Giuseppe Sanguineti

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.

Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control.

PURPOSE This retrospective study was conducted to review the results of treatment and to identify prognostic factors for local and regional control in a population of 378 patients with nasopharyngeal carcinomas treated in a single institution by radiation therapy alone. METHODS AND MATERIAL All patients were treated at The University of Texas M. D. Anderson Cancer Center between 1954 and 1992 following a consistent treatment philosophy but with evolving technique. There were 286 males and 92 females with a median age of 52 years (range: 16-86 years). The majority of the patients were Caucasian (282 patients, 75%). Thirty-two patients (8%) had one or more cranial nerve deficits. Three-fourths of the patients presented with AJCC Stage IV disease (T4, N0-3, 118 patients; T1-3, N2-3 164 patients). Histologically, 193 tumors (51%) were squamous cell carcinomas, 154 (41%) lymphoepitheliomas, and 31 (8%) unclassified carcinomas. Average total dose varied with T-stage and ranged from 60.2 to 72.0 Gy. Median follow-up time was 10 years. RESULTS For the entire population the 5-, 10-, and 20-year actuarial survival rates were 48, 34, and 18%, respectively, with 184 patients (49%) dying of nasopharyngeal cancer. Actuarial control rates at 5, 10, and 20 years were 71, 66, and 66% for the primary site and 84, 83, and 83% for the neck. A total of 100 patients (26%) had local failures and 51 patients (13%) had regional failures with a median time to recurrence of 8.2 months and 13 months, respectively. Advanced T-stage, squamous histology, and presence of cranial nerve deficits were poor prognostic factors for local control in both univariate and multivariate analyses. N-stage and tumor histology were significant factors for neck control. Treatment year, total dose within the ranges used, and duration of treatment did not have any significant effect on local or regional control. The actuarial incidence of Grade 3-5 late complications was 16, 19, and 29% at 5, 10, and 20 years, respectively. Twelve patients (3%) died of treatment-related complications; all but one fatal complication occurred before 1971 and the other in 1976. CONCLUSIONS This study shows very good long-term local and regional control rates for nasopharyngeal carcinomas after definitive radiotherapy and establishes a benchmark for newer treatment strategies. Improvements in treatment technique over the years have dramatically reduced the frequency of severe late complications. Patients with advanced stage tumors and differentiated squamous histology have a relatively poor prognosis when treated with conventional radiotherapy and are candidates for dose escalation or combined modality studies.

Dose–volume effects for normal tissues in external radiotherapy: Pelvis

A great deal of quantitative information regarding the dose-volume relationships of pelvic organs at risk has been collected and analysed over the last 10 years. The need to improve our knowledge in the modelling of late and acute toxicity has become increasingly important, due to the rapidly increasing use of inverse-planned intensity-modulated radiotherapy (IMRT) and the consequent need of a quantitative assessment of dose-volume or biological-based cost functions. This comprehensive review concerns most organs at risk involved in planning optimisation for prostate and other types of pelvic cancer. The rectum is the most investigated organ: the largest studies on dose-volume modelling of rectal toxicity show quite consistent results, suggesting that sufficiently reliable dose-volume/EUD-based constraints can be safely applied in most clinical situations. Quantitative data on bladder, bowel, sexual organs and pelvic bone marrow are more lacking but are rapidly emerging; however, for these organs, further investigation on large groups of patients is necessary.

Multi-Institutional Trial of Accelerated Hypofractionated Intensity-Modulated Radiation Therapy for Early-Stage Oropharyngeal Cancer (RTOG 00-22)

