groups. Finally, when the combined CY+IL-2 therapy was administered, an antisynergistic effect between these therapeutic agents was achieved both in normal and in immunodeficient mice. Thus, the addition of low-dose IL-2 (25×103 IU daily, from day 4 to day 7) to high-dose CY (300 mg/kg, days 3 and 8) significantly increased tumor growth in both the early and later periods, compared to the effect of CY alone. It is concluded that exogenous IL-2 can facilitate tumor growth of B16 melanoma cells in vivo.

Patterns of care for brachytherapy in Europe: updated results for Spain

ObjectiveThe aim of this follow-up pattern of care study was to evaluate current clinical practices, staffing and equipment, and to compare these results to a study performed 5 years previously.Materials and methodsThis descriptive, pattern of care study was carried out via an online questionnaire. The survey was sent to a total of 95 cancer care centres in Spain.ResultsSeventy-three centres (76.8%) responded to the survey. More than half (57.5%) of responding centres offered brachytherapy (BT). A mean of 120 patients/centre were treated by BT in 2007. The most common localisations were the endometrium (29.6% of cases), prostate (29.6%), cervix uteri (14.6%), breast (12.6%), head and neck (3.6%) and vagina (2.5%). Other sites accounted for less than 2% of cases each. Most centres that offered BT (33/40=82.5%) were equipped with a dedicated BT operating room. The most commonly reported dosimetric method was CT dosimetry (31 of 40 centres=77.5%), followed by plain film (30/40=75%), ultrasound (26/40=65%), MRI (8/40=20%), in vivo (7/40=17.5%) and PET-CT (5/40=12.5%) dosimetry.ConclusionThe three most common treatment sites (gynaecological, breast and prostate) remain unchanged from 2002, with prostate treatments showing large increase. Advanced dosimetric techniques (MRI, PET-CT and CT-dosimetry) continue to gain adherents. Some centres treat small numbers of patients, a finding that deserves more attention in terms of cost and quality of care. Although BT remains strong in Spain, it could be further strengthened by making modern dosimetric techniques and treatments more widely available.

PATTERNS OF CARE FOR BRACHYTHERAPY IN EUROPE, IN SPAIN AND ITALY: COMPARATIVE RESULTS

Aims and Background The aim of the study was to compare the facilities for brachytherapy in two similar countries, as are Italy and Spain. This survey reports the differences in the use of brachytherapy in these countries. Methods The data regarding brachytherapy was obtained in 2002 by means of a specially designed web site, because Internet allowed the access to the questionnaire in an easy and safe way. In the first edition of the survey, only the countries in which more than 50% of its centers had completed the questionnaire were included. Among these countries there were Italy and Spain. Results Data was available in 127 centers in Italy and 72 centers in Spain, where 35 and 39, respectively, provided brachytherapy. Although both countries had a similar number of radiotherapy patients and the average number of radiotherapy patients per center was similar in both countries (P = 0.29), there were several differences related to brachytherapy. For instance, the mean number of radiation oncologists regularly performing brachytherapy per center was higher in Spain (P = 0.001). There were also differences in the average number of patients per center in the following tumor sites: breast (P <0.001) and gynaecological (P <0.001). In fact, the average number of patients per center who were treated with brachytherapy in these tumor sites was higher in Spain than Italy. Conclusions Although the estimated workload of the radiation oncologists, physicists and radiation technologists was higher in Spain, no statistically significant differences were found in the average number of patients per center for the following tumor sites: bronchus, head and neck, intracoronary, esophagus, prostate, rectum and skin. Several differences in the use of the brachytherapy procedures applied were also found.