George E. Laramore

Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on the RTOG experience.

The development of second malignant tumors (SMTs), in patients who have had their first tumor treated successfully, represents a serious limitation of current therapeutic strategies for head and neck cancers. To improve our understanding of the current magnitude of the problem and the various factors that might influence its importance, we reviewed the Radiation Therapy Oncology Groups (RTOG) prospectively collected registry of all head and neck patients seen in participating member institutions between February 1977 and April 1980. A total of 928 patients were identified who had squamous cell carcinomas of the head and neck region, no prior or coincident history of another malignant tumor, and whose planned treatment consisted of radiation therapy only. A total of 110 second, independent, malignant tumors occurred in these patients. Overall, the estimated risk of developing a second tumor within 3 years of radiotherapy was 10%, within 5 years 15%, and within 8 years 23%. Minor differences in frequency were observed for different primary sites. These SMTs unquestionably influenced subsequent survival adversely. Analysis of the database also revealed that the extent of the primary tumor influenced the risk of a second; most occurred in patients who presented with the smallest primary tumors because of their better survival. Our data indicate that preventive medicine should have its greatest impact in those patients who are treated for an early stage primary tumor.

Original contributionSecond malignancies in patients who have head and neck cancer: Incidence, effect on survival and implications based on the RTOG experience

The development of second malignant tumors (SMTs), in patients who have had their first tumor treated successfully, represents a serious limitation of current therapeutic strategies for head and neck cancers. To improve our understanding of the current magnitude of the problem and the various factors that might influence its importance, we reviewed the Radiation Therapy Oncology Groups (RTOG) prospectively collected registry of all head and neck patients seen in participating member institutions between February 1977 and April 1980. A total of 928 patients were identified who had squamous cell carcinomas of the head and neck region, no prior or coincident history of another malignant tumor, and whose planned treatment consisted of radiation therapy only. A total of 110 second, independent, malignant tumors occurred in these patients. Overall, the estimated risk of developing a second tumor within 3 years of radiotherapy was 10%, within 5 years 15%, and within 8 years 23%. Minor differences in frequency were observed for different primary sites. These SMTs unquestionably influenced subsequent survival adversely. Analysis of the database also revealed that the extent of the primary tumor influenced the risk of a second; most occurred in patients who presented with the smallest primary tumors because of their better survival. Our data indicate that preventive medicine should have its greatest impact in those patients who are treated for an early stage primary tumor.

Precisely defining high-risk operable head and neck tumors based on RTOG 85-03 and 88-24: Targets for postoperative radiochemotherapy?

Local‐regional recurrence of disease remains the major obstacle to cure of advanced head and neck cancers.

TREATMENT OF LOCALLY ADVANCED ADENOID CYSTIC CARCINOMA OF THE HEAD AND NECK WITH NEUTRON RADIOTHERAPY

PURPOSE To examine the efficacy of fast neutron radiotherapy for the treatment of locally advanced and/or recurrent adenoid cystic carcinoma of the head and neck and to identify prognostic variables associated with local-regional control and survival. METHODS AND MATERIALS One hundred fifty-nine patients with nonmetastatic, previously unirradiated, locally advanced, and/or recurrent adenoid cystic carcinoma (ACC) of the head and neck region were treated with fast neutron radiotherapy during the years 1985-1997. One hundred fifty-one patients had either unresectable disease, or gross residual disease (GRD) after an attempted surgical extirpation. Eight patients had microscopic residual disease and were analyzed separately. Sixty-two percent of patients had tumors arising in minor salivary glands, 29% in major salivary glands, and 9% in other sites such as the lacrimal glands, tracheal-bronchial tree, etc. Fifty-five percent of patients were treated for postsurgical recurrent disease and 13% of patients had lymph node involvement at the time of treatment. The median duration of follow-up was 32 months (range 3-142 months). Actuarial curves for survival, cause-specific survival, local-regional control, and the development of distant metastases are presented for times out to 11 years. RESULTS The 5-year actuarial local-regional tumor control rate for the 151 patients with GRD was 57%; the 5-year actuarial overall survival rate was 72%; and the 5-year actuarial cause-specific survival rate was 77%. Variables associated with decreased local-regional control in the patients with GRD as determined by multivariate analysis included base of skull involvement (p < 0.01) and biopsy only versus an attempted surgical resection prior to treatment (p = 0.03). Patients without these negative factors had an actuarial local-regional control rate of 80% at 5 years. Patients with microscopic residual disease (n = 8) had a 5-year actuarial local-regional control rate of 100%. Base of skull involvement (p < 0.001), lymph node metastases at the time of treatment (p < 0.01), biopsy only prior to neutron radiotherapy (p = 0.03), and recurrent tumors (p = 0.04) were found to be associated with a diminished cause-specific survival as ascertained by multivariate analysis. Patients with base of skull involvement and positive lymph nodes at presentation had an increased rate of the development of distant metastases at 5 years, (p < 0.01 and p < 0.001, respectively). No statistical difference in outcome was observed between major and minor salivary gland sites. CONCLUSIONS Fast neutron radiotherapy is an effective treatment for locally advanced ACC of the head and neck region with acceptable toxicity. Further improvements in local-regional control are not likely to impact survival until more effective systemic agents are developed to prevent and/or treat distant metastatic disease.

FDG-PET/CT–guided intensity modulated head and neck radiotherapy: A pilot investigation†‡

2‐deoxy‐2[18F]fluoro‐d‐glucose–positron emission tomography (FDG‐PET) imaging can be registered with CT images and can potentially improve neck staging sensitivity and specificity in patients with head and neck squamous cell cancer. The intent of this study was to examine the use of registered FDG‐PET/CT imaging to guide head and neck intensity modulated radiotherapy (IMRT) planning.

