Maria Giulia Zampino

Surgical outcomes for colon and rectal cancer over a decade: results from a consecutive monocentric experience in 902 unselected patients

BackgroundThis study evaluates the surgical morbidity and long-term outcome of colorectal cancer surgery in an unselected group of patients treated over the period 1994–2003.MethodsA consecutive series of 902 primary colorectal cancer patients (489 M, 413 F; mean age: 63 years ± 11 years, range: 24–88 years) was evaluated and prospectively followed in a university hospital (mean follow-up 36 ± 24 months; range: 3–108 months). Perioperative mortality, morbidity, overall survival, curative resection rates, recurrence rates were analysed.ResultsOf the total, 476 colorectal cancers were localized to the colon (CC, 53%), 406 to the rectum (RC, 45%), 12 (1%) were multicentric, and 8 were identified as part of HNPCC (1%). Combining all tumours, there were 186 cancers (20.6%) defined as UICC stage I, 235 (26.1%) stage II, 270 (29.9%) stage III and 187 (20.6%) stage IV cases. Twenty-four (2.7%) cases were of undetermined stage. Postoperative complications occurred in 38% of the total group (37.8% of CC cases, 37.2% of the RC group, 66.7% of the synchronous cancer patients and 50% of those with HNPCC, p = 0.19) Mortality rate was 0.8%, (1.3% for colon cancer, 0% for rectal cancer; p = 0.023). Multivisceral resection was performed in 14.3% of cases. Disease-free survival in cases resected for cure was 73% at 5-years and 72% at 8 years. The 5- and 8-year overall survival rates were 71% and 61% respectively (total cases). At 5-year analysis, overall survival rates are 97% for stage I disease, 87% for stage II, 73% for stage III and 22% for stage IV respectively (p < 0.0001). The 5-year overall survival rates showed a marked difference in R0, R1+R2 and non resected patients (82%, 35% and 0% respectively, p < 0.0001). On multivariate analysis, resection for cure and stage at presentation but not tumour site (colon vs. rectum) were independent variables for overall survival (p < 0.0001).ConclusionA prospective, uniform follow-up policy used in a single institution over the last decade provides evidence of quality assurance in colorectal cancer surgery with high rates of resection for cure where only stage at presentation functions as an independent variable for cancer-related outcome.

First clinical experience of orally active epidermal growth factor receptor inhibitor combined with simplified FOLFOX6 as first‐line treatment for metastatic colorectal cancer

Gefitinib, an orally active inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, combined with chemotherapy, has shown efficacy as second‐line treatment for advanced colorectal cancer (CRC). Gefitinib combined with FOLFOX6 (oxaliplatin plus folinic acid and 5‐fluorouracil) was tested as a first‐line therapy.

The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death

Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS–ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 (XBP1), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.

K-ras status in squamous cell anal carcinoma (SCC): it's time for target-oriented treatment?

PurposeSquamous cell anal carcinoma (SCC) is an uncommon disease comprising only 1–5% of all intestinal tumours. SCC is now considered the prototype for the successful application of conservative treatment as chemoradiation instead of aggressive surgery. The EGFR status and k-ras mutations in SCC of the anal canal has not been well investigated. The purpose of our evaluation was to give information about this issue.MethodsFrom June 1999 to December 2008, 32 patients affected by SCC were treated in our institution with chemotherapy containing fluoropyrimidine and platinum salt concomitant with pelvic radiotherapy. Immunohistochemistry for EGFR and k-ras mutation was retrospectively evaluated.ResultsTwenty-six specimens were considered evaluable for biological objectives: K-ras mutation was performed in all cases, while EGFR in 12. In all cases of our series wild-type K-ras was observed.ConclusionsSuch information is, in our knowledge, the first reported in literature on this setting. This observation previously reported in other tumours has supported the effective use of EGFR-inhibitors in recurrent or metastatic disease. This observation could support the role of EGFR-inhibitors in the treatment of SCC.

