Use of PET/CT for staging and radiation therapy planning in patients with non-small cell lung cancer.

Positron emission tomography (PET) and more recently PET/computed tomography (CT) scanning represent major advances in the imaging of lung cancer and have an especially high impact on the management of patients who are candidates for potentially curative or "radical" radiotherapy (RT). This article reviews the current status of PET and PET/CT for staging patients before RT and considers the use of PET and PET/CT images for target volume definition. The relevant literature on the use of PET for staging lung cancer is reviewed and placed in the context of patients who are candidates for RT. Research that specifically considers the use of PET for RT planning is considered critically and some promising areas for future research are discussed. The available literature is almost exclusively devoted to non small cell lung cancer (NSCLC) with few relevant studies of small cell lung cancer (SCLC). The primary PET radiopharmaceutical shown to have value for staging and RT planning is 18F-fluorodeoxyglucose (FDG). In prospective studies where PET imaging was used to stage radical RT candidates, 25-30% of patients were excluded from radical therapy because of PET detected advanced disease. In all studies where "PET-assisted" and conventional target or treatment volumes were compared, there were major differences between PET and conventional volumes. Because PET-assisted staging is proven to be significantly more accurate than conventional staging and because all studies show major differences between PET-assisted and conventional treatment volumes in NSCLC, routine use of PET/CT for RT planning is recommended.

Positron emission tomography of stage IV mucosa-associated lymphoid tissue lymphoma confined to the four major salivary glands.

In a patient with stage IVA marginal zone lymphoma, (18)F-fluorodeoxyglucose-positron emission tomography indicated that the disease was confined to the four major salivary glands. The positron emission tomography findings encouraged the use of radiotherapy with curative intent in this case. After 30 Gy of external beam radiotherapy to the parotid and submandibular glands, the patient entered a complete remission and remains free from progression more than 4 years later.

Exacerbation, then clearance, of mutation-proven Darier's disease of the skin after radiotherapy for bronchial carcinoma: a case of radiation-induced epidermal differentiation?

We investigated a radiotherapy-induced flare and subsequent clearance of skin lesions of a patient with the rare, dominantly inherited genodermatosis, Darier's disease (DD). The DD gene, ATP2A2, was recently isolated and shown to be a cation pump responsible for regulating intracellular calcium homeostasis. A severe exacerbation of Darier's skin lesions developed within the radiation field when 40 Gy of palliative thoracic external-beam radiation therapy and concurrent chemotherapy (cisplatin and hydroxyurea) were delivered for non-small cell lung cancer. The DD lesions subsequently completely cleared from irradiated skin, as they did when a subsequent course of radiation alone was given for a loco-regional tumor recurrence. The two radiation therapy-treated areas of skin remained free from lesions of the skin disorder until the patient's death from progressive lung cancer 9 months later. The nucleotide sequence of the patient's ATP2A2 gene was determined by PCR-based cycle sequencing. We identified four nucleotide sequence variants in the ATP2A2 gene in this patient. Three were probable polymorphisms and the other appeared to be a novel disease-causing mutation (R751Q), situated in the transmembrane portion of the ATP2A2 protein. This finding confirmed the clinical diagnosis. Since epidermis turns over every 3-4 weeks, total and persistent clearance of the DD lesions by chemoradiotherapy suggests that this treatment induced sustained differentiation of the DD-affected skin by an unknown mechanism. Oncologists treating malignant disease in patients with DD should anticipate temporary deterioration in DD-involved irradiated skin. Radiation therapy has therapeutic potential in severe DD.

F-18 fluorodeoxyglucose positron emission tomography staging in radical radiotherapy candidates with nonsmall cell lung carcinoma: powerful correlation with survival and high impact on treatment.

