Effects of the conventional antitumor therapies surgery, chemotherapy, radiotherapy and immunotherapy on regulatory T lymphocytes in cancer patients.

BACKGROUND: Several clinical studies have clearly demonstrated that the immune status is one a major prognostic factor for the survival time in cancer patients. However the main clinical problem is to identify the most prognostically important index within the great number of immune parameters. Recently the evaluation of regulatory T (T-reg) (CD4CD25) lymphocyte count and function with respect to the T helper (TH) (CD4) number has been shown to represent the main immune parameters capable of representing the functional status of the anticancer immunity in cancer patients. This study evaluated the influence of the four main conventional anticancer therapies (surgery, chemotherapy, radiotherapy, immunotherapy) on the CD4/CD4CD25 ratio. PATIENTS AND METHODS: The study included 70 patients. The oncological treatments consisted of surgery in 14, chemotherapy in 36, radiotherapy in 12 and immunotherapy (subcutaneous low-dose, S.C.-low, interleukin, IL-2) in 8 patients. The normal value of the CD4/CD4CD25 ratio was greater then 4.0. RESULTS: Surgery induced a significant decline in the CD4/CD4CD25 mean ratio. Radiotherapy also induced also a dramatic significant decrease in the CD4/CD4CD25 ratio, whereas the effect of both chemotherapy and immunotherapy reflected the clinical response to the treatments. The CD4/CD4CD25 mean ratio was significantly enhanced in the patients who obtained control of the neoplastic growth, whereas it diminished in progressing patients. CONCLUSION: The commonly used anticancer therapies profoundly modify the levels of amounts of T-reg lymphocytes. Because of the fundamental role of T-reg cells in suppressing the anticancer immunity, thus diminishing survival, the monitoring of the CD4/CD4CD25 ratio could constitute an important clinical index during conventional anticancer therapies to predict the prognosis of cancer patients.

Free-from-progression period and overall short preoperative immunotherapy with IL-2 increases the survival of pancreatic cancer patients treated with macroscopically radical surgery.

BACKGROUND: The treatment of pancreatic cancer is still rudimentary, even in the case of locally limited tumors, because of the high frequency of recurrence due to severe suppression of the anticancer immunity that is further amplified by surgery-induced immunosuppression, evidenced by a decline in lymphocyte numbers during the postoperative period. Previous studies in colorectal cancer demonstrated that surgery-induced lymphocytopenia may be abrogated by a brief preoperative administration of IL-2. MATERIALS AND METHODS: The study included 30 consecutive patients who were randomized to be treated by radical surgery alone as a control group or by a preoperative immunotherapy with IL-2 (12 MIU/day SC for 3 consecutive days) plus surgery. RESULTS: Mean lymphocyte numbers significantly decreased in patients treated with surgery only, whereas it significantly rose in the IL-2-treated group. After a follow-up of 36 months, both the free-from-progression period (FFPP) and the overall survival were significantly higher in patients treated with IL-2. CONCLUSION: These preliminary results suggest that a short-period preoperative immunotherapy with IL-2 is sufficient to modify host tumor interactions in operable pancreatic cancer, with a subsequent abrogation of postoperative lymphocytopenia and a prolongation of FFPP and overall survival time.

Brain irradiation-induced lymphocytosis predicts response in cancer patients with brain metastases.

Lymphocytopenia is one of the main toxicities of radiotherapy and its severity is related to the irradiation dose. The occurrence of lymphocytopenia depends on the body site of radiotherapy; it is most pronounced with pelvic irradiation, whereas the effect of brain irradiation on the lymphocyte count is to be elucidated. This preliminary study was performed to evaluate changes in lymphocyte number occurring during brain irradiation in cancer patients with brain metastases. The study included 50 patients who received brain radiotherapy for single or multiple brain metastases at a total dose of 30 Gy. Overall, no significant changes in mean lymphocyte number occurred during brain radiotherapy. However, when lymphocyte variations were assessed in relation to the clinical response of brain metastases, a significant increase in the mean number of lymphocytes was found in patients who achieved objective regression of brain metastases on brain irradiation. The mean lymphocyte number decreased in nonresponding patients, albeit without a statistically significant difference with respect to the pretreatment values. The results of this study show that the efficacy of radiotherapy in the treatment of brain metastases is associated with a significant increase in mean lymphocyte number. Therefore, evidence of brain irradiation-induced lymphocytosis may predict the efficacy of radiotherapy.