PURPOSE To assess the results of a multi-institutional study of intensity-modulated radiation therapy (IMRT) for early oropharyngeal cancer. PATIENTS AND METHODS Patients with oropharyngeal carcinoma Stage T1-2, N0-1, M0 requiring treatment of the bilateral neck were eligible. Chemotherapy was not permitted. Prescribed planning target volumes (PTVs) doses to primary tumor and involved nodes was 66 Gy at 2.2 Gy/fraction over 6 weeks. Subclinical PTVs received simultaneously 54-60 Gy at 1.8-2.0 Gy/fraction. Participating institutions were preapproved for IMRT, and quality assurance review was performed by the Image-Guided Therapy Center. RESULTS 69 patients were accrued from 14 institutions. At median follow-up for surviving patients (2.8 years), the 2-year estimated local-regional failure (LRF) rate was 9%. 2/4 patients (50%) with major underdose deviations had LRF compared with 3/49 (6%) without such deviations (p = 0.04). All cases of LRF, metastasis, or second primary cancer occurred among patients who were current/former smokers, and none among patients who never smoked. Maximal late toxicities Grade >or=2 were skin 12%, mucosa 24%, salivary 67%, esophagus 19%, osteoradionecrosis 6%. Longer follow-up revealed reduced late toxicity in all categories. Xerostomia Grade >or=2 was observed in 55% of patients at 6 months but reduced to 25% and 16% at 12 and 24 months, respectively. In contrast, salivary output did not recover over time. CONCLUSIONS Moderately accelerated hypofractionatd IMRT without chemotherapy for early oropharyngeal cancer is feasible, achieving high tumor control rates and reduced salivary toxicity compared with similar patients in previous Radiation Therapy Oncology Group studies. Major target underdose deviations were associated with higher LRF rate.

Rectal dose–volume constraints in high-dose radiotherapy of localized prostate cancer

PURPOSE To investigate the relationship between rectal bleeding and dosimetric-clinical parameters in patients receiving three-dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer. METHODS In a retrospective national study (AIROPROS01-01, AIRO: Associazione Italiana Radioterapia Oncologica), planning/clinical data for 245 consecutive patients with stage T1-4N0-x prostate carcinoma who underwent 3D-CRT to 70-78 Gy (ICRU point) were pooled from four Italian institutions. The correlation between late rectal bleeding and rectal dose-volume data (the percentage of rectum receiving more than 50, 55, 60, 65, 70, and 75 Gy [V(50-70)]) and other dosimetric and clinical parameters were investigated in univariate (log-rank) and multivariate (Cox regression model) analyses. Median follow-up was 2 years. RESULTS Twenty-three patients were scored as late bleeders according to a modified RTOG definition (Grade 2: 16; Grade 3: 7); the actuarial 2-year rate was 9.2%. Excepting V75, all median and third quartile V(50-70) values were found to be significantly correlated with late bleeding at univariate analysis. The smallest p value was seen for V(50) below/above the third quartile value (66%). The V70 (cut-off value: 30%) was found to be also predictive for late bleeding. In the high-dose subgroup (74-78 Gy), Grade 3 bleeding was highly correlated with this constraint. The predictive value of both V(50) and V(70) was confirmed by multivariate analyses. CONCLUSIONS The present article provides evidence for correlation between rectal DVH parameters and late rectal bleeding in patients treated with curative intent with 3D-CRT. To keep the rate of moderate/severe rectal bleeding below 5-10%, it seems advisable to limit V(50) to 60-65%, V(60) to 45-50%, and V70 to 25-30%.

CARCINOMA OF THE NASOPHARYNX TREATED BY RADIOTHERAPY ALONE : DETERMINANTS OF DISTANT METASTASIS AND SURVIVAL

PURPOSE This retrospective study was conducted to identify the prognostic factors for distant metastasis and survival in a population of 378 patients with nasopharyngeal carcinomas treated by radiation therapy alone. MATERIALS AND METHODS All patients were treated at the University of Texas M.D. Anderson Cancer Center between 1954 and 1992, following a consistent dose and volume prescription policy. There were 286 males and 92 females. The median age was 52 years (range: 16-86 years). The majority of the patients were white Caucasians (282 patients,75%). Tumors were classified as squamous cell carcinomas (193; 51%), lymphoepitheliomas (154; 41%), or unclassified carcinomas (31, 8%). Three fourths of the patients presented with AJCC Stage IV disease (T4, N0-3, 118 patients; T1-3, N2-3 164 patients). The treatment techniques included opposed lateral fields with or without an anteroposterior or an anterior oblique pairs for dose supplementation to the primary site. Average total doses per T-stage ranged between 60.2 and 72.0 Gy. Median follow-up time was 10 years (range 0.3 to 28.6 years). RESULTS A total of 103 patients (27%) developed distant metastases at a median time of 8 months (range: 1-90 months). Actuarial rates for distant metastasis were 30%, 32%, 32% at 5, 10, and 20 years, respectively. Actuarial rates for disease specific survival at the same time points were 53%, 45%, and 39% with 184 patients (49%) dying of their nasopharyngeal cancer. Advanced T-stage, N-stage, and non-lymphoepithelioma histology were independent adverse prognostic factors for disease specific survival. Advanced N-stage and low neck disease were independent adverse prognostic factors for distant metastasis with a very high rate of distant metastases for those patients who presented with both adverse factors (relative risk 7.86). On average, patients with distant metastasis lived 5 months after they were diagnosed with metastatic disease (range: 0-172 months), although four patients (4%) survived more than 5 years after diagnosis. CONCLUSIONS This study demonstrates good long term survival rates after definitive radiotherapy for patients with nasopharyngeal carcinomas. Patients with advanced and lower neck disease have the highest risk of developing distant failures. Such patients can be considered the reference risk group to test the value of adjunctive chemotherapy.

