Joseph R. Simpson

Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy: report by the radiation therapy oncology group

This report details the patterns of tumor recurrence in two prospective randomized studies involving 551 patients with histologically proven unresectable or medically inoperable non‐oat cell carcinoma of the lung treated with definitive radiotherapy. Patients were treated according to two protocols, depending on the stage of the tumor: (1) Patients with T1, 2, 3‐NO, 1, 2 tumors were randomized to four different regimens: 4000 cGy split course (2000 cGy in five fractions, per 1 week, 2 weeks rest and additional 2000 cGy in five fractions, per 1 week) or 4000, 5000, or 6000 cGy continuous courses, five fractions per week. (2) Patients with T4, any N or N3, any T stage tumors were randomized to be treated with 3000 cGy tumor dose (TD), ten fractions in 2 weeks, 4000 cGy split course (described above), or 4000 cGy continuous course. In the patients with less advanced tumors (Study 1) the intrathoracic failure rate within the irradiated volume was 48% with 4000 cGy continuous, 38% with 4000 cGy split course or 5000 cGy continuous, and 27% for patients receiving 6000 cGy continuous course. The failure rate in the nonirradiated lung ranged from 25% to 30% in the various groups. Patients with adenocarcinoma or large cell undifferentiated carcinoma had better intrathoracic tumor control (35%) than those with squamous cell carcinoma (20%). The incidence of distant metastases was 75% to 80% in all histologic groups. Distant metastases appeared sooner after therapy in the patients with adenocarcinoma or large cell undifferentiated carcinoma. The initial failure rate in the brain was 7% in patients with squamous cell carcinoma, 19% with adenocarcinoma, and 13% in patients with large cell carcinoma. The ultimate incidence of brain metastases was 16% in squamous cell carcinoma, and 30% for adenocarcinoma or large cell undifferentiated carcinoma. Higher doses of irradiation will be necessary in order to improve the intrathoracic tumor control. Clinical trials by the Radiation Therapy Oncology Group, some of them involving multiple daily fractionation, are in progress. Furthermore, because of the high incidence of distant metastases, effective systemic cytotoxic agents are critically needed to improve survival of lung cancer patients. The high frequency of brain metastases suggests that, as in small cell carcinoma of the lung, elective irradiation of the brain may be necessary, if not to improve survival to enhance the quality of life of patients with adenocarcinoma and large cell carcinoma.

Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: a comparison with conventional techniques

BACKGROUND AND PURPOSE Intensity-modulated radiation therapy (IMRT) offers superior dosimetric conformity for normal tissue sparing in patients with oropharyngeal cancer. In this study, acute and late toxicity, and tumor control were compared between conventional beam arrangement (CRT) and IMRT. MATERIALS AND METHODS Between January 1970 and December 1999, 430 patients with carcinoma of the oropharynx were treated at the Mallinckrodt Institute of Radiology. There were 260 patients with tonsil primary tumors and 170 patients with tumors arising from the base of the tongue. Twenty-four (6%) patients had stage I disease, 88 (20%) had stage II, 128 (30%) had stage III, and 190 (44%) had stage IV disease. Patients were divided into five treatment groups. Group I consisted of 109 patients who received preoperative CRT. Group II consisted of 142 patients who received postoperative CRT. Group III consisted of 153 patients who received definitive CRT. Inverse planning IMRT (Peacock, NOMOS) was used to treat 14 patients postoperatively (Group IV) and 12 patients definitively without surgery (Group V). Acute and late normal tissue side-effects were scored according to the Radiation Therapy Oncology Group radiation morbidity criteria. The median follow-up was 3.9 years. RESULTS The 2-year local-regional control values for the five studied groups were 78, 76, 68, 100 and 88%, respectively. The 2-year disease-free survival values for the five studied groups were 68, 74, 58, 92 and 80%, respectively. IMRT significantly reduced the incidence of late xerostomia. CONCLUSIONS When IMRT was compared with conventional techniques, the dosimetric advantage of IMRT did translate into a significant reduction of late salivary toxicity in patients with oropharyngeal carcinoma. No adverse impact on tumor control and disease-free survival was observed in patients treated with IMRT.