A study of immunoendocrine strategies with pineal indoles and interleukin-2 to prevent radiotherapy-induced lymphocytopenia in cancer patients.

BACKGROUND: Lymphocytopenia represents one of the most evident side-effects of radiotherapy (RT), particularly in the case of irradiation of pelvis, since it is the main location of bone-marrow proliferating cells in adults. Because of the fundamental role of lymphocytes in suppressing anticancer immunity, RT-induced lymphocytopenia could negatively influence the prognosis of cancer patients and the therapeutic efficacy of RT itself. In experimental conditions, the biological toxicity of irradiation appeared to be reduced by antioxidant agents, such as pineal hormones melatonin. A preliminary study was conducted to evaluate the influence of different immunobiological strategies with pineal indoles melatonin (MLT), 5 methoxytriptamine (5-MTT) or low-dose IL-2, the lymphocyte growth factor, on pelvic irradiation-induced lymphocytopenia in cancer patients suffering from rectal cancer or uterine cervix carcinoma. PATIENTS AND METHODS: The study included 20 consecutive patients, who underwent pelvic irradiation for a total dose of 50.4 Gy. The patients were randomized to be concomitantly treated with MLT alone, with MLT plus 5-MTT or with s.c. low-dose IL-2 . RESULTS: RT induced a significant decline in the mean number of lymphocytes while neither MLT alone, nor MLT plus 5-MTT were able to significantly reduce this decline. Conversely, IL-2 caused a statistically significant reduction of the RT-induced effect, so that the mean number of lymphocytes was significantly higher in patients concomitantly treated by IL-2 than in the other groups. CONCLUSION: This preliminary study showed that low-dose IL-2 was sufficient to reduce, even though not to completely abrogate, RT-induced lymphocytopenia. Further studies with different schedules and doses of IL-2 will be required to optimize the protective effect of IL-2 on irradiation-induced lymphocytopenia in humans.

Efficacy of cancer chemotherapy in relation to synchronization of cortisol rhythm, immune status and psychospiritual profile in metastatic non-small cell lung cancer.

BACKGROUND: The prognosis of cancer and the efficacy of the various anticancer therapies depend not only on tumor characteristics, but also on the endocrine and immune status of patients. Moreover, studies have shown that the clinical course of the neoplastic disease is also influenced by the psychospiritual status of patients. It is thus probable that the influence of psychospirituality on tumor growth may be mediated by the immunoneuroendocrine system, as demonstrated by the recent advances in psychoneuroendocrinological research. However, at present there are only few data on the possible link between the psychospiritual status and immunoendocrine functions of cancer patients. This study was carried out to investigate the relationships existing among the psychospiritual profile, cortisol rhythm and lymphocyte number before and after chemotherapy, and the efficacy of chemotherapy itself in advanced cancer patients. PATIENTS AND METHODS: The study included 30 consecutive metastatic non-small cell lung cancer patients under chemotherapeutic treatment with cisplatin plus gemcitabine. The psychobiological investigations consisted of lymphocyte count, cortisol circadian rhythm, psychological profile using Rorschach test, and spiritual score, as assessed by a specific clinical test for spirituality. The control group consisted of 100 healthy volunteers. The patients who achieved a tumor regression, showed a significantly higher pre-treatment lymphocyte count and significantly lower alteration of the cortisol rhythm with respect to those who had no benefit from chemotherapy. Moreover, the lymphocyte mean number increased during chemotherapy in responder patients, whereas it progressively diminished in those who had disease progression. Lymphocytopenia and alterations of the cortisol rhythm prior to chemotherapy were associated with a loss of the psychosexual identity according the Rorschach test. Moreover, the mean spiritual score was lower in patients than in controls, although the difference was not significant. Finally, a low spiritual score prior to therapy was associated with a higher frequency of lymphocytopenia and cortisol rhythm alteration, as well as with a lower efficacy of chemotherapy itself. CONCLUSION: This preliminary study would suggest that the psychospiritual status of cancer patients may influence the efficacy of chemotherapy through the immunoneuroendocrine system.

