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Optimal management when unsuspected N2 nodal disease is identified during thoracotomy for lung cancer: cost-effectiveness analysis.

OBJECTIVES: Whether to proceed with lung resection when N2 nodal disease is identified at the time of thoracotomy for lung cancer is controversial. A decision analysis model was developed to address this question. METHODS: A meta-analysis was performed on data from reports published between 1990 and 2002 evaluating survival for (1) patients who were treated by initial resection for clinically unsuspected N2 nodal disease (initial resection) and (2) survival for patients undergoing resection after neoadjuvant therapy for N2 nodal disease (no initial resection). Hospital cost data for surgery were derived from our institution, and cost data for chemotherapy and radiation therapy were obtained from current literature. A decision model was developed to compare initial resection to no initial resection from the perspective of the medical center using survival, quality-adjusted life years survival, and cost-effectiveness as outcomes. RESULTS: The no initial resection option provided better median survival (2.1 versus 1.7 years), quality-adjusted life years (1.8 versus 1.3), and cost-effectiveness, with an incremental cost-effectiveness ratio of 17,119 dollars/quality-adjusted life year. Outcomes were influenced by survival estimates for each treatment option. CONCLUSIONS: When N2 nodal disease is discovered during thoracotomy, the approach of delaying resection until after neoadjuvant therapy provides the best survival and is more cost-effective. This is likely due to the beneficial effects of neoadjuvant therapy and the exclusion of patients with more aggressive disease from the surgical candidate pool.

Carcinoma, Non-Small-Cell Lung↗

Sentinel lymph node biopsy after neoadjuvant systemic therapy.

As sentinel node biopsy has emerged as a possible alternative to axillary node dissection in patients with operable breast cancer, this procedure is also emerging as a possible alternative in patients who have received prior neoadjuvant chemotherapy. Initial smaller, single-institution series with the latter approach have shown significant variability in the identification rates and false negative rates resulting in inconsistent--and at times disparate--conclusions regarding the appropriateness of this technique in this group of patients. Subsequent larger, multicenter series have shown, that the identification rates and false negative rates with sentinel node biopsy after neoadjuvant chemotherapy are similar to those when sentinel node biopsy is performed after breast cancer diagnosis. Thus, it appears that the sentinel node concept is also applicable in patients who have undergone neoadjuvant chemotherapy. This observation has the potential to expand the utility of neoadjuvant chemotherapy in patients with operable breast cancer.

Breast Neoplasms↗

[Anemia and neoadjuvant hormone therapy in radical surgery of localized cancer of the prostate].

RATIONALE: Erythropoiesis is stimulated by androgens either through a direct action on bone marrow cells or through increased erythropoietin production. Androgen deprivation is a known cause for anaemia. The aim of this study was to evaluate the effect of neoadjuvant hormone therapy prior to radical surgery on haemoglobin (Hb) and haematocrit (Ht) levels in localised prostate cancer. MATERIAL AND METHOD: 47 patients with clinical localised prostate cancer were given LH-RH analogs plus flutamide for complete androgenic blockade (CAB) for at least 3 months prior to radical prostatectomy. A blood profile was obtained prior to start CAB and 3 months after therapy, and peri-operative transfusional requirements were evaluated. To assess any significant changes. Student's t test was used in the statistical analysis of paired data. RESULTS: In our study all patients (100%) showed decreased Hb and Ht levels after 3 months on CAB. Mean decline for Hb was 1.9 g/dL (range 1.6-2.2) p:0.0001, and for Ht 5.8% (range 4.8-6.8) p:0.0001. Hb was lower than 12 g/dL in 10.6% patients after hormone therapy and anaemia results were normocytic-normochromic. 60% patients needed peri-operative blood transfusion, 2 units of packed cells on average. CONCLUSIONS: Neoadjuvant CAB prior to radical prostatectomy results in a significant decline of Hb and Ht levels after 3 months treatment. Such decline may contribute to increase peri-operative transfusional requirements in a group of patients undergoing aggressive surgery which in itself involves a significant blood loss.

Androgen Antagonists↗

[Preoperative chemoradiation in esophageal cancer: experience of a single center in 102 patients].