Patient geometry-driven information retrieval for IMRT treatment plan quality control.

PURPOSE Intensity modulated radiation therapy (IMRT) treatment plan quality depends on the planners level of experience and the amount of time the planner invests in developing the plan. Planners often unwittingly accept plans when further sparing of the organs at risk (OARs) is possible. The authors propose a method of IMRT treatment plan quality control that helps planners to evaluate the doses of the OARs upon completion of a new plan. METHODS It is achieved by comparing the geometric configurations of the OARs and targets of a new patient with those of prior patients, whose plans are maintained in a database. They introduce the concept of a shape relationship descriptor and, specifically, the overlap volume histogram (OVH) to describe the spatial configuration of an OAR with respect to a target. The OVH provides a way to infer the likely DVHs of the OARs by comparing the relative spatial configurations between patients. A database of prior patients is built to serve as an external reference. At the conclusion of a new plan, planners search through the database and identify related patients by comparing the OAR-target geometric relationships of the new patient with those of prior patients. The treatment plans of these related patients are retrieved from the database and guide planners in determining whether lower doses delivered to the OARs in the new plan are feasible. RESULTS Preliminary evaluation is promising. In this evaluation, they applied the analysis to the parotid DVHs of 32 prior head-and-neck patients, whose plans are maintained in a database. Each parotid was queried against the other 63 parotids to determine whether a lower dose was possible. The 17 parotids that promised the greatest reduction in D50 (DVH dose at 50% volume) were flagged. These 17 parotids came from 13 patients. The method also indicated that the doses of the other nine parotids of the 13 patients could not be reduced, so they were included in the replanning process as controls. Replanning with an effort to reduce D50 was conducted on these 26 parotids. After replanning, the average reductions for D50 of the 17 flagged parotids and nine unflagged parotids were 6.6 and 1.9 Gy, respectively. These results demonstrate that the quality control method has accurately identified not only the parotids that require dose reductions but also those for which dose reductions are marginal. Originally, 11 of out the 17 flagged parotids did not meet the Radiation Therapy Oncology Group sparing goal of V(30 Gy) < 50%. Replanning reduced them to three. Additionally, PTV coverage and OAR sparing of the original plans were compared to those of the replans by using pairwise Wilcoxon p test. The statistical comparisons show that replanning compromised neither PTV coverage nor OAR sparing. CONCLUSIONS This method provides an effective quality control mechanism for evaluating the DVHs of the OARs. Adoption of such a method will advance the quality of current IMRT planning, providing better treatment plan consistency.

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.