A spiritual approach in the treatment of cancer: relation between faith score and response to chemotherapy in advanced non-small cell lung cancer patients.

BACKGROUND: The recent advances in the psychooncological and psychoneuroimmunological investigations of cancer patients has allowed the rediscovery of the importance of spiritual faith in influencing the clinical course of neoplastic disease, not only in terms of supportive care but also as a potential prognostic variable. MATERIALS AND METHODS: Clinical criteria were worked out to explore the existence of a real status of faith, in an attempt to correlate the degree of faith with the clinical response to chemotherapy, consisting of cisplatin plus gemcitabine, and the overall survival time in a group of 50 metastatic nonsmall cell lung cancer patients. RESULTS: The tumor response rate achieved in patients with a high degree of faith was significantly higher than in the other group of patients. Moreover, the mean postchemotherapeutic lymphocyte number was significantly higher in the patients with evident spiritual faith than in the other patients. Finally, the percent age of 3-year survival observed in the patients with a high degree of faith was significantly higher than that in the patients with a low faith score. CONCLUSION: This preliminary study suggests that spiritual faith may positively influence the efficacy of chemotherapy and the clinical course of neoplastic disease, at least in lung cancer, by improving the lymphocyte-mediated anticancer immune response.

A study of surgical psychoncology in breast cancer: perioperative variation of prolactin serum levels in women with operable breast cancer in relation to their maternal psychological behaviour.

BACKGROUND: The pituitary hormone prolactin (PRL) may be a potential growth factor for breast cancer. High blood levels of PRL are associated with a poor prognosis in metastatic breast cancer whereas hyperprolactinemia after breast surgery may predict a better prognosis in women with operable breast cancer. The lack of postoperative hyperprolactinemia would represent the consequence of an alteration in the neuroendocrine control of breast cell proliferation. On this basis, a study was planned to establish the relation which exists between changes in PRL perioperative secretion and the psychological maternal behaviour in women with operable breast cancer. PATIENTS AND METHODS: The study included 20 patients with operable breast cancer. Serum levels of PRL were measured before and 7 days after breast surgery. The maternal behaviour was investigated by the Rorschach test. RESULTS: Surgery-induced hyperprolactinemia occurred in 7/20 patients. The Rorschach test documented an absence of a maternal profile in 13/20 patients. The proportion of surgery-induced hyperprolactinemia was significantly higher in patients presenting a normal maternal profile than in those who lacked a maternal behaviour. CONCLUSION: The results, by showing a higher proportion of postoperative hyperprolactinemia in women with breast cancer who maintained a maternal behaviour, would suggest that the poor prognosis associated with the absence of surgery-induced hyperprolactinemia in patients with operable breast cancer may, at least in part, be the consequence of a suppression of maternal psychological behaviour.

T-helper/T-regulator lymphocyte ratio as a new immunobiological index to quantify the anticancer immune status in cancer patients.

BACKGROUND: The evaluation of the immune status of cancer patients is not routinely included in clinical oncological practice mainly because of the great number of candidate immune parameters that could potentially be the best index of the status of anticancer immunity. Until recently, the T-helper/T-suppressor lymphocyte ratio (CD4/CD8) was considered to be an index of immunosuppression in cancer patients. Successive studies documented the existence of several subtypes of CD4+ lymphocytes, as well as showing that CD8+ cells were not in fact suppressive, but cytotoxic lymphocytes. More recently, the existence of a subtype of T-helper lymphocytes has been demonstrated provided by an evident suppressive activity on anticancer immunity. These are the so-called T-regulator (T-reg) lymphocytes, which may be detected as CD4+CD25+ cells. MATERIALS AND METHODS: A study was carried out to evaluate CD4+/CD4+CD25+ ratio, corresponding to the T-helper/T-reg cell ratio (TH/TR), in a group of 50 cancer patients in relation to their disease extension and in 20 healthy controls. RESULTS: The mean TH/TR ratio observed in patients with metasytases was significantly lower with respect to that found in both patients without metastases and controls. On the contrary, the absolute mean number of T-reg cells was higher in patients with metastases than in those without, but the difference was not statistically significant. CONCLUSION: The evaluation of T-reg cells in terms of their proportion with respect to T-helper cell total number seems to be more appropriate than the simple measurement of their absolute count, in order to quantify cancer-related immunosuppression. Thus, the TH/TR ratio could represent a useful biological marker to explore the immune status of cancer patients.

