Renzo Corvò

Treatment of Advanced Squamous-Cell Carcinoma of the Head and Neck with Alternating Chemotherapy and Radiotherapy

BACKGROUND For patients with advanced, unresectable squamous-cell carcinoma of the head and neck, radiotherapy is the standard treatment but has poor results. We therefore designed a randomized trial to determine whether alternating chemotherapy with radiotherapy would improve the survival of such patients. METHODS Patients in the trial had biopsy-confirmed unresectable, previously untreated Stage III or IV, squamous-cell carcinoma of the oral cavity, pharynx, or larynx. They were randomly assigned to chemotherapy consisting of four cycles of intravenous cisplatin (20 mg per square meter of body-surface area per day for five consecutive days) and fluorouracil (200 mg per square meter per day for five consecutive days) alternating with radiotherapy in three two-week courses (20 Gy per course; 2 Gy per day, five days per week), or to radiotherapy alone (up to 70 Gy; 2 Gy per day, five days per week). RESULTS The 80 patients given chemotherapy alternating with radiotherapy and the 77 given radiotherapy alone were comparable in terms of age, sex, performance status, disease stage, and site of the primary tumor. Complete responses were obtained in 42 percent of the patients in the combined-therapy group and 22 percent of those in the radiotherapy group (P = 0.037). The median survival was 16.5 months in the combined-therapy group and 11.7 months in the radiotherapy group (P less than 0.05); the 3-year survival was 41 percent and 23 percent, respectively. Severe mucositis occurred in 19 percent of the patients in the combined-therapy group and 18 percent of those in the radiotherapy group. CONCLUSIONS In patients with advanced unresectable squamous-cell carcinoma of the head and neck, chemotherapy alternating with radiotherapy increases the median survival and doubles the probability of survival for three years as compared with radiotherapy alone. However, since local disease cannot be controlled in over half the patients who receive the combined treatment and since almost two thirds die within three years, further improvements in management are necessary.

The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.

PURPOSE The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy. MATERIALS AND METHODS Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis. RESULTS From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16). CONCLUSIONS The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.

In vivo cell kinetics in head and neck squamous cell carcinomas predicts local control and helps guide radiotherapy regimen.

PURPOSE To determine whether pretherapy cell kinetics can predict local control for patients affected by head and neck squamous cell carcinomas (HN-SCCs) to be treated by primary radiotherapy and, moreover, guide to a choice between conventional and accelerated radiotherapy. PATIENTS AND METHODS Between 1989 and 1993, 83 patients with stage II to IV HN-SCC entered the study. Multiple primary tumor biopsies were obtained 6 hours after in vivo infusion of bromodeoxyuridine (BrdUrd). In vivo S-phase fraction labeling index (LI), duration of S phase (Ts), and potential doubling time (Tpot) were obtained by analysis of multivariate flow-cytometric data. Between April 1989 and January 1991, 49 patients were treated by conventional radiotherapy (70 Gy in 35 fractions over 7 weeks), whereas, afterwards, 34 patients entered an accelerated radiotherapy regimen with the concomitant boost technique (75 Gy in 40 fractions over 6 weeks). RESULTS Univariate analysis showed that, among patients treated by conventional radiotherapy, local control probability was affected by tumor stage (P = .02), Tpot (P < .001), and LI (P = .04). Similarly, among patients treated with accelerated radiotherapy, we found that local control probability was related to tumor stage (P = .03) and primary tumor site (P = .05). For the subgroup of patients with tumors characterized by fast growth (Tpot < or = 5 days), accelerated radiotherapy gave a better local control rate than conventional radiotherapy (P = .02). Cox multivariate analysis of the total number of patients showed that the only significant independent prognostic factors related to local control were tumor stage (P = .002) and Tpot (P = .004). Moreover, when the Cox analysis was restricted to the subgroup of patients treated with conventional radiotherapy, Tpot was the most significant factor to predict local outcome (P < .01). CONCLUSION Pretreatment tumor Tpot appears to be an important independent prognostic factor for local control of HN-SCC treated by primary radiotherapy.

