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.

Efficacy of HT 7 point acupressure stimulation in the treatment of insomnia in cancer patients and in patients suffering from disorders other than cancer.

AIM: The induction of sleep would depend on interaction between gabaergic system and the pineal gland through its main hormone melatonin. Until few years ago benzodiazepines were the only drugs effective in the treatment of insomnia. Recently, however, both melatonin and acupressure have appear to be active in sleep disorders. The aim of study was to evaluate the efficacy of HT 7 point acupressure in insomnia. METHODS: The study enrolled 25 patients affected by sleep disorders, 14 of whom had a neoplastic disease. They were treated by HT 7 stimulation for al least two consecutive weeks using a medical device named H7 Insomnia Control. RESULTS: An improvement in the quality of sleep was achieved in 15/25 (60%) patients, with a more evident efficacy in cancer patients (11/14 [79%]). CONCLUSION: This study confirms previous clinical data showing the efficacy of acupressure in the treatment of sleep disorders, particularly in cancer-related insomnia.

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.

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.

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.

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.

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 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.

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.

Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms.

It is known since many years that the pineal hormone melatonin (MLT) may play anticancer activity through several mechanisms, including antiproliferative and immunostimulating effects. Moreover, it exerts an important antioxidant action. Therefore, MLT could be useful in the treatment of human neoplasms, either alone or in association with chemotherapy. The present study was performed to evaluate the influence of a concomitant MLT administration on efficacy and toxicity of several chemotherapeutic combinations in metastatic solid tumor patients, suffering from non-small cell lung cancer (NSCLC) or gastrointestinal tumors. The study included 370 patients who were randomized to receive chemotherapy alone or chemotherapy plus MLT (20 mg/day orally in the evening every day). NSCLC patients received cisplatin (CDDP) plus etoposide or CDDP plus gemcitabine. Colorectal cancer patients were treated with oxaliplatin plus 5-fluorouracil (5-FU), or weekly CPT-11 or 5-FU and folates (FA). Finally, gastric cancer patients received CDDP, epirubicin, 5-FU and FA or weekly 5-FU plus FA. The overall tumor regression rate achieved in patients concomitantly treated with MLT was significantly higher than that found in those treated with chemotherapy alone. Moreover, the 2-year survival rate was significantly higher in patients concomitantly treated with MLT. These results confirm in human the anticancer therapeutic properties of the pineal hormone MLT, which may enhance the efficacy of the standard anticancer chemotherapies.

Biochemotherapy with immunomodulating pineal hormones other than melatonin: 5-methoxytryptamine as a new oncostatic pineal agent.

Several experiments have demonstrated that pineal gland plays a physiological anticancer role. Melatonin (MLT), its most investigated hormone, is a natural anticancer agent. However, MLT would not be the only endocrine molecule responsible for the anticancer property of the pineal gland. In fact, another pineal indole hormone, the 5-methoxytryptamine (5-MTT), has appeared to exert in vitro an antitumour activity superior to that of MLT itself. Previous studies have already shown the therapeutic anticancer action of MLT in association with chemotherapy also in human neoplasms. This study was performed to evaluate the influence of 5-MTT at physiological doses (1 mg/day orally during light phase) on the efficacy of chemotherapy with cisplatin plus etoposide in advanced non-small cell lung cancer patients with respect to that obtained in patients treated by chemotherapy alone or chemotherapy plus pharmacological doses of MLT (20 mg/day orally during the dark phase of the day). The study included 100 patients, who were randomised to receive chemotherapy alone or in association with MLT or 5-MTT. The overall response rate achieved in both patients concomitantly treated with MLT or 5-MTT was significantly higher with respect to that obtained in patients treated with chemotherapy alone. Moreover, both MLT and 5-MTT significantly reduced some chemotherapy-related toxicities, namely thrombocytopenia and neurotoxicity. This preliminary study shows that less known pineal hormone 5-MTT may exert at low doses the same anticancer therapeutic effect in association with chemotherapy, which may be obtained by pharmacological doses of the most investigated pineal hormone MLT.

A progress study of 100 cancer patients treated by acupressure for chemotherapy-induced vomiting after failure with the pharmacological approach.

