Role of histological regression grade after two neoadjuvant approaches with or without radiotherapy in locally advanced gastric cancer.

BACKGROUND: The degree of histopathological response after neoadjuvant therapy in locally advanced gastric cancer (GC) is a key determinant of patients' long-term outcome. We aimed to assess the pattern of histopathological regression after two neoadjuvant approaches and its impact on survival times. METHODS: Regression grade of the primary tumour (Becker criteria) and the degree of nodal response by a 4-point scale (grades A-D) were assessed. Grade A-true negative lymph nodes (LNs); grade B and C-infiltrated LNs with any or little evidence of nodal response; and grade D-complete pathological response in a previously infiltrated LN. A favourable pathological response was defined as Becker Ia-b and grade D. RESULTS: From 2004 to 2014, 80 patients with GC (cT3-4/N+ by CT-scan/EUS) were treated with either preoperative chemotherapy (ChT, n=34) or chemoradiation (CRT, n=46). Patients in the CRT group had a higher likelihood of achieving a Becker Ia-b response (58 vs 32%, P=0.001), a grade D nodal regression (30 vs 6%, P=0.009) and a favourable pathological response (23 vs 3%; P=0.019). Patients with a grade D nodal response had a longer 5-year PFS and OS compared with those with a grade B or C response. Patients with a baseline negative LN status had similar outcomes irrespective of the preoperative therapy received (5-year OS; ChT vs CRT, 58 vs 51%, P=0.92). CONCLUSIONS: Preoperative chemoradiation increases the likelihood of achieving favourable histopathological features that correlate with a 5-year OS>70% in GC patients.

Four-week neoadjuvant intensity-modulated radiation therapy with concurrent capecitabine and oxaliplatin in locally advanced rectal cancer patients: a validation phase II trial.

PURPOSE: To validate tolerance and pathological complete response rate (pCR) of a 4-week preoperative course of intensity-modulated radiation therapy (IMRT) with concurrent capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer. METHODS AND MATERIALS: Patients with T3 to T4 and/or N+ rectal cancer received preoperative IMRT (47.5 Gy in 19 fractions) with concurrent capecitabine (825 mg/m(2) b.i.d., Monday to Friday) and oxaliplatin (60 mg/m(2) on Days 1, 8, and 15). Surgery was scheduled 4 to 6 weeks after the completion of chemoradiation. Primary end points were toxicity and pathological response rate. Local control (LC), disease-free survival (DFS), and overall survival (OS) were also analyzed. RESULTS: A total of 100 patients were evaluated. Grade 1 to 2 proctitis was observed in 73 patients (73%). Grade 3 diarrhea occurred in 9% of the patients. Grade 3 proctitis in 18% of the first 50 patients led to reduction of the dose per fraction to 47.5 Gy in 20 treatments. The rate of Grade 3 proctitis decreased to 4% thereafter (odds ratio, 0.27). A total of 99 patients underwent surgery. A pCR was observed in 13% of the patients, major response (96-100% of histological response) in 48%, and pN downstaging in 78%. An R0 resection was performed in 97% of the patients. After a median follow-up of 55 months, the LC, DFS, and OS rates were 100%, 84%, and 87%, respectively. CONCLUSIONS: Preoperative CAPOX-IMRT therapy (47.5 Gy in 20 fractions) is feasible and safe, and produces major pathological responses in approximately 50% of patients.

Patterns of response after preoperative intensity-modulated radiation therapy and capecitabine/oxaliplatin in rectal cancer: is there still a place for ecoendoscopic ultrasound?

