Radical Resection in Entero-Pancreatic Neuroendocrine Tumors: Recurrence-Free Survival Rate and Definition of a Risk Score for Recurrence.

BACKGROUND: Surgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date. OBJECTIVE: The aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence. PATIENTS AND METHODS: This was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000-2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan-Meier method and risk factor analysis was performed using the Cox regression model. RESULTS: Overall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p < 0.01). CONCLUSIONS: Approximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs.

cAMP effects in neuroendocrine tumors: The role of Epac and PKA in cell proliferation and adhesion.

cAMP effects have been initially attributed to protein kinase A (PKA) activation. Subsequently, two exchange proteins directly activated by cAMP (Epac1/2) have been identified as cAMP targets. Aim of this study was to investigate cAMP effects in pancreatic-NET (P-NET) and bronchial carcinoids and in corresponding cell lines (QGP-1 and H727) on cell proliferation and adhesion and to determine PKA and Epac role in mediating these effects. We found that cAMP increased cyclin D1 expression in P-NET and QGP-1 cells, whereas it had opposite effects on bronchial carcinoids and H727 cells and it promoted cell adhesion in QGP-1 and H727 cells. These effects are mimicked by Epac and PKA specific analogs, activating the small GTPase Rap1. In conclusion, we demonstrated that cAMP exerted divergent effects on proliferation and promoted cell adhesion of different neuroendocrine cell types, these effects being mediated by both Epac and PKA and involving the same effector GTPase Rap1.

Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis.

BACKGROUND: Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. PATIENTS AND METHODS: A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS: Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. CONCLUSION: Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.

Second primary neoplasms in patients with lung and gastroenteropancreatic neuroendocrine neoplasms: Data from a retrospective multi-centric study.

BACKGROUND: Patients with sporadic neuroendocrine neoplasms may exhibit a higher risk of a second primary tumor than the general population. AIM: This study aimed to analyze the occurrence of second primary malignancies. METHODS: A retrospective cohort of 2757 patients with sporadic lung and gastro-entero-pancreatic neuroendocrine neoplasms, managed at eight Italian tertiary referral Centers, was included. RESULTS: Between 2000 and 2019, a second primary malignancy was observed in 271 (9.8%) neuroendocrine neoplasms patients with 32 developing a third tumor. There were 135 (49.8%) females and the median age was 64 years. The most frequent locations of the second tumors were breast (18.8%), prostate (12.5%), colon (9.6%), blood tumors (8.5%), and lung (7.7%). The second primary tumor was synchronous in 19.2% of cases, metachronous in 43.2%, and previous in 37.6%. As concerned the neuroendocrine neoplasms, the 5- and 10-year survival rates were 87.8% and 74.4%, respectively. PFS for patients with a second primary malignancy was shorter than for patients without a second primary malignancy. Death was mainly related to neuroendocrine neoplasms. CONCLUSION: In NEN patients the prevalence of second primary malignancies was not negligible, suggesting a possible neoplastic susceptibility. Overall survival was not affected by the occurrence of a second primary malignancy.

A novel insight into the anticancer mechanism of metformin in pancreatic neuroendocrine tumor cells.

The antidiabetic drug metformin displays anticancer properties in several neoplasms. In pituitary NETs, aryl hydrocarbon receptor-interacting protein (AIP) is up-regulated by the somatostatin analog octreotide. Metformin inhibited QGP-1 cell proliferation in a dose- and time-dependent manner, at concentrations similar to those achievable in treated patients (-31 ± 12%, p < 0.05 vs basal at 100 µM). Moreover, metformin decreased pancreatic neuroendocrine tumors (PAN-NETs) cell proliferation (-62 ± 15%, p < 0.0001 vs basal at 10 mM), without any additive effect when combined with octreotide. Both octreotide and metformin induced AIP up-regulation. AIP silencing abolished the reduction of mTOR phosphorylation induced by metformin and octreotide. Moreover, metformin decreased HSP70, increased Zac1 and AhR expression; these effects were abolished in AIP silenced QGP-1 cells. In conclusion, metformin acts as an anticancer agent in PAN-NET cells, its activity is mediated by AIP and its interacting proteins. These findings provide a novel insight into the antitumorigenic mechanism of metformin.

Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients.

The impact of KRAS mutations on cetuximab sensitivity in epidermal growth factor receptor fluorescence in situ hybridisation-positive (EGFR FISH+) metastatic colorectal cancer patients (mCRC) has not been previously investigated. In the present study, we analysed KRAS, BRAF, PI3KCA, MET, and IGF1R in 85 mCRC treated with cetuximab-based therapy in whom EGFR status was known. KRAS mutations (52.5%) negatively affected response only in EGFR FISH+ patients. EGFR FISH+/KRAS mutated had a significantly lower response rate (P=0.04) than EGFR FISH+/KRAS wild type patients. Four EGFR FISH+ patients with KRAS mutations responded to cetuximab therapy. BRAF was mutated in 5.0% of patients and none responded to the therapy. PI3KCA mutations (17.7%) were not associated to cetuximab sensitivity. Patients overexpressing IGF1R (74.3%) had significantly longer survival than patients with low IGF1R expression (P=0.006), with no difference in response rate. IGF1R gene amplification was not detected, and only two (2.6%) patients, both responders, had MET gene amplification. In conclusion, KRAS mutations are associated with cetuximab failure in EGFR FISH+ mCRC, even if it does not preclude response. The rarity of MET and IGF1R gene amplification suggests a marginal role in primary resistance. The potential prognostic implication of IGF1R expression merits further evaluation.

A phase II randomized multicenter trial of gefitinib plus FOLFIRI and FOLFIRI alone in patients with metastatic colorectal cancer.

BACKGROUND: Gefitinib inhibits the epidermal growth factor receptor tyrosine kinase and preclinical studies indicate that it may enhance CPT-11 cytotoxicity. This randomized phase II trial investigates the feasibility and efficacy of gefitinib and 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients were randomized to FOLFIRI +/- gefitinib 250 mg daily p.o. Patients randomized to FOLFIRI + gefitinib without disease progression after 6 months continued to receive gefitinib alone until disease progression. RESULTS: From October 2002 to September 2004, 100 patients were enrolled. Twenty-three patients (47.9%) in the FOLFIRI arm and 23 (45.1%) in the FOLFIRI + gefitinib arm experienced an objective response. The median progression-free survival and overall survival were 8.3 and 18.6 months in the FOLFIRI arm, and 8.3 and 17.1 months in the FOLFIRI + gefitinib arm, respectively. In the combination arm, grades 3-4 adverse events were experienced by 35 (67.3%) patients versus 25 patients (52.1%) in the FOLFIRI arm; 12 patients (23.1%) withdrew for an adverse event in the FOLFIRI + gefitinib arm and 5 (10.4%) in the FOLFIRI arm. CONCLUSIONS: These data show that adding gefitinib to FOLFIRI does not improve the efficacy of FOLFIRI regimen. These disappointing results could be related to the high toxicity observed that led to significant dose reductions and delays.

EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients.

BACKGROUND: Standardized conditions to distinguish subpopulations of colorectal cancer (CRC) patients more and less sensitive to cetuximab therapy remain undefined. MATERIALS AND METHODS: We retrospectively analyzed epidermal growth factor receptor (EGFR) copy number by fluorescence in situ hybridization (FISH) in paraffin-embedded tumor blocks from 85 chemorefractory CRC patients treated with cetuximab. Results were analyzed according to different score systems previously reported in colorectal and lung cancers. The primary end point of the study was identification of the EGFR FISH score that best associates with response rate (RR). RESULTS: Using receiver operating characteristic (ROC) analysis, the cut-off that best discriminated responders versus nonresponders to cetuximab was a mean of 2.92 EGFR gene copies per cell. This model showed sensitivity of 58.6% [95% confidence interval (CI) = 47.1-70.1) and specificity of 93.3% (95% CI = 80.6-100). EGFR FISH-positive patients (N = 43, 50.6%) had significantly higher RR (P = 0.0001) and significantly longer time to disease progression (P = 0.02) than EGFR FISH negative (N = 42, 49.4%). Other scoring systems resulted less accurate in discriminating patients with the highest likelihood of response to cetuximab therapy. CONCLUSIONS: CRC patients with high EGFR gene copy number have an increased likelihood to respond to cetuximab therapy. Prospective clinical trials with a careful standardization of assay conditions and pattern interpretation are urgently needed.

