Advanced Squamous Carcinoma Research Articles

Combined Modality Treatment With Chemotherapy, Radiation Therapy, Bevacizumab, and Erlotinib in Patients With Locally Advanced Squamous Carcinoma of the Head and Neck

: The aim of the study was to evaluate the feasibility and efficacy of adding bevacizumab and erlotinib to concurrent chemoradiation therapy for first-line treatment of patients with locally advanced squamous carcinoma of the head and neck. : Sixty previously untreated patients with squamous carcinoma of the head and neck (36 with oropharyngeal primaries; 83% men; median age, 56 years; 73% stage IV) received induction chemotherapy with 6 weeks of paclitaxel, carboplatin, infusional 5-fluorouracil, and bevacizumab; this treatment was followed by radiation therapy, weekly paclitaxel, bevacizumab, and erlotinib. : After a median follow up of 32 months, the estimated 3-year progression-free and overall survival rates are 71% and 82%, respectively. Sixty-five percent of patients had major responses after induction therapy; after completion of therapy, 95% of patients had either partial or complete response radiographically. As expected, grade 3/4 mucosal toxicity occurred frequently (88%) during combined modality; no unexpected toxicity resulted from the addition of bevacizumab and erlotinib. : The addition of bevacizumab and erlotinib to first-line combined modality therapy was feasible in a community-based setting, producing toxicity comparable to other effective combined modality regimens for head and neck cancer. The high level of efficacy suggests that incorporation of these targeted agents into first-line therapy should be further explored.

Vocal Handicap and Quality of Life After Treatment of Advanced Squamous Carcinoma of the Larynx and/or Hypopharynx

To evaluate and correlate voice-specific quality of life (QOL) and health-related QOL (HR-QOL) after treatment for advanced cancer of the larynx and/or hypopharynx. Cross-sectional study. Patients submitted to partial laryngectomy (PL), salvage PL (sPL), concomitant radiotherapy and chemotherapy (RT+Chemo), total laryngectomy (TL), salvage TL (sTL), total pharyngolaryngectomy (TP) and salvage total pharyngolaryngectomy (sTP). The following questionnaires were used: (1) Voice Handicap Index (VHI) and (2) University of Washington Quality of Life Questionnaire (UW-QOL; version 4). Eighty-four patients participated in the study. All the patients PL (10), sPL (1), and RT+Chemo (24) communicated by laryngeal voice. Of the 49 patients submitted to total removal of the larynx, 30 communicated with alaryngeal phonation, the major part being tracheoesophageal prosthesis (17). The worst subscale of VHI for the total patient group was functional (mean=13.15), and the value of the total score was 31. Patients submitted to PL, RT+Chemo, and TL presented slight handicap (medians of 27, 14, and 21.5, respectively). Patients treated with sTL, TP, and sTP presented moderate handicap (medians of 45, 37.5, and 31.5, respectively). HR-QOL was considered between good and excellent for 78.6% of the patients, and poor for 21.4%. The correlation between voice-specific QOL and HR-QOL was significant (P=0.0001). Patients treated for advanced cancer of the larynx/hypopharynx present slight to moderate voice handicap and good/excellent HR-QOL. Stricter analysis of both the VHI and UW-QOL data suggests that more attention be given to the vocal handicap of the individual patient.

Differentiating Squamous Cell Carcinoma of the Cervix and Epithelioid Trophoblastic Tumor

Epithelioid trophoblastic tumor (ETT) is a recently described subtype of gestational trophoblastic neoplasia (GTN). Its diagnosis requires a high level of suspicion because it is often mistaken for more common cervical or uterine corpus epithelial neoplasms. This is a 39-year-old woman who presented with a cervical mass and positive human chorionic gonadotropin and was diagnosed with both locally advanced squamous cell cervical carcinoma and nonmetastatic GTN. She was treated unsuccessfully with concurrent intravenous cisplatin plus pelvic radiation and single-agent intravenous methotrexate. A retrospective review of the cervical biopsy using immunohistochemistry as well as genotyping of the tumor changed the original diagnosis to ETT. It is known that ETT is relatively unresponsive to chemotherapy compared with most other types of GTN; therefore, surgery would have been the optimal treatment. She died despite multiple salvage chemotherapies. Malignant GTN is one of the most curable gynecologic malignancies; however, its correct diagnosis is critical for the appropriate treatment. It can be easily misdiagnosed as a carcinoma because of their morphologic similarity. Genetic fingerprinting and immunohistochemistry are potentially valuable tools to confirm the diagnosis of ETT.