PURPOSE: The main goals of preoperative chemoradiotherapy (CHRT) in rectal cancer are to achieve pathological response and to ensure tumor control with functional surgery when possible. Assessment of the concordance between clinical and pathological responses is necessary to make decisions regarding alternative conservative procedures. The present study evaluates the patterns of response after a preoperative CHRT regimen, and the value of endoscopic ultrasound (EUS) in assessing response. METHODS AND MATERIALS: A total of 51 EUS-staged T3 to T4 and/or N0 to N+ rectal cancer patients received preoperative CHRT (intensity-modulated radiation therapy and capecitabine/oxaliplatin (XELOX) followed by radical resection. Clinical response was assesed by EUS. Rates of pathological tumor regression grade (TRG) and lymph node (LN) involvement were determined in the surgical specimen. Clinical and pathological responses were compared, and the accuracy of EUS in assessing response was calculated. RESULTS: Twenty-four patients (45%) achieved a major pathological response (complete or >95% pathological response (TRG 3+/4)). Sensitivity, specificity, negative predictive value, and positive predictive value of EUS in predicting pathological T response after preoperative CHRT were 77.8%, 37.5%, 60%, and 58%, respectively. The EUS sensitivity, specificity, negative predictive value, and positive predictive value for nodal staging were 44%, 88%, 88%, and 44%, respectively. Furthermore, EUS after CHRT accurately predicted the absence of LN involvement in 7 of 7 patients (100%) with major pathological response of the primary tumor. CONCLUSION: Preoperative IMRT with concomitant XELOX induces favorable rates of major pathological response. EUS has a limited ability to predict primary tumor response after preoperative CHRT, but it is useful for accurately determining LN status. EUS may have a potential value in identifying patients with a very low risk of LN involvement in association with a good pathological response as potential candidates for conservative local surgical protocols.

Patterns of response after preoperative treatment in gastric cancer.

PURPOSE: To analyze the rate of pathologic response in patients with locally advanced gastric cancer treated with preoperative chemotherapy with and without chemoradiation at our institution. METHODS AND MATERIALS: From 2000 to 2007 patients were retrospectively identified who received preoperative treatment for gastric cancer (cT3-4/ N+) with induction chemotherapy (Ch) or with Ch followed by concurrent chemoradiotherapy (45 Gy in 5 weeks) (ChRT). Surgery was planned 4-6 weeks after the completion of neoadjuvant treatment. Pathologic assessment was used to investigate the patterns of pathologic response after neoadjuvant treatment. RESULTS: Sixty-one patients were analyzed. Of 61 patients, 58 (95%) underwent surgery. The R0 resection rate was 87%. Pathologic complete response was achieved in 12% of the patients. A major pathologic response (<10% of residual tumor) was observed in 53% of patients, and T downstaging was observed in 75%. Median follow-up was 38.7 months. Median disease-free survival (DFS) was 36.5 months. The only patient-, tumor-, and treatment-related factor associated with pathologic response was the use of preoperative ChRT. Patients achieving major pathologic response had a 3-year actuarial DFS rate of 63%. CONCLUSIONS: The patterns of pathologic response after preoperative ChRT suggest encouraging intervals of DFS. Such a strategy may be of interest to be explored in gastric cancer.

microRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells.

PURPOSE: microRNAs (miRNA) are small RNAs that function as post-transcriptional regulators of gene expression. Recent evidence has shown that some miRNAs can act as oncogenes or tumor suppressors. This study was conducted to evaluate the potential association of miRNA expression with clinical outcome in patients with gastric cancer. EXPERIMENTAL DESIGN: Expression of 250 human mature miRNAs was measured by real-time PCR on paraffin-embedded tumor samples of 21 patients with gastric cancer stage III uniformly treated with surgical resection followed by chemoradiation. We identified the miRNAs correlated with disease-free and overall survival times, and the results were evaluated including 24 other patients. In vitro cell proliferation and radiosensitivity studies were done to support clinical data. RESULTS: The results revealed that down-regulation of miR-451 was associated with worse prognosis. miR-451 was detected by in situ hybridization in epithelial cells and showed decreased expression in gastric and colorectal cancer versus nontumoral tissues. Overexpression of miR-451 in gastric and colorectal cancer cells reduced cell proliferation and increased sensitivity to radiotherapy. Microarray and bioinformatic analysis identified the novel oncogene macrophage migration inhibitory factor (MIF) as a potential target of miR-451. In fact, overexpression of miR-451 down-regulated mRNA and protein levels of MIF and decreased expression of reporter genes with MIF target sequences. Moreover, we found a significant inverse correlation between miR-451 and MIF expression in tumoral gastric biopsies. CONCLUSIONS: These findings support the role of miR-451 as a regulator of cancer proliferation and open new perspectives for the development of effective therapies for chemoradioresistant cancers.

cT3N0 rectal cancer: potential overtreatment with preoperative chemoradiotherapy is warranted.