Efficacy of IL-2 immunotherapy in metastatic renal cell carcinoma in relation to the psychic profile as evaluated using the Rorschach test.

BACKGROUND: Despite the well-documented importance of the psycho-emotional status in modulating the anticancer immunity, at present no study has been performed to analyse the influence of the psychological condition on the efficacy of IL-2 cancer immunotherapy. Previous clinical studies have already suggested that the evidence of anxiety may negatively affect the therapeutic efficacy of IL-2 immunotherapy of cancer. Moreover, previous psycho-oncological investigations showed that the suppression of sexual pleasure and sexual identity would represent one of the most frequent psychological profiles in cancer patients. On this basis, a study was planned in an attempt to evaluate relations existing between psychological status, analysed using the Rorschach test and efficacy of IL-2 immunotherapy in the treatment of metastatic renal cell cancer patients. PATIENTS AND METHODS: The study included 30 consecutive metastatic RCC patients. IL-2 was injected s.c. at a dose of 3 million IU twice/day 5 days/week for 4 consecutive weeks, corresponding to one complete immunotherapeutic cycle, followed by a second cycle after a 21-day rest period. RESULTS: A complete response (CR) was achieved in only 1/30 (3%) patients; a partial response (PR) was obtained in 6/30 (20%) patients. The tumor response rate (CR +PR) was 7/30 (23%) patients. The performance of a psychological analysis was accepted by 24/30 (80%) patients. A normal sexual identity was present in 7/24 (29%) patients. The tumor response rate achieved in patients with sexual identity was significantly higher compared to these who had no sexual identity or who refused the psychological investigation (p<0.05 and p<0.01, respectively). In the same way, the increase in mean lymphocyte number obtained in patients with sexual identity was significantly higher compared to that found in the other two groups of patients. CONCLUSION: This study demonstrated that the psychological status prior to treatment may be associated with the clinical response to IL-2 cancer immunotherapy.

Immune and endocrine mechanisms of advanced cancer-related hypercortisolemia.

BACKGROUND: Cancer progression depend on the immune and endocrine status of the patients. In particular, it has been observed that abnormally high levels of cortisol and/or an altered circadian secretion are associated with a poor prognosis in advanced cancer patients. The present study was performed to establish whether cancer-induced hypercortisolemia depends on an activation of the hypothalamic-pituitary axis or on a direct adrenal stimulation by inflammatory cytokines, such as IL-6, which have been proven to induce cortisol secretion. PATIENTS AND METHODS: The study included 50 metastatic solid tumor patients, who were evaluated before the onset of chemotherapy. Venous blood samples were collected in the morning to measure IL-10, IL-6, ACTH and cortisol serum levels. Moreover, to analyze its circadian secretion, cortisol levels were also evaluated on venous blood samples collected at 4.00 p.m. RESULTS: Abnormally high morning levels of cortisol were observed in 19/50 (38%) patients. Moreover, a lack of a normal circadian rhythm of cortisol was seen in 8/50 (16%) patients. None of the patients showed high levels of ACTH. Abnormally high concentrations of IL-6 and IL-10 were present in 21/50 (42%) and in 14/50 (28%) patients, respectively. Mean serum levels of both IL-6 and IL-10 were significantly higher in patients with hypercortisolemia than in those with normal cortisol values (p<0.005 and p<0.001, respectively). According to previous clinical studies, these results confirm that the advanced neoplastic disease may be associated with enhanced cortisol levels and alterations of its circadian secretion. The lack of enhanced ACTH secretion excludes the possibility that the abnormal cortisol production is due to the activation of the hypothalamic-pituitary axis. On the contrary, the evidence of significantly higher concentrations of IL-6 in hypercortisolemic patients would suggest that cancer-related enhanced cortisol production may depend on a direct adrenal stimulation by IL-6 itself The well-demonstrated stimulatory role of cortisol on IL-10 production would explain the enhanced IL-10 secretion in hypercortisolemic patients. CONCLUSION: Cancer-related hypercortisolemia would seem to depend on alterations of the feedback mechanisms between endocrine and cytokine secretions, occurring in the neoplastic disease.

