Degree Of Tumor Regression Research Articles

Utility of large sections (macrosections) in breast cancer pathology

Large sections (LSs), (synomim: macrosections), are used in daily routine practice of breast pathology to better investigate the disease and to allow a thorough diagnosis. It has been demonstrated that costs do not differ from conventional blocking and the turn-around-time could be no longer than 24 hours. Immunohistochemistry or molecular studies are feasible by selecting areas of interest from LS and cutting them to obtain small conventional blocks. LSs are also employed in surgical pathology of various organs, among which breast is comprised. LS in breast pathology is useful to a proper definition of stage disease, tumor size (TS), tumor extent (TE), tumor multifocality (TM) and resection margins. The presence and extension of in situ carcinoma is more completely observed, overcoming the difficulties of gross inspection at naked eye. In the multidisciplinary era, LSs allow the correlations between radiological and pathological data. In addition, LSs play an important role in cases treated with neo-adjuvant (NAD) chemotherapy, as they are useful to better evaluate the residual cancer burden and the degree of tumour regression. The aim of the present paper is to review the value of LS in breast pathology.

The impact of the radiation-induced regression of positive nodes on survival in patients with rectal cancer treated with chemoradiotherapy

Although preoperative chemoradiotherapy exerts a destructive effect on positive lymph nodes, microscopic examination reveals different degrees of tumor regression. The aim of the present study is to investigate the impact of the radiation-induced regression of positive nodes on survival in patients with rectal cancer treated with preoperative chemoradiotherapy. From 2001 to 2015, 229 patients with T3 rectal cancer underwent total mesorectal excision after preoperative chemoradiotherapy. The patients were classified into 3 groups according to their lymph node status: residual cancer cells in positive nodes (Group A), total regression of positive nodes after preoperative chemoradiotherapy with complete fibrosis (Group B), and the entire lymph node filled with lymph nodules and the absence of fibrosis (Group C). The survival of the 3 groups was compared, and a Cox model was used to evaluate the prognostic value of the regression of the positive nodes by preoperative chemoradiotherapy. Groups A, B, and C included 57, 18, and 154 patients, respectively. Group B showed significantly better overall survival than Group A (P=.041) and similar outcomes to Group C (P=.383). Among the patients with positive lymph nodes prior to treatment (Groups A and B), the total regression of the positive nodes after preoperative chemoradiotherapy was the only independent factor to be associated with good overall survival (hazard ratio; 6.26, 95% confidence interval; 1.28-113.0, P=.020). Total regression of positive nodes by preoperative chemoradiotherapy improves the prognosis of patients with rectal cancer with positive lymph nodes prior to treatment.

Fibroblast-derived Neuregulin 1 Promotes Compensatory ErbB3 Receptor Signaling in Mutant BRAF Melanoma

Rapidly accelerated fibrosarcoma (RAF) inhibitors are first-line treatments for patients harboring V600E/K mutant BRAF melanoma. Although RAF inhibitors produce high response rates, the degree of tumor regression is heterogeneous. Compensatory/adaptive responses to targeted inhibitors are frequently initiated by the activation of growth factor receptor tyrosine kinases, including ErbB3, and factors from the tumor microenvironment may play an important role. We have shown previously that mutant v-raf murine sarcoma viral oncogene homolog B1 (BRAF) melanoma cells have enhanced activation of ErbB3 following RAF inhibition. However, the source of neuregulin 1 (NRG1), the ligand for ErbB3, is unknown. In this study, we demonstrate that NRG1 is highly expressed by dermal fibroblasts and cancer-associated fibroblasts (CAFs) isolated from mutant BRAF melanomas. Conditioned medium from fibroblasts and CAFs enhanced ErbB3 pathway activation and limited RAF inhibitor cytotoxicity in V600 mutant BRAF-harboring melanomas. Targeting the ErbB3/ErbB2 pathway partially reversed the protective effects of fibroblast/CAF-derived NRG1 on cell growth properties of RAF inhibitor-treated melanoma cells. These findings support the idea that NRG1, acting in a paracrine manner, promotes resistance to RAF inhibitors and emphasize that targeting the ErbB3/ErbB2 pathway will likely improve the efficacy of RAF inhibitors for mutant BRAF melanoma patients.