Neutron vs photon irradiation of inoperable salivary gland tumors: results of an RTOG-MRC Cooperative Randomized Study.

A total of 32 patients with inoperable, recurrent or unresectable malignant salivary gland tumors were entered on a randomized RTOG/MRC study comparing fast neutron radiotherapy with conventional photon radiotherapy. Twenty-five patients were entered from the United States and 7 patients were entered from Scotland. Seventeen patients were randomized to receive neutrons and 15 patients were randomized to receive photons. Sixty-one percent of the neutron-treated patients and 75% of the photon-treated patients presented with inoperable or unresectable tumors, while 39% of the neutron-treated and 25% of the photon-treated patients had recurrent disease. Twenty-five patients were study-eligible and analyzable. The minimum follow-up time is 2 years. The complete tumor clearance rates at the primary site were 85% (11/13) for neutrons and 33% (4/12) for photons following protocol treatment (p = 0.01). The complete tumor clearance rates in the cervical lymph nodes were 86% (6/7) for neutrons and 25% (1/4) for photons. The overall loco/regional complete tumor response rates were 85% and 33% for neutrons and photons respectively. The loco/regional control rates at 2 years for the 2 groups are 67% for neutrons and 17% for photons (p less than 0.005). The 2-year survival rates are 62% and 25% for neutrons and photons respectively (p = 0.10). These findings are consistent with previously published uncontrolled series.

Fast Neutron Radiotherapy for Locally Advanced Prostate Cancer: Final Report of a Radiation Therapy Oncology Group Randomized Clinical Trial

Between June 1977 and April 1983 the Radiation Therapy Oncology Group (RTOG) sponsored a Phase III randomized trial investigating the use of fast neutron radiotherapy for patients with locally advanced (Stages C and D1) adenocarcinoma of the prostate gland. Patients were randomized to receive either conventional photon radiation or fast neutron radiation used in a mixed-beam (neutron/photon) treatment schedule. A total of 91 analyzable patients were entered into the study, and the two patient groups were balanced with respect to the major prognostic variables. Actuarial curves are presented for local/regional control and “overall” survival. Ten-year results for clinically assessed local control are 70% for the mixed-beam group versus 58% for the photon group (p = 0.03) and for survival are 46% for the mixed-beam group versus 29% for the photon group (p = 0.04). This study suggests that a regional method of treatment can influence both local tumor control and survival in patients with locally advanced adenocarcinoma of the prostate gland.

Tissue micro-array: A cost and time-effective method for correlative studies by regional and national cancer study groups

Tissue micro-arrays have been used for molecular and immunohistochemical studies. We sought to evaluate whether such arrays could substitute for whole sections in correlative studies performed by the Radiation Therapy Oncology Group. Four multitumor 150-sample arrays were built using formalin-fixed, paraffin-embedded, archival prostate, brain, and head/neck tumor blocks from RTOG tissue bank. p53 immunostaining of arrays and whole sections was done. Blind evaluation of each slide was made, and agreement rates between the two techniques were determined in various scenarios. Cost was also evaluated. Results demonstrate excellent agreement for p53 between slides and arrays. Agreement improved when three or four replicate arrays were used. Findings based on one to four arrays agree well with those obtained from analysis of the whole tissue samples. Minimal tissue damage, improved tissue salvage, cost reduction, ease of interpretation, and significant time savings were realized by using the arrays. Tissue micro array technique is a valuable tool for evaluation of patient materials associated with clinical trials.

Implications of positive surgical margins

The recently concluded Head and Neck Intergroup trial tested the addition of three courses of cis‐platinum containing chemotherapy to standard treatment of surgery and postoperative radiotherapy for patients with advanced operable squamous cell carcinoma of the head and neck. Only patients with negative surgical margins were eligible for the trial. One hundred twelve patients with positive surgical margins were dropped from the trial but continued to be followed. These patients received a variety of treatments. Positive surgical margins were most often seen in nonglottic primaries and with increasing frequency as the N stage increased. Patients with positive margins who achieved a complete clinical response to subsequent treatment had a median survival of 33.8 months vs. 9.1 months for those with less than a complete clinical response. The addition of chemotherapy did not significantly alter the median survival of the positive margin patients.

Original contributionNeutron vs photon irradiation of inoperable salivary gland tumors: Results of an RTOG-MRC cooperative randomized study☆

A total of 32 patients with inoperable, recurrent or unresectable malignant salivary gland tumors were entered on a randomized RTOG/MRC study comparing fast neutron radiotherapy with conventional photon radiotherapy. Twenty-five patients were entered from the United States and 7 patients were entered from Scotland. Seventeen patients were randomized to receive neutrons and 15 patients were randomized to receive photons. Sixty-one percent of the neutron-treated patients and 75% of the photon-treated patients presented with inoperable or unresectable tumors, while 39% of the neutron-treated and 25% of the photon-treated patients had recurrent disease. Twenty-five patients were study-eligible and analyzable. The minimum follow-up time is 2 years. The complete tumor clearance rates at the primary site were 85% (11/13) for neutrons and 33% (4/12) for photons following protocol treatment (p = 0.01). The complete tumor clearance rates in the cervical lymph nodes were 86% (6/7) for neutrons and 25% (1/4) for photons. The overall loco/regional complete tumor response rates were 85% and 33% for neutrons and photons respectively. The loco/regional control rates at 2 years for the 2 groups are 67% for neutrons and 17% for photons (p less than 0.005). The 2-year survival rates are 62% and 25% for neutrons and photons respectively (p = 0.10). These findings are consistent with previously published uncontrolled series.