To compare treatment plans deliverable by volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT) for various disease sites. Single arc (VMAT1), double arc (VMAT2), and HT plans were created for 8 CT data sets for the following representative cases: prostate, prostate bed, anal cancer, oropharynx cancer with bilateral neck disease, unilateral neck case, pituitary tumor, parasagittal meningioma, and GE junction. Dose volume histogram analysis of the target coverage (PTV) and organs at risk was performed. All plans were normalized for 100% of the prescription dose to cover at least 95% of the PTV. Multiple non-coplanar arcs were used for brain cases. Prostate PTV 77.4 Gy Conformity index (CI): HT 1.3 VMAT1 1.23 VMAT2 1.19 Bladder V70Gy: HT 8.3% VMAT1 8.4% VMAT2 8.4% Rectum V70Gy: HT 7.9% VMAT1 7.6%VMAT2 7.2% Bladder Max Gy: HT 81.5 VMAT 82.9 VMAT2 80.7 Rectum Max Gy: HT 83.8 VMAT1 84 VMAT2 80.8; Prostate Bed and Lymph Nodes: PTV 45Gy PTVmax%: HT 106 VMAT1 113 VMAT2 107 CI: HT 1.3 VMAT1 1.2 VMAT2 1.1 Small Bowel%>45Gy: HT 2 VMAT1 3 VMAT2 1.6 Bladder Mean Gy HT 28.3 VMAT1 31.2 VMAT2 28.7 Rectum Mean Gy HT 25.9 VMAT1 26.3 VMAT2 26.1; Anal PTV 50.Gy PTVmax% HT 105.3 VMAT1 108.6 CI HT 1.28 VMAT1 1.08 Bladder mean Gy HT 28.5 VMAT1 32.2 Genitalia mean Gy HT 6.7, VMAT1 5.6 Small Bowel% >45Gy HT 1.75 VMAT1 3.7 Small bowel mean Gy HT 22 VMAT1 19.5; Oropharynx PTV 70Gy CI HT 1.13, VMAT1 1.7, VMAT2 1.13, PTVmax% HT 108 VMAT1 113 VMAT 108, Dysphagia structure Mean Gy HT 42.2 VMAT1 51.8 VMAT2 40.5 Vocal Folds mean Gy HT 30.1 VMAT1 47 VMAT2 30.1, Combined Parotid Mean HT 26.5 VMAT1 37.6 VMAT2 28.9, Oral Cavity HT 35.2 VMAT1 50 VMAT2 36.4 Unilateral Neck PTV 60Gy PTVmax% HT 105.5 VMAT1 110 VMAT2 108, CI HT 1.14 VMAT1 1.7 VMAT2 1 Contralateral parotid mean Gy HT 8.7 VMAT1 7.7 VMAT2 8.3 Oral Cavity mean Gy HT 21.5 VMAT1 16.2 VMAT2 18.7 Vocal Folds mean Gy HT 16.8 VMAT1 14.7 VMAT 16 Meningioma PTV 60Gy PTVmax% HT 103.6 VMAT 107.8, CI HT 1.2 VMAT 1.16 Brain mean Gy HT 5.2 VMAT 5.8, Pituitary PTV 50Gy PTVmax% HT 104.1 VMAT 106.5 CI HT 1.18 Temporal lobe Mean Gy HT 11.3 VMAT 13.3 Brain Stem Max Gy HT 51.9 VMAT1 51.8 GE Junction PTV 50.4 Gy PTVmax% HT 113% VMAT 107% CI HT 1.45 VMAT 1.19, Lung V20 % HT 4% VMAT 2.6% Small Bowel mean Gy HT 13.5 VMAT 10.4 Liver mean Gy HT 13.8 VMAT 10.1. 1) VMAT and HT can produce similar plans that achieve clinically acceptable dosimetric goals for radiotherapy cases evaluated in this study. 2) Plan quality can be improved for VMAT by using double arc rotation, especially for complex cases with multiple target volumes.