Abstract 4696: Combining AZD8186, an inhibitor of PI3Kbeta, with inhibitors of PI3Kalpha and mTORC1/2 gives comprehensive pathway suppression and enhanced antitumor activity in PTEN null tumors

Abstract The PI3K pathway drives the progression of many human tumours via mutation of PI3KCA or AKT, loss of tumour suppressors PTEN or TSC1/2, or over-expression of receptor tyrosine kinases, such as EGFR, Erb2, or IGFR. Targeting the PI3K pathway has been challenging due to toxicities with the first generation compounds. Despite this, positive clinical activity has been achieved, particularly in combination. Maximum benefit with inhibitors of the PI3K pathway is likely to be in combination, with agents that target other pathways, or PI3K signalling at different nodes. In cells, AZD8186 inhibits PI3Kbeta- and PI3Kdelta-dependent phosphorylation of AKT with IC50s of 3nM and 17nM respectively. Tumour cells can become dependent on PI3Kbeta when they lose PTEN protein function. PI3Kbeta inhibitors are differentiated from PI3Kalpha, mTOR and AKT inhibitors as they do not modulate peripheral glucose and other aspects of the canonical PI3Kalpha signalling pathway. Therefore in tumours where PI3Kbeta is activated it may be possible to combine AZD8186 with other inhibitors of the PI3K pathway to achieve comprehensive pathway suppression. Delivering comprehensive pathway suppression has become critically important with the realisation that resistance to the PI3K inhibitors can occur through feedback-mediated or mutation-mediated reactivation of the pathway through alternate PI3K isoforms. We have explored intra-pathway combinations of AZD8186 with inhibitors of PI3Kalpha (AZD8835 and BYL719) and mTOR (AZD2014 and everolimus) in PTEN protein deficient models. In particular, combining AZD8186 with inhibitors of mTOR increased efficacy across a range of tumour models. In TNBC (HCC-70) or renal (786-0) xenograft models, combined inhibition resulted in tumour regression. The degree of tumour regression was influenced by dose and schedule. For example, intermittent dosing of AZD8186 with continuous AZD2014 regressed 786-0 tumours by between 38% and 82%, while HCC70 showed a 21% regression. Tumour regressions were also observed when AZD8186 and AZD2014 were dosed intermittently, a 5 day on AZD8186 with 2 day on AZD2014 concurrent dosing schedule in 786-0 gave 41% and 22% regression respectively in HCC70. The anti-tumour effects were associated with increased depth and duration of inhibition of AKT pathway biomarkers, but significantly also modification of biomarkers associated with cellular metabolic function and survival pathways. The ability of intermittent doses of the combination regimen to deliver tumour regression establishes the principle that it is possible to move away from chronic pathway suppression, offering the flexibility to mitigate potential tolerability challenges, potential acute resistance mechanisms, but also drive increased phenotypic effects in the tumour. Citation Format: Urs Hancox, Urszula Polanska, James T. Lynch, Carol Lenaghan, Cath Trigwell, Oona Depuelch, Phillippa Dudley, Juliana Maynard, Lara Ward, Kevin Hudson, Jon Curwen, Francisco Cruzalegui, Stephen Green, Klinowska Teresa, Simon T. Barry. Combining AZD8186, an inhibitor of PI3Kbeta, with inhibitors of PI3Kalpha and mTORC1/2 gives comprehensive pathway suppression and enhanced antitumor activity in PTEN null tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4696. doi:10.1158/1538-7445.AM2015-4696

Tumour volume changes assessed with high-quality KVCT in lung cancer patients undergoing concurrent chemoradiotherapy.

We evaluated tumour volume changes in patients with lung cancer undergoing concurrent chemoradiotherapy using image-guided radiotherapy (RT). The kilovoltage image was obtained using CT on rail at every five fractions. The gross tumour volumes (GTVs), including the primary tumour and lymph nodes (LNs), were contoured to analyse the time and degree of tumour regression. 46 patients [32, non-small-cell lung cancer (NSCLC), and 14, small-cell lung cancer (SCLC)] were included in this study. In total, 281 CT scans and 82 sites of GTVs were evaluated. Significant volume changes occurred in both the NSCLC and SCLC groups (p < 0.001 and 0.002), and the average GTV change compared with baseline was 49.85 ± 3.65 [standard error (SE)]% and 65.95 ± 4.60 (SE)% for the NSCLC and SCLC groups, respectively. A significant difference in the degree of volume reduction between the primary tumour and LNs was observed in only the NSCLC group (p < 0.0001) but not in the SCLC group (p = 0.735). The greatest volume regression compared with the volume before the five fractions occurred between the 15 and 20 fractions in the NSCLC group and between the 5 and 10 fractions in the SCLC group. Both primary tumour and LNs were well defined using CT on rail. Significant volume changes occurred during RT, and there was a difference in volume reduction between the NSCLC and SCLC groups, regarding the degree and timing of the tumour reduction in the primary tumour and LNs. NSCLC and SCLC groups showed differences in the degree and timing of volume reduction. The primary tumour and LNs in NSCLC regressed differently.