Clinical results of stereotactic body radiotherapy (SBRT) in the treatment of isolated local recurrence of pancreatic cancer after R0 surgery: A retrospective study.

OBJECTIVE: To evaluate the efficacy and the feasibility of SBRT for selected patients with isolated local recurrence of pancreatic cancer after radical surgery. METHODS: A retrospective analysis was performed on patients treated with SBRT for isolated local recurrence from resected pancreatic adenocarcinoma, after multidisciplinary board evaluation. Prescription dose was 45 Gy in 6 fractions for all patients. Primary end-point was freedom from local progression (FFLP). Secondary end-points were overall survival (OS), progression free survival (PFS) and toxicity. Local control was defined according to RECIST criteria. Acute and late toxicity was scored according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0. RESULTS: Between January 2011 and February 2015, 31 patients with isolated local recurrence of resected pancreatic cancer were treated with SBRT. Pancreato-duodenectomy (PD) was performed on 24 patients and distal pancreatectomy (DP) in 7 cases, all with radical resection (R0). Median local recurrence disease free interval (DFI) was 14 months. Median follow-up was 12 months. FFLP was 91% and 82% at 1 and 2-years, respectively. Median PFS was 9 months. Median OS was 18 months. At univariate analysis, OS was correlated with a DFI>18 months. No cases of acute G3 toxicity or greater occurred. CONCLUSIONS: SBRT seems to be an effective and safe therapeutic option for isolated local recurrence of pancreatic cancer after surgery. Encouraging local control rate, very low toxicity profile and effective pain control suggest the crucial role of SBRT in the treatment of these long-survivors selected patients.

Can Stereotactic Body Radiation Therapy Be a Viable and Efficient Therapeutic Option for Unresectable Locally Advanced Pancreatic Adenocarcinoma? Results of a Phase 2 Study.

PURPOSE: To assess the efficacy of stereotactic body radiotherapy in patients with unresectable locally advanced pancreatic cancer. MATERIALS AND METHODS: All patients received a prescription dose of 45 Gy in 6 fractions. Primary end point was freedom from local progression. Secondary end points were overall survival, progression-free survival, and toxicity. Actuarial survival analysis and univariate or multivariate analysis were investigated. RESULTS: Forty-five patients were enrolled in a phase 2 trial. Median follow-up was 13.5 months. Freedom from local progression was 90% at 2 years. On univariate ( P < .03) and multivariate analyses ( P < .001), lesion size was statistically significant for freedom from local progression. Median progression-free survival and overall survival were 8 and 13 months, respectively. On multivariate analysis, tumor size ( P < .001) and freedom from local progression ( P < .002) were significantly correlated with overall survival. Thirty-two (71%) patients with locally advanced pancreatic cancer received chemotherapy before stereotactic body radiotherapy. Median overall survival from diagnosis was 19 months. Multivariate analysis showed that freedom from local progression ( P < .035), tumor diameter ( P < .002), and computed tomography before stereotactic body radiotherapy ( P < .001) were significantly correlated with overall survival from diagnosis. CONCLUSION: Stereotactic body radiotherapy is a safe and effective treatment for patients with locally advanced pancreatic cancer with no G3 toxicity or greater and could be a promising therapeutic option in multimodality treatment regimen.

Phase II study of vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-resistant disease.