It has been 25 years since the accompanying review article has been published, and although much has changed, much remains the same, at least in its general form. The focus of our 1983 review of the organization of the hematopoietic stem-cell compartment has been expanded to the stem-cell compartments of other cellrenewal tissues, normal tissues not formerly considered cellrenewal tissues, and perhaps most pertinently, to tumors themselves. This work is continuing to yield important potentially clinically relevant information. Our review article focused on the hematopoietic system because it was then, as now, the most frequent dose-limiting normal tissue. The review emphasized the differences in the hematopoietic damage of different cytotoxic agents used clinically. Cyclophosphamide is different from other alkylating agents in its relative sparing of stem cells, whereas radiation, busulfan, L-PAM, and the nitrosoureas are potent stem-cell toxins. Drugs primarily affecting dividing cells (such as methotrexate, fluorouracil, and vinblastine) tend to spare the slowly dividing stem cells. This is why not all iatrogenic hematopoietic depression is the same. When caused by cycle-active agents, the more potent proliferatively inactive stem cells are more likely spared than when the cytopenia is caused by busulfan or radiation. Although bone marrow toxicity is still important, damage to other normal tissues has become increasingly important. We recognized the importance of the stroma in supporting hematopoiesis in the bone marrow and demonstrated the detrimental effects of busulfan, L-pam, the nitrosoureas, ionizing radiation, and aging on the ability of the marrow to support transplanted stem cells and the resulting hematopoiesis. Similar stromal effects should be equally critical in other normal tissues. Since the time of this review, the CNS has been shown to have stem cells present in the adult, which are important for cell renewal after injury. The major concept important to understanding the hematopoietic stem-cell compartment is the heterogeneity of cells classified as stem cells. We believe that the model suggested in Figure 1 of the review is still valid. What is needed is much greater understanding of the founder cells. If clonal succession that allows normal hematopoiesis to be provided by only a few founder cells at a given time is true in mice, what can we say about humans? Most importantly, how is this clonal succession controlled? Is the selection of a particular stem cell for division stochastic, or are there determining causes? One may think of this as similar to radioactive decay, where the selection of the particular nucleus to decay is considered in probabilistic terms. Is there a similar biologic uncertainty principle? Probabilistic notions may be appropriate but these may be necessary only because there is insufficient understanding of the system biology of the stem-cell compartment. The information underlying the model suggested in our review is all derived from murine studies. Most important today is to ascertain whether these concepts pertain to man and, if so, in which cell renewal systems they are present. We know that in mice the circulating stem cells are less robust than those in the bone marrow, but this is true on average and does not mean that there aren’t some early stem cells regularly circulating. More to the clinical point is the nature of stem-cell traffic in humans. Recent studies of neuronal stem cells suggest traffic within the CNS. Knowing the location, robustness, and traffic dynamics should greatly help in fashioning less toxic therapies, particularly regional therapies such as ionizing radiation. As new types of treatment of cancer emerge, new toxicities are produced. We must determine whether these are the result of damage to the stem cells of the organ at risk and, if so, whether the stem-cell organization of the hematopoietic system is a useful model for understanding this toxicity. Twenty-five years ago there was no suggestion of tumor stem cells responsible for tumor growth and metastasis. Although appreciable cell death and terminal maturation were noted as necrosis and terminal differentiated cells, respectively, viable tumor cells were all believed to have the ability to proliferate into new tumors in situ or at a distant site. There is now some evidence for, and much discussion of, possible tumor stem cells that have properties reminiscent of those of the hematopoietic system: slow proliferation, limited differentiation markers, and both self-renewing and maturing progeny. One may wonder whether in tumors of cell renewal tissues such as the bone marrow, lymphatic tissue, skin, and GI system, the putative tumor stem cells may be stem-cell deviants. Perhaps heterogeneity of stem cells described in our review is relevant to tumors. Tumors derived from founder cells may have different prognoses than those of later stem cells. Clonal succession may be present in tumors and one can imagine that in some leukemias there are both normal and malignant stem cells. When a complete remission occurs, perhaps new stem cells are recruited to support hematopoiesis. Does chance or definable JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 6 FEBRUARY 2

As commonly used, adjuvant paclitaxel after doxorubicin in high-risk breast cancer patients results in a prolonged delay of the onset of radiation therapy after breast-conserving surgery. Concurrent delivery of breast irradiation with paclitaxel would allow for earlier initiation of radiation. We report on the toxicity of concurrent paclitaxel and breast irradiation after doxorubicin and cyclophosphamide. Twenty-four patients were treated with concurrent breast radiation and paclitaxel. All patients received four cycles of doxorubicin and cyclophosphamide followed by four cycles of paclitaxel, 175 mg/m2 every 3 weeks. The radiation therapy started after the first cycle in 3 patients, after the second cycle in 16, and after the third in 5. The breast received 4680-5040 cGy external beam irradiation, followed by a boost of 1000-2000 cGy. Fifteen patients received supraclavicular irradiation, and a posterior axillary supplement was used in five patients. Median follow-up after completion of irradiation was 11.5 months (range 2-29 months) with 21 patients followed >or=6 months, 12 followed >or=12 months, and 7 followed >or=18 months. Using Radiation Therapy Oncology Group (RTOG) acute toxicity scoring criteria, 7 patients experienced grade 1 skin and/or soft tissue reactions and 17 patients had grade 2 reactions. The average total duration of radiation treatment was 49 days (range 41-57 days). Only eight patients had radiation therapy interruptions for a median of 3.5 days (range 2-8 days): two more than 5 days. None had a chemotherapy dose reduction. One patient discontinued paclitaxel after the third cycle due to bilateral upper extremity neuropathy. No cases of pneumonitis or brachial plexopathy were seen. Concurrent treatment with every 3-week paclitaxel and breast irradiation was well tolerated. Additional study is needed to determine optimal timing, long-term toxicity, and potential benefits of concurrent radiation therapy and paclitaxel.