MULTIDISCIPLINARY APPROACH IN THE TREATMENT OF PATIENTS WITH RECTAL CANCER

Surgical treatment is the "gold standard" in the treatment of patients with rectal cancer. The aim of surgical treatment is to minimize the rate of local recurrence, the occurrence of which depends largely on the quality of procedures. Relationship between the tumor and own fascia of the rectum is the cornerstone in the choice of treatment strategy. Even using modern surgical techniques, most tumors of the rectum below the peritoneum should be treated using preoperative radiotherapy. Preoperative radiation can reduce the incidence of local recurrence and to create conditions for increasing the number of sphincter-preserving operations. The degree of tumor regression after chemoradiation is directly correlated with survival and local recurrence. Tumor regression creates prerequisites for decrease of postoperative complications and mortality related to the implementation of extensive radical surgery in patients with a tumor of the rectum. The use of standardized systems for the assessment of tumor regression can provide valuable information for centers specializing in the treatment of patients with such pathology. MRI of the pelvic organs is a very effective tool in the initial evaluation of the degree local and regional spreading of colorectal cancer including relationship to the mesorectal fascia. Difficulties in predicting of complete pathologic regression of the tumor by MRI are associated primarily with the problem of differential diagnosis between tumor and post-radiation changes in the rectal wall and surrounding tissues. A multidisciplinary approach provides the accuracy of staging and facilitates the development of an optimal treatment strategy in patients with rectal cancer.

Tumor regression in rectal cancer after intensified neoadjuvant chemoradiation: a morphometric and clinicopathological study.

BackgroundHigh interobserver variation is a well known drawback of conventional tumor regression grading, and reaching consensus among pathologists may require a considerable effort. Therefore, in this study, morphometry was tried to assess tumor regression, and its prognostic role was explored.MethodsTumor regression was quantified by a point counting method to yield tumor area fraction (TAF) as an index of remaining vital tumor.ResultsIn a series of 104 patients with clinically advanced rectal cancer treated with neoadjuvant radiochemotherapy, TAFs were distributed continuously towards complete regression which was observed in 8.7% of the cases. Plotting TAFs grouped by a conventional regression grading (Dworak’s) revealed considerable overlap between groups. In a control series of untreated cancers, only TAFs of cancers with an expansive invasive border were setoff clearly from TAFs obtained for the study cases, but TAFs of control cases with an infiltrative invasive border and mucinous carcinomas extended well into the range of TAFs recorded for regressing tumors. Locoregional recurrence (N = 10) was significantly associated with perineural tumor infiltration and capsule transgressing lymph node metastasis/tumor deposits but not with the degree of tumor regression. Overall survival was better for patients with major regressions (≤20th percentile by morphometry, or Dworak regression grade (DRG) 4/5), although statistical significance was not reached.ConclusionsMorphometry of tumor regression is feasible and explains why conventional regression grading is so difficult to perform. Assessment of tumor regression, by subjective grading or morphometry, does not appear to convey major prognostic information, at least not substantially beyond histopathological tumor staging. This observation discourages expending too much effort on developing this aspect of the pathomorphological workup of the resection specimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s12957-015-0572-z) contains supplementary material, which is available to authorized users.

Prognostic Significance of Partial Tumor Regression After Preoperative Chemoradiotherapy for Rectal Cancer

Complete tumor regression after preoperative chemoradiotherapy for rectal cancer has been associated with better disease-free and overall survival. The survival experience for patients with partial tumor regression is less clear. The aim of this meta-analysis was to evaluate the prognostic significance of partial response after preoperative chemotherapy on disease-free survival in rectal cancer patients. Relevant studies were identified by a search of MEDLINE and EMBASE databases with no restrictions to October 31, 2012. We included long-course radiotherapy that reported the association between degree of tumor regression and disease-free survival of rectal cancer. Direct, indirect, and graph methods were used to extract HRs. Study-specific HRs on the disease-free survival were pooled using a random-effects model. Eleven articles in total were selected. Analysis was performed first among the 6 studies that separated partial response from the complete response and later among all 11 of the studies. Pooled HR was 0.49 (95% CI, 0.28-0.85) for the 6 studies that compared partial response with poor response. It was 0.41 (95% CI, 0.25-0.67) when all 11 of the studies were analyzed together. The studies were limited by not being prospective, randomized trials, and the tumor regression grades were not uniform. Partial tumor response is associated with a 50% improvement in disease-free survival and should be considered as a favorable prognostic factor.