PURPOSE: Although combined-modality therapy (CMT) is the preferred treatment for T3 and/or lymph node (LN)-positive rectal cancer, the German rectal cancer study published in 2004 demonstrated that 18% of patients deemed suitable for preoperative CMT by endorectal ultrasound (ERUS) may be overstaged. Because data also suggest that LN-negative rectal cancer after total mesorectal excision may not require radiotherapy, it is reasonable to consider omitting radiotherapy for the cT3N0 subset. We therefore determined the accuracy of pre-CMT ERUS or magnetic resonance imaging (MRI) staging, to explore the validity of a nonpreoperative CMT approach for cT3N0 disease. PATIENTS AND METHODS: One hundred eighty-eight ERUS-/MRI-staged T3N0 rectal cancer patients received preoperative CMT (fluorouracil based and 45-50.4 Gy) followed by radical resection. Rates of pathologic complete response (pCR) and mesorectal LN involvement were determined. RESULTS: Tumors were located a median of 5 cm from the anal verge. Sphincter-preserving surgery was performed in 143 patients (76%). Overall pCR was 20%, and 41 patients (22%) had pathologically positive mesorectal LNs. The incidence of positive LNs significantly increased with T stage: ypT0, 3%; ypT1, 7%; ypT2, 20%; ypT3-4, 36% (P = .001). CONCLUSION: The accuracy of preoperative ERUS/MRI for staging mid to distal cT3N0 rectal cancer is limited because 22% of patients have undetected mesorectal LN involvement despite CMT. Therefore, ERUS-/MRI-staged T3N0 rectal cancer patients should continue to receive preoperative CMT. Although 18% may be overstaged and therefore overtreated, our data suggest that an even larger number would be understaged and require postoperative CMT, which is associated with significantly inferior local control, higher toxicity, and worse functional outcome.

Rectal cancer treatment: improving the picture.

Multidisciplinary approach for rectal cancer treatment is currently well defined. Nevertheless, new and promising advances are enriching the portrait. Since the US NIH Consensus in the early 90's some new characters have been added. A bird's-eye view along the last decade shows the main milestones in the development of rectal cancer treatment protocols. New drugs, in combination with radiotherapy are being tested to increase response and tumor control outcomes. However, therapeutic intensity is often associated with toxicity. Thus, innovative strategies are needed to create a better-balanced therapeutic ratio. Molecular targeted therapies and improved technology for delivering radiotherapy respond to the need for accuracy and precision in rectal cancer treatment.

Role of concanavalin A lectin in recognition of pterygium remnant after surgical excision: preliminary results of a prospective study.

BACKGROUND: Pterygium is one of the most common conjunctival diseases among ophthalmic pathologies. The frequency of recurrences is high, either after surgical treatment or after treatment combined with mitomycin C or beta-radiation therapy. AIMS: The purpose of this study was to determine whether concanavalin A (ConA) lectin bound to the pterygial surface can be used to detect recurrence or remnants of pterygium after surgical excision. MATERIALS AND METHODS: This was a prospective study on 20 patients with pterygium, divided in five stages, pre-surgery, early post-surgery (24h), late post-surgery (seven days), very late post-surgery (four weeks) and two months after the procedure. A drop of fluorescein-marked Con A (35 microg/mL) was instilled in the lower conjunctival eyelid sac and the eye was exposed to the light of a Wood's lamp for an average of five seconds. RESULTS: Out of the 20 patients, eight patients were found to have fluorescent stretch marks over the scar corresponding to residual pterygial tissue at four weeks; two months after the procedure of re-surgery we observed no fluorescent remnants. All residual pterygia were confirmed through histochemistry studies. CONCLUSION: It was possible to detect remnants of pterygium in postoperative patients and recurrences in early pre-clinical stages through the visualization of fluorescent ConA bound to the pterygial surface.

