Supplemental material, sj-docx-1-tam-10.1177_17588359211059873 for PANHER study: a 20-year treatm... more Supplemental material, sj-docx-1-tam-10.1177_17588359211059873 for PANHER study: a 20-year treatment outcome analysis from a multicentre observational study of HER2-positive advanced breast cancer patients from the real-world setting by Laura Pizzuti, Eriseld Krasniqi, Isabella Sperduti, Maddalena Barba, Teresa Gamucci, Maria Mauri, Enzo Maria Veltri, Icro Meattini, Rossana Berardi, Francesca Sofia Di Lisa, Clara Natoli, Mirco Pistelli, Laura Iezzi, Emanuela Risi, Nicola D'Ostilio, Silverio Tomao, Corrado Ficorella, Katia Cannita, Ferdinando Riccardi, Alessandra Cassano, Emilio Bria, Maria Agnese Fabbri, Marco Mazzotta, Giacomo Barchiesi, Andrea Botticelli, Giuliana D'Auria, Anna Ceribelli, Andrea Michelotti, Antonio Russo, Beatrice Taurelli Salimbeni, Giuseppina Sarobba, Francesco Giotta, Ida Paris, Rosa Saltarelli, Daniele Marinelli, Domenico Corsi, Elisabetta Maria Capomolla, Valentina Sini, Luca Moscetti, Lucia Mentuccia, Giuseppe Tonini, Mimma Raffaele, Luca Marchetti, ...
Introduction In breast cancer patients, endocrine therapy may exert a negative impact on sexual f... more Introduction In breast cancer patients, endocrine therapy may exert a negative impact on sexual functioning in both genders, with potentially relevant consequences concerning quality of life and treatment adherence. The availability of effective interventions to maintain and/or restore sexual health in breast cancer patients is a key issue to a research agenda. Objectives To summarize and critically discuss the most updated and qualitatively relevant literature on the therapeutic approach to sexual impairment in breast cancer patients, with a focus on patients treated with endocrine therapy. Methods We searched PubMed from its inception to February 2022 for observational and intervention trials including participants with sexual dysfunctions. We were particularly interested in studies of breast cancer patients with sexual dysfunctions while undergoing endocrine therapy. We developed a search strategy with the aim of maximizing the number of articles considered for screening and pote...
Results from randomized trials evaluating taxane versus non-taxane containing regimens in adjuvan... more Results from randomized trials evaluating taxane versus non-taxane containing regimens in adjuvant breast cancer treatment indicate an advantage in DFS and OS for the taxane-arms, but the best schedule of administration, in combination with anthracyclines or in sequence, is still a debated issue, even if the sequential strategy appears to be less toxic. Up to now, the majority of clinical trials employed the "standard" sequence, with anthracycline-based combinations fi rst, followed by taxanes. Few small phase II trials evaluated the reverse sequence, with taxanes administered fi rst, most of them in metastatic or neoadjuvant setting, suggesting efficacy and lower toxicity. An important issue to be considered is the hypothesized differences in the ability of the drugs to induce cross-resistance to each other, as suggested by data of a preclinical study, and from clinical study with a cross-over design; results of these trials suggest that the best strategy would be to administer a taxane prior to an anthracycline, also according to the Norton and Simon hypothesis. Moreover, trials evaluating the best sequence of anthracyclines and taxanes in adjuvant breast cancer setting are of small sample size, and an adequately powered randomized phase III trial is needed before definitive conclusions are reached.
The survival advantage of a pronounced lymphocytic infiltration within and around the primary tum... more The survival advantage of a pronounced lymphocytic infiltration within and around the primary tumor and some hyperplastic reactions in the regional lymph nodes in specimens of colorectal cancer has been reported in many studies. However, none of these studies allowed the grade of these immunomorphological reactivities to compete with more traditional prognostic variables, using the proportional hazard models. In this study the survival rates of 219 patients who underwent operation for rectal cancer were analyzed statistically according to sex, age, tumor site, type of operation, histology, nuclear grade, p-TNM stage of disease and to the following immunomorphological parameters: lymphocytic infiltration (LI) within and around the primary tumor, paracortical activity (PCA), cortical activity (CA) and sinus histiocytosis (SH) of the regional lymph nodes. The presence of an evident local and regional immune reactivity was significantly related to a less advanced stage of disease and better differentiated tumor. The multivariate survival analysis (Cox model) identified LI, PCA and SH and p-TNM stage as independent prognostic factors. Survival within each stage progressively increased in presence of one or more favourable immunomorphologic features. These results indicate that an adequate prospective evaluation of LI, PCA and SH should improve our ability to assess prognosis in rectal cancer and, therefore, allow a more rational utilization of adjuvant therapy.