Influence of induction chemotherapy on patients’ compliance to radiotherapy in patients with locally advanced head and neck squamous cell carcinoma.

5558 Background: Induction chemotherapy (IC) is regaining its rule in the management of locally advanced head and neck squamous cell carcinoma (LAHNSCC). IC is a successful strategy for organ preservation, improves clinical response and reduces distant relapse, but it adds considerable morbidity and mortality. While large randomized trials comparing IC followed by chemo-radiotherapy with chemo-radiotherapy alone are ongoing, we are assessing the patient’s compliance to complete radiotherapy after IC. Methods: Retrospectively the medical records of patients with LAHNSCC, who were planned to receive IC followed by concurrent chemo-radiotherapy, were reviewed. Patients are considered compliant when they complete thirty five fractions of radiotherapy. Non-compliant is defined as; less than thirty fractions of radiation or more than one week interruption of radiation. Results: Seventy two patients were included, sixty one male and eleven female. IC regimens were cisplatin and 5-flurouracil (PF) in fifty one pa...

INCA-GYN001: Erlotinib added to cisplatin and definitive radiotherapy in untreated patients with locally advanced squamous cell cervical carcinoma—Final report of a phase II trial.

5033 Background: Concurrent cisplatin (C) based chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical cancer (LACC). New strategies that increase the complete response (CR) rates may lead to longer progression-free(PFS) and overall survival(OS). Pre-clinical data indicates that inhibition of the epidermal growth factor receptor (EGFR) potentiates the effect of RT. We previously reported a phase I trial of the tyrosine kinase EGFR inhibitor erlotinib (E) administered concurrently with standard CRT for LACC that confirmed the safety of E at 150mg/day and preliminary efficacy data on the phase II. Methods: Eligibility - stage IIB to IIIB squamous cell cervical carcinoma; no prior therapy; ECOG PS 0-2; adequate end-organ function. Patients (pts) received E 150mg/day one week before and combined with C (40mg/m2, weekly, X 5) and RT (external beam - 4500cGy in 25 fractions, followed by 4 fractions/600cGy/weekly of brachytherapy). Pre and post treatment tumor tissue was obtained for molecular analysis.Response was assessed after a 3 month-interval with MRI, CT, PET and biopsy. Results: Patient characteristics: median age 44 (27-68), stage IIB 22 (57.9%), IIIA 1 (2.6%) and IIIB 15 (39.5%). 41 pts were enrolled and 3 excluded. 38 patients were available for toxicity. Two pts did not complete planned treatment (one presented Raynaud's Syndrome and had C interrupted and one presented grade 4 hepatotoxicity). Of 36 pts who completed E+CRT, median duration of treatment was 77 (64-129) days and median follow-up was 39.4 months(m) (IC95%35.5-43.3). Overall E+CRT was well tolerated. Most common grade 3 toxicity was skin rash (13%). Of 36 evaluable for response, 34 pts, (94.4%-IC 95% 79.99- 99.03) had CR and two pts had partial response. Cumulative OS and PFS survivals were 91.7% and 80.6% at 24m, and 80% and 73.8%, respectively, at 36m of follow-up, superior to historical control. Conclusions: In this cohort of LACC patients the combination of E+CRT is efficacious and feasible, with a CR rate of 94.4%. This combination is worth exploring in a randomized clinical trial. Molecular correlative studies will be presented at the meeting.

