Strategy for dose escalation using 3-dimensional conformal radiation therapy for lung cancer.

PURPOSE: Local failure is a major obstacle to the cure of locally advanced non-small-cell lung cancer. 3-Dimensional conformal radiation therapy (3-DCRT) selects optimal treatment parameters to increase dose to tumor and reduce normal tissue dose, potentially permitting dose escalation. There are several ongoing trials of dose escalation using 3-Dimensional conformal radiation therapy for non-small-cell lung cancer. We performed this analysis to determine if data derived from dose volume histograms could be used as the basis for designing the method of dose escalation in these trials. METHODS AND MATERIALS: Between 1990 and 1993, 31 patients were treated with 3-DCRT and had complete normal tissue dose volume histograms created as part of the planning process. The stage distribution was stage I/II 13%, stage IIIa in 45%, and stage IIIb in 42%. The median radiation dose to gross disease was 70.2 Gy (52.2-72 Gy). Elective mediastinal irradiation (50.4 Gy) was administered to 52% (16/31) of patients. RESULTS: The major toxicity encountered in this experience was pulmonary. Dose-volume-histogram data were used to analyze the predictors of toxicity and showed a correlation between risk of pulmonary toxicity and indices of dose to lung parenchyma. Grade 3 or higher pulmonary toxicity occurred in 38% (3/8) of pts with >30%of lung volume receiving > or =25 Gy, versus 4% (1/23) of pts. with < or = 30% lung receiving > or = 25 Gy (p=0.04). Grade 3 or higher pulmonary toxicity occurred in 29% (4/14) of patients with a predicted pulmonary normal tissue complication probability of 12% or higher versus 0% (0/17) in patients with a predicted probability of less than 12% (p=0.03). The single fatality occurred in a patient with a calculated pneumonitis probability of 85% and a high percent (49%) lung volume receiving >= 25 GY. CONCLUSION: This preliminary experience demonstrates a correlation between lung dose-volume-histogram data and the risk of severe pulmonary toxicity. This provides an opportunity to modify the method of radiation dose escalation. Dose-volume-histogram data can allow escalation according to the risk to the lung parenchyma (which is the major organ of concern) rather than escalation according to tumor dose levels. Because of teh major inter-patient variability of intrathoracic tumor bulk and anatomic distribution, this strategy is intuitively appropriate. This approach may facilitate completion of dose escalation studies and identification of maximum tolerable pulmonary dose levels.

Spinal epidural tumor in patients with prostate cancer. Clinical and radiographic predictors of response to radiation therapy.

The authors retrospectively reviewed 50 episodes of spinal epidural tumor that occurred in 42 patients with metastatic prostate cancer and were treated with external-beam radiation. Treatment response was evaluated in terms of symptoms, neurologic status, and, in most cases, reduction of tumor on repeat myelography. At the completion of therapy, 92% of treated patients experienced pain relief and 67% had significant to complete improvement on neurologic examination. Thirty days after treatment, repeat myelography was performed in 40 of the 50 cases; compared with the initial findings immediately preceding radiation therapy (RT), the results of 58% of these studies had normalized completely, results were improved in 25%, and the results had not changed in 18%. The presence of a high-grade compression fracture of the vertebral body was an indicator of poor prognosis for tumor response on repeat myelography. The ability of a patient to walk before treatment and tumor response on repeat myelography were associated significantly with improved outcome of RT and with survival. The authors conclude that RT can effectively palliate epidural lesions from metastatic prostate cancer. The prognosis for the long-term response to therapy may be indicated by pretreatment ambulatory status and posttreatment imaging of the epidural space.

Twice daily thoracic irradiation for limited small cell lung cancer.