Delayed Regional Metastases, Distant Metastases, and Second Primary Malignancies in Squamous Cell Carcinomas of the Larynx and Hypopharynx†

Objective To determine the impact of delayed regional metastases, distant metastases, and second primary tumors on the therapeutic outcomes in squamous cell carcinomas of the larynx and hypopharynx.

Carcinoma of the nasopharynx: factors affecting prognosis

This is a retrospective analysis of 143 patients with histologically confirmed epidermoid carcinoma of the nasopharynx treated with definitive irradiation. Patients were treated with a combination of Cobalt-60, 4 to 6 MV X rays, and 18 to 25 MV X rays to the primary tumor and the upper necks, excluding the spinal cord at 4000 to 4500 cGy to total doses of 6000 to 7000 cGy. At 10 years the actuarial primary tumor failure rate was 15% in T1, 25% in T2, 33% in T3, and 60% in T4 lesions. The corresponding failure rate in the neck was 18% for N0, 14% for N1, and 33% for N2 and N3 lymphadenopathy. The incidence of distant metastasis was related to the stage of the cervical lymphadenopathy: 16% in patients with N0-N1 nodes compared with 40% in the N2-3 node group. The actuarial 10-year disease-free survival rate was 55% to 60% for T1-3N0-1 tumors, 45% for T1-3N2-3 tumors, 35% for T4N0-1, and 20% for T4N2-3 lesions. The overall 10-year survival rate was about 40% for patients with T1-2N0-1 tumors, 30% for those with T3 any N stage tumors, and only 10% for the patients with T4 lesions. Multivariate analysis showed that tumor stage and histological type, cranial nerve involvement, patient age, and doses of irradiation to the nasopharynx were significant prognostic factors for local/regional tumor control. Increasing doses of irradiation resulted in nasopharynx tumor control in 80% of the patients receiving 6600 to 7000 cGy and 100% of those receiving over 7000 cGy in the T1, T2, and T3 tumors. However, the tumor control rate did not rise above 55% even for doses over 7000 cGy in the T4 lesions. Local tumor control was higher in patients who had simulation (55/78 = 71%) compared with those on whom simulation was not performed (34/61 = 56%) (p = 0.10). Moreover, patients with more than 75% of the reviewed films judged as adequate had 69% primary tumor control (66/96) compared with 53% (23/43) for those with fewer than 75% adequate portal films (p = 0.07).

Regional nodal management and patterns of failure following conservative surgery and radiation therapy for stage I and II breast cancer.

PURPOSE To determine the incidence, pattern of regional nodal failure, and treatment sequelae as determined by the extent of lymphatic irradiation. METHODS AND MATERIALS The records of 511 patients with 519 Stage I and II breast cancers treated with breast conserving surgery with or without axillary dissection and irradiation were reviewed. The extent of nodal irradiation was at the discretion of the attending radiation oncologist and varied considerably over the years. Management of the axilla consisted of axillary dissection alone in 351, axillary dissection and supplemental irradiation in 74, irradiation alone in 75, and simply observation in 21 patients. RESULTS Overall, axillary recurrence was uncommon (1.2%), but was slightly more frequent after irradiation alone (2.7%) than after surgery alone (0.3%), p = 0.14. There was no benefit for supplemental axillary irradiation after an axillary dissection yielding negative or 1 to 3 positive nodes. In the 21 patients in whom the axilla was observed, axillary recurrence was not observed. Supraclavicular failures were rare in women with negative or 1 to 3 positive axillary lymph nodes (0.5%), and not significantly affected by elective irradiation. Internal mammary node recurrence was seen in only one patient, and was not significantly influenced by elective internal mammary irradiation. Both arm and breast edema were significantly more common in women having breast and nodal irradiation than after breast irradiation alone. These sequelae were not influenced significantly by the number of lymph nodes obtained in the axillary dissection specimen. Radiation pneumonitis was seen with increased frequency with more extensive nodal radiotherapy. Pneumonitis was not found to be affected by the administration or sequencing of chemotherapy. CONCLUSION There is little justification for axillary or supraclavicular irradiation following an axillary dissection which yields negative or minimally involved (1 to 3 positive) lymph nodes. There were too few patients with extensive axillary node metastases (> or = 4 positive) in our series to draw conclusions about the optimal extent of nodal irradiation in this subset. Elective internal mammary lymph node irradiation increases technical complexity, does not appear to be advantageous, and when combined with supraclavicular irradiation places the patient at highest risk for pneumonitis.