Proposal for a Multifactorial Prognostic Score That Accurately Classifies 3 Groups of Gastric Carcinoma Patients With Different Outcomes After Neoadjuvant Chemotherapy and Surgery

We have developed a multifactorial histopathological prognostic score (PRSC) for patients with gastric cancer treated with neoadjuvant chemotherapy before surgery for the accurate discrimination of patient subgroups with differing outcomes. For patients with gastric cancer who undergo multimodal treatment, the postoperative staging classifications used for nontreated tumors may not accurately predict patient prognosis. We evaluated 428 gastric carcinoma specimens after a cisplatin-based chemotherapy. The factors for the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) ypT-category, ypN-category, and histopathological tumor regression were assigned a value from 1 to 3 as follows: ypT0 to 2 = 1 point; ypT3 = 2 points; ypT4 = 3 points; ypN0 = 1 point; ypN1 to 2 = 2 points; ypN3a to 3b = 3 points; less than 10% residual tumor per tumor bed = 1 point; 10% to 50% residual tumor per tumor bed = 2 points; and greater than 50% residual tumor per tumor bed = 3 points. A 3-tiered PRSC based on the sum value was established (group A: 3-4 points; group B: 5-7 points; group C: 8-9 points) and was found to correlate with patient prognosis. The PRSC showed a clear discrimination of 3 significantly different prognostic groups (group A: 76 patients; group B: 210 patients; group C: 142 patients; P < 0.001). In multivariate analyses, including the completeness of resection, tumor diameter, lymphatic vessel invasion, tumor grading, and Lauren classification, the PRSC was the only independent prognostic factor for overall survival (hazard ratio [HR] = 2.03; 95% confidence intervals [CI], 1.49-2.78; P < 0.001). It was slightly superior to the UICC/AJCC staging system (HR = 1.66; 95% CI, 1.20-2.27; P = 0.002) when analyzed with tumor regression as an additional independent factor (HR = 1.27; 95% CI, 1.01-1.62; P = 0.044) included in the analysis. The proposed PRSC reveals the most accurate prediction of survival for patients with gastric carcinoma after neoadjuvant chemotherapy followed by surgery. The PRSC clearly identifies 3 subgroups with different prognoses and may be helpful for therapeutic decisions.

Post-radiation fibrosis does not correlate with tumour regression following neoadjuvant chemoradiotherapy for rectal cancer

Aims Patients with locally advanced rectal cancer are generally offered neoadjuvant chemoradiotherapy in an effort to downstage the tumour prior to surgery; however, the degree of tumour regression achieved is highly variable and is difficult to predict. We postulated that tumour regression and the degree of post-radiation fibrosis would be causally related. Methods 133 patients undergoing neoadjuvant chemoradiother-apy were classified as ‘good responders’ (Dworak regression grade 3 or 4), ‘intermediate’ (grade 2), or ‘non-responders’ (grade 0 or 1). A semiquantitative three-step fibrosis score was developed and applied to all cases. Results There was no correlation between tumour regression score and fibrosis score, with each response group showing similar per centages of fibrosis (15–20% score 1, 30–35% score 2 and approximately 50% score 3). Conclusions Post-radiation fibrosis does not correlate with tumour regression. Rather the degree of fibrosis may correlate with differences in fibroblast gene expression signatures, and this is the subject of further study. The fibrotic response may be patient-dependent rather than tumour-dependent, and this may have predictive value in terms of subsequent complications of radiotherapy.

Effect of the novel anti-androgen ARN-509 on response and seizure in castration-resistant prostate cancer models.

28 Background: ARN-509 is a second-generation anti-androgen discovered in a screen to identify full androgen receptor (AR) antagonists in the context of AR over-expressing prostate cancer cells, a model for castration resistant prostate cancer (CRPC). It has been reported that other second-generation anti-androgens, MDV3100 and BMS-641988, can induce seizures at high dose in pre-clinical species and man and that this is mediated through antagonism of the CNS-based GABAA receptor. To define the clinical potential of ARN-509, we carried out a comprehensive assessment of its in vitro and in vivo activity in validated models of CRPC and assessed its seizure inducing potential. Methods: ARN-509 and MDV3100 were profiled in a series of assays to monitor both on- and off-target activity. Comparative in vivo efficacy in the LNCaP/AR mouse xenograft model of CRPC and pharmacokinetics were determined. Seizure inducing potential was assessed in an acute pentylenetetrazol (PTZ) infusion model. Results: In vivo, in the LNCaP/AR model of CRPC, an ARN-509 dose of 10 mg/kg/day exhibited tumors regressions equivalent in frequency and magnitude to a 30 mg/kg/day dose of MDV3100. Tumor re-growth following once daily dosing (30 mg/kg) for 28 days revealed that ARN-509 treated tumors exhibited a more durable response than MDV3100 treated tumors as evidenced by a significantly longer time to re-growth. At doses that yielded equivalent degree of tumor regression, the steady state plasma and brain levels were significantly lower for ARN-509 (10 mg/kg) than MDV3100 (30 mg/kg). ARN-509 and MDV3100 exhibit similar binding affinity to the GABAA receptor; IC50 3.0 and 2.7 mM, respectively. In vivo seizure potential of ARN-509 and MDV3100 was assessed in an acute PTZ infusion model in mice. MDV3100 was found to produce a dose dependant lowering of seizure threshold, while ARN-509 had no effect at any dose tested. Conclusions: ARN-509 is a second-generation anti-androgen with significant efficacy and an appropriate safety profile that supports its clinical development in both CRPC and earlier stages of prostate cancer. ARN-509 is currently in a phase I/II study in CRPC patients. [Table: see text]