Thoracic failure is a significant obstacle to the cure of limited stage small-cell lung cancer (LSCLC) patients treated with combined modality therapy. In 1985 we initiated a prospective trial to evaluate the impact of twice daily thoracic irradiation without concomitant chemotherapy on control of intrathoracic tumor in LSCLC. Twenty-nine patients treated in this fashion were compared with 36 patients treated from 1979-1982 with once daily thoracic irradiation and concomitant chemotherapy. Both groups received the same induction chemotherapy; cyclophosphamide, Adriamycin, and vincristine (CAV) alternating with cisplatin and etoposide. For consolidation, the twice daily patients received thoracic irradiation, 45 Gy in 1.5 Gy fractions given twice daily, and the once daily patients received thoracic irradiation, 45 Gy in 2.5 Gy fractions given once daily with concomitant cyclophosphamide and vincristine. After completion of radiotherapy both groups received maintenance chemotherapy. The complete response (CR) rate after thoracic irradiation was higher for twice daily patients (86% (25/29) compared to the once daily patients [61% (22/36), p = 0.02]. However, this advantage was offset by the shorter duration of thoracic control among CR patients treated with twice daily thoracic irradiation compared to once daily thoracic irradiation (32% vs 67% at 2 years, p less than 0.05). In view of the enhanced initial response of LSCLC to twice daily thoracic irradiation, this basic radiotherapeutic approach seems appropriate, but new strategies using higher doses of twice daily thoracic irradiation or concomitant chemotherapy appear to be necessary to enhance long-term thoracic control.

Improved dose distributions for 3D conformal boost treatments in carcinoma of the nasopharynx.

This study was designed to demonstrate the feasibility of 3-dimensional (3D) treatment planning in patients with carcinoma of the nasopharynx, and to explore its potential therapeutic advantage over the traditional 2-dimensional (2D) approach in this disease. Qualitative and quantitative comparisons between the two techniques were made for the boost portion of the treatment (19.8 Gy of a total 70.2 Gy treatment schedule) in 10 previously untreated patients and for the entire treatment in 5 patients with locally recurrent disease. The 2D and 3D plans were compared in each patient using dose-volume histograms (DVH's), tumor control probabilities (TCP's), normal tissue complication probabilities (NTCP's), and a new biologic figure of merit that describes the probability of uncomplicated control. Although there was no attempt to optimize the 3D treatment approach by using this method throughout the total treatment course (rather than for the boost only), it was still found that for each of the endpoints examined the 3D approach resulted in improved plans. An average of 22% of the target volume was underdosed at the 95% isodose level with the 2D plans compared to 7% with the 3D plans. The improved treatment planning by 3D increased the mean dose to the tumor volume by an average of 13% over 2D planning. The dose to normal structures such as the mandible and parotid glands was reduced with the 3D plans while the brain stem and spinal cord remained within tolerance limits. The probability of uncomplicated tumor control was increased by an average of 15% with 3D treatment planning compared to the 2D approach. Our findings demonstrate the potential of 3D planning for improving the treatment of carcinoma of the nasopharynx, but prospective studies are required to define the true clinical advantages of this methodology.

Observations on the natural history and treatment of recurrent major salivary gland cancer.

In an attempt to define the natural history and the indications for postoperative radiotherapy (RT) in locally recurrent major salivary gland cancers, we reviewed 78 patients treated between 1965 and 1982. All patients underwent resection of the tumor. Group 1 (N = 38) had complete resection of tumors, with low or intermediate grade histology and without lymph node spread. Group 2 consisted of the remaining 40 patients who had high-risk features (HR) (high grade histology, lymph node metastases, and close or positive margins of resection). Half of the Group 2 patients received radiation therapy. Overall survival was 63% at 5 years, and 35% at 15 years. Survival of Group 1 was 83% at 5 years and 58% at 15 years. Local control for Group 1 was 69% at 5 years, 54% at 15 years, and was size-dependent. Group 2 survival was 40% at 5 years and 29% at 10 years. Local control at 5 and 10 years was 49% and 35%. Our data indicate that surgery alone yielded good local control in patients with small tumors (less than or equal to 3 cm) and no HR features, suggesting that postoperative RT may be unnecessary for these patients. Other patients have suboptimal local control, and although there is a rationale for the use of postoperative radiotherapy, we cannot assess its impact in this retrospective study.