Supratrochlear Artery Island Paramedian Forehead Flap for Reconstructing the Exenterated Patient

Orbital exenteration may be needed for surgical extirpation of advanced squamous or basal carcinoma of the eye or ocular adnexa. Many surgeons prefer to allow the exenterated socket granulate by secondary intention. This leads to morbidity and can be very disturbing for the patient. Moreover, it delays the delivery of adjunctive radiation often required in these individuals. We suggest a 1-stage operation that can be undertaken at the time of exenteration or as a delayed procedure to reconstruct the orbit and ensure rapid wound healing and patient rehabilitation. There is minimal donor site morbidity. A total of 5 exenterated orbits have been reconstructed by a new technique utilizing islanded median forehead flap based upon ipsilateral supratrochlear vessels. The donor site could be closed primarily in all patients. The healing was uneventful; the median hospital stay was 3 days. Although there is inevitable scarring of the forehead, this improves considerably over a period of time and does not appear to cause undue aesthetic concerns among our patients. Thus an islandised ipsilateral paramedian forehead flap based upon supratrochlear vessels is another option to close an exenteration defect.

Antitumor Effect of Temsirolimus against Oral Squamous Cell Carcinoma Associated with Bone Destruction

The mammalian target of rapamycin (mTOR) is engaged in the molecular pathogenesis of oral squamous cell carcinoma, which frequently invades the maxilla or the mandible. However, the effects of a mTOR inhibitor on bone destruction associated with oral squamous cell carcinoma are still unclear. In this study, we investigated the antitumor effect of temsirolimus-mediated mTOR inhibition against advanced oral squamous cell carcinoma. Temsirolimus inhibited the proliferation and migration of HSC-2 oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. Significantly, we clearly show that temsirolimus inhibited osteoclast formation both in vitro and in vivo. Reverse transcriptase-PCR analysis showed that temsirolimus decreased the mRNA expression of receptor activator for nuclear factor-κB ligand, known as an osteoclast differentiation factor in bone stromal ST2 cells. Moreover, temsirolimus normalized blood-free calcium concentration in mouse models for humoral hypercalcemia. These findings suggest that mTOR signaling is a potential target of oral squamous cell carcinoma associated with bone destruction, and hence we describe the efficacy of temsirolimus for the treatment of advanced oral squamous carcinoma.

Prophylactic Gastrostomy before Chemoradiation in Advanced Head and Neck Cancer: a Multiprofessional Web-based Survey to Identify Current Practice and to Analyse Decision Making

Aims Patients with advanced squamous carcinoma of the head and neck who are treated with concurrent chemoradiotherapy schedules are often referred for gastrostomy tube (G-tube) insertion. Decision making to select appropriate patients is inconsistent and the factors that lead healthcare workers to make this recommendation are not well understood. Therefore, by means of a web-based questionnaire we sought the views of a variety of healthcare professionals as to their current practice with regard to various issues surrounding the recommendation of G-tube insertion use in these patients and analysed the responses with regard to decision making. Materials and methods Questions were generated after discussion among and agreement from all members of a single National Health Service Trust head and neck multidisciplinary team and were hosted on a website. Appropriate individuals were identified through their governing body organisations and invited by e-mail to complete the questionnaire. The results were pooled and analysed. Results Recommendations for gastrostomy were not based on tumour subsite. Four of 14 patient-related factors were significantly associated with the recommendation for gastrostomy. Medical and allied healthcare professionals (including nursing staff) significantly differed in their opinions as to the effect of G-tubes on the resumption of oral intake ( P = 0.009). Conclusions There is no national consensus on which patients to recommend for gastrostomy and consideration should be given to the development of clinical decision-making models in an attempt to systematise the decision-making process.

Concurrent Chemoradiotherapy With Paclitaxel and Nedaplatin Followed by Consolidation Chemotherapy in Locally Advanced Squamous Cell Carcinoma of the Uterine Cervix: Preliminary Results of a Phase II Study

