Safety of COVID-19 Vaccine in Patients with Cancer in a High-Volume Comprehensive Cancer Center.

BACKGROUND: Few data are available on the safety of COVID-19 vaccines in cancer patients undergoing active cancer-directed treatment. PATIENTS AND METHODS: This case series analyzes outcomes in terms of adverse events in 5297 patients undergoing anti-cancer treatment who were vaccinated with anti-SARS-CoV-2 Pfizer-BioNTech vaccine at a single cancer center from March 6, 2021 to May 9, 2021. Adverse events were retrieved from the national Italian pharmacovigilance platform (http://www.vigicovid.it). RESULTS: Of the 5297 patients treated for either solid tumors (87%) or onco-hematologic malignancies (13%) who were vaccinated, 8 adverse drug reactions (ADRs) were reported. One was a severe ADR and 7 were non-severe ADRs. Non-severe ADRs resolved within 48 hours. CONCLUSION: BNT162b2 Pfizer-BioNTech vaccine was safely administered in the largest cohort of cancer patients reported to date.

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.

BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Predictive classifier for intensive treatment of head and neck cancer.

BACKGROUND: This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer. METHODS: This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta-Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH-NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS). RESULTS: Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16-negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85-0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84-0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90-1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75-0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78-0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86-1.08; P for interaction = .011). CONCLUSIONS: LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.

Therapeutic Intensification and Induction Chemotherapy for High-Risk Locally Advanced Squamous Cell Carcinoma.

OPINION STATEMENT: The treatment of HNSCC has rapidly evolved over the past 30 years and multidisciplinary management is required, especially for locally advanced disease (LAHNSCC). Concomitant chemoradiation (cCRT) is the standard of care and cetuximab/RT (CET/RT) is an alternative treatment option, especially for patients unfit for concurrent cisplatin. Several intensification strategies have been explored to improve the outcome of the concomitant treatment. The combination of cisplatin plus cetuximab concurrent to RT failed to improve overall survival (OS) in two phase III trials. Induction chemotherapy (IC) has a proven role in organ preservation; however, its ability in prolonging OS has not been clearly demonstrated. Immune checkpoint inhibitors (ICIs), specifically anti PD-1 inhibitors, have been recently approved for the treatment of patients with recurrent/metastatic platinum-refractory disease. Recent clinical trials are exploring the role of immunotherapy at earlier stages of the disease in combination with concomitant treatments. The purpose of this article is to review current evidence regarding treatment intensification strategies for LAHNSCC (except nasopharyngeal carcinomas) with particular emphasis on the role of induction chemotherapy.

Association of a gene-expression subtype to outcome and treatment response in patients with recurrent/metastatic head and neck squamous cell carcinoma treated with nivolumab.

BACKGROUND: Immune checkpoint inhibitors have been approved and currently used in the clinical management of recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. The reported benefit in clinical trials is variable and heterogeneous. Our study aims at exploring and comparing the predictive role of gene-expression signatures with classical biomarkers for immunotherapy-treated R/M HNSCC patients in a multicentric phase IIIb trial. METHODS: Clinical data were prospectively collected in Nivactor tiral (single-arm, open-label, multicenter, phase IIIb clinical trial in platinum-refractory HNSCC treated with nivolumab). Findings were validated in an external independent cohort of immune-treated HNSCC patients, divided in long-term and short-term survivors (overall survival >18 and <6 months since the start of immunotherapy, respectively). Pretreatment tumor tissue specimen from immunotherapy-treated R/M HNSCC patients was used for PD-L1 (Tumor Proportion Score; Combined Positive Score (CPS)) and Tumor Mutational Burden (Oncopanel TSO500) evaluation and gene expression profiling; classical biomarkers and immune signatures (retrieved from literature) were challenged in the NIVACTOR dataset. RESULTS: Cluster-6 (Cl6) stratification of NIVACTOR cases in high score (n=16, 20%) and low score (n=64, 80%) demonstrated a statistically significant and clinically meaningful improvement in overall survival in the high-score cases (p=0.00028; HR=4.34, 95% CI 1.84 to 10.22) and discriminative ability reached area under the curve (AUC)=0.785 (95% CI 0.603 to 0.967). The association of high-score Cl6 with better outcome was also confirmed in: (1) NIVACTOR progression-free survival (p=4.93E-05; HR=3.71, 95% CI 1.92 to 7.18) and objective-response-rate (AUC=0.785; 95% CI 0.603 to 0.967); (2) long survivors versus short survivors (p=0.00544). In multivariate Cox regression analysis, Cl6 was independent from Eastern Cooperative Oncology Group performance status, PDL1-CPS, and primary tumor site. CONCLUSIONS: These data highlight the presence of underlying biological differences able to predict survival and response following treatment with immunotherapy in platinum-refractory R/M HNSCC that could have translational implications improving treatment selection. TRIAL REGISTRATION NUMBER: EudraCT Number: 2017-000562-30.