The (dis-)advantages of preoperative chemoradiation in patients with esophageal cancer (EC) are still controversial as data are lacking showing a clear cut benefit. Therefore, data of neoadjuvant therapy of our hospital have been analyzed. Since 1994 102 patients with an EC (33 % adenocarcinoma, 67 % squamous cell cancer, scc) were operated after receiving preoperative chemoradiation (36 Gy radiation, 1.8 Gy/day for 4 weeks, 500 mg/m (2) 5-FU for 4 weeks and 20 mg/m (2) Cisplatin, day 1-5, week 1 and 4). Operation was performed usually 8-10 weeks after treatment start. In 11.7 % of patients with an adenocarcinoma a complete pathological response (CR, pT0N0M0) was observed and a pT0 stage in 20.6 %. 38.2 % of these patients were staged as pN0. Postoperative morbidity was observed in 66 % (anastomotic leakage in 20 %, recurrent nerve palsy in 23 %). In-hospital mortality was 5.9 %. 5-year survival was calculated as 30.5 %, in patients wit a CR 66 %.26.5 % of patients with a scc revealed a CR. However no effect at all was observed in 32 % of these patients. 56 % were staged as pN0. Postoperative morbidity was observed in 87 % (anastomotic leakage in 16 %, recurrent nerve palsy in 32 %). In-hospital mortality was 11.8 %. 5-year survival was calculated as 19.2 %, in patients with a CR 45 %. The impact of pN stage was significant (p = 0.0052). These results underline the benefit of neoadjuvant therapy in patients with a CR. Further on, a pN0 stage is an important prognostic indicator. However, it remains open, whether neoadjuvant therapy leads to a downstaging of lymph node involvement, as histological confirmation in clinically positive lymph node is seldom performed prospectively.

Adenocarcinoma↗

Reduction in angiogenesis after neoadjuvant chemoendocrine therapy in patients with operable breast carcinoma.

BACKGROUND: The intensity of angiogenesis, as measured by microvessel density, is a strong independent predictor of survival in breast carcinoma patients. The impact of chemotherapy and/or endocrine therapy on this process is unknown. METHODS: Histologic samples from patients randomized to a trial of neoadjuvant (NEO) versus adjuvant (ADJ) chemoendocrine therapy for operable breast carcinoma were obtained. Samples from 195 patients (90 NEO samples and 105 ADJ samples) were analyzed. Immunostaining was performed with the CD34 monoclonal antibody and the scoring of microvessels was performed using the Chalkley method. RESULTS: The median score of the NEO patients was 5.7 (95% confidence interval [CI], 5.3-6.0) and the median score of the ADJ patients was 6.3 (95% CI, 6-6.7) (P=0.025). Using previously validated scoring categories, there were fewer samples with a poor prognosis (score > or =7) in the NEO group (26%) compared with the ADJ group (32%) (P=0.04). CONCLUSIONS: The results of the current study suggest that NEO chemoendocrine therapy causes a reduction in microvessel density in primary breast carcinomas, which could be secondary to tumor regression or due to a direct effect on angiogenesis.

Adult↗

Anti-tumor immune responses following neoadjuvant immunotherapy with a recombinant adenovirus expressing HSP72 to rodent tumors.

Gene modification of tumor cells is commonly utilized in various strategies of immunotherapy preventive both as treatment and a means to modify tumor growth. Gene transfer prior to surgery as neoadjuvant therapy has not been studied systematically. We addressed, whether direct intra-tumoral injection of a recombinant adenovirus expressing the immunomodulatory molecule, heat shock protein 72 (ADHSP72), administered prior to surgery could result in sustainable anti-tumor immune responses capable of affecting tumor progression and survival in a number of different murine and rat tumor models. Using intra-dermal murine models of melanoma (B16), colorectal carcinoma (CT26), prostate cancer (TrampC2) and a rat model of glioblastoma (9L), tumors were treated with vehicle or GFP expressing adenovirus (ADGFP) or ADHSP72. Tumors were surgically excised after 72 h. Approximately 25-50% of animals in the ADHSP72 treatment group but not in control groups showed sustained resistance to subsequent tumor challenge. Tumor resistance was associated with development of anti-tumor cellular immune responses. Efficacy of ADHSP72 as neoadjuvant therapy was dependent on the size of the initial tumor with greater likelihood of immune response generation and tumor resistance associated with smaller tumor size at initial treatment. ADHSP72 neoadjuvant therapy resulted in prolonged survival of animals upon re-challenge with autologous tumor cells compared to ADGFP or vehicle control groups. To study the effects on tumor progression of distant metastases, a single tumor focus of animals with multifocal intra-dermal tumors was treated. ADHSP72 diminished progression of the secondary tumor focus and prolonged survival, but only when the secondary tumor focus was <50 mm3 . Our results indicate that gene modification of tumors prior to surgical intervention may be beneficial to prevent recurrence in specific circumstances.