Detecting changes in tumor hypoxia with carbonic anhydrase IX and pimonidazole.

We have used immunohistochemistry to examine the dynamics of tumor hypoxia.. Expression of CAIX is known to be influenced by tumor hypoxia, and this protein has been shown to be an endogenous hypoxia marker in several models. However, due to its long half-life, it could also be present in oxygenated tissue that had recently been hypoxic. To investigate this issue we have compared CAIX expression to the exogenous hypoxia marker, pimonidazole using HT29 (human colorectal cancer) xenografts. We manipulated tumor hypoxia with carbogen and hydralazine, treatments that respectively increased and decreased tumor oxygenation. (Carbogen was given 75 minutes and hydralazine 30 minutes before sacrifice). In tumors from the control group, CAIX and pimonidazole exhibited similar (though not identical) spatial distribution, and for both markers, the fraction of the section staining positively was similar (13.2% and 12.6% respectively). The mice treated with hydralazine showed a significant increase in pimonidazole accumulation (37.2%, p = 0.03), though the CAIX positive fraction was unchanged (14.2%). In contrast, in the carbogen group pimonidazole staining decreased to 3% (p = 0.01) though CAIX expression was again unaltered. These results suggest that comparison of CAIX and pimonidazole will allow for the detection of reoxygenation.

Prognostic factors for disease-free survival in patients with T3-4 or N+ rectal cancer treated with preoperative chemoradiation therapy, surgery, and intraoperative irradiation.

PURPOSE: Fluoropyrimidine-radiosensitizing agents in conjunction with preoperative radiotherapy have proven to induce tumor and nodal downstaging effects, sphincter preservation promotion, and mid-term favorable survival rates. Intraoperative electron beam radiation therapy may improve pelvic control in patients with locally advanced rectal cancer stages. Potential predictive factors for response and disease-free survival, with intense local multidisciplinary approach, are analyzed. METHODS AND MATERIALS: One hundred fifteen patients with rectal cancer were treated with oral 5-fluorouracil or Tegafur with preoperative radiotherapy, surgery, and intraoperative electron beam radiation therapy to identify potential pre- and on-treatment characteristics that might be of prognostic value for disease outcome. Univariate and multivariate analyses were performed. RESULTS: Older patients and those treated with Tegafur were more likely to achieve a major histologic response, categorized as persistence of minimal residual microscopic disease foci in the surgical specimen ("mic" response). Factors unfavorably associated with disease-free survival in the multivariate model were male gender and persistence of macroscopic disease in the rectal wall ("mac" response). Accordingly, 3-year disease-free survival rates in the groups of patients with 0, 1, or 2 of these risk factors were 100%, 81%, and 53%, respectively (p < 0.001). CONCLUSIONS: Females with an intense pathologic response (pT(mic) residue) to preoperative chemoradiotherapy have an excellent 3-year disease-free survival. This information might be of interest for stratification of patients in the development of adjuvant treatment trials.

Targeting hypoxia and angiogenesis through HIF-1alpha inhibition.

Hypoxia is an important phenomenon in the tumor microenvironment. Hypoxic tumors are more aggressive and resistant to anti-neoplastic treatments. HIF-1alpha plays a major role in the response of tumors to hypoxia, and it is mainly responsible for the "angiogenic switch". HIF-1alpha contributes to tumor aggressiveness, invasiveness, and resistance to radiotherapy and chemotherapy. Targeting HIF-1alpha is an attractive strategy, with the potential for disrupting multiple pathways crucial for tumor growth. We review recent findings on the potential efficacy of small molecules to downregulate HIF-1alpha. These promising drugs inhibit HIF-1alpha synthesis or transcriptional activity by blocking a variety of steps in several different signaling pathways. Blocking HIF-1alpha activity should not only downregulate tumor angiogenesis, but also interfere with glycolytic metabolism and tumor cell growth. This strategy could also improve the efficiency of established tumor therapies.