Cancer chemotherapy-induced lymphocytosis: a revolutionary discovery in the medical oncology.

The recent advances in the investigation of tumor immunobiology have suggested that cancer chemotherapy, in addition to its well known cytotoxic activity, may play modulatory effects on the endogenous production of cytokines involved in the control of both tumor angiogenesis and antitumor immunity. Cancer chemotherapy constantly acts with inhibitory effects on anti-bacterial, anti-viral and anti- mycotic immune responses, whereas its action on anticancer immunity, which is mainly mediated by lymphocytes, has still to be better investigated and defined. The present study was carried out to evaluate the influence of chemotherapy on lymphocyte count and its relation to the clinical response in cancer patients suffering from the most commonly frequent tumor histotypes, including lung, colorectal, breast and prostate carcinomas. The study included 144 consecutive metastatic solid tumor patients. Lung cancer patients were treated with cisplatin plus gemcitabine, colorectal cancer patients received oxaliplatin plus 5-fluorouracil, while those affected by breast cancer or prostate carcinoma were treated with taxotere alone. An objective tumor regression was achieved in 66 out of 144 (46 percent) patients, whereas the remaining 78 patients had only a stable disease (SD)or a progressive disease. Independently of tumor histotype and chemotherapeutic regimen, a lymphocytosis occurred in patients who achieved an objective tumor regression in response to chemotherapy, and lymphocyte mean count observed at the end of the chemotherapeutic treatment was significantly higher with respect to the values seen before the onset of treatment. On the contrary, lymphocyte mean number decreased on chemotherapy in patients with SD or PD, even though the decline was statistically significant with respect to the pretreatment values in the only patients who had a PD in response to chemotherapy. This study would suggest that chemotherapy itself may paradoxically act, at least in part, as a cancer immunotherapy by inducing lymphocytosis, as well as previously demonstrated for the only immunotherapy with IL-2, probably by modulating the cytokine network and correcting the altered endogenous production of cytokines, responsible for cancer-related immunodeficiency.

A phase II study of tamoxifen in hormone-resistant metastatic prostate cancer: possible relation with prolactin secretion.

Recent experimental observations, showing the potential role of prolactin (PRL) as a tumor growth factor for prostate cancer and the unfavourable prognostic significance of enhanced chromogranin-A-secreting neuroendocrine cell proliferation, could contribute to a better understanding of the mechanisms responsible for the occurrence of hormone-resistance in the prostate cancer. Moreover, it has been shown that tamoxifen, which consistently exerts estrogenic activity in males, may inhibit prostate cancer cell proliferation in experimental studies. At present, there are no clinical data in humans. This preliminary phase II study was planned in an attempt to evaluate the therapeutic efficacy of tamoxifen in hormone-refractory metastatic prostate cancer. The study included 14 consecutive metastatic prostate cancer patients, who had progressed under the classical endocrine therapy with LHRH-analogs and/or anti-androgens. Patients received the same treatment plus tamoxifen at 20 mg/day orally. A decline greater than 50% in prostate-specific antigen (PSA) levels occurred in 4/14 (29%) patients within the first 2 months of therapy, with a median duration of 5 months. Mean pre-treatment levels of PRL were significantly higher in responder patients than in those who progressed. Moreover, abnormally high pre-treatment levels of PRL were found in 5/14 (36%) patients. The percent of clinical responses observed in patients with pre-treatment hyperprolactinemia was significantly higher than that found in patients with normal pre-treatment PRL concentrations. Finally, a significant decline in mean PRL levels upon tamoxifen therapy occurred only in the responder patients. This preliminary study seems to justify further clinical research to confirm the potential efficacy of tamoxifen in the treatment of hormone-refractory prostate cancer and to identify possible parameters, which may predict the response to treatment.