Cetuximab and Radiotherapy Versus Cisplatin and Radiotherapy for Locally Advanced Head and Neck Cancer: A Randomized Phase II Trial

PURPOSE No randomized trials have been conducted to directly compare radiotherapy (RT) with concomitant cisplatin (CDDP) versus concomitant cetuximab (CTX) as first-line treatment of locally advanced squamous cell carcinoma of the head and neck. In this randomized trial, we compared these two treatment regimens in terms of compliance, toxicity, and efficacy. PATIENTS AND METHODS Eligible patients were randomly assigned in a 1:1 ratio to receive either CDDP 40 mg/m(2) once per week or CTX 400 mg/m(2) as loading dose followed by CTX 250 mg/m(2) once per week concomitant to radical RT. For primary end points, compliance to treatment was defined as number of days of treatment discontinuation and drug dosage reduction. The acute toxicity rate was defined according to the National Cancer Institute Common Toxicity Criteria. Efficacy end points were local recurrence-free survival, metastasis-free survival, cancer-specific survival, and overall survival. RESULTS The study was discontinued early because of slow accrual after the enrollment of 70 patients. RT discontinuation for more than 10 days occurred in 13% of patients given CTX and 0% given CDDP (P = .05). Drug dosage reduction occurred in 34% given CTX and 53% given CDDP (difference not significant). Toxicity profiles differed between the two arms, with hematologic, renal, and GI toxicities more frequent in the CDDP arm, and cutaneous toxicity and the need for nutritional support more frequent in the CTX arm. Serious adverse events related to treatment, including four versus one toxic deaths, were higher in the CTX arm (19% v 3%, P = .044). Locoregional control, patterns of failure, and survivals were similar between the treatment arms. CONCLUSION CTX concomitant to RT lowered compliance and increased acute toxicity rates. Efficacy outcomes were similar in both arms. These results raise the issue of appropriately selecting patients with head and neck cancer who can benefit from CTX in combination with RT.

Swallowing dysfunction in head and neck cancer patients treated by radiotherapy: Review and recommendations of the supportive task group of the Italian Association of Radiation Oncology

PURPOSE Dysphagia is a debilitating complication in head and neck cancer patients (HNCPs) that may cause a high mortality rate for aspiration pneumonia. The aims of this paper were to summarize the normal swallowing mechanism focusing on its anatomo-physiology, to review the relevant literature in order to identify the main causes of dysphagia in HNCPs and to develop recommendations to be adopted for radiation oncology patients. The chemotherapy and surgery considerations on this topic were reported in recommendations only when they were supposed to increase the adverse effects of radiotherapy on dysphagia. MATERIALS AND METHODS The review of literature was focused on studies reporting dysphagia as a pre-treatment evaluation and as cancer and cancer therapy related side-effects, respectively. Relevant literature through the primary literature search and by articles identified in references was considered. The members of the group discussed the results and elaborated recommendations according to the Oxford CRBM levels of evidence and recommendations. The recommendations were revised by external Radiation Oncology, Ear Nose and Throat (ENT), Medical Oncology and Speech Language Pathology (SLP) experts. RESULTS Recommendations on pre-treatment assessment and on patients submitted to radiotherapy were given. The effects of concurrent therapies (i.e. surgery or chemotherapy) were taken into account. CONCLUSIONS In HNCPs treatment, disease control has to be considered in tandem with functional impact on swallowing function. SLPs should be included in a multidisciplinary approach to head and neck cancer.