The Emotional Modulation of Cognitive Processing: An fMRI Study

The functional neuroanatomy of visual processing of surface features of emotionally valenced pictorial stimuli was examined in normal human subjects using functional magnetic resonance imaging (fMRI). Pictorial stimuli were of two types: emotionally negative and neutral pictures. Task performance was slower for the negatively valenced than for the neutral pictures. Significant blood oxygen level dependent (BOLD) increases occurred in the medial and dorsolateral prefrontal cortex, midbrain, substantia innominata, and/or amygdala, and in the posterior cortical visual areas for both stimulus types. Increases were greater for the negatively valenced stimuli. While there was a small but significant BOLD decrease in the subgenual prefrontal cortex, which was larger in response to the negatively valenced pictures, there was an almost complete absence of other decreases prominently seen during the performance of demanding cognitive tasks [Shulman, G. L., Fiez, J. A., Corbetta, M., Buckner, R. L., Miezin, F. M., Raichle, M. E., & Petersen, S. E. (1997). Common blood flow changes across visual tasks: II. Decreases in cerebral cortex. Journal of Cognitive Neuroscience, 9, 648-663]. These results provide evidence that the emotional valence and arousing nature of stimuli used during the performance of an attention-demanding cognitive task are reflected in discernable, quantitative changes in the functional anatomy associated with task performance.

Adenoid cystic salivary gland carcinoma: A histopathologic review of treatment failure patterns†

Seventy‐one cases of adenoid cystic salivary gland carcinoma were reviewed according to treatment modality and clinical course. Thirty‐six patients (51%) were treated by combined surgery and radiation therapy. The tumors were classified by their histotogic patterns into tubular, cribriform, and solid forms. Distant metastases, in 52%, were the most frequent and ominous sources of failure. In 35% of cases, distant metastases developed despite local control at the primary site. In this group, the disease had a more fulminant course with shorter survival. Histopathologically, the cribriform subtype was associated with multiple local recurrences, greater local aggressiveness, and a poorer salvage rate as compared with the tubular subtype. Late onset of local recurrences and distant metastases was especially assocated with the cribriform subtype. Overall prognosis in terms of distant metastases and survival was worst for the solid subtype. Control of local disease is best achieved with combined surgery and radiation therapy. The high incidence of distant metastases may not be affected by this regimen. The ultimate outcome of therapy is poorly predicted. Survival appears to be based on the pattern in which distant metastases develop. Overly aggressive and mutilating surgical approaches for these tumors are not recommended in many instances. The need for the development of new, more effective forms of therapy is emphasized.