Capecitabine Initially Concomitant to Radiotherapy Then Perioperatively Administered in Locally Advanced Rectal Cancer

PURPOSE To evaluate the impact of neoadjuvant capecitabine, concomitant to radiotherapy, followed by capecitabine monotherapy, in operable locally advanced rectal cancer (LARC) by measuring pathologic response and conservative surgery rate, toxicity profile, and disease-free survival (DFS). METHODS AND MATERIALS From October 2002 to July 2006, a total of 51 patients affected by LARC (T3-T4 or any node positive tumor), received capecitabine (825 mg/m(2), orally, twice daily continuously) concomitant to radiotherapy on the pelvis (50.4 Gy/ 28 fractions), followed by two cycles of capecitabine (1,250 mg/m(2), orally, twice daily, 14 days on 7 days off) up until 2 weeks before surgery. Tailored adjuvant systemic treatment was discussed according to pathologic stage. RESULTS Of 51 patients, (median age 61 years, range 38-82 years; 19 women and 32 men; ECOG performance status 0/1/2: 46/4/1), 50 were evaluable for response: 18% complete pathologic remission; 12% T-downstaging, and 30% N-downstaging. One patient died before surgery from mesenteric stroke. Grade 3 acute toxicities were 2% diarrhea, 8% dermatitis, 2% liver function test elevation, and 2% hand-foot syndrome. Sphincter preservation rates for tumors < or =6 cm from the anal verge were 62% and 80% for the whole population. Median follow up was 43.0 months (range 0.8-68.6 months). Five-years DFS was 85.4% (95% CI = 75.3-95.4%). CONCLUSIONS Based on our study results, we conclude that this regimen is well tolerated and active and compares favorably with existing capecitabine-based approaches.

Dual inhibition of mTOR pathway and VEGF signalling in neuroendocrine neoplasms: from bench to bedside.

After years of limited progress in the treatment of neuroendocrine neoplasms (NENs), an increasing number of therapeutic targets have recently emerged as potential tools to improve disease outcome. The mammalian target of rapamycin (mTOR) pathway and vascular endothelial growth factor (VEGF) signalling are implicated in the regulation of cell growth, proliferation, neo-angiogenesis and tumour cell spread. Their combined blockade, in a simultaneous or sequential strategy, represents an intriguing biological rationale to overcome the onset of resistance mechanisms. However, is becoming increasingly imperative to find the optimal sequential strategy according to the best toxicity profile, and also to identify predictive biomarkers. We will provide an overview of the pre-clinical and clinical data relating to mTOR pathway/VEGF signalling as a potential targets of treatment in NENs.

High-Intensity Focused Ultrasound Effect in Breast Cancer Nodal Metastasis

To the Editor, The aim of this letter is to describe our experience with the treatment of a nonresectable retroperitoneal lymph node with high-intensity focused ultrasound (HIFU). A 69-year-old woman developed a malignant tumor in the left breast in February 2006 and underwent quadrantectomy and sentinel lymph node excision at our institution. Pathological examination showed invasive mixed ductal and lobular carcinoma, and no invasion was seen in the adjacent blood vessels, lymphatics, or lymph nodes. The patient also has a past positive oncologic history for squamous cell carcinoma of the anal canal, which was treated with radical surgery and radiochemotherapy 2 years earlier, with no evidence of recurrence at the time of the quadrantectomy. After breast tumor excision, the patient received radiotherapy (21 Gy) and adjuvant hormonal therapy from May 2006 to February 2008. She remained free of disease until March 2008, when in a follow-up ultrasound (US) scan a single 30-mm hypoechoic solid mass was detected close to the hepatic hilum and was considered likely to be a metastatic lymph node. Multidetector computed tomography (MDCT) showed the presence of a large hilar hepatic node with inhomogeneous enhancement after contrast injection. It also excluded any other apparent site of disease. To characterize the finding, percutaneous US-guided core biopsy of the mass was performed using an 18 G needle. Pathology and immunohistochemistry confirmed the presence of metastatic cells from breast cancer. The surgical team did not consider the patient a suitable candidate for resection due to her history of cardiac failure and existing comorbidities. The lesion was also not considered suitable for percutaneous ablation due to the potential risk of thermal injury of the adjacent structures; therefore, observation of the lesion and continuation of chemotherapy with nonsteroid aromatase inhibitors was decided. Two months later (May 2009), the lesion showed growth of 1 cm on MDCT. The patient was re-evaluated in a multidisciplinary meeting comprising surgeons, oncologists, radiotherapists, and interventional radiologists. A consensus regarding the patient’s disease state was reached, thus leading to a new treatment plan. The patient was enrolled in a phase I study for HIFU treatment of solid tumors associated with chemotherapy using aromatase inhibitors. The patient had a Karnofsky performance scale score of 80%, with no contraindication to general anesthesia. The lesion was visualized before the procedure using US, and no gas interfered in the acoustic pathway. Informed consent was obtained. She was status NPO for 6 h before the procedure. The skin overlying the lesion was carefully shaved to avoid also any possible interference of hair in the acoustic pathway of HIFU, and a urinary catheter was inserted before treatment. General anesthesia was administered by the anesthetics team to achieve the patient’s complete immobilization and to prevent any pain. A purified-water balloon was used to push and compress bowel loops to avoid the presence of air G. Orgera (&) G. Bonomo L. Monfardini P. Della Vigna F. Orsi Unit of Interventional Radiology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy e-mail: gianluigi.orgera@ieo.it