AIM: The recent rediscovery of the natural traditional medical sciences has contributed to improve the treatment of the human diseases and, in particular, it has been shown that the pharmacological approach is not the only possible strategy in the treatment of nausea and vomiting, since bioenergetic approaches, such as acupressure and acupuncture, may also counteract the onset of vomiting due to different causes. Previous preliminary clinical studies had already suggested a possible efficacy of acupressure also in the treatment of chemotherapy-induced vomiting resistant to the classical antiemetic drugs. The aim of this study was to confirm these preliminary data. METHODS: The study was performed in 100 consecutive metastatic solid tumour patients, who underwent chemotherapy for their advanced neoplastic disease, and who had no benefit from the standard antiemetic agents, including corticosteroids, antidopaminergics and 5-HT 3R-antagonists. Acupressure was made by a stimulation of PC6 acupoint. RESULTS: The emetic symptomatology was reduced by acupressure in 68/100 (68%) patients, without significant differences in relation to tumour histotype. The lowest efficacy was observed in patients treated by anthracycline-containing regimens, without, however, statistically significant differences with respect to the other chemotherapeutic combinations. CONCLUSION: This study confirms previous preliminary clinical results, which had already suggested the potential efficacy of acupressure in the treatment of vomiting due to cancer chemotherapy. Therefore, acupressure may be successfully included within the therapeutic strategies of cancer chemotherapy-induced vomiting.

A case-control study of Panicum Miliaceum in the treatment of cancer chemotherapy-induced alopecia.

AIM: Alopecia still remains one of the most untreatable side-effects induced by cancer chemotherapy. According to the phytotherapeutic tradition, Panicum Miliaceum has been proven to be effective in the prevention of hair loss for different reasons. At present, however, there are no data about its possible efficacy in the treatment of cancer chemotherapy-induce alopecia. The aim of this study was to analyze the efficacy of Panicum Miliaceum in cancer patients treated with the most potent chemotherapeutic drugs in terms of hair loss, consisting of cisplatin (CDDP) and anthracyclines. METHODS: This case-control study included 28 cancer patients concomitantly treated with Panicum Miliaceum and 56 patients receiving the same combinations of chemotherapy alone as a control group. Panicum Miliaceum was given orally at 300 mg (daily dose) 3 times per day, every day until the end of chemotherapy. The grade of hair loss was assessed by World Health Organization (WHO) criteria. RESULTS: The percentage of alopecia of third grade observed in patients concomitantly treated with Panicum Miliaceum in association with CDDP-containing regimens was significantly lower than that found in those who received the chemotherapy only. The percentage was also lower under anthracycline-containing schedules, without, however, statistically significant differences. Panicum Miliaceum therapy was substantially well tolerated in all patients. RESULTS: This preliminary study would suggest that the concomitant treatment with Panicum Miliaceum may be effective in preventing hair loss induced by CDDP-containing chemotherapies, whereas the benefit was lower in patients treated with anthracyclines. Future randomized studies will be necessary to confirm these preliminary

Effect of acupressure on nausea and vomiting induced by chemotherapy in cancer patients.

AIM: Corticosteroids, antidopaminergig agents and 5-HT3 antagonists are the most commonly used drugs in the treatment of chemotherapy-induced vomiting. Acupuncture and acupressure have also appeared to exert antiemetic effects. The aim of this study was to evaluate the efficacy of acupressure in the treatment of chemotherapy-induced vomiting resistant to the standard antiemetic therapies. METHODS: The study included 40 consecutive advanced cancer patients with untreatable chemotherapy-induced vomiting. Colorectal cancer, lung cancer and breast cancer were the neoplasm most frequent in our patients. According to tumour histotype, patients received chemotherapeutic regimens containing the main emetic cytotoxic agents, including cisplatin and athracyclines. Acupressure was made by PC6 point stimulation for at least 6 h/day at the onset of chemotherapy. RESULTS: The therapeutic approach was well accepted by the overall patients. An evident improvement in the emetic symptomatology was achieved in 28/40 (70%) patients, without significant differences in relation to neither tumor histotype, nor type of chemotherapeutic agent. CONCLUSIONS: This preliminary study seems to suggest that a bioenergetic approach by acupressure on PC6 point may be effective in the treatment of chemotherapy-induced vomiting resistant to the conventional pharmacological strategies, as previously demonstrated for vomiting occurring during pregnancy.

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.

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.