Dosiomic-based prediction of dysgeusia in head & neck cancer patients treated with radiotherapy.

PURPOSE: To investigate the potential of dosiomics in predicting radiotherapy-induced taste distortion (dysgeusia) in head & neck (H&N) cancer. METHODS: A cohort of 80 H&N cancer patients treated with radical or adjuvant radiotherapy and with a follow-up of at least 24 months was enrolled. Treatment information, as well as tobacco and alcohol consumption were also collected. The whole tongue was manually delineated on the planning CT and mapped to the dose map retrieved from the treatment planning system. For every patient, 6 regions of the tongue were examined; for each of them, 145 dosiomic features were extracted from the dose map and fed to a logistic regression model to predict the grade of dysgeusia at follow-up, with and without including clinical features. A mean dose-based model was considered for reference. RESULTS: Both dosiomics and mean dose models achieved good prediction performance for acute dysgeusia with AUC up to 0.88. For the dosiomic model, the central and anterior ⅔ regions of the tongue were the most predictive. For all models, a gradual reduction in the performance was observed at later times for chronic dysgeusia prediction, with higher values for dosiomics. The inclusion of smoke and alcohol habits did not improve model performances. CONCLUSION: The dosiomic analysis of the dose to the tongue identified features able to predict acute dysgeusia. Dosiomics resulted superior to the conventional mean dose-based model for chronic dysgeusia prediction. Larger, prospective studies are needed to support these results before integrating dosiomics in radiotherapy planning.

First-line cetuximab + platinum-based therapy for recurrent/metastatic head and neck squamous cell carcinoma: A real-world observational study-ENCORE.

BACKGROUND: ENCORE, an observational, prospective, open-label study, investigated real-world treatment practices and outcomes with cetuximab plus platinum-based therapy (PBT) in first-line (1L) recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). AIMS: This multinational study aimed to investigate the long-term use of cetuximab plus PBT for 1L R/M SCCHN in a clinical setting. In particular, this study aimed to explore clinical considerations such as the decision to prescribe cetuximab plus PBT in R/M SCCHN, the mode and duration of treatment, and patient outcomes. METHODS AND RESULTS: Previously untreated patients with R/M SCCHN whose planned treatment was cetuximab plus PBT were enrolled from 6 countries. Among 221 evaluable patients, planned treatments included cetuximab plus carboplatin (31.2%), cisplatin plus 5-fluorouracil (31.7%), or carboplatin plus 5-fluorouracil (23.1%); 3.2% included a taxane, and 45.2% did not include 5-fluorouracil. Cetuximab treatment was planned for a fixed duration (≤24 weeks) in 15 patients (6.8%) and until disease progression in 206 (93.2%). Median progression-free survival and overall survival were 6.5 and 10.8 months, respectively. Grade ≥3 adverse events occurred in 39.8% of patients. Serious adverse events occurred in 25.8% of patients; 5.4% were cetuximab-related. CONCLUSION: In patients with R/M SCCHN, first-line cetuximab plus PBT was feasible and modifiable in a real-world setting with similar toxicity and efficacy as in the pivotal phase III EXTREME trial. CLINICAL TRIAL REGISTRATION NUMBER: EMR 062202-566.

The efficacy of immunonutrition in improving tolerance to chemoradiotherapy in patients with head and neck cancer, receiving nutritional counseling: study protocol of a randomized, open-label, parallel group, bicentric pilot study.