Impact of the time interval between surgery and postoperative radiation therapy on locoregional control in advanced head and neck cancer.

Between January 1975 and December 1980, 111 patients with AJCC stages III and IV squamous cell carcinoma of the head and neck were treated with surgery followed by planned postoperative radiation therapy. A previous analysis of a subgroup of these patients showed that, when radiation was delayed more than 6 weeks from surgery, a higher incidence of regional failure occurred compared with the incidence observed when therapy began within a 6 week period. We have looked back at this group of patients plus others in an attempt to determine whether other factors played a role in the results obtained. In the current study, 50 patients had a delay of 6 weeks or more and, of these, 11 (22%) suffered a locoregional recurrence. However, 8 of these 11 patients received suboptimal radiation doses (less than 56 Gy) for permanent control of the disease. In fact, of 17 patients who received at least 60 Gy and had more than a 6 week delay, only 2 (12%) had locoregional failure. This was similar to the incidence of failure in the patients who received at least 60 Gy and who started radiation within the first 6 weeks from surgery (3/20 [15%]). The effect of delay was apparent only in those who received less than 60 Gy (27% vs. 7%, P less than 0.05). Therefore, we cannot validate the previous conclusion that a greater than 6 week delay in the delivery of postoperative radiation therapy in advanced head and neck cancers produces poorer results. The current analysis suggests that a prolonged delay in postoperative radiation therapy in itself does not have a negative impact on locoregional control as long as appropriate tumorcidal doses of more than 60 Gy are employed.

Malignant tumors of major salivary gland origin. A matched-pair analysis of the role of combined surgery and postoperative radiotherapy.

Between 1966 and 1982, 46 patients with previously untreated malignant tumors of major salivary gland origin received combined surgery and postoperative radiotherapy. They were compared with 46 patients treated with surgery only between 1939 and 1965, who were matched according to prognostic criteria. Radiation doses ranged from 4000 to 7740 cGy (median, 5664 cGy). The 5-year determinate survival rates for patients given combined therapy with stage I and II disease vs patients given surgery only was 81.9% vs 95.8%, while for stages III and IV it was 51.2% vs 9.5%, respectively. Local control for stage III and IV disease in patients given combined therapy vs patients given surgery only at 5 years was 51.3% vs 16.8%. For patients with nodal metastases, 5-year determinate survival for the combined-therapy group vs the surgery-only group was 48.9% vs 18.7%, and the corresponding local-regional control was 69.1% vs 40.2%. The results of this analysis suggest that postoperative radiotherapy significantly improves outcome for patients with stage III and IV disease and for patients with lymph node metastases.

Clinical staging for cutaneous T-cell lymphoma.

The Mycosis Fungoides Cooperative Group has been following patients with cutaneous T-cell lymphoma, including mycosis fungoides and the Sézary syndrome variant. Previous analyses identified the extent of skin involvement and the number of sites of clinically enlarged lymph nodes as important prognostic variables. These two variables were used to classify 340 patients into four clinical stages. Repeat analysis based on additional followup data shows the usefulness of this clinical staging system for identifying patients with differing survival experience. An alternative grouping suggested by fitting a survival model to the data also has been studied. Staging systems based only on skin involvement and lymph nodes are recommended for general use because the information needed is readily available, requiring only physical examination.

Status report of 376 mycosis fungoides patients at 4 years: Mycosis Fungoides Cooperative Group.

The frequency and prognostic importance of various characteristics of patients registered by the Mycosis Fungoides Cooperative Group between November 1974 and December 1977 are reported. Variables which were considered include demographic and historical factors, symptoms, extent of disease, and other physical findings. A staging system which is based on the extent of skin involvement and the number of nodal sites clinically involved is described. Finally, a description of therapeutic results to date for patients randomized into Mycosis Fungoides Cooperative Group protocols is presented.