Stereotactic Ablative Radiotherapy for stage I histologically proven non-small cell lung cancer: An Italian multicenter observational study

OBJECTIVES Aim of this retrospective multicenter observational study was to provide data on outcomes and prognostic factors in patients affected with stage I histologically confirmed NSCLC treated with Stereotactic Ablative Radiotherapy (SABR, or Stereotactic Body Radiotherapy, SBRT) outside clinical trials. MATERIALS AND METHODS We analyzed a cohort of 196 patients with histological/cytological diagnosis of NSCLC. Median age at treatment was 75 years old; median tumor diameter was 2.48 cm, and median GTV 13.3 cc. One hundred fifty-five patients had stage IA disease (79.1%) and 41 patients stage IB disease (20.9%). Total doses ranged from 48 to 60 Gy in 3-8 fractions. Primary endpoints of the study were safety (acute and late toxicity) and efficacy (Local Control, Disease-Free Survival, Overall and Cancer-Specific Survival). RESULTS Median follow-up time was 30 months. The percentage of grade ≥2 pulmonary toxicity was 3%, and the 30 and 60 days mortality rate was 0%. Local Recurrence-Free Survival was 89.7% at 3 years. Fifty-nine patients (30.1%) had at least one failure (local and/or nodal and/or distant), with a Disease-Free Survival (DFS) rate at 3 years of 65.5%. Overall Survival (OS) and Cancer-Specific Survival (CSS) rates were 68% and 82.1% at 3 years, respectively. Median time to any recurrence was 15 months, while median overall survival time was 54 months. At multivariate analysis, stage IB was the only variable associated to a decrease in DFS, OS and CSS (HR 2.77, p = 0.006; HR 2.38, p = 0.009; HR 4.06, p ≤ 0.001, respectively). A difference in survival according to stage was also evident at the log-rank test (p ≤ 0.0001 for CSS and OS). CONCLUSION The results of the present study support the routine use of SABR for stage I NSCLC in a daily practice environment. The only prognostic factor that has been confirmed by our analysis was tumor stage (IA vs. IB).

POTENTIAL DOUBLING TIME IN HEAD AND NECK TUMORS TREATED BY PRIMARY RADIOTHERAPY: PRELIMINARY EVIDENCE FOR A PROGNOSTIC SIGNIFICANCE IN LOCAL CONTROL

PURPOSE The aim of the study was to determine preliminarily whether cell kinetic parameters evaluated using in vivo infusion of bromodeoxyuridine (BrdUrd) and flow cytometry, play a role as prognostic factors of loco-regional control in squamous cell head and neck carcinoma treated with radiotherapy. METHODS AND MATERIALS Between April 1989 and December 1991, 42 patients with unresectable Stage II-IV squamous cell carcinoma of the oral cavity, pharynx or larynx were given an infusion of BrdUrd solution prior to primary tumor biopsy sampling at 4-6 hr later. The simultaneous labeling S-phase fraction (LI) and duration (Ts) as well as the estimated potential doubling time (Tpot) were measured using flow cytometric analysis of BrdUrd and DNA content. Twenty-six patients received standard radiotherapy (70 Gy/35 fractions/7 weeks) whereas 15 patients were treated with the concomitant boost technique (75 Gy/40 fractions/6 weeks). RESULTS A complete set of flow cytometric data was available for 31 patients. The median value of LI, Ts, and Tpot were 9%, 9 hr and 5 days, respectively. Univariate analysis among the patients treated homogeneously by standard radiotherapy, indicated that local control was affected by Tpot value (p = 0.02). When the same analysis was performed for the patients treated with either standard radiotherapy or concomitant boost regimen, we found a p = 0.04. Thus, patients with a tumor Tpot value < or = 5 days had a significantly lower three-year local control than patients with Tpot > 5 days. Log-rank test univariate analysis showed, in addition, that nodal status was the strongest prognostic factor of local control (p = 0.005). Age, tumor stage, tumor site, performance status, grading, radiotherapy regimen, DNA ploidy and LI value were, instead, not significantly related to loco-regional control. Finally, when comparing the type of radiotherapy for tumors with Tpot < or = 5 days, we found a trend toward a better local control after concomitant boost regimen, with respect to standard regimen (p = 0.06). CONCLUSION The present preliminary results suggest that Tpot could play a role as additional prognostic factor influencing the disease outcome in head and neck carcinoma treated by radiotherapy.