The favorable prognostic significance of surgery-induced hyperprolactinemia in node-positive breast cancer patients: ten-year disease-free survival results.

It has been shown that each manipulation of the mammary region, including breast surgery, may stimulate prolactin secretion. However, it has also been observed that in more than 50% of breast cancer patients surgical removal of the tumor is not followed by enhanced prolactin secretion. This might be indicative of an altered psychoneuroendocrine control of the mammary gland, which could lead to the onset of more biologically aggressive breast cancer. In fact, surgery-induced hyperprolactinemia has been proven to be associated with a better prognosis in terms of survival in node-negative breast cancer patients. The present study was performed to investigate the impact of postoperative hyperprolactinemia on the disease-free survival (DFS) of breast cancer patients with axillary node involvement. The study included 100 consecutive node-positive breast cancer patients who were followed for at least 10 years. Surgery-induced hyperprolactinemia occurred in 45/100 (45%) patients without any significant correlation with the main prognostic variables including number of involved nodes and ER status. The two groups of patients received the same adjuvant therapies. After a median follow-up of 151 months, the recurrence rate in patients with surgery-induced hyperprolactinemia was significantly lower than in patients with no postoperative hyperprolactinemia (23/45 vs 43/55, p<0.01). Moreover, DFS was significantly longer in hyperprolactinemic patients than in patients who had no enhanced secretion of prolactin postoperatively. In agreement with the results described previously in node-negative breast cancer, our study demonstrates the favorable prognostic significance of surgery-induced hyperprolactinemia in terms of DFS duration also in breast cancer patients with axillary node involvement, independent of the other well-known prognostic variables, thereby confirming that the psychoneuroendocrine status of cancer patients may influence the prognosis of their disease.

Radiotherapy-induced lymphocytopenia: changes in total lymphocyte count and in lymphocyte subpopulations under pelvic irradiation in gynecologic neoplasms.

Lymphocytopenia is one of the most negative biological prognostic factors in cancer patients. Lymphocytopenia may depend on tumor progression, or on various anticancer therapies. In particular, radiotherapy (RT) may induce direct lymphocyte damage. The present study was carried out to evaluate the influence of pelvic irradiation on lymphocyte number and lymphocyte subpopulations in patients with gynecologic tumors. The study included 40 patients affected by locally limited or advanced uterine tumors, who underwent pelvic irradiation for a total dose of 50.4 Gy. RT induced a significant decline in total lymphocyte number, with values lower than 500/mm3 in 29/40 (73%) patients and with a mean decrease of 71 +/- 4%. In the same way, T lymphocyte, CD4, CD8 and NK cell mean numbers significantly decreased under RT. The decline in NK and CD8 cells was limited to the first 2-3 weeks of irradiation, whereas that involving T lymphocytes and CD4 cells was progressive and persistent until the end of RT. Finally, the decline in total lymphocyte number was significantly greater in patients who had no tumor regression in response to RT. This study confirms that pelvic RT may induce severe lymphocytopenia which could negatively influence the efficacy of RT itself.

Cortisol response to an acute injection of IL-2 in healthy subjects and cancer patients: a first immunoneuroendocrine standardized clinical test to explore the interactions between immune and neuroendocrine systems.