The fundamental imperative of adjuvant treatment of early breast cancer is to improve long-term s... more The fundamental imperative of adjuvant treatment of early breast cancer is to improve long-term survival and minimize toxicity. The inclusion of docetaxel in adjuvant chemotherapy regimens has improved patient survival in comparison to anthracycline-containing regimens, even if the incidence of acute side effects has increased in some studies. However, late or persistent toxic effects are becoming more important due to an increasing proportion of patients remaining disease free after treatment for early breast cancer. Several studies have recently reported that docetaxel-containing regimens without anthracyclines are equally active, and have no apparent cardiotoxicity. At present, docetaxel-based combinations represent an appropriate choice in the adjuvant treatment of HER2-negative breast cancer, and several studies are ongoing aiming at a better evaluation of the efficacy of this agent in order to optimize its role.
The predictive value of tumor lymphocytic infiltration was studied in 186 gastric cancer patients... more The predictive value of tumor lymphocytic infiltration was studied in 186 gastric cancer patients curatively resected. All patients were followed-up for over 10 years. LI was negatively correlated with p-TN stage of disease. A poorer prognosis was detected in patients with minor or no tumor lymphocytic infiltration. LI was an independent prognostic parameter according to the Cox model and logistic regression analysis. These findings suggest that LI should also have been considered in the current staging of gastric cancer.
The sentinel-node technique was first introduced by Morton in high-risk melanoma of the skin. Rec... more The sentinel-node technique was first introduced by Morton in high-risk melanoma of the skin. Recently, this technique has also been used in patients with T1 breast cancer. Lymphoscintigraphy and the gamma probe are currently used in sentinel lymph-node detection. Many investigators have used this technique in clinical practice and there is no standard procedure in terms of the timing of lymphoscintigraphy, type of vital stain, radiolabelled tracer, etc. This heterogeneity might account for the broad range of false-negatives reported in the literature. The aim of our study was to carefully review and analyse the literature in order to identify the most reliable technique for use in sentinel node detection. The results of the review seem to indicate that the simultaneous use of preoperative lymphoscintigraphy, intraoperative gamma probe and vital staining is capable of ensuring the best results. These data have been confirmed in our experience of 15 patients. The sentinel node search was successful in 100% of the cases, and the percentage of false negative was 0%. The use of the best technique available might prove extremely important, particularly in randomised clinical trials, comparing sentinel node biopsy with axillary dissection. In the patient group undergoing sentinel node biopsy, the axillary pathological staging is based exclusively on this technique and therefore its reliability must be assured if it is to serve as a precise guide in the planning of adjuvant treatments.
Primary limb melanoma may recur in terms of satellitosis, in transit metastases and/or regional n... more Primary limb melanoma may recur in terms of satellitosis, in transit metastases and/or regional node involvement. Hyperthermic antiblastic perfusion (HAP) permits the isolation of involved extremity from the systemic circulation and to deliver high doses of antineoplastic drugs. The association of cytostatic drugs to hyperthermia (> or = 41.5 degrees C) results in a synergistic effect with an increased therapeutic effectiveness. The overall 5 and 10-year survival rates in relation to the disease stages are st. II 75% and 67%; st. IIIA 59% and 42%; st. IIIAB 36% and 30% respectively. The results confirm that HAP is considered the treatment of choice of loco-regional spreading limb melanoma. Recently, the tumor necrosis factor (TNF) has been combined with Melphalan and hyperthermia. This trimodality association seems to be superior to Melphalan and hyperthermia alone only in patient with bulky tumors (i.e., multiple nodules), as a matter of fact the complete tumor response rates observed in these patients have been 67% and 20% respectively. The greater effectiveness of trimodality association has to be confirmed by multicentric randomized trials.