Between 1976 and 1983, 40 women with intraductal carcinoma of the breast without invasion underwent excisional biopsy and irradiation as an alternative to mastectomy. The median age was 53 years (range, 28 to 77 years) and the median follow-up time since initiation of radiation was 44 months (range, 14 to 97 months). Twenty-seven patients presented with a palpable mass; in 13 patients the tumor was detected only by mammography. A limited axillary dissection was performed in 13 patients, and all lymph nodes removed were negative. Treatment was administered to the breast and adjacent chest wall to a dose of 4,600 to 5,000 rad, with 26 patients also receiving a boost dose of 1,000 to 2,000 rad to the site of the primary. Four patients have developed a recurrence in the treated breast, at 17, 19, 35, and 63 months after the beginning of radiation therapy. The 5-year actuarial rate of local recurrence is 10%. Three of the recurrences were in those four patients who presented with a nipple discharge and a central primary. In two cases, the recurrence consisted of only intraductal carcinoma; in the other two, both intraductal and invasive cancer were found. All four patients with recurrence underwent mastectomy and are well without evidence of distant metastases at 1, 12, 15, and 15 months since mastectomy. Cosmetic results were excellent. No patient has developed distant metastases. Since the number of patients treated is small and the period of follow-up is short, one must be cautious in the interpretation of these results. Nonetheless, the treatment of intraductal carcinoma of the breast by excision and irradiation appears to give acceptable local control and excellent survival when suitable precautions of patient selection and evaluation are taken.

Breast-conserving surgery ("lumpectomy") with primary radiation therapy is gaining acceptance as an alternative to mastectomy for breast cancer. Currently, little is known about the specific immediate and long-range biopsychosocial effects of breast-conserving therapy as compared to more traditional mastectomy procedures. Physicians' speculations about the women who chose breast-conserving treatment as opposed to mastectomy seem to have been influenced by the scientific debate concerning the efficacy of this procedure. This study is a preliminary investigation of the attitudes and experiences of women receiving breast-saving therapy for carcinoma of the breast.

Eight patients with relapsed B-cell non-Hodgkin's lymphoma were treated with intensive chemoradiotherapy and reconstituted with autologous bone marrow rendered free of tumour cells by the B-cell-specific monoclonal antibody anti-B 1 and complement. Before the autologous marrow transplantation patients were induced with chemotherapy, radiotherapy, or both, into a minimum disease state with less than 5% bone-marrow involvement with tumour. All patients treated achieved a complete clinical response and had stable haematological engraftment by 8 weeks. No significant acute or chronic toxic effects have occurred. B cells could be detected by 2 months after transplantation and normal immunoglobulin levels were achieved by 6 months. Six of eight patients are disease free in unmaintained remission more than 20, 19, 10, 8, 5, and 3 months after transplantation.

In order to assess the cosmetic results of treatment, the results in 239 patients with early breast cancer treated by primary radiation treatment without adjuvant chemotherapy were reviewed. Four patients had bilateral cancers, making a total of 243 breasts available for analysis. Follow-up ranged from 24 to 78 months with a median of 33 months. The parameters measured were breast edema, retraction, telangiectasia, arm edema, and the overall cosmetic appearance. The cosmetic results declined over the first 3 years after treatment, but then stabilized. At 5 years, the overall cosmetic results were judged by physicians as excellent in 77%, good in 9%, fair in 9%, and poor in 5%. A fair or poor cosmetic result was highly correlated with the development of moderate or severe breast retraction. Telangiectasia was uncommonly the only cause of a fair or poor cosmetic result. Breast and arm edema were rarely noted to be significant, but were more common in patients who underwent axillary dissection. In 210 cases, a supplementary boost dose of radiation was delivered to the primary tumor area, and in 33 cases a boost was not used. This boost consisted of an interstitial iridium-192 implant in 204 cases and either high-energy photons or electrons in the remainder. At 4 years, no patient treated without a boost had a fair or poor result compared with 22% who received a boost (P = 0.13). The conclusion is that, in general, primary radiation treatment provides highly satisfactory cosmetic results for patients with early breast cancer.