PURPOSE: The aim of the study was to evaluate the activity of vinorelbine (VNLB) in a population of advanced ovarian cancer patients, with particular attention to defining its role in platinum-resistant disease. PATIENTS AND METHODS: Thirty-three patients were recruited and treated with VNLB 25 mg/m2 intravenously (IV) weekly. the median age was 53 years, performance status 0 to 2, and number of previous chemotherapy regimens two (range, one to five). Twenty-four patients were platinum-resistant; the remaining nine either were platinum-sensitive (four cases) or had undetermined sensitivity (five cases). RESULTS: The mean delivered dose-intensity of VNLB was 67% of the planned level, because 60% of the cycles were delayed due to neutropenia or anemia. Four partial responses (PRs) and one complete response (CR) were observed, for an overall response rate of 15% (95% exact confidence interval, 5.1% to 31.9%). All the responses occurred in the subgroup of 24 platinum-resistant cases, in whom the response rate was 21% (95% exact confidence interval, 7.1% to 42.1%). Seven patients became stabilized on VNLB, and 27% of the cases showed a reduction in serum cancer antigen 125 (CA 125) levels. G3/G4 side effects consisted of neutropenia, anemia, and worsening of preexisting peripheral neuropathy. No treatment-related deaths occurred. CONCLUSION: VNLB led to a 21% response rate in the population of heavily pretreated and platinum-resistant ovarian cancer patients. Further studies of VNLB alone or in combination with taxanes are warranted in patients with less pretreatment.

Reliability of immunoradiometric assays for sex-hormone binding globulin, androstenedione, 17-Beta estradiol and tumor-markers cea and cb15.3 to assess the biological response of megestrol-acetate treatment in patients with advanced breast-cancer.

This study evaluated the effect of megestrol acetate administration on the serological assessment of some sex steroid hormones in women with advanced hormone-sensitive breast cancer. The serum levels of 17-beta estradiol, androstenedione and sex hormone binding globulin (SHBG) were measured by means of radioimmunometric assays, before and during drug administration. A significant suppressive effect on SHBG and androstenedione levels in comparison with the baseline values was reached in 100% (40/40) and 51% (20/39) of patients, respectively, after two months of therapy; by contrast, 17-beta estradiol levels showed an increase above the baseline levels in 18 out of 22 patients. These findings might be explained on the basis of a possible interference in vivo of megestrol acetate metabolites particularly in the estradiol assay, since a direct influence of the solubilized megestrol acetate was not observed in vitro. The hormone levels generally did not shaw any relationship with the course of the disease, so their serial determinations do not seem to be useful to assess the clinical status or evaluate response to therapy. In our group of patients, CEA and CA15.3 serum determinations were also carried out to monitor the efficacy of treatment. CEA and CA15.3 levels reflected the course of the disease in 58.9% (23/39) and 65.8% (25/38) of patients, respectively. The two tumor markers displayed a similar sensitivity in detecting cancer progression (64% CEA and 63% CA15.3), but CA15.3 seemed to have a better diagnostic value in evaluating the response to therapy and signalling tumor relapse.

Phase-ii trial of oral doxifluridine plus oral levo-leucovorin in unresectable hepatocellular-carcinoma.

Systemic chemotherapy with currently available agents in unresectable HCC has a minimal impact on disease progression and a predictable response rate of <20%. Doxifluridine (5 deoxy-5-fluorouridine, dFUR) is a new fluropyrimidine derivative that demonstrated higher antitumoral activity than other fluoropyrimidines in murine tumors and optimal gastrointestinal absorption when administered orally. Therefore, we evaluated the activity and feasibility of a combination of dFUR and l-leucovorin in unresectable HCC by the following schedule: l-leucovorin 25 mg orally followed 2 hours later by dFUR 1,200 mg/m(2), day 1 through 5, cycles being repeated every 10 days. Thirtyseven patients with unresectable HCC entered the study and are evaluable for response and toxicity. Three partial responses have been observed, to a global response rate of 8% (95% confidence interval 2-22%). After a median observation time of 12 months, the median survival was 7 months, with a median time to progression of 4 months; Main toxicity was diarrhea; severe in 30% of the patients. One patient died as a result of uncontrollable diarrhea. In view of the limited activity observed, further trials with this schedule are not warranted.

Glutamine supplementation in cancer patients receiving chemotherapy: a double-blind randomized study.