BACKGROUND: Successful treatment of nonsmall cell lung carcinoma (NSCLC) with radical radiotherapy (RT) requires accurate delineation of tumor extent. Conventional computed tomography-based noninvasive staging often estimates intrathoracic thoracic tumor extent incorrectly and fails to detect distant metastasis. High sensitivity and specificity are reported for F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) staging in potentially resectable NSCLC. The authors investigated FDG-PET staging in radical RT candidates with unresectable NSCLC. METHODS: The authors prospectively studied 153 consecutive patients with unresectable NSCLC who were candidates for radical RT after conventional staging and had PET scans. Patients were allocated both "before PET" and "after PET" stages. Subsequent management was recorded. Survival analysis was used to compare validity of pre-PET and post-PET staging. RESULTS: After PET, 107 patients (70%) actually received radical therapies (radical RT with or without concurrent chemotherapy, n = 102; radical surgery, n = 5); 46 patients (30%) received palliative treatment because of PET-detected distant metastasis (n = 28; 18%) or extensive locoregional disease (n = 18; 12%). Palliative therapies were RT (n = 33), chemotherapy (n = 12), or supportive care (n = 1). All five surgically treated patients underwent potentially curative resections after downstaging by PET. For radically treated patients, post-PET stage (P = 0.0041) but not pre-PET stage (P = 0.19) was strongly associated with survival. Radically treated patients survived longer than those treated palliatively (P = 0.02; 1-year survival, 69% and 44%, respectively; 2-year survival, 44% radical; no palliative patients had 2-yr follow-up). CONCLUSIONS: Positron emission tomography-assisted staging detected unsuspected metastasis in 20%, strongly influenced choice of treatment strategy, frequently impacted RT planning, and was a powerful predictor of survival. Potential impact of FDG-PET is even greater in radical RT candidates with NSCLC than in surgical candidates.

Characteristics of 49 patients who survived for 5 years following radical radiation therapy for non-small cell lung cancer: the potential for cure.

PURPOSE: To investigate the long-term curative potential of radical radiation therapy (RT) for non-small cell lung cancer (NSCLC) by studying characteristics of patients from a large prospective database who survived >5 years after RT, and by analyzing survival beyond 5 years. METHODS AND MATERIALS: Five-year survivors were identified from a database containing information on 488 patients given radical RT following presentation to the Peter MacCallum Cancer Institute with NSCLC between 1984 and 1990. Additional data were obtained from case notes of survivors. RT was computed tomography (CT)-planned, conventionally-fractionated, and given without chemotherapy. RESULTS: Actuarial survival for 49 5-year survivors was 65% at 10 years. Five 5-year survivors had documented disease progression within the first 5 years and subsequently died. Of 44 patients free-from-progression (FFP) at 5 years, an estimated 81% remained FFP in the second 5 years. Age and histology were not significant prognostic factors, and only 22 patients (4.5%) had weight loss >10%. For 277 patients who had not undergone thoracotomy, median RT dose was 60 Gy and survival at 5 and 10 years was 7% and 3%, respectively. For 207 patients who received radical RT post-thoracotomy, median dose was 60 Gy and survival at 5 and 10 years was 24% and 18%, respectively. Five-year survivors of post-thoracotomy RT had been treated for gross residual disease (n = 10), positive-margin (n = 6), or probable microscopic residual disease (n = 17). Failure to regain ECOG performance status = 0 post-thoracotomy was associated with reduced survival (p<0.0012). FFP in the second 5 years was superior for patients who had postoperative radiotherapy (90%) compared to patients without thoracotomy (62%, p = 0.008). CONCLUSION: Most patients FFP >5 years after radical RT for NSCLC remained FFP in the following 5 years and were apparently cured. RT alone can cure small but significant numbers of patients. Long-term results of combined chemotherapy/RT protocols, which are associated with increased median survival, are awaited for comparison.

What is the prognosis for patients who relapse after primary radiation therapy for early-stage low-grade follicular lymphoma?