On the basis of personal experience and a review of the literature, the authors have evaluated th... more On the basis of personal experience and a review of the literature, the authors have evaluated the results obtained with hyperthermic antiblastic perfusion (HAP) for the treatment of stage II, III and IIIAB limb melanoma. The evaluation showed that today HAP may be considered a safe and effective treatment, with a major complication rate ranging between 1% and 4%. In terms of tumor response, locoregional control and survival, this treatment has provided better results than other regional chemotherapeutic modalities and undoubtedly better results than those obtained with conventional, even radical, surgery. The multivariate analysis showed that, of the treatment-related prognostic factors, the minimum tumor temperature influenced the percentage of complete response (CR) to the greatest extent (P<0.03), with a positive trend also with regard to the dosage of the antiblastic drug employed (P<0.08). In turn, the complete response rate was a determinant as far as locoregional control (50%; P<0.0009) and disease-free (51.4%; P=0.0009) and overall survival (63%; P<0.009) rates were concerned. Of the tumor-related prognostic factors, the number of lesions (P<0.0014), sex (P<0.04), and the number of disease recurrences (P<0.01) appear to influence overall survival.
Adjuvant treatment in hormone-receptor positive, HER2-negative early breast cancer is controversi... more Adjuvant treatment in hormone-receptor positive, HER2-negative early breast cancer is controversial. Chemotherapy benefit in this subset of patients is generally small, and a wide variability exists among dif-ferent subgroups of patients, depending on various patient and tumor characteristics. To select subsets of patients who will really benefit from chemotherapy, one of the possible strategy is based on multigene expression analysis. This approach is providing deeper insights into the biological heterogeneity of breast cancer, allowing to further sub-divide hormone-receptor positive tumors into groups, with different clinical behavior and response to treatments. Among less expensive and better validated methods, high levels of Ki67, a routinely assessed immunohistochemical marker of cell proliferation, can suggest the use of chemotherapy in this subset of patients. Generally, regimen used should include a taxane. In fact, retrospective analyses of clinical trials suggest that anthracyclines may be less active in hormone-receptor positive HER2-negative patients, while several other trials and meta-analyses involving taxanes, showed a benefit in terms of risk of relapse and death reduction. Among taxanes, docetaxel should be preferred because of a better therapeutic index, and a higher activity in comparison to paclitaxel. At present, reliable and accurate evaluation of histopathological and immunohistochemical factors may allow the choice of omitting adjuvant chemotherapy in patients with low risk hormone receptor positive HER2-negative breast cancer. Uncertainty still exists about chemotherapy benefit for a substantial proportion of women of this subgroup. Nevertheless, the addition of taxanes, mainly docetaxel, to anthracyclines, seems to overcome the relative chemoresistance of hormone-receptor positive tumors, providing a benefit in disease free survival and overall survival.
Objective: To assess the prognostic value of various immunomorphological variables in the prognos... more Objective: To assess the prognostic value of various immunomorphological variables in the prognosis of gastric cancer after curative resection. Design: Retrospective study. Setting: University hospital, Italy. Subjects: 180 Patients who underwent curative resection for carcinoma of the distal two thirds of stomach between January 1960 and December 1978. Curative was defined as no residual cancer at the resection margins and no distant metastases. Interventions: All living patients were followed-up, and missing survival data were obtained from the Official Census Registry. Main outcome measures: Correlation between survival and nuclear grade, lymphocytic infiltration, and types of lymph node reaction such as sinus histiocytosis, paracortical lymphoid cellular hyperplasia, and follicular hyperplasia in the cortical area. Results: Crude 5 year and 10 year survival rates were 46% and 36%, respectively. Sex, site, and histological type of the tumour did not correlate with survival. Multivariate analysis showed that only pTNM stage of disease and degree of sinus histiocytosis were significantly related to survival. Conclusion: There may be an argument for using the presence or absence of sinus histiocytosis to stratify patients in prospective studies of adjuvant treatment.