Adjuvant androgen deprivation impacts late rectal toxicity after conformal radiotherapy of prostate carcinoma

To evaluate whether androgen deprivation impacts late rectal toxicity in patients with localised prostate carcinoma treated with three-dimensional conformal radiotherapy. One hundred and eighty-two consecutive patients treated with 3DCRT between 1995 and 1999 at our Institution and with at least 12 months follow-up were analysed. three-dimensional conformal radiotherapy consisted in 70–76 Gy delivered with a conformal 3-field arrangement to the prostate±seminal vesicles. As part of treatment, 117 patients (64%) received neo-adjuvant and concomitant androgen deprivation while 88 (48.4%) patients were continued on androgen deprivation at the end of three-dimensional conformal radiotherapy as well. Late rectal toxicity was graded according to the RTOG morbidity scoring scale. Median follow up is 25.8 (range: 12–70.2 months). The 2-year actuarial likelihood of grade 2–4 rectal toxicity was 21.8±3.2%. A multivariate analysis identified the use of adjuvant androgen deprivation (P=0.0196) along with the dose to the posterior wall of the rectum on the central axis (P=0.0055) and the grade of acute rectal toxicity (P=0.0172) as independent predictors of grade 2–4 late rectal toxicity. The 2-year estimates of grade 2–4 late rectal toxicity for patients receiving or not adjuvant hormonal treatment were 30.3±5.2% and 14.1±3.8%, respectively. Rectal tolerance is reduced in presence of adjuvant androgen deprivation.

Rectum contouring variability in patients treated for prostate cancer: impact on rectum dose–volume histograms and normal tissue complication probability

BACKGROUND Recent investigations showed some correlation between three-dimensional (3D) treatment planning dose-volume data (dose-volume histograms: DVH, dose statistics) and rectal toxicity for patients treated for prostate cancer. However, no data are available about the possible impact of inter-institute variability in contouring the rectum, so that the possibility of reliably using information from single-centre studies remains doubtful. PURPOSE Within a retrospective three-institutes study on correlation between dose-volume treatment planning data and rectum bleeding in patients treated for prostate cancer, an investigation about the impact of inter- and intra-observer variability in contouring the rectum was performed. MATERIALS AND METHODS Ten patients were considered for a dummy run exercise and three observers (one per Institute) contoured the rectum (including filling). An anatomically based definition of rectum extension was previously accepted by the three observers. Six of the ten patients were randomly chosen in the subgroup of patients (large spacing, LS) with a distance between computed tomography (CT) slices (outside the prostate region) equal to 10 mm; for the remaining four patients the distance between CT slices was 5 mm over the whole rectum volume (small spacing, SS). The original 3D treatment planning was recovered on the Cadplan treatment planning system for each patient and rectum dose statistics (mean, median and maximum rectum dose), volume, DVH and NTCP values were calculated for each observer. For DVH analysis, the values of V(50), V(55), V(60), V(65) and V(70) (defined as the % of rectum volume receiving at least 50, 55, 60, 65, 70 Gy) were considered. Normal tissue complication probabilities (NTCPs) were calculated for the original ICRU dose and for a 75.6 Gy ICRU dose (NTCP and NTCP(75.6), respectively). Intra-observer variability was investigated by asking the observers to redraw the same rectum contours 6 months later and comparing the two contouring sessions. RESULTS In general, a good agreement was found for most patients and, in particular, for all SS patients. The impact of inter-observer variability was quite significant on dose statistics and DVH in two of six LS patients. Looking at the patient population, some systematic deviations, even if quite small, were demonstrated between institute B and institute C (volume, P = 0.02) and between institute A and institute B (mean/median dose, V(50)-V(65), NTCP(75.6); P < 0.05). Four of six LS patients (0/4 in the SS group) presented a maximum difference among observers at the cranial and/or caudal limit of the rectum equal to 1 cm. For these patients, inter-observer variability was significantly higher than for the others (P < 0.03). When inter-observer variability was expressed in terms of standard deviations (SD), values around 2-3 Gy and 0.5 Gy for LS and SS patients, respectively, were found for mean/median dose; values around 3-4% and 0.5-2% for LS and SS patients, respectively, were found for V(50)-V(70). The average SD for NTCP and NTCP(75.6) were 0.4 and 0.6%, respectively (0.5 and 0.9% for LS patients; 0.2 and 0.3% for SS patients). Intra-observer variability was found to be lower than inter-observer variability even if the impact on dose statistics and DVH was visible. CONCLUSIONS Once a robust definition of rectum is assessed, inter- and intra-institute variability in contouring the rectum appear relatively modest. However, the results suggest that the number of LS patients in DVH correlation studies should be as low as possible; the low number of these patients in the multi-centric trial involving our institutions should not have significant impact on the results of the study.