Preliminary clinical studies would suggest that the immune alterations characterizing severe human illnesses, such as autoimmune diseases and cancer itself, may depend at least in part on an anomalous psychoneuroendocrine regulation of the immunity. Unfortunately, at present the psychoneuroimmune interactions may be clinically investigated only by separately analyzing the neuroendocrine and the immune systems, since there is no standardized clinical test capable of detecting the physiological response of the endocrine secretion to an immune stimulation. One of the main endocrine functions influenced by the immune activation is the hypothalamic-pituitary-adrenal axis. In fact, several cytokines have appeared to stimulate cortisol secretion by acting at a central site. On this basis, a study was planned to evaluate cortisol response to an acute IL-2 injection in healthy subjects and metastatic cancer patients, in an attempt to standardize a clinical neuroendocrinoimmune test capable of documenting possible alterations of the link between neuroendocrine and immune systems. The study included 10 healthy subjects as a control group and 10 cancer patients with metastatic disease. Control subjects were evaluated in basal conditions to determine the physiological circadian rhythm of cortisol, and after the subcutaneous (SC) injection of IL-2 (3 and 9 million IU). IL-2 at 3 million IU stimulated cortisol release in all healthy controls and in none of the cancer patients. IL-2 at 9 million IU induced a significant increase in cortisol mean levels in cancer patients, whose values, however, were still significantly lower with respect to those seen in controls in response to IL-2 at 3 million IU. No important IL-2 related side-effect occurred. This study shows that an acute SC injection of low-dose IL-2 with a following evaluation of cortisol secretion may constitute a first standardized immunoendocrine test, capable of exploring the status of the physiological link between neuroendocrine and immune systems, and of documenting the existence of important alterations in human diseases related to an immune dysfunction, such as advanced cancer, which has appeared to be characterized by a hyposensitivity of the hypothalamic-pituitary-adrenal axis to an acute cytokine administration.

Enhancement of the efficacy of chemotherapy with oxaliplatin plus 5-fluorouracil by pretreatment with IL-2 subcutaneous immunotherapy in metastatic colorectal cancer patients with lymphocytopenia prior to therapy.

The present study was carried out to evaluate the influence of a short-period IL-2 administration on the efficacy of chemotherapy in metastatic colorectal cancer patients with pretreatment lymphocytopenia, which was defined as a lymphocyte count of less than 1500/mm3. The study included 144 consecutive metastatic colorectal cancer patients, who underwent chemotherapy with oxaliplatin plus 5-fluorouracil. Lymphocytopenia was seen in 41/144 (28%) patients, who were randomized to receive chemotherapy alone or chemotherapy after a prechemoimmunotherapy with IL-2 (3 MIU twice/day for 3 consecutive days), whereas patients with a normal pretreatment lymphocyte count received only chemotherapy. A normalization of the lymphocyte number was achieved in 12/19 lymphocytopenic patients pretreated with IL-2. The objective tumor regression rate achieved in patients with a normal lymphocyte count prior to chemotherapy was significantly higher compared to that obtained in lmphocytopenic patients treated with chemotherapy alone (54/103 vs. 3/22, p < 0.01), whereas no significant difference occurred between patients with normal lymphocyte count and lymphocytopenic patients pretreated with IL-2 (54/103 vs. 8/19). This study confirms that pretreatment lymphocytopenia is associated with reduced efficacy of chemotherapy in metastatic colorectal cancer patients. Moreover, it suggests that pretreatment with IL-2 before the onset of chemotherapy may enhance the efficacy of chemotherapy in lymphocytopenic patients. Therefore, the administration of IL-2 before the onset of chemotherapy to improve the immune status of cancer patients may be considered as a new chemoimmunotherapeutic combination, which may be recommended in the treatment of advanced cancer patients, particularly in those with cancer-related immune alterations.

Acute effects of pamidronate administration on serum levels of interleukin-6 in advanced solid tumour patients with bone metastases and their possible implications in the immunotherapy of cancer with interleukin-2.

Bisphosphonates are potent inhibitors of bone resorption and are commonly used in the treatment of bone metastases. In addition, they seem to influence cytokine secretion. Since the efficacy of IL-2 cancer immunotherapy, in part, depends on endogenous cytokine secretion, bisphosphonates could be effective in modulating IL-2 activity. High pretreatment levels of IL-6 seem to correlate with resistance to IL-2. On this basis, a pilot study was performed to evaluate the in vivo effects of the bisphosphonate, pamidronate, on blood levels of IL-6. The study included 7 patients with bone metastases due to solid tumours. Pamidronate was injected intravenously at 60 mg over 3 h. Venous blood samples were drawn before, at 1-h intervals during pamidronate infusion, then after 1 and 3 days. Mean serum levels of IL-6 significantly decreased during pamidronate infusion, then after 1 and 3 days, IL-6 mean levels still remained lower than control level, but differences were not significant. This preliminary study shows that pamidronate infusion induces a rapid but transient decline in IL-6 blood concentrations, and suggests a possible use of bisphosphonates to modulate the efficacy of IL-2 cancer immunotherapy.