Supplemental material, sj-docx-1-tam-10.1177_17588359211059873 for PANHER study: a 20-year treatm... more Supplemental material, sj-docx-1-tam-10.1177_17588359211059873 for PANHER study: a 20-year treatment outcome analysis from a multicentre observational study of HER2-positive advanced breast cancer patients from the real-world setting by Laura Pizzuti, Eriseld Krasniqi, Isabella Sperduti, Maddalena Barba, Teresa Gamucci, Maria Mauri, Enzo Maria Veltri, Icro Meattini, Rossana Berardi, Francesca Sofia Di Lisa, Clara Natoli, Mirco Pistelli, Laura Iezzi, Emanuela Risi, Nicola D'Ostilio, Silverio Tomao, Corrado Ficorella, Katia Cannita, Ferdinando Riccardi, Alessandra Cassano, Emilio Bria, Maria Agnese Fabbri, Marco Mazzotta, Giacomo Barchiesi, Andrea Botticelli, Giuliana D'Auria, Anna Ceribelli, Andrea Michelotti, Antonio Russo, Beatrice Taurelli Salimbeni, Giuseppina Sarobba, Francesco Giotta, Ida Paris, Rosa Saltarelli, Daniele Marinelli, Domenico Corsi, Elisabetta Maria Capomolla, Valentina Sini, Luca Moscetti, Lucia Mentuccia, Giuseppe Tonini, Mimma Raffaele, Luca Marchetti, ...
Introduction In breast cancer patients, endocrine therapy may exert a negative impact on sexual f... more Introduction In breast cancer patients, endocrine therapy may exert a negative impact on sexual functioning in both genders, with potentially relevant consequences concerning quality of life and treatment adherence. The availability of effective interventions to maintain and/or restore sexual health in breast cancer patients is a key issue to a research agenda. Objectives To summarize and critically discuss the most updated and qualitatively relevant literature on the therapeutic approach to sexual impairment in breast cancer patients, with a focus on patients treated with endocrine therapy. Methods We searched PubMed from its inception to February 2022 for observational and intervention trials including participants with sexual dysfunctions. We were particularly interested in studies of breast cancer patients with sexual dysfunctions while undergoing endocrine therapy. We developed a search strategy with the aim of maximizing the number of articles considered for screening and pote...
Results from randomized trials evaluating taxane versus non-taxane containing regimens in adjuvan... more Results from randomized trials evaluating taxane versus non-taxane containing regimens in adjuvant breast cancer treatment indicate an advantage in DFS and OS for the taxane-arms, but the best schedule of administration, in combination with anthracyclines or in sequence, is still a debated issue, even if the sequential strategy appears to be less toxic. Up to now, the majority of clinical trials employed the "standard" sequence, with anthracycline-based combinations fi rst, followed by taxanes. Few small phase II trials evaluated the reverse sequence, with taxanes administered fi rst, most of them in metastatic or neoadjuvant setting, suggesting efficacy and lower toxicity. An important issue to be considered is the hypothesized differences in the ability of the drugs to induce cross-resistance to each other, as suggested by data of a preclinical study, and from clinical study with a cross-over design; results of these trials suggest that the best strategy would be to administer a taxane prior to an anthracycline, also according to the Norton and Simon hypothesis. Moreover, trials evaluating the best sequence of anthracyclines and taxanes in adjuvant breast cancer setting are of small sample size, and an adequately powered randomized phase III trial is needed before definitive conclusions are reached.
The survival advantage of a pronounced lymphocytic infiltration within and around the primary tum... more The survival advantage of a pronounced lymphocytic infiltration within and around the primary tumor and some hyperplastic reactions in the regional lymph nodes in specimens of colorectal cancer has been reported in many studies. However, none of these studies allowed the grade of these immunomorphological reactivities to compete with more traditional prognostic variables, using the proportional hazard models. In this study the survival rates of 219 patients who underwent operation for rectal cancer were analyzed statistically according to sex, age, tumor site, type of operation, histology, nuclear grade, p-TNM stage of disease and to the following immunomorphological parameters: lymphocytic infiltration (LI) within and around the primary tumor, paracortical activity (PCA), cortical activity (CA) and sinus histiocytosis (SH) of the regional lymph nodes. The presence of an evident local and regional immune reactivity was significantly related to a less advanced stage of disease and better differentiated tumor. The multivariate survival analysis (Cox model) identified LI, PCA and SH and p-TNM stage as independent prognostic factors. Survival within each stage progressively increased in presence of one or more favourable immunomorphologic features. These results indicate that an adequate prospective evaluation of LI, PCA and SH should improve our ability to assess prognosis in rectal cancer and, therefore, allow a more rational utilization of adjuvant therapy.