The purpose of this study was to evaluate the efficacy of glutamine in preventing doxifluridine-induced diarrhea and the potential impact of glutamine on the tumor growth. We investigated 65 patients with advanced breast cancer receiving doxifluridine in a double-blind randomized fashion: 33 patients took glutamine (30 g/d, divided in 3 doses of 10 g each) for 8 consecutive days (5-12h) during each interval between chemotherapy, which was administered from day 1 to 4. Thirty-two patients took an equal dose of placebo (maltodextrine). The incidence of diarrhea was registered after each cycle of chemotherapy and severity was scored by the National Cancer Institute (NCI), Bethesda, Maryland, classification. The tumor response was evaluated by the World Health Organization (WHO) criteria. A total of 278 and 259 cycles (median 10 cycles), respectively, were delivered in glutamine and placebo groups. There were 34 and 32 episodes of diarrhea in glutamine and placebo groups, with no statistical difference overall, in the severity and duration of tumor growth, there was no difference in the response rate (21% and 28% of complete or partial response, respectively), in median time to response (2 mo), or in median duration of response. In conclusion, glutamine did not prevent the occurrence of the doxifluridine-induced diarrhea and did not have any impact on tumor response to chemotherapy.

[Combination of 5-Fluorouracil and folinic acid--is it still the standard therapy for advanced colorectal carcinoma?]. / La combinazione di 5-FU/FA rappresenta ancora la terapia standard per il carcinoma del colon-retto in stadio avanzato?

After a long period in which the only therapeutic approach for the management of colorectal cancer was the optimization of fluoropyrimidine-based chemotherapy, the last few years have seen the emergence of newly active chemotherapeutic agents endowed with novel mechanisms of action, such as oxaliplatin (OHP), irinotecan (CPT11), raltitrexed and oral 5-fluorouracil (5-FU) pro-drugs which can offer new therapeutic possibilities. The availability of these different classes of cytotoxic agents has introduced the possibility of combination chemotherapy. The most widely studied combinations are 5-FU/folinic acid (FA)/CPT11 and 5-FU/FA/OHP, both of which have been tested in two randomized studies. These trials consistently demonstrated that the addition of CPT11 or OHP to widely accepted infusional/bolus 5-FU/FA regimens is superior to the same 5-FU/FA schedule alone in term of response rate (rate of about > 50%) and time to progression. It's worth nothing that both trials with the combination of 5-FU/FA/CPT11 showed a significant survival benefit. Toxicity profiles were more pronounced with the combination therapies but the quality of life evaluation showed that the combinations had no negative impact on the evolution of the global health status over time. A current ongoing randomized study compares 5-FU/FA/CPT11 with 5-FU/FA/OHP in order to identify the best first-line chemotherapy. Preliminary results in terms of objective response and toxicity are similar for both treatments. Raltitrexed is a thymidilate synthase inhibitor with activity comparable to 5-FU and a convenient administration schedule. In our institution, we performed a phase II single center trial to assess the efficacy of the combination of raltitrexed and CPT11. The principal aim of the study was the overall response rate. We observed a very promising 51% overall response rate. Most relevant side effects were diarrhea in about 20% of patients, asthenia and vomiting. Two recent studies have assessed the efficacy and tolerability of raltitrexed-OHP combination therapy. The results showed that the combination is active (ORR: 46-62%) and tolerable. Promising results have also been obtained in phase I studies with the OHP/CPT11 combination. All these data need to be confirmed in phase II-III clinical trials. In conclusion, combination therapy with CPT11 plus 5-FU/FA produces a 2-3 month survival advantage over 5-FU/FA alone and represents the new reference in the first-line chemotherapy of colorectal cancer. The association of 5-FU/FA and OHP improves response rates and progression-free survival. The increase in toxicity of these combinations is predictable and reversible and does not compromise quality of life. These important data suggest that there is now a limited role for single-agent first-line chemotherapy of metastatic colorectal cancer.

A pilot safety study of capecitabine, a new oral fluoropyrimidine, in patients with advanced neoplastic disease.