Lymphadenectomy exacerbates tumor growth while lymphadenectomy plus the adoptive transfer of autologous cytotoxic cells and low-dose cyclophosphamide induces regression of an established murine fibrosarcoma.

Tumor-draining lymph node (TDLN) ablation is routinely performed in the management of cancer; nevertheless, its usefulness is at present a matter of debate. TDLN are central sites where T cell priming to tumor antigens and onset of the antitumor immune response occur. However, tumor-induced immunosuppression has been demonstrated at TDLN, leading to downregulation of antitumor reaction and tolerance induction. Tolerance in turn is a main impairment for immunotherapy trials. We used a murine immunogenic fibrosarcoma that evolves to a tolerogenic state, to study the cellular and molecular mechanisms underlying tolerance induction at the level of TDLN and to design an appropriate immunotherapy. We determined that following a transient activation, the established tumor induces signs of immunosuppression at TDLN that coexist with local and systemic evidences of antitumor response. Therefore, we evaluated the feasibility of removing TDLN in order to eliminate a focus of immunosuppression and favor tumor rejection; but instead, a marked exacerbation of tumor growth was induced. Combining TDLN ablation with the in vivo depletion of regulatory cells by low-dose cyclophosphamide and the restoring of the TDLN-derived cells into the donor mouse by adoptive transference, resulted in lowered tumor growth, enhanced survival and a considerable degree of tumor regression. Our results demonstrate that important antitumor elements can be eliminated by lymphadenectomy and proved that the concurrent administration of low-dose chemotherapy along with the reinoculation of autologous cytotoxic cells provides protection. We suggest that this protocol may be useful, especially in the cases where lymphadenectomy is mandatory.

Post-radiation CT changes and recurrent nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is endemic in Southern Asia. Radiation therapy remains the mainstay of treatment strategies for NPC. Although approximately 19% - 56% of patients develop a recurrent disease 5 years after their primary treatment, recognition of post-radiation changes and early detection of relapse are important in improving the outcome of NPC. Our aim was to analyze the post-radiation changes and recurrent diseases related to NPC using computed tomography (CT) scans and to investigate their relationship. CT scans of 510 pathologically proven NPC patients who have been followed up for more than 2 years after radiation were reviewed. The tumor's response to the radiation therapy and its relevance to recurrence were evaluated. For patients who were followed up for more than 2 years, their CT scans-obtained within 3 months, during the 4th to the 6th month, and beyond 7 months after radiation therapy, showed a normal nasopharyngeal cavity with a slight thickening in the wall in 93.5%, 95.0% and 84.8% of the patients respectively. The degree of tumor regression had no significant relevance to the risk of recurrence within the initial 3 months (P = 0.094). During this term, the relapse rates in the cases in which the nasopharyngeal walls were displayed as normal, slightly or moderately thickening, or with obvious residual masses on CT scans were 7.1%, 11.7%, 23.5% and 23.1% respectively. The degree of tumor regression beyond 3 months after radiation therapy had a considerable reverse relevance to the risk of recurrence (P = 0.000). The relapse rates were 13.2%, 14.1%, 10.2% and 2.1%, respectively, in the cases with a normal and a slightly thickening nasopharyngeal wall during the 4th to the 6th month, the 7th to the 12th month, the 13th to the 24th month, and beyond 25 months after radiation. In contrast, the percents in cases with moderate or more aggressive thickening walls in the corresponding periods were 62.5%, 88.9%, 100% and 100%. Within 6 months after radiation therapy, shown by CT scans, the metastatic lymph nodes disappeared, markedly decreased, slightly decreased, or enlarged in 37.4%, 51.8%, 4.7%, and 0.4%, respectively, of the patients. During 6 to 12 months after radiation therapy, the proportions were 78.5%, 19.2%, 0.6% and 1.7% correspondingly. Beyond 12 months, the proportions were 83.7%, 7.9%, 0%, and 8.4%. The regression degree of the malignant nodes after radiation therapy showed a remarkable reverse relevance to the risk of recurrence in lymph nodes (P = 0.000). In the cases with disappearing, markedly decreased, slightly decreased, or enlarged malignant nodes within six months after radiation, the relapse rates were 2.9%, 4.5%, 12.5% and 100%, respectively. If the nasopharyngeal walls are shown to remain moderately thick on a CT scan beyond 6 months after radiotherapy, the risk of relapse will increase. The baseline images taken within 3 months after radiotherapy and regular follow-up studies are the key to pick up the tumor recurrences in an earlier stage.