BACKGROUND: Nutritional support, including nutritional counseling and oral nutritional supplements (ONSs), has been recommended at the earliest opportunity in head and neck (H&N) cancer patients. The limited available evidence on the efficacy of immunonutrition during chemoradiotherapy (CT-RT) in H&N cancer patients is positive with regard to some secondary endpoints, but is still scanty, particularly with regard to toxicity and treatment tolerance. We hypothesize that early systematic provision of ONSs with a high-protein-high-calorie mixture containing immunonutrients (Impact) compared to standard high-calorie-high-protein nutritional blends, in addition to nutritional counseling, may be beneficial to patients with H&N cancer during CT-RT. Hence, we designed the present study to evaluate the efficacy, in terms of treatment tolerance, toxicity and response, body weight, body composition, protein-calorie intake, quality of life (QoL), fatigue, muscle strength and immunological profile of the early systematic provision of ONSs enriched in immunonutrients compared to isonitrogenous standard blends, in H&N cancer patients undergoing CT-RT. METHODS: This is a pragmatic, bicentric, randomized (1:1), parallel-group, open label, controlled, pilot clinical trial. DISCUSSION: Many efforts are still to be taken to improve the efficacy of nutritional support in oncology. Immunonutrition represents a promising approach also in H&N cancer patients, but the evidence on its efficacy in improving clinical outcomes during CT-RT is still inconclusive. The present pilot study, which guarantees the early provision of nutritional assessment and support to all the enrolled patients in accordance with the recent guidelines and recommendations, could represent one of the first proofs of the clinical effectiveness of early oral immunonutrition in cancer patients undergoing CT-RT and could stimulate further large randomized trials, potentially resulting in the improvement of supportive care quality. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov Identifier: NCT04611113.

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group.

BACKGROUND AND PURPOSE: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005). CONCLUSION: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.

Induction chemotherapy before chemoradiotherapy in locally advanced head and neck cancer: the future?

There is increasing interest in the use of induction chemotherapy before concurrent chemotherapy and radiotherapy in the treatment of locally advanced head and neck cancer. A modest but significant improvement in survival has been observed with cisplatin and 5-fluorouracil (PF) induction before radiotherapy over that seen with radiotherapy alone. The addition of docetaxel to the PF regimen (TPF) appears to provide further survival benefits. The phase II part of a phase II/III trial compared three cycles of TPF induction chemotherapy before concomitant PF chemoradiotherapy with PF chemoradiotherapy alone in 101 patients with locally advanced stage III-IV head and neck cancer. The incidences of hematologic and nonhematologic toxicities during concurrent chemoradiotherapy were not higher in the TPF plus chemoradiotherapy group, and the feasibility of chemoradiotherapy was not compromised. Radiologically evaluated complete response rates at 6-8 weeks from the end of chemoradiotherapy (the primary endpoint) were 21% (95% confidence interval [CI], 11%-36%) with chemoradiotherapy alone and 50% (95% CI, 35%-65%; p = .004) with TPF plus chemoradiotherapy. A median overall survival time of 33.3 months and a 1-year survival rate of 78% were observed with chemoradiotherapy alone, whereas the median survival time was 39.6 months in the TPF plus chemoradiotherapy group, with a 1-year survival rate of 86%. To conclude, increasing evidence suggests that TPF induction chemotherapy improves clinical response and does not compromise subsequent chemoradiotherapy. The results of the ongoing phase III part of the phase II/III study should provide further information about the efficacy and safety of this approach for patients with locally advanced head and neck cancer.

The Slippery Role of Induction Chemotherapy in Head and Neck Cancer: Myth and Reality.

Chemoradiotherapy as an alternative to surgery can be offered to patients affected by loco-regionally advanced head and neck cancer (HNC). Induction chemotherapy is a valid option, supported by few positive trials, but its real efficacy is still a matter of debate. The standard regimen for induction chemotherapy in Europe is a combination of docetaxel (75 mg/m2) and reduced dose doses of cisplatin (75 mg/m2) and 5-fluorouracil (750 mg/m2 day, for five consecutive days) (TPF). It is less toxic and more effective than the historical therapy PF (cisplatin 100 mg/m2 and fluorouracil 1,000 mg/m2/day for five consecutive days). However, in some studies treatment-related mortality has been reported to be as high as 6%. Therefore, some less toxic combinations, such as a modified TPF regimen and the combination of carboplatin plus paclitaxel have been studied. These regimens are showing promising results but deserve further validation in comparative trials. Furthermore, several trials are underway in order to enhance TPF with immune checkpoints inhibitors. Compared to chemoradiotherapy, induction chemotherapy followed by chemoradiation was shown to be non-inferior, and it could decrease the distant metastatic progression, especially in high-risk populations. For selected patients, induction chemotherapy could be a strong option. The chemoselective process that leads to immediate surgery for non-responders, the high response rate (complete responses are sometimes observed), and the survival data, are all arguments in favor of induction chemotherapy, if performed in experienced centers involving health professionals in the context of a skilled multidisciplinary team.