5-fluorouracil (5-FU) is still one of the most prescribed cytostatic drugs, but gastrointestinal toxicity limits its use. Capecitabine, an orally administered prodrug of 5-FU, is activated by a cascade of three enzymes, resulting in the preferential release of 5-FU at the tumor site; it was developed in an attempt to avoid the problem of gastrointestinal toxicity of fluoropyrimidines. The aim of the present study was to investigate the safety profile of capecitabine at the daily oral dose of 502 mg/m2, given in two divided doses 12 hr apart for at least 10 days of treatment. In conformity with Italian law, 11 patients (8 females and 3 males) with advanced or metastatic pretreated solid tumors (4 colon-rectum, 3 breast, 2 stomach, 1 ovary, 1 lung) were enrolled. Treatment duration ranged from 1.5 to 14 days. Ten of the 11 patients received the planned 10 days of treatment. One patient was discontinued on the second treatment day when he presented with symptoms of intracranial hypertension with multiple brain metastases documented by CT scan. Toxicity consisted of 1 case of mild edema; no adverse events characteristic of fluoropyrimidines were recorded. No abnormalities in hematologic, renal, hepatic or electrolyte values were seen. In conclusion, capecitabine, given at this dose and for a relatively short period, proved to be well tolerated. Further investigation is recommended to define the promising antitumor efficacy documented in many human xenograft models in mice.

Preliminary experience with high-dose cisplatin, reduced glutathione and natural interferon-alpha in dacarbazine-resistant malignant melanoma.

AIMS AND BACKGROUND: The incidence of malignant melanoma is rapidly increasing in many countries, and when this disease has reached advanced stages, standard therapies have little impact. Dacarbazine (DTIC) is the most effective chemotherapeutic agent with an overall response rate of 20-25%, but durable responses are uncommon. Interesting results with the use of cisplatin (CDDP) have been reported in DTIC-resistant melanoma. Moreover, malignant melanoma is an immunogenic tumor and a potential target for biological response modifier (BRM) therapies. The aim of the present study was to evaluate the efficacy and tolerability of a chemo-immunotherapeutic regimen including high-dose CDDP combined with glutathione (GSH) to limit platinum-related toxicity, and natura interferon-alpha (IFN-alpha) in patients with DTIC-resistant metastatic melanoma. METHODS: The treatment schedule included GSH 1,500 mg/m2 i.v. and CDDP 40 mg/m2 i.v. for 4 consecutive days every 3 weeks, with a maximum of 6 courses, and IFN-alpha 3 MIU i.m. 3 times a week, continuative for a maximum of 12 months. RESULTS: Twelve patients were enrolled in this phase II trial. Accrual was stopped due to treatment-related toxicity. Ten patients were evaluable for response; there were 2 partial responses, lasting 5+ and 9+ months, respectively, and 2 cases of stable disease, lasting 3+ and 8+ months. None of these patients completed the therapeutic program due to treatment-related side effects. CONCLUSIONS: This regimen seems to be only partially active in DTIC-resistant metastatic melanoma. Hematologic and non-hematologic (nausea and vomiting, peripheral neurotoxicity, and asthenia) side effects are significant and GSH is not effective in limiting CDDP-related neurotoxicity in pretreated patients. Therefore, there is no indication to employ this regimen as second-line treatment in metastatic melanoma and these disappointing results highlight the urgent need for new therapeutic approaches.

Response assessment in oncology: limitations of anatomic response criteria in the era of tailored treatments.

Evaluation of tumor response is a vital element in clinical oncology research, particularly in the development of new drugs. Tumor response also plays a significant role in treatment decisions made by clinicians in practice. The underlying concept of tumor response, however, was developed as a result of limited understanding of tumor biology coupled with restricted availability of both effective treatments and imaging modalities. In recent years, impressive advances have been made in the treatment of cancer. Groundbreaking advances in our understanding of the molecular biology of tumor growth and proliferation have been made. New biologic agents have been approved for the treatment of several malignancies and, in many cases, biomarkers have been identified that can help predict those patients who will benefit. Pre-operative chemotherapy is now established for a number of tumor types. Modern imaging technologies allowing functional characterization of tumors have been introduced into clinical practice. In this new therapeutic landscape, the existing concept of tumor response risks becoming an anachronism, and revision of the criteria used to define tumor response is warranted. In this paper, we critically review the limitations of the classic criteria for tumor response assessment, and briefly discuss the potential role of alternative methodologies in providing a new, functional definition of tumor response.