The treatment of mycosis fungoides: adjuvant topical mechlorethamine after electron beam therapy.

The feasibility of employing adjuvant topical mechlorethamine after electron beam therapy in the treatment of patients with mycosis fungoides is demonstrated. Patients treated with a planned adjuvant topical mechlorethamine schedule had a median disease-free interval of 25 months compared to 17 months for the group treated with electron beam therapy alone. Projected relapse-free survivals are slightly better in the adjuvant group--37% versus 29%. Patients receiving adjuvant topical mechlorethamine after the electron beam were observed to have a low incidence of contact allergy to the medication. The topical medication can be continued if a contact allergy develops by using a planned desensitization program. We currently treat all mycosis fungoides patients with electron beam therapy, randomizing half to receive adjuvant topical mechlorethamine.

Topical mechlorethamine therapy for mycosis fungoides.

Patients with limited skin involvement by mycosis fungoides were treated with daily topical mechlorethamine. Seven of thirteen patients had a complete remission of diseases. Six of these seven experienced a contact dermatitis and four underwent a successful topical desensitization programme. The possible beneficial therapeutic effects of developing a contact allergy are discussed.

The long term effects of radiation of T and B lymphocytes in the peripheral blood after regional irradiation.

The long term alterations of T and B lymphocytes in the peripheral blood of patients treated with regional irradiation for various malignancies were examined. Eighty patients were tested at various intervals after the completion of irradiation. Absolute lymphocyte counts, the percentages of T cells and B cells, and the blastogenic response to phocyte reaction (MLR) were determined. Nearly all patients initially had absolute lymphocytopenia and one-third of the patients tested 3 years after completion of irradiation had lymphocyte counts which were more than two standard deviations below the normal range. The depression was not specific for either the T-or B-lymphocyte subpopulations. The PHA response was impaired for extended periods of time after the completion or irradiation. Differences in the mean response of lymphocytes to PHA were noted for all concentrations of the mitogen, but were most marked with suboptimal concentrations of PHA. The MLR was below the lower limits of normal in 70% of the recently irradiated patients. There was a gradual recovery of the ability to respond in the MLR, and all patients tested more than 4.5 years after the completion of therapy had a normal response. These results were compared with those obtained in patients treated with total lymphoid irradiation for Hodgkin's disease. Although three appeared to be a difference in the effect of radiation on lymphocyte subpopulations in the two groups, the effects on lymphocyte function were similar.

Hyperkeratotic and verrucous features of mycosis fungoides.

A patient had unusual verrucous and hyperkeratotic plaques and tumors confined to the right leg for 24 years. The histopathologic examination was diagnostic of the infiltrative or plaque stage of mycosis fungoides. The patient was treated with a megavoltage radiation technique that was specially adapted to ensure a homogeneous dose distribution to all the lesions. This treatment may be applicable in other deeply infiltrative cutaneous lesions.

Mechlorethamine desensitization in therapy for mycosis fungoides. Topical desensitization to mechlorethamine (nitrogen mustard) contact hypersensitivity.

Five patients with mycosis fungoides who had developed contact dermatitis to a nitrogen mustard, mechlorethamine hydrochloride, even in low concentrations (1 to 5 mg/100 ml), received daily total-body applications of extremely dilute solutions (0.01 to 0.1 mg/100 ml) of mechlorethamine. The concentrations of the drug were approximately doubled weekly if the patient could tolerate it, or they were raised more slowly if the patient could not. Attempts to desensitize one patient were discontinued since he was unable to tolerate a greater concentration than 1.0 mg/100 ml after trying for one year. Another patient was able to tolerate a concentration of 3 mg/100 ml after three months, at which time his skin had completely cleared and treatment was stopped. Three other patients were desensitized during a period of 8 to 13 months to the point of tolerating the full therapeutic concentration used in our clinic (20 mg/100 ml) without experiencing dermatitis or pruritus.