Norma Malavasi

Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer

BACKGROUND Cetuximab improves activity of chemotherapy in metastatic colorectal cancer (mCRC). Gene copy number (GCN) of epidermal growth factor receptor (EGFR) has been suggested to be a predictive factor of response to cetuximab in patients (pts) with mCRC; on the contrary, K-ras mutation has been associated with cetuximab resistance. PATIENTS AND METHODS We have conducted a phase II study with cetuximab administered weekly for 3 weeks as single agent and then with 5-fluorouracil and radiation therapy as neo-adjuvant treatment for locally advanced rectal cancer (LARC). EGFR immunohistochemistry expression, EGFR GCN and K-ras mutation were evaluated on diagnostic tumor biopsy. Dworaks tumor regression grade (TRG) was evaluated on surgical specimens. RESULTS Forty pts have been treated; 39 pts are assessable. TRG 3 and 4 were achieved in nine (23.1%) and three pts (7.7%) respectively; TRG 3-4 rate was 55% and 5.3% in case of high and low GCN, respectively (P 0.0016). Pts with K-ras mutated tumors had lower rate of high TRG: 11% versus 36.7% (P 0.12). In pts with wild-type K-ras, TRG 3-4 rate was 58.8% versus 7.7% in case of high or low GCN, respectively (P 0.0012). CONCLUSIONS In pts with LARC, EGFR GCN is predictive of high TRG to cetuximab plus 5-FU radiotherapy. Moreover, our data suggest that a wild-type K-ras associated with a high EGFR GCN can predict sensitivity to cetuximab-based treatment.

Neoadjuvant Treatment With Single-Agent Cetuximab Followed by 5-FU, Cetuximab, and Pelvic Radiotherapy: A Phase II Study in Locally Advanced Rectal Cancer

PURPOSE Preoperative chemoradiotherapy followed by surgery represents the standard of care for locally advanced rectal cancer (LARC). Cetuximab has proved activity in advanced colorectal cancer, and its incorporation in preoperative treatment may increase tumor downstaging. METHODS AND MATERIALS After biopsy and staging, uT3/uT4 N0/+ LARC received single-agent cetuximab in three doses, followed by weekly cetuximab plus 5-fluorouracil (5-FU), concomitantly with RT. Sample size was calculated according to Bryant and Day test, a two-stage design with at least 10 pathologic complete remissions observed in 60 patients (pts) able to complete the treatment plan. RESULTS Forty pts with LARC were entered: male/female = 34/6; median age: 61 (range, 28-77); 12 uT3N0 Ed(30%); 25 uT3N1 (62%); 3 uT4N1 (8%); all Eastern Cooperative Oncology Group = 0. Thirty-five pts completed neoadjuvant treatment; 5 (12%) withdrew therapy after one cetuximab administration: three for hypersensitivity reactions, one for rapid progression, and one for purulent arthritis. They continued 5-FU in continuous infusion in association with RT. Thirty-one pts (77%) presented with acnelike rash; dose reduction/interruption of treatment was necessary in six pts (15%): two for Grade 3 acnelike rash, two for Grade 3 gastrointestinal toxicity, and two for refusal. Thirty-eight pts were evaluable for pathological response (one patient refused surgery, and one was progressed during neoadjuvant treatment). Pathological staging was: pT0N0 three pts (8%), pT1N0 1 pt (3%); pT2N0 13 pts (34%), and pT3 19 pts (50%) (N0:9, N1:5; N2:5); pT4 2 pts (5%). CONCLUSIONS Preoperative treatment with 5-FU, cetuximab, and pelvic RT is feasible with acceptable toxicities; however, the rate of pathologic responses is disappointingly low.

FOLFOX6 and bevacizumab in non-optimally resectable liver metastases from colorectal cancer

Background:In patients with colorectal liver metastases (CLM) R0 resection significantly improves overall survival (OS).Methods:In this report, we present the results of a phase II trial of FOLFOX6+bevacizumab in patients with non-optimally resectable CLM. Patients received six cycles of FOLFOX6+ five of bevacizumab. Patients not achieving resectability received six additional cycles of each. A PET-CT was performed at baseline and again within 1 month after initiating treatment.Results:From September 2005 to July 2009, 21 patients were enrolled (Male/Female: 15/6; median age: 65 years). An objective response (OR) was documented in 12 cases (57.1%; complete responses (CRs): 3, partial response (PR): 9); one patient died from toxicity before surgery. Thirteen patients underwent radical surgery (61.9%). Three (23%) had a pathological CR (pCR). Six patients (46.1%) experienced minor postsurgical complications. After a median 38.8-month follow-up, the median OS was 22.5 months. Patients achieving at least 1 unit reduction in Standard uptake value (SUV)max on PET-CT had longer progression-free survival (PFS) (median PFS: 22 vs 14 months, P=0.001).Conclusions:FOLFOX6+bevacizumab does not increase postsurgical complications, yields high rates of resectability and pCR. Early changes in PET-CT seem to be predictive of longer PFS.

Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy.

Background:Epidermal growth factor receptor (EGFR), evaluated by immunohistochemistry, has been shown to have prognostic significance in patients with colorectal cancer. Gene copy number (GCN) of EGFR and KRAS status predict response and outcome in patients treated with anti-EGFR therapy, but their prognostic significance in colorectal cancer patients is still unclear.Methods:We have retrospectively reviewed the baseline EGFR GCN, KRAS status and clinical outcome of 146 locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiotherapy. Pathological response evaluated by Dworaks tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS) were analysed.Results:Tumour regression grade 4 and TRG3–4 were achieved in 14.4 and 30.8% of the patients respectively. Twenty-nine (19.9%) and 33 patients (19.2%) had an EGFR/nuclei ratio >2.9 and CEP7 polisomy >50% respectively; 28 patients (19.2%) had a KRAS mutation. Neither EGFR GCN nor KRAS status was statistically correlated to TRG. 5-year DFS and OS were 63.3 and 71.5%, respectively, and no significant relation with EGFR GCN or KRAS status was found.Conclusion:Our data show that EGFR GCN and KRAS status are not prognostic factors in LARC treated with preoperative chemoradiation.

Role of carcinoembryonic antigen, magnetic resonance imaging, and positron emission tomography-computed tomography in the evaluation of patients with suspected local recurrence of colorectal cancer

The role of carcinoembryonic antigen (CEA), magnetic resonance imaging (MRI), and positron emission tomography (PET)-computed tomography (CT) in detection of local recurrence of colorectal cancer is evaluated in 71 patients, selected due to suspected relapse at CT follow-up. Recurrence was confirmed by histology in 18 cases and excluded in 25 cases. Sensitivity, specificity, positive and negative predictive values, and accuracy were as follows: 44.4%, 92.5%, 66.7%, 83.1%, and 80.3% for CEA; 88.9%, 73.6%, 53.3%, 95.1%, and 77.5% for MRI; and 94.4%, 73.6%, 54.8%, 97.5%, and 78.9% for PET-CT. A diagnostic protocol integrating CEA and dedicated imaging studies is to be advocated.

Complete pathological response in a patient with multiple liver metastases from colon cancer treated with Folfox-6 chemotherapy plus bevacizumab: a case report

The complete pathological response after primary chemotherapy could represent an important prognostic factor in patients affected by colorectal liver metastases.In recent studies, increasing complete pathological response seems to be correlated with longer overall survival periods and it is recognized as an important prognostic factor in patients treated with pre-operative chemotherapy.The correlation of radiological information on residual neoplastic disease after neoadjuvant treatment, obtained with CT and PET, has to be evaluated; in fact the complete disappearance of liver metastasis on radiological imaging does not always mean a complete disappearance of tumor tissue on histological examination; when it is documented with surgical procedures and confirmed by pathologists examination, we can consider the complete pathological response.In recent years the addition of monoclonal antibodies to conventional chemotherapy may further increase the proportion of patients referred for surgery; bevacizumab before surgery has been shown to be feasible and safe, although concerns still exist regarding possible post-surgical and wound healing complications or bleeding. The limitation of the radiologic assessment of response as a surrogate for pathological response is even more relevant when antiangiogenic treatments are used. Excellent responses to bevacizumab-containing regimens do occur and referral to surgical oncology is a crucial step for documentation of complete pathological response.