The fundamental imperative of adjuvant treatment of early breast cancer is to improve long-term s... more The fundamental imperative of adjuvant treatment of early breast cancer is to improve long-term survival and minimize toxicity. The inclusion of docetaxel in adjuvant chemotherapy regimens has improved patient survival in comparison to anthracycline-containing regimens, even if the incidence of acute side effects has increased in some studies. However, late or persistent toxic effects are becoming more important due to an increasing proportion of patients remaining disease free after treatment for early breast cancer. Several studies have recently reported that docetaxel-containing regimens without anthracyclines are equally active, and have no apparent cardiotoxicity. At present, docetaxel-based combinations represent an appropriate choice in the adjuvant treatment of HER2-negative breast cancer, and several studies are ongoing aiming at a better evaluation of the efficacy of this agent in order to optimize its role.
The predictive value of tumor lymphocytic infiltration was studied in 186 gastric cancer patients... more The predictive value of tumor lymphocytic infiltration was studied in 186 gastric cancer patients curatively resected. All patients were followed-up for over 10 years. LI was negatively correlated with p-TN stage of disease. A poorer prognosis was detected in patients with minor or no tumor lymphocytic infiltration. LI was an independent prognostic parameter according to the Cox model and logistic regression analysis. These findings suggest that LI should also have been considered in the current staging of gastric cancer.
The sentinel-node technique was first introduced by Morton in high-risk melanoma of the skin. Rec... more The sentinel-node technique was first introduced by Morton in high-risk melanoma of the skin. Recently, this technique has also been used in patients with T1 breast cancer. Lymphoscintigraphy and the gamma probe are currently used in sentinel lymph-node detection. Many investigators have used this technique in clinical practice and there is no standard procedure in terms of the timing of lymphoscintigraphy, type of vital stain, radiolabelled tracer, etc. This heterogeneity might account for the broad range of false-negatives reported in the literature. The aim of our study was to carefully review and analyse the literature in order to identify the most reliable technique for use in sentinel node detection. The results of the review seem to indicate that the simultaneous use of preoperative lymphoscintigraphy, intraoperative gamma probe and vital staining is capable of ensuring the best results. These data have been confirmed in our experience of 15 patients. The sentinel node search was successful in 100% of the cases, and the percentage of false negative was 0%. The use of the best technique available might prove extremely important, particularly in randomised clinical trials, comparing sentinel node biopsy with axillary dissection. In the patient group undergoing sentinel node biopsy, the axillary pathological staging is based exclusively on this technique and therefore its reliability must be assured if it is to serve as a precise guide in the planning of adjuvant treatments.
Primary limb melanoma may recur in terms of satellitosis, in transit metastases and/or regional n... more Primary limb melanoma may recur in terms of satellitosis, in transit metastases and/or regional node involvement. Hyperthermic antiblastic perfusion (HAP) permits the isolation of involved extremity from the systemic circulation and to deliver high doses of antineoplastic drugs. The association of cytostatic drugs to hyperthermia (> or = 41.5 degrees C) results in a synergistic effect with an increased therapeutic effectiveness. The overall 5 and 10-year survival rates in relation to the disease stages are st. II 75% and 67%; st. IIIA 59% and 42%; st. IIIAB 36% and 30% respectively. The results confirm that HAP is considered the treatment of choice of loco-regional spreading limb melanoma. Recently, the tumor necrosis factor (TNF) has been combined with Melphalan and hyperthermia. This trimodality association seems to be superior to Melphalan and hyperthermia alone only in patient with bulky tumors (i.e., multiple nodules), as a matter of fact the complete tumor response rates observed in these patients have been 67% and 20% respectively. The greater effectiveness of trimodality association has to be confirmed by multicentric randomized trials.