Preoperative chemoradiation with oral tegafur within a multidisciplinary therapeutic approach in patients with T3-4 rectal cancer.

PURPOSE: The aim of this study was to evaluate the activity in terms of downstaging histologic patterns of residual tumor and clinical tolerance of a neoadjuvant chemoradiation program with oral tegafur for rectal cancer. METHODS AND MATERIALS: From May 1998 to May 2001, 62 consecutive patients with cT(3-4) or cN(+) rectal cancer, or both, were treated with 45-50 Gy (1.8 Gy/day; 25 fractions) and oral tegafur 1200 mg/day. Surgery was performed 6 weeks after the completion of chemoradiation. All patients received a boost with intraoperative electron beam radiotherapy (IOERT) over the presacral space. RESULTS: Grade 3-4 hematologic toxicity consisted on Grade 3 anemia in 1 patient. Nonhematologic toxicity was mild. Fifteen patients (23%) had Grade 3 dermatitis, 16 (25%) had Grade 3, and 2 (3%) had Grade 4 proctitis. The median dose of radiotherapy was 50.4 Gy. Surgery consisted on anterior resection in 38 patients (61%) and abdominoperineal amputation in 24 (39%). Five complete pathologic responses were observed (8%), and 29 patients (47%) had a minimal microscopic residual tumor (mic category). The total downstaging rate was 68%. With a median follow-up of 46 months, the pelvic control rate was 95%, disease-free survival 74.1%, and overall survival 76.5%. CONCLUSIONS: Neoadjuvant chemoradiation with oral tegafur is feasible, well tolerated, and active, with the additional advantage of offering the convenience of oral chemotherapy.

Intraoperative presacral electron boost following preoperative chemoradiation in T3-4Nx rectal cancer: initial local effects and clinical outcome analysis.

BACKGROUND AND PURPOSE: To analyze early results of a single institution experience using adjuvant intraoperative electron radiation therapy (IOERT) presacral boost in locally advanced rectal cancer following preoperative chemoradiation. MATERIALS AND METHODS: In a 63 month period (March 1995-June 2000), 100 consecutive T(3-4)N(x) rectal cancer patients were treated with preoperative chemoradiation (45-50 Gy plus oral Tegafur or 5-Fluorouracil continuous intravenous infusion), radical surgery and IOERT presacral boost (mean dose, 12.5 Gy; range, 10-15 Gy). Adjuvant chemotherapy (5-FU-leucovorin: 4-6 cycles) was given to 52 patients. The median age was 63 years, and 39 patients were >or=70 years old (65 males). Clinical staging was performed with computed tomography (94%) and/or endorectal ultrasound (71%) categorizing 90 cT(3), 10 cT(4), 20 cN(x), and 36 cN(+). Abdomino-perineal resection was performed in 41 cases. RESULTS: The IOERT cancellation rate was 6%. With a median follow-up of 23 months in IOERT treated patients, three developed pelvic recurrence: one anastomotic and one in the posterior vaginal wall (simultaneously with distant metastatic disease); and one presacral (in-field IOERT) as the only site of initial failure. Distant metastasis has been observed in 14 patients (exceptionally in pT(0-1) downstaged patients: 1/20; 5%). Overall treatment tolerances, including neoadjuvant and surgical segments, were acceptable. The actuarial 4-year estimations of local control, disease-free and overall survival are 94, 75 and 65%, respectively. CONCLUSIONS: IOERT electron boost to the presacral region is feasible to integrate systematically in the intensive combined treatment of locally advanced rectal cancer, including neoadjuvant chemoradiation segment. Topography of pelvic recurrences identified 2/3 relapses located in non-IOERT boosted anatomic intrapelvic sites: posterior vaginal wall and anastomotic suture. Presacral recurrence in locally advanced rectal cancer seems to be of low incidence, in a non-subspecialized academic surgical practice coordinated with a multidisciplinary oncology evaluation context, if an IOERT boost is included as a component of treatment together with preoperative chemoradiation.