Sequential versus alternating chemotherapy and radiotherapy in stage III-IV squamous cell carcinoma of the head and neck: a phase III study.

A cooperative randomized study was begun in August 1983 to compare a sequential program of induction chemotherapy followed by definitive treatment, arm A, with an alternation of chemotherapy and radiotherapy (three courses of 20 Gy in ten daily fractions), arm B. The same chemotherapy was used in both arms: 6 mg/m2, vinblastine, hour 0; 30 mg, bleomycin, hour 6; 200 mg, methotrexate, hours 24 to 26; 45 mg, leucovorin, hour 48. One hundred sixteen patients entered the study, 55 in arm A and 61 in arm B. The patients all had previously untreated squamous cell carcinoma of the head and neck (SCCHN). Forty-five patients had stage III and 71 had stage IV disease. The two arms were fully comparable. As of April 1986, 116 patients were evaluable for survival, while 112 were evaluable for toxicity and 105 for response. Response analysis shows that there were 14 complete responses (CR) and 11 partial responses (PR), for an overall response rate (ORR) of 52% in arm A, and 30 CRs and seven PRs, for an ORR of 64.9% in arm B. The difference in terms of CR between the two arms was statistically significant (P less than .03). Progression-free survival (PFS) was also statistically different, with an advantage for arm B (P less than .05), but without differences in overall survival. Arm B correlates with a significant increase in mucositis compared with arm A (P less than .001).

Predictability, efficacy and safety of radiosensitization of glioblastoma-initiating cells by the ATM inhibitor KU-60019.

We have previously shown that pharmacological inhibition of ataxia telangiectasia mutated (ATM) protein sensitizes glioblastoma‐initiating cells (GICs) to ionizing radiation (IR). Herein, we report the experimental conditions to overcome GIC radioresistance in vitro using the specific ATM inhibitor KU‐60019, two major determinants of the tumor response to this drug and the absence of toxicity of this treatment in vitro and in vivo. Repeated treatments with KU‐60019 followed by IR substantially delayed GIC proliferation in vitro and even eradicated radioresistant cells, whereas GIC treated with vehicle plus radiation recovered early and expanded. The tumor response to the drug occurred under a cutoff level of expression of TP53 and over a cutoff level of expression of phosphatidylinositol 3‐kinase (PI3K). No increased clastogenicity or point mutagenicity was induced by KU‐60019 plus radiation when compared to vehicle plus radiation. No significant histological changes to the brain or other organs were observed after prolonged infusion into the brain of KU‐60019 at millimolar concentrations. Taken together, these findings suggest that GIC‐driven tumors with low expression of TP53 and high expression of PI3K might be effectively and safely radiosensitized by KU‐60019.

Cell kinetics and tumor regression during radiotherapy in head and neck squamous-cell carcinomas

Head and neck squamous‐cell carcinoma (HN‐SCC) patient management is mainly based on TNM classification and needs be improved by considering other potentially useful prognostic factors. We examined the pre‐radiotherapy tumor potential doubling time (Tpot) evaluated after in vivo infusion of bromodeoxyuridine and flow‐cytometric analysis and the early clinical tumor regression after 40 Gy (40 Gy‐TR). Tpot values and clinical 40 Gy‐TR classes (minor and major) were available for 82 HN‐SCC patients. Radiation therapy completion was done either with I dose per day (conventional regimen) or 2 doses per day (accelerated regimen). Local control was also available for follow‐up times above 4 years. We found that major 40 Gy‐TR was strongly correlated with fast tumor growth, characterized by Tpot values below 5 days, and that patients with major 40 Gy‐TR showed better local control than those with minor 40 Gy‐TR, independently from the radiotherapy regimen type. We also found that treatment completion with accelerated radiotherapy gave better local control for patients with major 40 Gy‐TR and fast tumor growth than conventional radiotherapy. Multivariate analysis, performed on all patients, assigned an independent prognostic value to Tpot, tumor classification and 40 Gy‐TR.