Sunitinib in patients with metastatic renal cell carcinoma: Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Context Current treatment options for metastatic renal cell carcinoma (RCC) are limited and there is a need to identify novel and effective therapies. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor, which has shown activity in an initial study of cytokine-refractory metastatic RCC patients. Objective To confirm the antitumor efficacy of sunitinib as second-line treatment in patients with metastatic clear-cell RCC, the predominant cell type of this malignancy. Design, Setting, and Patients Open-label, single-arm, multicenter clinical trial. Patients were enrolled between February and November 2004, with follow-up continuing until disease progression, unacceptable toxicity, or withdrawal of consent. The reported data apply through August 2005. Patients ( N = 106) had metastatic clear-cell RCC, which had progressed despite previous cytokine therapy. Intervention Repeated 6-week cycles of sunitinib, 50 mg per day given orally for 4 consecutive weeks followed by 2 weeks off per treatment cycle. Main Outcome Measures Assessment of clinical response, degree of tumor regression on imaging studies using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Primary end point was overall objective response rate (complete plus partial). Secondary end points were progression-free survival and safety. Response was evaluated by independent third-party core imaging laboratory and by treating physicians (investigator assessment). Results All 106 patients received sunitinib and were included in the intent-to-treat population for safety analyses. Of these, 105 patients were evaluable for efficacy analyses. The objective response rate according to an independent third-party assessment resulted in 36 patients with partial response (34%; 95% confidence interval, 25%–44%), and a median progression-free survival of 8.3 months (95% confidence interval, 7.8–14.5 months). The most common adverse events experienced by patients were fatigue in 30 (28%) and diarrhea 21 (20%). Neutropenia, elevation of lipase, and anemia were the most common laboratory abnormalities observed in 45 (42%), 30 (28%), and 27 (26%) patients, respectively. Conclusion The results of this trial demonstrate the efficacy and manageable adverse-event profile of sunitinib as a single agent in second-line therapy for patients with cytokine-refractory metastatic clear-cell RCC. Trial Registration clinicaltrials.gov Identifier: NCT00077974.

Sunitinib in Patients With Metastatic Renal Cell Carcinoma

Current treatment options for metastatic renal cell carcinoma (RCC) are limited and there is a need to identify novel and effective therapies. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor, which has shown activity in an initial study of cytokine-refractory metastatic RCC patients. To confirm the antitumor efficacy of sunitinib as second-line treatment in patients with metastatic clear-cell RCC, the predominant cell type of this malignancy. Open-label, single-arm, multicenter clinical trial. Patients were enrolled between February and November 2004, with follow-up continuing until disease progression, unacceptable toxicity, or withdrawal of consent. The reported data apply through August 2005. Patients (N = 106) had metastatic clear-cell RCC, which had progressed despite previous cytokine therapy. Repeated 6-week cycles of sunitinib, 50 mg per day given orally for 4 consecutive weeks followed by 2 weeks off per treatment cycle. Assessment of clinical response, degree of tumor regression on imaging studies using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Primary end point was overall objective response rate (complete plus partial). Secondary end points were progression-free survival and safety. Response was evaluated by independent third-party core imaging laboratory and by treating physicians (investigator assessment). All 106 patients received sunitinib and were included in the intent-to-treat population for safety analyses. Of these, 105 patients were evaluable for efficacy analyses. The objective response rate according to an independent third-party assessment resulted in 36 patients with partial response (34%; 95% confidence interval, 25%-44%), and a median progression-free survival of 8.3 months (95% confidence interval, 7.8-14.5 months). The most common adverse events experienced by patients were fatigue in 30 (28%) and diarrhea 21 (20%). Neutropenia, elevation of lipase, and anemia were the most common laboratory abnormalities observed in 45 (42%), 30 (28%), and 27 (26%) patients, respectively. The results of this trial demonstrate the efficacy and manageable adverse-event profile of sunitinib as a single agent in second-line therapy for patients with cytokine-refractory metastatic clear-cell RCC. clinicaltrials.gov Identifier: NCT00077974.