Aggressive Treatment Approach for Cloacogenic Carcinoma of the Anorectum: Report from a Single Cancer Center

Background/Aims: The prognosis of cloacogenic carcinoma of the anorectum has rarely been investigated, and its clinical behavior is supposed to be similar to common squamous anal cancers. During the last 10 years, chemoradiation treatment (CRT) has been considered the standard of care for anal cancer. Methods: We retrospectively investigated the treatment of cloacogenic cancers treated within the framework of a multidisciplinary cancer center team during an 8-year period. The medical records of 7 patients affected by cloacogenic carcinoma were analyzed. Three patients presented distant metastases at the time of diagnosis. CRT using 5-fluorouracil + mitomycin or cisplatin was considered the gold standard for those cases amenable to cure. Results: After a mean follow-up time of 33 months (range 9–100), disease recurrence or progression was observed in 6 patients, which caused death in 3 of them. Three- and 5-year actuarial overall survival rates were 71 and 48%, respectively. Conclusions: Our data seem to suggest that the cloacogenic origin could present prognostic relevance within the wide spectrum of anal cancers. This should be carefully considered when submitting patients to aggressive and prolonged treatments. However, this hypothesis needs to be confirmed by larger series of this disease.

Human papillomavirus in anal squamous cell carcinoma: an angel rather than a devil?

Anal cancer is a rare disease with an increasing incidence worldwide but, unfortunately, even today the scientific community still has a limited knowledge and limited options of treatment. More than 50% of patients with anal cancer presenting at diagnosis with locoregional disease have good chances of cure with chemoradiotherapy (CT–RT). However, once patients develop metastatic spread, the prognosis is very poor. Human papillomavirus (HPV) is present in more than 80% of anal cancers and while multiple etiologic connections between HPV infection and anal cancer have already been well elucidated, its prognostic and/or predictive role is currently under investigation, especially among immunocompetent patients affected by this disease. In a single-institutional set, we have retrospectively analysed clinical data of 50 consecutive cases homogeneously treated with CT–RT for stage I–III anal squamous cell carcinoma. We found that HPV-positive anal cancers had a statistically significant improved five-year disease-free survival (DFS) compared to HPV-negative group. These findings could be explained by an increased chemo/radiosensitivity of HPV-positive tumours. Further efforts should be directed towards a better understanding of HPV-related oncogenesis and towards designing novel tailored strategies for the management of this disease both in terms of prevention and treatment.

Primary pure gastric yolk sac tumor

We describe here a case of pure gastric yolk sac tumor (YST). A 62-year-old patient underwent gastrectomy with D2 dissection. The histological report confirmed the diagnosis of YST and that two of the 14 regional lymph nodes removed were metastatic. Three courses of PEB regimen chemotherapy were delivered subsequently. Three months later the patient experienced dysphagia from stenosis of the anastomosis and a computerized tomography scan showed tumor recurrence with peritoneal nodules; the patient died one year after surgery. The origin of gastric YST is unclear but involvement of migrating germ cells during embryonic development or multipotential neoplastic protoepithelial cells of the gastric mucosa have been suggested. Generally the prognosis of gastric YST is poor and the standard therapeutic approach beyond surgery is still uncertain.