To evaluate the efficacy and toxicities of concurrent chemoradiotherapy (CCRT) and consolidation chemotherapy in patients with locally advanced squamous cell cervical carcinoma. Patients with LASCC (FIGO Stage IIB-IIIB) were treated with pelvic external beam radiotherapy (45 Gy for Stage IIB and 50 Gy for Stage III) and high-dose-rate intracavitary brachytherapy (50 Gy for Stage IIB and 35 Gy for Stage III). The cumulative dose at point A was 50 Gy for Stage IIB and 65 Gy for Stage III. Concurrent chemotherapy with paclitaxel (35 mg/m(2)) and nedaplatin (20 mg/m(2)) was given every week for 6 weeks. Consolidation chemotherapy with paclitaxel (135 mg/m(2)) and nedaplatin (60 mg/m(2)) was administered every 3 weeks for 4 cycles. All patients completed CCRT, and 28 of 34 patients completed consolidation chemotherapy. The complete response rate was 88% (95% CI, 73-96%). The most common Grade 3 or higher toxicities were leukopenia/neutropenia (10.9% of the cycles). During a median follow up of 23 months (range, 14-30 months), 5 patients had locoregional failure and 1 patient had distant metastasis. The estimated 2-year progression-free survival and overall survival were 82% (95% CI, 68-95%) and 93% (95% CI, 83-100%), respectively. Grade 3 late complications occurred in 3 patients (9%). CCRT with paclitaxel and nedaplatin followed by consolidation chemotherapy is well tolerated and effective in patients with locally advanced squamous cell cervical carcinoma. Further randomized trials of comparing this regimen with the standard treatment are worth while.

β-Tubulin-II Expression Strongly Predicts Outcome in Patients Receiving Induction Chemotherapy for Locally Advanced Squamous Carcinoma of the Head and Neck: A Companion Analysis of the TAX 324 Trial

TAX 324 was a phase III trial comparing induction chemotherapy (IC) with docetaxel, cisplatin, and fluorouracil (TPF) with cisplatin and fluorouracil (PF) followed by concomitant chemoradiotherapy in locally advanced squamous cell cancer of the head and neck (LASCCHN). This study evaluates a series of tumor markers in pretreatment biopsies from that trial TAX 324 and correlates expression with survival. Pretherapy biopsy specimens were available for 265 of 501 participants. Expression of a series of six markers (p53, thymidylate synthase, glutathione s-transferase pi [GST-pi], Bcl 2, beta tubulin II [betaT-2], and HER2 neu) was evaluated by immunohistochemistry. For patients with low betaT-II expression, median overall survival (OS) was 58.6 months (95% CI, not reached [NR]), compared with 18.2 months for patients with high betaT-II expression (95% CI, 13.11 to 30.06: hazard ratio [HR], 2.39; 95% CI, 1.67 to 3.72; P < .0001). Progression-free survival in patients with low betaT-II expression was 43.2 months (95% CI, 24.4 to NR) versus 9.8 months (95% CI, 7.06 to 18.53) for high betaT-II expression, with a HR of 1.9 (95% CI, 1.43 to 2.77; P < .0001). The predictive value of betaT-II expression was greater in the TPF versus PF arm than in the PF arm. Increased tumor expression of betaT-II is strongly associated with adverse outcome in LASCCHN patients treated with IC, and our data suggest low expression of betaT-II may predict patients most likely to benefit from induction TPF therapy. Further, simple models which combine expression of betaT-II with a carefully defined set of additional immunohistochemical markers may have significant prognostic impact for patients with LASCCHN.

Operation combined with preoperative radiochemotherapy on esophageal squamous carcinoma

Objective To evaluate the effects of preoperative radiochemotherapy on pathological staging and prognosis in the patients with advanced esophageal squamous carcinoma(ESCC). Methods 1997-2007,477 patients with advanced ESCC were randomized into four groups:neoadjuvant chemothera-py, neoadjuvant radiotherapy, neoadjuvant radiochemotherapy, and surgery alone (control group). The tumor resection rate, pathological stage, treatment-related complication, and survival among groups were compared. Results The radical resection rate for the patients in radiotherapy and radiochemotherapy groups was increased in comparison with the control group (P ＜ 0.05). Their pathological stage after esophagectomy was regressed significandy than that of the control group (50.8% ,54.2% vs 0% ,P ＜0.05). The chemotherapy group showed significant improvement on resection rate and pathological staging compared with the control group. The treatment related complication in three neoadjuvant groups had no significant difference from that of the control group (P ＞ 0. 05). The 3-year survival rate of radiotherapy and radiochemotherapy groups were significantly higher than that of the control group(69.5% ,72.9% vs 53.4%, P ＜ 0.05). The 5-year survival rate of radiochemotherapy and radiotherapy groups were was high-er than that of the control group(P ＜ 0.05), meanwhile the 5-year survival rate of radiochemotherapy was higher than that of radiotherapy group, but no statistical difference (P ＞ 0. 05). Conclusion Preoperative radiochemotherapy seems to provide an efficient therapy in radical resection and survival of patients with advanced ESCC. Key words: Esophageal carcinoma; Radiochemotherapy; Pathological stage