Prognostic role of programmed death ligand 1 (PD-L1) and the immune microenvironment in laryngeal carcinoma.

OBJECTIVES: The immune system is crucial in the evolution of head and neck cancer. Programmed cell death ligand 1 (PD-L1) seems to rely on close relations between neoplastic cells and immune cells in the tumor microenvironment. The main aim of this study was to apply univariate/multivariate analysis to investigate the prognostic significance of PD-L1, tumor-infiltrating lymphocytes (TILs), and tertiary lymphoid structures (TLS) in laryngeal carcinoma (LSCC). MATERIALS AND METHODS: PD-L1 (in terms of combined positive score [CPS]), TILs and TLS were assessed at pathology on 70 consecutive samples of LSCC. RESULTS: A CPS ≥ 1 coincided with a lower recurrence rate (RR) (p = 0.007) and longer disease-free survival (DFS) than a CPS < 1 (p = 0.0027). Cases with higher TIL counts showed a lower RR (p = 0.036) and longer DFS than those with lower TIL counts (p = 0.0062). Cases revealing TLS had a lower RR (p = 0.004) and longer DFS (p = 0.0034) than those with no TLS. On multivariate analysis, the presence of TLS retained its positive prognostic value (p = 0.024), while CPS remained significant as regards disease recurrence (p = 0.050). CONCLUSIONS: PD-L1 seems to be an indirect marker of effective anti-tumor response in LSCC, possibly being expressed as a result of a greater immune pressure on cancer cells. The presence of TLS emerged as a positive prognostic factor. Further prospective studies are needed to characterize the role of PD-L1 as a marker of anti-tumor immune response and prognostic factor in LSCC, also with regard to the effectiveness of immunotherapeutic protocols.

Selection of systemic therapy in patients with locally advanced and recurrent/metastatic head and neck cancer: RAND-based expert opinion by an Italian multidisciplinary panel.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease often presenting at an already advanced stage. Cisplatin chemoradiotherapy is the standard treatment for locally advanced disease, although its efficacy varies according to different studies. Thus, treatment selection is a challenge, especially in older patients, who frequently have several comorbidities. Moreover, the majority of patients with recurrent and/or metastatic disease are unsuitable for local treatment, either surgery or radiation therapy. The only treatment option for them is systemic therapy, but prognosis remains poor, with a median overall survival of less than 12 months. METHODS: A group of Italian key opinion leaders in the field of HNSCC gathered several times in 2018 in order to retrieve a set of statements to help clinicians in their daily decision-making process for the treatment of patients with different scenarios of HNSCC. RESULTS AND CONCLUSION: The panel agreed on 22 statements that were identified as "good clinical points" based on the available literature or after discussion of the most relevant aspect of the underlying diseases when no international consensus was available. The panel identified a number of possible scenarios (namely 71) in which these statements may be helpful to guide decision-making for the best treatment selection.

Role of chemotherapy in 5000 patients with head and neck cancer treated by curative surgery: A subgroup analysis of the meta-analysis of chemotherapy in head and neck cancer.

OBJECTIVE: To evaluate the effect of chemotherapy added to a surgical locoregional treatment (LRT) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: We studied the sub-group of trials with surgical LRT included in the meta-analysis on chemotherapy in head and neck cancer (MACH-NC). Data from published and unpublished randomized trials comparing the addition of chemotherapy to LRT in HNSCC patients were sought using electronic database searching for the period 1965-2000, hand searching and by contacting experts in the field. Trials with less than 60 patients, or preoperative radiotherapy or where the type of LRT could not be individually determined were excluded. All individual patient data were checked for internal consistency, compared with published reports, and validated with trialists. Data were pooled using a fixed-effect model. Heterogeneity was assessed using Cochrane test and I2 statistic. RESULTS: Twenty-four trials were eligible (5000 patients). Chemotherapy improved overall survival (HR = 0.92 [95%CI: 0.85-0.99] p = 0.02). There was a significant interaction between treatment effect and timing of chemotherapy (p = 0.08 at pre-specified threshold of 0.10) with a greater effect for concomitant chemotherapy (HR = 0.79, 95%CI: 0.69-0.92). The benefit of chemotherapy was greater in women (HRwomen = 0.63, 95%CI: 0.50-0.80) compared to men (HRmen = 0.96, 95%CI: 0.89-1.04; p for interaction = 0.001). CONCLUSIONS: This analysis confirmed the benefit of concomitant chemotherapy added to surgical LRT. The role of induction therapy as yet to be determined as it did not improve OS. Women may benefit more than men from chemotherapy.