Adenoviridae↗

Preliminary results of a prospective randomized study comparing radical prostatectomy versus radical prostatectomy associated with neoadjuvant hormonal combination therapy in T2-3 N0 M0 prostatic carcinoma. The European Study Group on Neoadjuvant Treatment of Prostate Cancer.

OBJECTIVES: To evaluate the short- and long-term effects of neoadjuvant hormonal treatment in locally confined prostate cancer. METHODS: We report the preliminary results of 354 patients (199 with a clinical T2 tumor and 155 with a clinical T3 tumor) of whom 164 randomly received neoadjuvant total androgen deprivation using a luteinizing-hormone-releasing hormone (LHRH) analog (goserelin) plus flutamide for a period of 3 months. RESULTS: Serum prostate-specific antigen (PSA) levels and prostatic volume decreased from a mean of 19.9 ng/mL and 37.7 cm3 to a mean of 0.8 ng/mL and 26.5 cm3 after 3 months of neoadjuvant therapy. "Clinical down-staging" was seen in 32% in the neoadjuvantly treated group. "Pathological downstaging" percentages were 6% and 16% in the direct radical prostatectomy group and neoadjuvantly-treated group, respectively (P < 0.01). In patients with clinical T2 tumors, a significant difference in number of positive margins was shown in favor of the neoadjuvantly treated group (P < 0.01). In patients with clinical T3 tumors, a significant difference could not be detected (P = 0.14). In 215 patients with a mean follow-up time of 15 months, the calculated 95% confidence intervals of mean time of PSA progression-free survival were 26 to 35 months in the neoadjuvantly-treated group and 28 to 37 months in the direct radical prostatectomy group, indicating no significant differences between treatment groups. However, follow-up time is currently too short to draw definite conclusions. CONCLUSIONS: These early data confirm high understaging percentages in clinical staging. The clinical relevance of the statistically significant smaller numbers of patients with positive margins in the neoadjuvantly treated group with a clinical T2 tumor will have to be confirmed when further follow-up allows an accurate evaluation of time to PSA progression, local recurrence, and distant metastases. Presently, neoadjuvant therapy is not advisable outside clinical research settings.

Androgen Antagonists↗

Long-term results of neoadjuvant radiation therapy for breast cancer.

Our aim was to determine the long-term outcome and the possible role of neoadjuvant (preoperative) radiation therapy for breast cancers unsuitable for primary conservative surgery. From 1977 to 1992, 75 unifocal non-inflammatory and non-metastatic T2 and T3 breast cancers were treated in our department. All these patients underwent initial radiotherapy, followed by secondary limited surgery. A population of 74 patients, aged from 32 to 82 years (median 56 years), presenting 49 T2 and 26 T3 tumors, was studied. Seventy-two patients (96%) underwent secondary tumorectomy and three patients (4%) reduction mammaplasty. The secondary tumorectomy was followed by a postoperative boost. There were nine recurrences, treated by mastectomy in eight cases and by tumorectomy in one case. Twenty-five patients showed secondary dissemination. Forty-seven patients are still alive and free of disease. The cosmetic results were considered excellent or satisfactory in 71 cases. Under good conditions, preoperative radiotherapy (as well as preoperative chemotherapy) allows the possibility of conservative surgery for cancers of more than 3 cm. The choice between the two modalities depends on the patient's condition and on a precise analysis of all prognostic factors that would justify the need for systemic treatment.

Adult↗

A phase II study of neoadjuvant gemcitabine plus doxorubicin in stage IIIB breast cancer: a preliminary report.