Capecitabine-Based Chemoradiotherapy with Adjuvant Capecitabine for Locally Advanced Squamous Carcinoma of the Uterine Cervix: Phase II Results

Cisplatin-based chemoradiotherapy is the standard treatment for locally advanced cervical cancer but causes considerable toxicity. Capecitabine and radiotherapy show preclinical synergy and clinical activity. The activity, tolerability, and oral administration of capecitabine make it an attractive adjunctive therapy. In this phase II study, patients with untreated International Federation of Gynecology and Obstetrics stage IIB-IIIB cervical cancer received capecitabine, 825 mg/m(2) twice daily (Monday-Friday), during radiation (45 Gy per 25 fractions external-beam radiotherapy and 26 Gy high-dose rate brachytherapy to point A, maximum 8 weeks), followed by six cycles of capecitabine, 1,000 mg/m(2) twice daily (days 1-14 every 21 days). The overall response rate in 60 patients was 88% (95% confidence interval [CI], 77.4%-95.2%), including complete responses (CRs) in 80% of patients. The 1-year progression-free and overall survival rates were 86% (95% CI, 77%-95%) and 95% (95% CI, 89%-100%), respectively. At 23 months, 76% of patients were progression free (95% CI, 65%-88%) and CR was maintained in 90% (95% CI, 81%-99%) of the 48 patients achieving a CR. There were three grade 3 or 4 treatment-related events: reversible grade 4 hypokalemia, grade 3 diarrhea, and grade 3 hand-foot syndrome. Capecitabine-based chemoradiotherapy with adjuvant capecitabine is a well-tolerated option with an early signal of efficacy meriting further evaluation.

Treatment of advanced, recurrent, resistant to previous treatments basal and squamous cell skin carcinomas with a synergistic formulation of interferons. Open, prospective study

BackgroundAggressive non-melanoma skin cancer (deeply infiltrating, recurrent, and morphea form lesions) are therapeutically challenging because they require considerable tissue loss and may demand radical disfiguring surgery. Interferons (IFN) may provide a non-surgical approach to the management of these tumors. The aim of this work was to evaluate the effect of a formulation containing IFNs-α and -γ in synergistic proportions on patients with recurrent, advanced basal cell (BCC) or squamous cell skin carcinomas (SCSC).MethodsPatients with extensive, recurrent, resistant to other procedures BCC or SCSC received the IFN formulation peri- and intralesionally, three times per week for 3 weeks. They had been previously treated with surgery and/or radiotherapy or chemotherapy. Thirteen weeks after the end of treatment, the original lesion sites were examined for histological evidence of remaining tumor.ResultsSixteen elder (median 70 years-old) patients were included. They beared 12 BCC and 4 SCSC ranging from 1.5 to 12.5 cm in the longest dimension. At the end of treatment 47% CR (complete tumor elimination), 40% PR (>30% tumor reduction), and 13% stable disease were obtained. None of the patients relapsed during the treatment period. The median duration of the response was 38 months. Only one patient with complete response had relapsed until today. Principal adverse reactions were influenza-like symptoms well known to occur with interferon therapy, which were well tolerated.ConclusionThe peri- and intralesional combination of IFNs-α and -γ was safe and showed effect for the treatment of advanced, recurrent and resistant to previous treatments of BCC and SCSC in elder patients. This is the first report of such treatment in patients with advance non-melanoma skin cancer. The encouraging result justifies further confirmatory trials.Trial registrationCurrent Controlled Trials RPCEC00000052.