Palliative radiotherapy for inoperable carcinoma of the lung: Final report of a rtog multi-institutional trial

Between June 1973 and February 1979, 409 patients with inoperable advanced non-oat cell carcinoma of the lung were randomized on RTOG protocol 73-02. Three treatment arms were evaluated: 40 Gy split course, 30 Gy continuous course, and 40 Gy continuous course. Patients were also randomized to receive cytoxan or no further therapy following irradiation. Three hundred sixteen patients were evaluable. Palliation of symptoms was achieved in 60% with 1/4 of the patients becoming symptom-free. Complete regression of local and regional tumor was produced in 15% and partial regression in 26%. There is no significant difference between the treatment arms in these objective response rates. Median survival times were approximately 6 months. No significant benefit was demonstrated by the adjuvant use of Cytoxan. Although the number of complete responses produced was relatively small, patients achieving a complete response had a significantly longer median survival than the remaining patients, i.e., 14.5 months versus 6 months. Significant toxicity occurred in fewer than 6% of patients. Radiation pneumonitis counted for the majority of these adverse reactions. Toxicity occurred somewhat more often in the group treated with 40 Gy split course therapy. Implications for further studies are discussed.

Role of irradiation in the management of superior vena cava syndrome

The records of 125 patients treated for superior vena cava syndrome secondary to malignant disease were reviewed retrospectively. The mean age of patients was 55 years. Bronchogenic carcinoma was the cause of the syndrome in 79% of cases, malignant lymphoma 18%, and other tumors 6%. Approximately 80% of the patients obtained good to excellent symptomatic relief. High initial dose radiation therapy (300-400 cGy daily for three fractions) yielded good symptomatic relief in less than 2 weeks in 70% of patients; conventional dose radiation therapy (200 cGy daily, five weekly fractions) yielded the same response in 56% of patients (p = 0.09). Lymphoma patients displayed a 1 year survival of 41%, small cell carcinoma 24%, and other types of bronchogenic carcinoma 17%. Combination of radiation and chemotherapy did not improve response rate, degree of symptomatic relief or long-term survival. Patients exhibiting symptomatic relief within 30 days had a significantly better survival rate than those who did not (p = 0.002). Thirteen percent of patients showed a recurrence of superior vena cava syndrome. There was no correlation between tumor regression and symptomatic relief. Side effects of therapy were minimal; dysphagia was the most common complaint (26% of patients).

Isolated local-regional recurrence of breast cancer following mastectomy: Radiotherapeutic management

Two hundred twenty-four patients with their first, isolated local-regional recurrence of breast cancer were irradiated with curative intent. Patients who had previous chest wall or regional lymphatic irradiation were not included in the study. With a median follow-up of 46 months (range 24 to 241 months), the 5- and 10-year survival for the entire group were 43% and 26%, respectively. Overall, 57% of the patients were projected to be loco-regionally controlled at 5 years. The 5-year local-regional tumor control was best for patients with isolated chest wall recurrences (63%), intermediate for nodal recurrences (45%), and poor for concomitant chest wall and nodal recurrences (27%). In patients with solitary chest wall recurrences, large field radiotherapy encompassing the entire chest wall resulted in a 5- and 10-year freedom from chest wall re-recurrence of 75% and 63% in contrast to 36% and 18% with small field irradiation (p = 0.0001). For the group with recurrences completely excised, tumor control was adequate at all doses ranging from 4500 to 7000 cGy. For the recurrences less than 3 cm, 100% were controlled at doses greater than or equal to 6000 cGy versus 76% at lower doses. No dose response could be demonstrated for the larger lesions. The supraclavicular failure rate was 16% without elective radiotherapy versus 6% with elective radiotherapy (p = 0.0489). Prophylactic irradiation of the uninvolved chest wall decreased the subsequent re-recurrence rate (17% versus 27%), but the difference is not statistically significant (p = .32). The incidence of chest wall re-recurrence was 12% with doses greater than or equal to 5000 cGy compared to 27% with no elective radiotherapy, but again was not statistically significant (p = .20). Axillary and internal mammary failures were infrequent, regardless of prophylactic treatment. Although the majority of patients with local and/or regional recurrence of breast cancer will eventually develop distant metastases and succumb to their disease, a significant percentage will live 5 years. Therefore, aggressive radiotherapy should be used to provide optimal local-regional control.(ABSTRACT TRUNCATED AT 400 WORDS)