The American Brachytherapy Society recommendations for low-dose-rate brachytherapy for carcinoma of the cervix

Purpose : This report presents guidelines for using low-dose-rate (LDR) brachytherapy in the management of patients with cervical cancer. Methods : Members of the American Brachytherapy Society (ABS) with expertise in LDR brachytherapy for cervical cancer performed a literature review, supplemented by their clinical experience, to formulate guidelines for LDR brachytherapy of cervical cancer. Results : The ABS strongly recommends that radiation treatment for cervical carcinoma (with or without chemotherapy) should include brachytherapy as a component. Precise applicator placement is essential for improved local control and reduced morbidity. The outcome of brachytherapy depends, in part, on the skill of the brachytherapist. Doses given by external beam radiotherapy and brachytherapy depend upon the initial volume of disease, the ability to displace the bladder and rectum, the degree of tumor regression during pelvic irradiation, and institutional practice. The ABS recognizes that intracavitary brachytherapy is the standard technique for brachytherapy for cervical carcinoma. Interstitial brachytherapy should be considered for patients with disease that cannot be optimally encompassed by intracavitary brachytherapy. The ABS recommends completion of treatment within 8 weeks, when possible. Prolonging total treatment duration can adversely affect local control and survival. Recommendations are made for definitive and postoperative therapy after hysterectomy. Although recognizing that many efficacious LDR dose schedules exist, the ABS presents suggested dose and fractionation schemes for combining external beam radiotherapy with LDR brachytherapy for each stage of disease. The dose prescription point (point A) is defined for intracavitary insertions. Dose rates of 0.50 to 0.65 Gy/h are suggested for intracavitary brachytherapy. Dose rates of 0.50 to 0.70 Gy/h to the periphery of the implant are suggested for interstitial implant. Use of differential source activity or loading minimizes excessive central dose rates. These recommendations are intended only as guidelines. The responsibility for medical decisions ultimately rests with the treating radiation oncologist. Conclusion : Guidelines are suggested for LDR brachytherapy for cervical cancer. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies.

The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix

Purpose: This report presents guidelines for using high-dose-rate (HDR) brachytherapy in the management of patients with cervical cancer, taking into consideration the current availability of resources in most institutions. Methods: Members of the American Brachytherapy Society (ABS) with expertise in HDR brachytherapy for cervical cancer performed a literature review, supplemented their clinical experience to formulate guidelines for HDR brachytherapy of cervical cancer. Results: The ABS strongly recommends that definitive irradiation for cervical carcinoma must include brachytherapy as a component. Each institution should follow a consistent treatment policy when performing HDR brachytherapy, including complete documentation of treatment parameters and correlation with clinical outcome, such as pelvic control, survival, and complications. The goals are to treat Point A to at least a total low-dose-rate (LDR) equivalent of 80–85 Gy for early stage disease and 85–90 Gy for advanced stage. The pelvic sidewall dose recommendations are 50–55 Gy for early lesions and 55–65 Gy for advanced ones. The relative doses given by external beam radiation therapy (EBRT) vs. brachytherapy depend upon the initial volume of disease, the ability to displace the bladder and rectum, the degree of tumor regression during pelvic irradiation, and institutional preference. As with LDR brachytherapy, every attempt should be made to keep the bladder and rectal doses below 80 Gy and 75 Gy LDR equivalent doses, respectively. Interstitial brachytherapy should be considered for patients with disease that cannot be optimally encompassed by intracavitary brachytherapy. While recognizing that many efficacious HDR fractionation schedules exist, some suggested dose and fractionation schemes for combining the EBRT with HDR brachytherapy for each stage of disease are presented. These recommendations are intended only as guidelines, and the suggested fractionation schemes have not been thoroughly tested. The responsibility for the medical decisions ultimately rests with the treating radiation oncologist. Conclusion: Guidelines are established for HDR brachytherapy for cervical cancer. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies. These guidelines will be modified, as image-based treatment becomes more widely available.

Pathological features of rectal cancer after preoperative radiochemotherapy.