Mitomycin C with continuous fluorouracil or with cisplatin in combination with radiotherapy for locally advanced anal cancer (European Organisation for Research and Treatment of Cancer phase II study 22011-40014)

Purpose To assess the feasibility and activity of radio-chemotherapy with mitomycin C (MMC) and cisplatin (CDDP) in locally advanced squamous cell anal carcinoma with reference to radiotherapy (RT) combined with MMC and fluorouracil (5-FU). Patients and methods Patients with measurable disease >4 cm N0 or N+ received RT (36 Gy + 2 week gap + 23.4 Gy) with either MMC/CDDP or MMC/5-FU (MMC 10 mg/m 2 d1 of each sequence; 5-FU 200 mg/m 2/day c.i.v. daily; CDDP 25 mg/m 2 weekly). Forty patients/arm were needed to exclude a RECIST objective response rate (ORR), 8 weeks after treatment, of <75% (Fleming 1, α = 10%, β = 10%). Results The ORR was 79.5% (31/39) (lower bound confidence interval [CI]: 68.8%) with MMC/5-FU versus 91.9% (34/ 37) (lower bound CI: 82.8%) with MMC/CDDP. In the MMC/5-FU group, two patients (5.1%) discontinued treatment due to toxicity versus 11 (29.7%) in the MMC/CDDP group. Nine grade 3 haematological events occurred with MMC/CDDP versus none with 5-FU/MMC. The rate of other toxicities did not differ. There was no toxic death. Thirty-one patients in the MMC/5-FU arm (79.5%) and 18 in the MMC/CDDP arm (48.6%) were fully compliant with the protocol treatment ( p = 0.005). Conclusions Radio-chemotherapy with MMC/CDDP seems promising as only MMC/CDDP demonstrated enough activity (RECIST ORR >75%) to be tested further in phase III trials; MMC/5-FU did not. MMC/CDDP also had an overall acceptable toxicity profile.

Treatment intensification by induction chemotherapy (ICT) and radiation dose escalation in locally advanced squamous cell anal canal carcinoma (LAAC): Definitive analysis of the intergroup ACCORD 03 trial

4033 Background: Concomitant radiochemotherapy (CRT) is the standard treatment of LAAC. The addition of an ICT (2 cycles of 5 FU-Cisplatin) and of a higher dose of irradiation boost (HDRT) to CRT were evaluated in a factorial 2X2 arms trial (A= ICT; B=ICT+HDRT; C= Reference arm = Pelvic RT 45 Gy/25 fractions with 2 cycles of 5FU-Cisplatin and a boost of 15 Gy; D= HDRT). The aim of the study was to detect a increase from 70 to 85% of colostomy-free survival (CFS) at 3 years. Methods: 307 pts with T2 &gt; 4 cm or T3-T4 Nx or any T, N1–3 M0 LAAC were included. Mean age was 59 y and sex-ratio was 1/6. The 4 arms were well balanced concerning the sex-ratio, age, stage, T size and differentiation. Results: 306/307 pts were eligible. Toxicities were similar in the 4 arms (toxic deaths: A=4, B=2, C=2, D=1). The compliance was: 99% for ICT, 100% for pelvic RT-CT, and 96% for the boost. The tumour complete response (+ partial response) at 2 months were: A=78% (+18%), B=86% (+13%), C=74% (+21%), D=74 % (+22%) (NS). The median follow-up was 43 months. Overall failure rates were 28% (A=28%, B=21%, C=30%, D= 30%). The actuarial results at 3 years were: CFS was 83%: A= 83%, B= 85%, C= 86%, D= 80% with no significant difference of ICT nor HDRT (A+B=84% vs C+D=83% for ICT; A+C= 84% vs B+D=83% for HDRT). Local control was 88%: A= 80%, B= 96%, C= 90 %, D= 87%: (NS). Event-free survival was 71% : A= 70%, B= 78%, C= 67%, D= 68%: (NS). Overall survival was 78% at 3 y (73% at 5 y) with no difference between arms. Specific survival was 84 % : A= 79%, B= 88,5%, C= 89%, D= 79%: (NS) Conclusions: Neither ICT nor HDRT improved the CFS at 3 years, nor the secondary end points. No significant financial relationships to disclose.