Sepsis in head and neck cancer patients treated with chemotherapy and radiation: Literature review and consensus.

The reporting of infection/sepsis in chemo/radiation-treated head and neck cancer patients is sparse and the problem is underestimated. A multidisciplinary group of head and neck cancer specialists from Italy met with the aim of reaching a consensus on a clinical definition and management of infections and sepsis. The Delphi appropriateness method was used for this consensus. External expert reviewers then evaluated the conclusions carefully according to their area of expertise. The paper contains seven clusters of statements about the clinical definition and management of infections and sepsis in head and neck cancer patients, which had a consensus. Furthermore, it offers a review of recent literature in these topics.

Neoadjuvant docetaxel, cisplatin, 5-fluorouracil before concurrent chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck versus concomitant chemoradiotherapy: a phase II feasibility study.

PURPOSE: To determine the feasibility of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CHT-RT) compared with the same CHT-RT regimen alone in locally advanced head-and-neck squamous cell carcinoma. METHODS AND MATERIALS: We treated 24 patients (20 men and 4 women) who had Stage III-IVM0 squamous cell carcinoma of the oral cavity, oropharynx, nasopharynx, or hypopharynx. The median patient age was 59 years (range, 41-73 years). The stage distribution was as follows: Stage II, 1 patient; Stage III, 6 patients; and Stage IV, 17; 18 patients had a performance status of 0 and 6 had a performance status of 1. None had undergone previous CHT or RT. Group 1 underwent three cycles of CHT (carboplatin area under the curve 1.5 on Days 1-4 and 5-fluorouracil 600 mg/m(2)/d continuous infusion for 96 h) starting on Days 1, 22, and 43 during RT (one daily fraction, 66-70 Gy within 33-35 fractions). Group 2 underwent three cycles of neoadjuvant TPF (docetaxel 75 mg/m(2), cisplatin 80 mg/m(2), 5-fluorouracil 800 mg/m(2)/d continuous infusion for 96 h) followed by the same CHT-RT regimen. RESULTS: After the first 16 patients, 8 in Group 1 and 8 in Group 2, the concomitant CHT-RT schedule was modified. The limiting toxicity observed during concomitant CHT-RT was similar in Groups 1 and 2, independent of neoadjuvant TPF administration. An excess of G3-G4 mucositis and other relevant toxicity that did not allowing completion of CHT-RT without interruption occurred in 44% of the patients. A reduction of at least one cycle of concurrent CHT was required in 31% of patients. On the basis of these data, the next 8 patients (Group 3) received three cycles of neoadjuvant TPF followed by two cycles only of CHT (cisplatin 20 mg/m(2) on Days 1-4 and 5-fluorouracil 800 mg/m(2)/d continuous infusion for 96 h) (PF) during Weeks 1 and 6 of the planned 7 weeks of RT. In Group 3, 25% of the patients developed World Health Organization G3-G4 mucositis. No World Health Organization hematologic G3-G4 toxicity was seen. RT interruption was required for 2 patients (25%). In 1 patient (12%), one cycle of CHT was omitted. During neoadjuvant TPF (Groups 2 and 3), the principal toxicities were G3-G4 neutropenia (37.5%) and G2 mucositis (44%). At the end of therapy, the CR rate was 62.5% for CHT-RT alone (Group 1) and 80% for neoadjuvant TPF followed by CHT-RT (Groups 2 and 3). CONCLUSION: Three cycles of neoadjuvant TPF followed by two cycles of PF during RT are feasible without limiting toxicity. Three cycles of TPF were well tolerated and did not compromise subsequent concomitant CHT-RT. A randomized multicenter Phase III study has been started with the aim of comparing two cycles of PF during RT as standard treatment vs. the experimental arm with three cycles of neoadjuvant TPF followed by two cycles of PF during RT.

The role of chemotherapy in locally advanced head and neck squamous cell carcinoma.