Diagnostic Delay in Oncology: A Case Report of Metastatic Seminoma

Germ cell tumours are the most common malignancy among young men; cryptorchidism is a possible risk factor for the development of testicular cancer. Psycho-oncology studies indicate that diagnostic delay can often be explained by different social conditions and that symptoms worsened under lack of appropriate treatment can lead to an urgent admission to the hospital. Nevertheless, germ cell tumours are considered curable malignancies even in advanced stages since the introduction of a chemotherapy regimen based on bleomycin, etoposide and cisplatin. Cell lines derived from germ cell tumours are sensitive to cisplatin-based treatment more than other solid cancers, which is reflected in the good clinical response. We report an unusual manifestation of malignancy in an adult man presenting with a metastatic seminoma of the left testicle. The large ulcerate and necrotic mass suggested a secondary infection from a tumour site. The patient reported surgical orchiopexy for left cryptorchidism in his childhood. Despite worsening of physical features, he had not sought help at the hospital for social reasons. The patient achieved complete clinical remission after receiving standard chemotherapy, and a good objective response of the primitive mass was clearly visible. Complete response was persistent at the 30-month clinical follow-up. The chemotherapy administration was later complicated by acute haemorrage in the site of the primitive tumour that needed urgent surgical management; in addition to this, the artificial graft material was rejected and the arterial prosthesis had to be removed. This case report can be considered for epidemiologic contribute, for clinical relevance despite diagnostic delay and for psycho-oncology studies.

Pulmonary Strongyloidiasis Mimicking Cancer Symptoms : A Case of Hyperinfection in a Patient With Metastatic Lung Cancer

A 67-year-old man was diagnosed with metastatic (bone, adrenal glands, brain) lung mixed adeno and squamous cell carcinoma in December 2004. The patient started chemotherapy with cis-platin and gemcitabine for 3 cycles and Zoledronic acid. From February 2005 acetate cortisone and low-dose dexametazone was prescribed because of the evidence of adrenal glands deficiency. Early after the third cycle he presented gastrointestinal symptoms (nausea, vomiting), worsening in general conditions, dry cough, dyspnea, and hemophtoe without fever. Routine hematologic laboratory analysis was unremarkable. An otorhynolaringology examination excluded bleeding signs from the upper airways and a bronchoscopy did not reveal pathologic findings on the bronchial mucosa. Furthermore, a bronchial washing performed for both microbiological and cytologic study revealed a bloody lavage fluid. Chest computed tomography (CT) scan showed a diffuse, bilateral ground-glass interstitial and alveolar involvement mainly at right upper lobe and at left low lobe, initially suggesting a pulmonary hemorrhagic disease or a Pneumocystis carinii infection (Fig. 1A). At cytology, bronchioalveolar lavages (BAL) showed several rhabditiform larvae of Strongyloides stercoralis (SS) (Fig. 1B), while special stains (grocott, PAS, Ziehl-Neelsen) did not evidence other microorganisms. SS was also isolated in cultures of the BAL. Two stool specimens (before starting treatment and after 2 days) were both negative for SS. HIV test was negative. Thus, the patient was diagnosed as having pulmonary strongyloidiasis. Treatment with thiabendazole was instituted and patient symptoms resolved in one week. Sputum cytology (performed after 4 days) didn’t show the presence of the parasite. After a follow-up of 4 months the patient died for cancer progression. SS is an intestinal nematode worldwide distributed that harbor within a host for prolonged periods of time but may cause fatal opportunistic infections in immunocompromised patients. Human infection begins with the penetration of skin by filariform larvae that migrate hematogenously to the lung. Larvae then ascend the airway, are swallowed, and mature in the gut. SS completes its life cycle within the host through an asexual autoinfective cycle, allowing the infection to persist in the host indefinitely. In the immunocompromised host, hyperinfections and wide dissemination of larvae may lead to hemorragic pneumonitis (because of larva-induced mucosal injury during larval migration in the hyperinfection syndrome), enteritis, septicemia (gram-negative bacteriemia is common) and death. It tend to disseminate once immunity is suppressed and commonest causes of “cell-mediated” immunodeficiency-related strongyloidiasis include malnutrition, immunosuppressive drug therapy (mainly steroids), transplants, hematologic malignancies, HIV infection. Although it is uncommon among patients receiving therapy for solid cancer, in this case the association of chemotherapy and corticosteoids may have played a crucial role. Mortality from disseminated strongyloidiasis approaches 80%; early diagnosis together with prompt initiation of thiabendazole therapy provides the greatest survival opportunity for patient with SS infestation. This case underlines the possibility that cancer management may create an immunosuppression condition that increase the susceptibility not only to common infectious agents but also to more “exotic” pathogens, such as SS. Before starting an immunosuppressive therapy, especially for patients from the endemic area, routine stools screening should be considered.