Combined modality therapy with radiation therapy (RT), chemotherapy, bevacizumab, and erlotinib in the treatment of patients (pts) with locally advanced squamous carcinoma of the head and neck

6012 Background: Concurrent chemotherapy/RT is the standard of treatment for locally advanced head and neck cancer. Agents targeting EGFR and the angiogenesis pathway have also demonstrated activity. In this phase II trial, we added bevacizumab and erlotinib to an active combined modality regimen in the first-line treatment of pts with locally advanced head and neck cancer. Methods: Eligible pts had previously untreated squamous carcinoma of any head and neck site, with T3/T4 primary lesions and/or N1-N3 nodal involvement. Additional eligibility: ECOG PS 0 or 1; adequate organ function; indwelling central venous catheter; standard bevacizumab exclusions. All pts received induction therapy with 2 courses of paclitaxel (200mg/m2), carboplatin (AUC 6.0), 5-FU (200mg/m2 per day, 24 hour CI days 1–21), and bevacizumab (15 mg/kg); cycles were repeated at 21-day intervals. Pts then received concurrent RT (68.4 Gy, 1.8 Gy/day), paclitaxel (50 mg/m2 weekly x 6), bevacizumab (15 mg/kg weeks 1 and 4), and erlotinib (150 mg daily x 7 weeks). PFS was the primary endpoint. Results: Between December 2006 and July 2008, 60 pts were enrolled; the first 48 pts are included in this preliminary report. The median age was 56 years; T3/T4 = 9/8; N1/N2/N3 = 13/27/4. 45 pts (94%) completed the 6-week induction therapy, and 41 pts (85%) completed all therapy. After induction therapy, 56% of pts had objective response; 77% had objective response after completion of therapy. After a median follow-up of 16 months, the 18-month progression-free and overall survivals are 85% and 87%, respectively. Grade 3/4 toxicity during induction therapy included neutropenia (46%), neutropenic fever (6%), mucositis (14%), diarrhea (14%), and hand/foot syndrome (11%). Severe local toxicity (mucositis/esophagitis) occurred in 31 patients (76%) during combined modality therapy (56% grade 3/20% grade 4). Conclusions: The addition of bevacizumab and erlotinib to concurrent chemotherapy/RT was feasible, with no unexpected toxicity. After short followup, the regimen appears highly active. Updated results will be presented. [Table: see text]

Neoadjuvant chemotherapy/gefitinib followed by concurrent chemotherapy/radiation therapy/gefitinib for patients with locally advanced squamous carcinoma of the head and neck

The authors evaluated the feasibility, toxicity, and efficacy of gefitinib added to first-line combined-modality therapy for patients with locally advanced squamous carcinoma of the head and neck. Patients with biopsy-proven locally advanced squamous carcinoma of the head and neck who had low expected cure rates with local treatment modalities alone were eligible for this treatment. All patients received a 6-week induction course of docetaxel, carboplatin, infusional 5-fluorouracil, and gefitinib (250 mg daily). Gefitinib was continued while patients received concurrent weekly docetaxel and radiation therapy. After the completion of radiation therapy, gefitinib was continued until patients developed disease progression or for a maximum of 24 months. Sixty-two patients (53% with stage IV disease) received protocol treatment, and 50 patients (81%) were able to complete the regimen. The addition of gefitinib increased the incidence of grade 3/4 mucositis (27%) and diarrhea (16%) during induction therapy but did not appear to add substantially to toxicity during concurrent chemoradiation. The estimated 3-year progression-free and overall survival rates for the entire group were 41% and 54%, respectively. The addition of gefitinib was associated with a moderate increase in toxicity with this combined modality regimen, particularly during induction therapy. Although this regimen was efficacious, the survival results overlap with results reported with chemoradiation alone. The role of epidermal growth factor receptor inhibitors in first-line, combined-modality therapy for patients with head and neck cancer remains undefined.