The purpose of this ongoing study is to determine the response and safety of a combination of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) plus doxorubicin as neoadjuvant therapy for stage IIIB breast cancer. Thirty-nine chemotherapy-naive patients were enrolled in the study. The median age was 54 years (range, 32 to 74 years), and the median Karnofsky performance status was 100. Gemcitabine 1,200 mg/m(2) was given on days 1 and 8, and doxorubicin 60 mg/m(2) on day 1, followed by surgery or radiotherapy. Ninety-seven of 117 cycles (83%) were administered at full dose. An overall response rate of 95% was obtained, with a complete response in 18% (seven patients) and a partial response in 77% (30 patients). Twenty-eight patients (72%) underwent breast surgery after a maximum of three cycles of neoadjuvant therapy. World Health Organization grade 3/4 toxicities included leukopenia in nine cycles (8%), neutropenia in 16 cycles (14%), febrile neutropenia in 11 cycles (9%), and anemia in two cycles (2%). The most important nonhematologic toxicity was grade 2/4 mucositis in 16 cycles (14%), and/or grade 2/3 diarrhea in 10 cycles (9%). Neoadjuvant therapy with gemcitabine plus doxorubicin results in a high tumor response rate with moderate oral and hematologic toxicity. Semin Oncol 28 (suppl 10):57-61.

Adult↗

Surgical Management of Young Women with High-Risk Breast Cancer Receiving Neoadjuvant Systemic Therapy on the I-SPY2 Trial.

BACKGROUND: Mastectomy rates in women with breast cancer are higher in younger women than in older women. The impact of this more extensive surgery on overall survival (OS) and locoregional recurrence in younger women is unknown, especially after neoadjuvant systemic therapy (NST). This study evaluated surgical management and outcomes of patients aged &#x2264; 45 versus > 45 years enrolled in multicenter NST clinical trial, I-SPY2.0 (NCT01042379, PMID 37325931). METHODS: We conducted a secondary data analysis comparing locoregional treatment in patients aged &#x2264; 45 versus > 45 years with clinical or molecular high-risk clinical stage II-III breast cancer treated from April 2010 to June 2022. Multivariate Cox proportional hazards models were used to evaluate associations between type of breast surgery with OS and locoregional recurrence-free interval by age group and tumor receptor subtype. RESULTS: Of 1737 patients, 698 (40.2%) were aged &#x2264; 45 years. There were no significant differences in patient or tumor characteristics or residual cancer burden distribution between age groups. Although breast-conserving surgery was significantly less common in younger women (36.8% vs 48.5%, p < 0.001), surgery type was not associated with OS or locoregional recurrence-free interval for patients aged &#x2264; 45 years. CONCLUSIONS: Greater extent of breast surgery was not associated with improved outcomes in women aged &#x2264; 45 years. Choice of surgical procedure in the management of breast cancer is multifactorial, but young age alone&#xa0;does not warrant mastectomy following NST.

Breast cancer↗

Surgical treatment of small cell carcinoma of the lung: advantage of preoperative chemotherapy.

To assess the effect of chemotherapy on postoperative survival of patients with small cell lung carcinoma (SCLC), 46 patients who underwent surgery at Kyoto University between 1976 and 1991 were retrospectively reviewed. Seventeen patients (37.0%) received chemotherapy prior to as well as after surgery (neoadjuvant therapy group), 23 (50.5%) received chemotherapy only after surgery (adjuvant therapy group), and the other six received no chemotherapy (non-chemotherapy group). The 5-year survival rate of patients with c-Stage I or II disease in the neoadjuvant therapy group was as high as 80.0%, which seemed to be higher, although with no statistical significance, than that in the adjuvant therapy group (37.7%, P = 0.10). The 5-year survival rate of patients with c-Stage III (IIIa or IIIb) disease in the neoadjuvant therapy group, although not satisfactory (10.0%), was significantly higher than that in the adjuvant therapy group (0.0%, P = 0.04). No patients in the non-chemotherapy group had survived 5 years. Moreover, multivariate analysis showed that failure to employ preoperative chemotherapy was the strongest prognostic factor causing a poor prognosis (P = 0.01). On the other hand, eight (30.8%) out of 26 patients with c-Stage I or II disease postoperatively proved to have mediastinal lymph node involvement (pN2-3), and two (7.7%) proved to have intrapulmonary metastasis (PM). Considering the advantage of preoperative chemotherapy and the discrepancy between c- and p-stage, sufficient chemotherapy prior to surgery should be employed, and may realize a good prognosis in patients with c-Stage I or II disease. In contrast, patients with c-Stage III disease are not appropriate as candidates for surgery even if preoperative chemotherapy is performed.