The standard therapy for rectal carcinoma is surgical, however, preoperative radiochemotherapy will play an increasing role especially in locally advanced disease. To estimate the prognosis and the effect of radiochemotherapy the postradiochemotherapeutical pathological features are important to assess. We examined the surgical specimens of 17 patients after preoperative radiochemotherapy to estimate and grade the histological reactions. A proposal for a grading system for tumor regression (not yet available in the literature) has also been described. All but one of the carcinomas showed different degrees of tumor regression. A total regression was not observed after standardised pathological work up. In only one case a locally curative resection was not possible. We think that preoperative radiochemotherapy is able to reduce tumor mass thus achieving operability in non-curatively operable cases. We recommend standards of pathological work up and regression grading for further studies comparing surgery and radiochemotherapy of rectal carcinoma.

Octreotide combined with goserelin in the therapy of advanced pancreatic cancer--results of a pilot study and review of the literature.

The two hormone analogues octreotide and goserelin have been shown to decelerate growth of human pancreatic cancer in vitro and in vivo. The objective of this pilot study was to investigate the efficacy and toxicity of the combination of these two agents in patients with advanced pancreatic cancer. Octreotide was injected subcutaneously in dosages increasing weekly, starting with 50 micrograms twice daily, until the level of maintenance therapy of 500 micrograms three times a day was reached. In addition, 3.8 mg goserelin acetate was administered subcutaneously at monthly intervals. A median of 7 cycles (range 1-27 cycles) were applied; 13 out of 14 patients entered into the study were evaluable for response and all 14 were evaluated for toxicity. In one patient with initially non-resectable pancreatic cancer, systemic therapy yielded a partial remission lasting 9 months. The degree of tumour regression then allowed a consecutive macroscopic radical tumour resection followed by an additional 6 months of no evidence of disease while the same drug combination was continued. In an additional 9 patients, no change of disease was observed, in some cases for a remarkably long time (up to 27 months). Nevertheless, the objective response rate of 7% (95% confidence interval 0 +/- 21%) was low. In 5 patients a clear improvement in their performance status was seen soon after the start of therapy; 3 patients showed progression of the disease at first evaluation or earlier and 1 patient was not evaluable at the time of study assessment. According to the product-limit method of Kaplan and Meier, the time to progression was 3.0 +/- 1.8 months [median +/- asymptotic standard error (ASE)] and overall survival was 6.0 +/- 1.5 months (median +/- ASE). Toxicity was rare and only of mild to moderate degree. Overall, the regimen under investigation did not meet the criteria for sufficient antitumoural effectiveness. Nevertheless, this study reinforces the concept that pancreatic cancer is principally responsive to endocrine therapy and therefore the further investigation of hormonal manipulation seems worth while in the future.

Combined Modality Approach for High-Risk Breast Cancer: The Milan Cancer Institute Experience

After 20 years of successive clinical trials, the results achieved at the Milan Cancer Institute have helped to establish the effectiveness of adjuvant combination chemotherapy in high-risk women with resectable breast cancer. The most significant findings can be summarized as follows: (1) the clinical benefit in terms of relapse-free and total survival can be prolonged up to 20 years from surgery; (2) the use of anthracyclines (doxorubicin) can contribute to improved treatment outcome; (3) dose intensity and dose size are the leading prognostic variables; and (4) adjuvant treatments are not associated with important iatrogenic morbidity. New modalities that could profoundly change current treatment strategies will involve high-dose sequential chemotherapy and primary chemotherapy. In fact, the use of rhG-CSF-elicited hematopoietic progenitors will grant a substantial reduction in granulocytopenia and related toxicities; this, in turn, will permit the administration of regimens based on high dose size and dose intensity. As far as primary chemotherapy is concerned, the shift from mutilating to breast-conserving operations has led to important advantages in a society concerned for body integrity. In the few studies with sufficient follow-up, objective tumor response to primary chemotherapy has been translated into superior relapse-free survival compared with that of nonresponders. In particular, from the first Milan study the knowledge is clearly emerging that the response rate is inversely related to the initial tumor volume and that the degree of tumor regression (complete pathologic remission versus moderate versus minimal response) appears to represent a marker of outcome. Should this crucial observation be confirmed in other ongoing trials, then the amount of tumor shrinkage could rank among the most important prognostic variables because it is reproducible and inexpensive. As a consequence, the achievement of complete (or near complete) pathologic remission will become the major goal of properly intensified drug regimens to ensure a durable relapse-free survival rate. To make legitimate the wide adoption of the strategy involving primary chemotherapy, most breast cancer specialists correctly advocate that the initial promising results be validated through classic randomized trials. The question to answer appears simple: Will preoperative chemotherapy be superior to postoperative chemotherapy in terms of relapse-free and total survival? In our opinion, the simple attempt to shift from postoperative (adjuvant) to preoperative (primary) chemotherapy may not be enough, although formally correct, to maximize treatment outcome, and thus become the new strategy of choice.(ABSTRACT TRUNCATED AT 250 WORDS)