Increase in soluble interleukin-2 receptor and neopterin serum levels during immunotherapy of cancer with interleukin-2.

Both immunostimulatory and immunosuppressive events would occur during the immunotherapies of cancer, including interleukin 2 (IL-2) therapy. The marked increase in soluble IL-2 receptor (SIL-2R) levels during IL-2 therapy could represent a potentially negative biological effect, because of the receptor's capacity to bind IL-2 and compete for it with IL-2 cell surface receptor. Since it has been observed that macrophages stimulate in vitro the release of SIL-2R, a study was started to evaluate in vivo the role of macrophages in IL-2-induced SIL-2R rise by measuring neopterin, which is a marker of macrophage activity. The study included 9 advanced renal cancer patients, treated subcutaneously with IL-2 at 1.8 x 10(6) IU/m2 twice daily for 5 days/week for 6 weeks. Both SIL-2R and neopterin serum mean levels significantly increased during IL-2 treatment, and the highest concentrations were reached on the second week of therapy. SIL-2R rise was significantly correlated to that of neopterin. This study, by showing a positive correlation between SIL-2R and neopterin rise, would suggest a macrophage involvement in the stimulation of SIL-2R release during IL-2 immunotherapy of cancer.

Is there a role for melatonin in the treatment of neoplastic cachexia?

It is known that neoplastic cachexia shows metabolic characteristics different from other common causes of malnutrition, and that it is mainly due to an abnormal secretion of TNF, whose levels are often high in patients with advanced neoplasia. Previous clinical studies have suggested that the pineal hormone melatonin (MLT), which plays an essential role in the neuroendocrine regulation of biological systems, may improve the clinical status of advanced cancer patients and inhibit TNF secretion. To investigate the relationship between MLT, TNF and cancer-related weight loss, 100 untreatable metastatic solid tumour patients entered this study to receive either supportive care alone, or supportive care plus MLT (20 mg/day orally in the evening). Patients were observed for 3 months, and were considered evaluable when they were observed for at least 2 months. There were 86 evaluable patients, the other 14 patients having died from rapid progression of disease. The per cent of weight loss greater than 10% was significantly higher in patients treated by supportive care alone than in those concomitantly treated by MLT, with no difference in food intake (P < 0.01). Mean serum levels of TNF progressively increased in the supportive care group, but to levels that were not significantly different from pretreatment values. In contrast, TNF mean concentrations significantly decreased (P < 0.05) in patients concomitantly treated by MLT. These results suggest that the pineal hormone MLT may be effective in the treatment of the neoplastic cachexia by decreasing TNF blood concentrations.

Interleukin-12 in early or advanced cancer patients.

Interleukin-2 (IL-2) and interleukin-12 (IL-12) may represent the most important antitumour cytokines in human neoplasms. IL-2 blood levels decrease in advanced solid malignancies, but currently there are no data on IL-12 secretion in cancer patients. This study was performed to obtain preliminary data about IL-12 secretion in patients with solid malignant tumours, either in relation to the extension of disease, or to other cytokines, including IL-2, IL-6 and IL-10. The study included 40 solid cancer patients, 24 of whom showed distant organ metastases. Cytokine serum levels were measured by an enzyme immunoassay of blood samples collected during the morning. No patient had abnormally low levels of IL-12, but the levels were high in 14/14 (35%) patients. Mean levels of IL-12 were significantly higher in metastatic patients compared with non-metastatic patients (P < 0.05). Moreover, metastatic patients with high blood concentrations of IL-12 showed significantly lower levels of IL-10 than metastatic patients with normal IL-12 values, while no difference was seen in IL-2 mean concentrations. IL-6 mean levels were lower in metastatic patients with increased IL-12 levels, but this was non-significant. This preliminary study shows that advanced solid cancers are not characterised by a diminished secretion of IL-12, but rather IL-12 levels tend to be abnormally high in metastatic cancer patients.