The role of chemotherapy in multimodality treatment for locally advanced head and neck squamous cell carcinoma, although firmly established, presents several unresolved issues. Concomitant platinum-based chemoradiation (CRT) is a standard treatment for unresectable, resectable but nonsurgically treated, and postoperative high-risk patients with locally advanced head and neck squamous cell carcinoma. However, no clear conclusion can be drawn regarding the optimal platinum compound or combinations to use, the type of schedule, and number of cycles (ie, platinum total dose) to be delivered. Cetuximab administered concomitantly with radiotherapy has not been directly compared with CRT but offers a potential different approach using a noncytotoxic systemic agent. In the organ preservation setting, CRT, although yielding a superior 5-year larynx preservation rate, showed similar outcomes to induction chemotherapy (IC) followed by radiation in terms of 5-year laryngectomy-free survival and overall survival, with a higher incidence of grade 3-4 mucositis. The role of IC in nonorgan preservation programs has not yet been established. Phase III trials comparing concomitant CRT versus IC followed by CRT are ongoing with results anticipated in the near future.

Adding gemcitabine to paclitaxel/carboplatin combination increases survival in advanced non-small-cell lung cancer: results of a phase II-III study.

PURPOSE: Paclitaxel/carboplatin (PC) is one of the reference combinations in the treatment of non-small-cell lung cancer (NSCLC). No triplet novel agent combination has until now shown superiority over a two-drug combination for advanced NSCLC. We therefore conducted a clinical trial to test if paclitaxel/carboplatin/gemcitabine (PCG) increases overall survival (OS) and response rate (RR) over PC. METHODS: Stage IIIB patients not suitable for radical radiation treatment and stage IV chemotherapy-naive patients with measurable disease and performance status of 0 to 2 were randomly assigned to PC arm (paclitaxel 200 mg/m2 and carboplatin area under the concentration-time curve 6 day 1/q21 days) or the PCG arm (paclitaxel 200 mg/m(2) and carboplatin area under the concentration-time curve 6 day 1, and gemcitabine 1,000 mg/m2 days 1 and 8 every 21 days). RESULTS: A total of 324 patients were randomly assigned to the two arms. The RR for PC arm and PCG arm were 20.2% and 43.6% [corrected] (P < .0001). The median time to the progression was 5.1 months in the PC group and 7.6 months in the PCG group (P = .012; hazard ratio [HR] 1.34; 95% CI: 1.06 to 1.72). Median OS was 8.3 months and 10.8 months (P = .032; HR 1.309; 95% CI: 1.03 to 1.67) in favor of the PCG arm. One-year survival was 34% (PC arm) and 45% (PCG arm; P = .032). Only hematologic toxicity (neutropenia, thrombocytopenia, and anemia) was significantly increased in the PCG arm and the experimental arm required more platelet and red blood cell transfusions, and more granulocyte colony-stimulating factor usage. No toxic/early deaths were observed. CONCLUSION: The PCG regimen offers a significant survival advantage over PC in advanced NSCLC, making PCG a treatment option for advanced NSCLC patients.

Randomized phase III trial of neoadjuvant chemotherapy in head and neck cancer: 10-year follow-up.

In 1986, we initiated a multicenter, randomized trial to compare induction chemotherapy with cisplatin and 5-fluorouracil followed by locoregional treatment (surgery and radiotherapy or radiotherapy alone) with locoregional treatment alone in patients with head and neck squamous cell carcinoma. Here we report the long-term results of the trial. A total of 237 patients with nonmetastatic stage III or IV head and neck carcinoma were randomly assigned to receive four cycles of neoadjuvant chemotherapy followed by locoregional treatment (group A) or locoregional treatment alone (group B). Among all patients, overall survival at 5 and 10 years was 23% (95% confidence interval [CI] = 15.3% to 30.9%) and 19% (95% CI = 11.6% to 26.4%), respectively, for those in group A and 16% (95% CI = 9.6% to 23.4%) and 9% (95% CI = 3.5% to 14.7%), respectively, for those in group B (P = .13). Among operable patients, we observed no difference between group A and group B in overall survival at 5 and 10 years (group A, 31% [95% CI = 14.9% to 47.3%] and 22.7% [95% CI = 7.1% to 38.3%], respectively; group B, 43.3% [95% CI = 25.6% to 61.0%] and 14.2% [95% CI = 0.1% to 28.3%], respectively; P = .73). Among inoperable patients, overall survival at 5 and 10 years was 21% (95% CI = 12.3% to 30.1%) and 16% (95% CI = 7.7% to 23.9%), respectively, for group A and 8% (95% CI = 1.5% to 12.3%) and 6% (95% CI = 0.1% to 9.1%), respectively, for group B (log-rank P = .04). Four cycles of neoadjuvant chemotherapy is a promising approach for treating patients with inoperable advanced head and neck cancer but not for treating patients with operable disease.