PURPOSE: To investigate the potential for long-term survival for patients who relapsed after primary radiation therapy (RT) for early-stage low-grade follicular lymphoma and to assess the relative importance of prognostic factors. METHODS AND MATERIALS: Records were reviewed for 79 patients with stage I (n = 32) and II (n = 47) follicular small cleaved cell (fsc, n = 48) and follicular mixed small cleaved cell and large-cell (fmx, n = 31) lymphoma who relapsed after radical RT at Stanford University. Most patients had received doses of 35 to 45 Gy to involved (n = 30) or extended fields (n = 39) or total/subtotal lymphoid irradiation (n = 9). RESULTS: Median time to relapse was 2 years. Most relapses were detected on history (30%) or physical examination (66%). Positive relapse investigations included lymphangiogram (n = 19), chest radiograph (n = 5), and bone marrow biopsy (n = 6). Known extent of relapsed disease was: stage I, n = 30; stage II, n = 26; stage III, n = 10; and stage IV, n = 8. Patients were managed with "watchful waiting" (37%), further RT (39%), chemotherapy [CT, (17%)], or RT + CT (5%). Actuarial survival rates after relapse at 5, 10, 15, and 20 years were 56%, 35%, 17%, and 17% respectively. Median survival was 5.3 years after relapse. Median survival for relapse stage I, II, III, and IV was 10.2, 5.5, 3.0, and 1.1 years respectively. Progression-free survival rates at 5, 10, 15, and 20 years after relapse were 44%, 22%, 22%, and 22% respectively. Factors associated with reduced survival were increasing age, increasing relapse stage, symptoms, histologic transformation and > or = 3 relapse sites. Survival was the same for initial management with "watchful waiting" or RT. CONCLUSION: Approximately 20% of patients experienced prolonged survival after relapse. Younger, asymptomatic patients with stage I-II relapsed disease had the best outcome but results were inferior to those for newly diagnosed stage I-II disease.

Overview of treatment of localized low-grade lymphomas.

The results of treatment of localized low-grade lymphoma have been reviewed with particular emphasis on the results of long-term follow-up of patients treated with radiation therapy at Stanford University. These data and results from numerous other centers suggest that 40% to 50% of patients with stage I and II follicular low-grade lymphomas can expect to achieve clinical cure of their disease with radiation therapy. Randomized trials published to date do not support the use of adjuvant chemotherapy. Although a policy of initial observation with deferral of treatment until the occurrence of disease progression is a well established approach to patients with advanced disease, no randomized studies exist that support this as a safe alternative to radiation therapy for early stage disease. New systemic therapies are required for the treatment of occult disease to prevent the occurrence of relapse outside of irradiated volumes.

Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University.

PURPOSE: To evaluate retrospectively the results of radiotherapy for 177 patients with stage I (n = 73 [41%]) and II (n = 104 [59%]) follicular small cleaved-cell and follicular mixed small cleaved-cell and large-cell non-Hodgkin's lymphoma (NHL) treated in the Department of Radiation Oncology, Stanford University between 1961 and 1994. PATIENTS AND METHODS: Histology was follicular small cleaved-cell in 101 (57%) cases and follicular mixed small cleaved-cell and large-cell in 76 (43%). Forty-five patients (25%) had staging laparotomy; 34 (19%) had extranodal involvement. All patients had received radiotherapy, either to one side of the diaphragm (involved or extended field) or to both sides (total lymphoid irradiation [TLI] or subtotal lymphoid irradiation [STLI]. Radiotherapy doses ranged from 35 to 50 Gy. RESULTS: The median follow-up duration was 7.7 years. The longest follow-up duration was 31 years. Actuarial survival rates at 5, 10, 15, and 20 years were 82%, 64%, 44%, and 35%, respectively. The median survival time was 13.8 years. At 5, 10, 15, and 20 years, 55%, 44%, 40%, and 37% of patients, respectively, were relapse-free. Only five of 47 patients who reached 10 years without relapse subsequently developed recurrence. Survival and freedom from relapse (FFR) were significantly worse for older patients. Relapse rates were lower following treatment on both sides of the diaphragm or staging laparotomy. Univariate analysis showed that youth and staging laparotomy were associated with significantly better survival and that FFR was better following treatment on both sides of the diaphragm or laparotomy. CONCLUSION: Radiotherapy remains the treatment of choice for early-stage low-grade follicular lymphomas. Patients who have remained free of disease for 10 years are unlikely to relapse.