On the basis of personal experience and a review of the literature, the authors have evaluated th... more On the basis of personal experience and a review of the literature, the authors have evaluated the results obtained with hyperthermic antiblastic perfusion (HAP) for the treatment of stage II, III and IIIAB limb melanoma. The evaluation showed that today HAP may be considered a safe and effective treatment, with a major complication rate ranging between 1% and 4%. In terms of tumor response, locoregional control and survival, this treatment has provided better results than other regional chemotherapeutic modalities and undoubtedly better results than those obtained with conventional, even radical, surgery. The multivariate analysis showed that, of the treatment-related prognostic factors, the minimum tumor temperature influenced the percentage of complete response (CR) to the greatest extent (P<0.03), with a positive trend also with regard to the dosage of the antiblastic drug employed (P<0.08). In turn, the complete response rate was a determinant as far as locoregional control (50%; P<0.0009) and disease-free (51.4%; P=0.0009) and overall survival (63%; P<0.009) rates were concerned. Of the tumor-related prognostic factors, the number of lesions (P<0.0014), sex (P<0.04), and the number of disease recurrences (P<0.01) appear to influence overall survival.
Adjuvant treatment in hormone-receptor positive, HER2-negative early breast cancer is controversi... more Adjuvant treatment in hormone-receptor positive, HER2-negative early breast cancer is controversial. Chemotherapy benefit in this subset of patients is generally small, and a wide variability exists among dif-ferent subgroups of patients, depending on various patient and tumor characteristics. To select subsets of patients who will really benefit from chemotherapy, one of the possible strategy is based on multigene expression analysis. This approach is providing deeper insights into the biological heterogeneity of breast cancer, allowing to further sub-divide hormone-receptor positive tumors into groups, with different clinical behavior and response to treatments. Among less expensive and better validated methods, high levels of Ki67, a routinely assessed immunohistochemical marker of cell proliferation, can suggest the use of chemotherapy in this subset of patients. Generally, regimen used should include a taxane. In fact, retrospective analyses of clinical trials suggest that anthracyclines may be less active in hormone-receptor positive HER2-negative patients, while several other trials and meta-analyses involving taxanes, showed a benefit in terms of risk of relapse and death reduction. Among taxanes, docetaxel should be preferred because of a better therapeutic index, and a higher activity in comparison to paclitaxel. At present, reliable and accurate evaluation of histopathological and immunohistochemical factors may allow the choice of omitting adjuvant chemotherapy in patients with low risk hormone receptor positive HER2-negative breast cancer. Uncertainty still exists about chemotherapy benefit for a substantial proportion of women of this subgroup. Nevertheless, the addition of taxanes, mainly docetaxel, to anthracyclines, seems to overcome the relative chemoresistance of hormone-receptor positive tumors, providing a benefit in disease free survival and overall survival.
Objective: To assess the prognostic value of various immunomorphological variables in the prognos... more Objective: To assess the prognostic value of various immunomorphological variables in the prognosis of gastric cancer after curative resection. Design: Retrospective study. Setting: University hospital, Italy. Subjects: 180 Patients who underwent curative resection for carcinoma of the distal two thirds of stomach between January 1960 and December 1978. Curative was defined as no residual cancer at the resection margins and no distant metastases. Interventions: All living patients were followed-up, and missing survival data were obtained from the Official Census Registry. Main outcome measures: Correlation between survival and nuclear grade, lymphocytic infiltration, and types of lymph node reaction such as sinus histiocytosis, paracortical lymphoid cellular hyperplasia, and follicular hyperplasia in the cortical area. Results: Crude 5 year and 10 year survival rates were 46% and 36%, respectively. Sex, site, and histological type of the tumour did not correlate with survival. Multivariate analysis showed that only pTNM stage of disease and degree of sinus histiocytosis were significantly related to survival. Conclusion: There may be an argument for using the presence or absence of sinus histiocytosis to stratify patients in prospective studies of adjuvant treatment.
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