Aged↗

Adjunctive value of cell proliferation but not of apoptosis to interpret pathologic effects on prostatic cancer after neoadjuvant endocrine therapy.

BACKGROUND: The current histological evaluation of the effects of endocrine therapy has difficulty in distinguishing pathologic degeneration caused by androgen ablation from residual poorly differentiated tumor. Therefore, we examined the changes in cell proliferation and apoptosis before and after endocrine therapy and analyzed whether they correlated with pathologic effects and histological differentiation. METHODS: Between January 1986 and December 1995, 52 patients with clinical stage B2 and C prostate cancer underwent radical prostatectomy after neoadjuvant endocrine therapy (median duration 3.8 months). Proliferative and apoptotic activities of pretreatment biopsy specimens and radical prostatectomy specimens were analyzed with MIB-1 monoclonal antibody and in situ end-labeling of fragmented DNA. RESULTS: The mean proliferative index (PI) of radical prostatectomy specimens was significantly lower than that of biopsy specimens (P = 0.000003) and the decrease in PI after endocrine therapy was significantly related to histological differentiation (P = 0.014). There was a weak relationship between the decrease in PI after endocrine therapy and pathologic effects (P = 0.054), while in pathologically effective cases (Grades 2 and 3), three out of 16 (19%) showed a < 50% decrease in PI after endocrine therapy, and may be regarded as having poorly differentiated tumors. The mean apoptotic index (AI) of prostatectomy specimens tended to be higher than that of biopsy specimens (P = 0.054). The increase in AI after endocrine therapy was not related to histological differentiation and pathologic effects. CONCLUSION: Pathologic effects caused by endocrine therapy may be in part misled by routine histopathologic staining and the change in PI may help in recognizing the pathologic effects of endocrine therapy and have adjunctive value for the interpretation of the effects of endocrine therapy.

Aged↗

[Difference between Japan and western countries in the treatment strategy for esophageal cancer].

The most conspicuous difference between Japan and Western countries in the treatment strategy for esophageal cancer is the attitude to lymph node dissection. Japanese surgeons have aimed at complete eradication of lymphatic spread of cancer cells and have reached the level of three-field lymph node dissection. In Western countries, however, surgeons rely more on chemotherapy or radiotherapy because they consider that most patients who present with esophageal cancer already have disseminated disease. Phase II studies of neoadjuvant chemotherapy and chemoradiotherapy have yielded encouraging results, and recently, positive reports on phase III studies of neoadjuvant therapy vs. surgery alone began to be announced. No such studies have included surgery with radical lymph node dissection. With the rapid advance in information technology, radical esophagectomy has gradually gained acceptance in the West, while many trials of neoadjuvant therapy have been carried out in Japan. Theoretically, the next step should be a phase III study of neoadjuvant therapy vs. surgery in which highly radical procedures such as three-field lymph node dissection are carried out.

Chemotherapy, Adjuvant↗

[A case of T4 esophageal squamous cell carcinoma in esophagogastric junction effectively treated by neoadjuvant FAP therapy].

A 59-year-old man was admitted to our hospital because of vomiting and body weight loss. Upper GI series and upper digestive tract endoscopy revealed type 3 cancer lesion in the area from the lower thoracic esophagus to the middle gastric body. In the biopsy specimen squamous cell cancer was shown. We perfomed neoadjuvant chemotherapy because the computed tomography revealed invasion to the diaphragm and aorta. After chemotherapy a 65% reduction was obtained, and we performed total gastrectomy with lower esophagectomy and lower mediastinal and abdominal lymph node dissection and Roux-en Y reconstruction in the left thoracoabdominal serial incision. In the histological examination, Grade 1 response was obtained in the primary specimen and Grade 3 response in the lymph node specimens. In the 44 months since surgery, the patient has remained well and disease free. It was suggested that a combination of neoadjuvant chemotherapy and surgery was successful treatment for this case.

Antineoplastic Combined Chemotherapy Protocols↗