Value of granulocyte colony stimulating factor in radiotherapy induced neutropenia: clinical and laboratory studies.

We report the effect of granulocyte colony stimulating factor (G-CSF) on neutropenia occurring during extended field radiotherapy in two groups of patients. The first group comprised 8 patients receiving craniospinal irradiation for a variety of central nervous system (CNS) neoplasms. None of these patients received cytotoxic chemotherapy. G-CSF was administered when the absolute neutrophil count (ANC) approached 1.5 x 10(9)/l. Neutropenia was promptly corrected in all cases, thereby avoiding unscheduled interruptions in radiotherapy. Following each G-CSF administration, ANC reached a peak on the following day and then declined steadily. Mean ANC rose from 1.33 x 10(9)/l on the day of G-CSF treatment to 7.07 x 10(9)/l the next day. Patients received 2-6 G-CSF injections during radiotherapy. Experiments were carried out in vitro to assess the risk of G-CSF causing increased CNS tumour cell proliferation. 11 human CNS tumour cultures (2 medulloblastomas, 2 primitive neuroectodermal tumours and 7 astrocytic tumours) were cultured in the presence of G-CSF at a range of concentrations up to 100 ng/ml. Their proliferation was compared with that of a G-CSF dependent murine leukemia cell line (NFS-60). None of the human tumour cultures demonstrated a significant increase in proliferation in response to G-CSF. 4 patients undergoing "mantle" type radiotherapy for Hodgkin's Disease or Non-Hodgkin's Lymphoma also received G-CSF treatment for neutropenia. All 4 had previously received cytotoxic chemotherapy. The number of G-CSF injections given per patient during radiotherapy ranged from 3-6. Mean ANC rose from 1.76 x 10(9)/l to 10.8 x 10(9)/l the next day. These results suggest that G-CSF is a reliable treatment for radiotherapy induced neutropenia and that an intermittent dosage schedule is effective.

Use of recombinant granulocyte-colony stimulating factor to treat neutropenia occurring during craniospinal irradiation.

PURPOSE: To investigate the effectiveness of recombinant human Granulocyte-Colony Stimulating Factor, a hematopoietic growth factor which stimulates neutrophil production, in the treatment of neutropenia caused by Craniospinal Irradiation. METHODS AND MATERIALS: Four consecutive patients who developed neutropenia (neutrophils less than 1.5 X 10(9)/l in peripheral blood) during craniospinal irradiation for primary intracranial tumors received intermittent subcutaneous injections of Granulocyte-Colony Stimulating Factor. Two of the patients had medulloblastoma, one had a primitive neuroectodermal tumor and the other a pinealocytoma. No patient received prior or concurrent chemotherapy. RESULTS: In all cases peripheral blood neutrophil counts returned rapidly to normal levels following Granulocyte-Colony Stimulating Factor injections and treatment delays were therefore avoided. Platelet counts were unaffected by Granulocyte Colony Stimulating Factor treatment. In one case, slight elevation of peripheral blood monocyte and lymphocyte counts occurred after each Granulocyte-Colony Stimulating Factor injection. No toxicity was encountered. CONCLUSION: Our results suggest that Granulocyte-Colony Stimulating Factor is a safe and effective treatment for neutropenia caused by extended field radiotherapy.

Effect of recombinant human erythropoietin on anemia caused by a murine mammary carcinoma.

CA NT is a transplantable murine mammary carcinoma that causes progressive anemia accompanied by granulocytosis and splenomegaly. Serum erythropoietin (Epo) levels, as measured by RIA, did not become elevated in anemic tumor-bearing mice; there was no correlation between hematocrit and serum Epo levels. Treatment with recombinant human (rHu) Epo prevented anemia in tumor-bearing mice when given in large doses, commencing on days 3-5 of tumor growth. Recombinant human Epo-treated mice had smaller spleens than controls. When treatment commenced on day 7, the development of anemia was retarded but not completely prevented. Treatment commenced on day 14 was less effective. This study demonstrates that treatment with rHu Epo can markedly influence the course of tumor-induced anemia.