A phase II, randomized trial of neo-adjuvant chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap-02 Italian Collaborative Study

BackgroundThe efficacy and tolerability of the regimen containing paclitaxel and cisplatin (TP) in the neo-adjuvant treatment of locally advanced squamous cell cervical cancer are unknown. The TIP regimen (TP plus ifosfamide) showed high efficacy but high toxicity and it is used as an internal control. Patients and methodsIn all, 154 patients were randomized to TP (paclitaxel 175 mg/m2 + cisplatin 75 mg/m2; n = 80) or TIP (TP + ifosfamide 5 g/m2; n = 74), three cycles, followed by radical surgery. Pathological response to chemotherapy was classified as optimal [no residual tumor (complete response) or residual disease with ≤3 mm stromal invasion (PR1)] or suboptimal response. ResultsPatient characteristics (TP/TIP): stage IB2 (56%/64%), IIA (18%/14%), IIB (20%/19%), III–IVA (5%/4%) and median age (42 years/45 years). The optimal response rate in the TP group was 25%, 95% confidence interval (CI) = 16% to 37% and 43%, 95% CI = 31% to 55% in the TIP group. Grades 3–4 leukopenia (6%/53%) and neutropenia (26%/76%) were significantly more frequent on TIP. ConclusionTP performance was below expectation since the lower 95% confidence limit of the optimal response rate failed to reach the prespecified minimum requirement of efficacy, i.e. 22%. The TIP regimen confirmed its activity but was associated with higher haematological toxicity than TP.

Management of the N0 neck in moderately advanced squamous carcinoma of the larynx

Objective To assess the oncological efficacy of selective neck dissection (SND) in patients with T3-4 N0 laryngeal squamous carcinoma. Subjects and Methods A total of 327 patients underwent 654 neck dissections; each side of the neck was individually evaluated. Results Three percent of patients who had SND developed regional recurrence (RR) in comparison with 11.7 percent of patients who underwent modified radical neck dissection (MRND) ( P = 0.005). Only 3 (0.9%) patients developed RR outside the field of SND. The presence of extracapsular extension ( P = 0.002) in node-positive (pN+) group and of microvascular invasion ( P = 0.007), together with the type of neck dissection (ND) ( P = 0.0003) in node-negative (pN0) group had statistical impact on RR. The development of RR significantly affected disease-specific survival ( P = 0.0001). Equivalent rates of RR were found in pN+ (2.6%) or pN0 (3.2%) patients treated with SND ( P = 0.98) as well as in pN+ patients who underwent SND (2.6%) or MRND (4.7%) ( P = 0.85). Conclusion This study confirmed the adequacy of SND as a satisfactory staging and therapeutic procedure, and suggests its use in the treatment of limited node-positive (N+) neck.

Somatic Alterations of the Serine/Threonine Kinase LKB1 Gene in Squamous Cell (SCC) and Large Cell (LCC) Lung Carcinoma

Somatic LKB1 serine/threonine kinase alterations are rare in sporadic cancers, with the exception lung adenocarcinoma, but no mutations in squamous cell or large cell primary carcinoma were discovered. We screened the LKB1 gene in 129 primary nonsmall cell lung carcinomas, adjacent healthy lung tissue, and control blood samples. Forty-five percent of nonsmall cell lung tumors harbored either intron or exon alterations. We identified R86G, F354L, Y272Y and three polymorphisms: 290+36G/T, 386+156G/T, and 862+145C/T (novel). R86G (novel) and F354L mutations were found in six squamous cell carcinomas and three large cell cancer carcinomas, but not in the adjacent healthy tissue or controls samples. The F354L mutation was found in advanced squamous cell carcinomas with elevated COX-2 expression, rare P53, and no K-RAS mutation. Results indicate that the LKB1 gene is changed in a certain proportion of nonsmall cell lung tumors, predominately in advanced squamous lung carcinoma. Inactivation of the gene takes place via the C-terminal domain and could be related to mechanisms influencing tumor initiation, differentiation, and metastasis.