Recent discoveries indicate that hematopoietic stem cells have limits on their proliferative capacity and are unable to divide indefinitely. There is great heterogeneity within the compartment as to the extent of this proliferative limitation. At any given time it appears that hematopoiesis is maintained by the progeny of only a few stem cells. When these are exhausted the progeny from other stem cells take their place. The observations of proliferative limitation, heterogeneity, and clonal succession must be incorporated into any model of stem cell organization. These new discoveries and the models incorporating them have important clinical implications. They may explain the inability of normal tissues to develop drug resistance and they also offer a mechanism by which cell renewal systems decrease the development of malignancies. In the selection of chemotherapeutic agents not only the effectiveness of the drug upon the tumor must be considered, but also how specific agents affect the stem cell compartment. These data have important implications in the use of bone marrow transplantation for both malignant and nonmalignant disease.

Between April 1969 and July 1977, 83 patients, 16 years or younger, with pathologically staged IA-IIIB Hodgkin's disease were seen and treated at the Joint Center for Radiation Therapy. The five-year actuarial relapse-free and overall survivals were 82 and 95%, respectively, with a median follow-up from diagnosis of 65 months. Relapse occurred in 6/50 Stage IA-IIA, 2/9 Stage IIB, 4/9 Stage IIIA, and 3/15 Stage IIIB patients. Of patients who relapsed, 11/15 are currently disease-free following retreatment with chemotherapy. Nine patients with Stage IV disease were also evaluated. Four of seven patients initially treated with chemotherapy remain free of disease. Forty-two patients in this study were treated with mantle and para-aortic irradiation alone, thus avoiding the risk of sterility associated with pelvic irradiation or MOPP chemotherapy while retaining a high probability for long-term disease-free survival. Complications of radiation therapy included growth retardation and thyroid function abnormalities in some patients. Standing height measurements were normal regardless of age at initial treatment, however, 16 of 23 patients 3-12 years old at initial treatment had sitting heights measuring more than one standard deviation below the mean. Intraclavicular distances were shortened in some patients and examples are shown. Thyroid stimulating hormone levels were elevated in 21 of 37 patients evaluated. Radiation therapy, without adjuvant chemotherapy remains an important treatment approach for children with early stage Hodgkin's disease.

The results of primary radiation therapy in 176 consecutive patients with clinical Stage I and II carcinoma of the breast were reviewed. Median follow-up time was 47 months. The overall breast relapse rate was 7%. Patients undergoing interstitial implantation had a significantly lower breast relapse rate (1%) than patients not undergoing implantation (11 %). Breast relapse was more common in patients undergoing incisional or needle biopsy (17 %), compared to patients treated after excisional biopsy (5 %). In patients undergoing excisional biopsy, but not interstitial implantation, breast relapse was related to external beam dose. Twelve percent of the patients who received less than 1600 ret dose relapsed in the breast, compared to none of the 19 patients who received more than 1700 ret dose. These results imply that supplemental irradiation to the primary tumor area is required following excisional biopsy of a primary breast cancer when 4500–5000 rad is delivered to the entire breast.

Bone marrow pluripotent stem cells (CFUs) demonstrate capacity for both proliferation and differentiation. The proliferative capacity of CFUs has been measured by serial transplantability and by the Rs, a measurement of CFU production in a single 14-day transfer. In the present study, the self-renewal capacity fo both adherent and nonadherent CFUs from long-term bone marrow cultures was measured. Culture conditions were established such that nonadherent cells were derived from the adherent cell layer. Both adherent and non-adherent cells produced spleen colonies, demonstrating that significant proliferative potential was present in both locations; however, at all times in culture, the CFUs within the adherent stromal cell layer had a significantly greater self-renewal capacity than did the nonadherent CFUs. During the initial establishment of the cultures, the self-renewal capacity of the adherent CFUs decreased as the total number of CFUs per flask increased. After 3 weeks in culture, the self-renewal potential of the adherent CFUs stabilized and was maintained. These results suggest two different mechanisms of stem cell proliferation. In order to increase the most primitive stem cell pool size, there was initial proliferation of early stem cells with a concomitant decrease in self renewal capacity. Once this pool was established, the self-renewal capacity of the adherent CFUs maintained for 13 weeks in culture suggests that CFU production and cell maintenance were achieved by clonal succession.

Between April 1969 and December 1974, 37 patients with surgically staged III A Hodgkin's disease were treated with total nodal irradiation (TNI). Their probability of relapse-free survival at 7 years is 51% and overall survival 82% with the majority of patients remaining disease free after retreatment with MOPP (10 of 16). In contrast, 21 stage III B patients treated with TNI and MOPP chemotherapy over the same time period have a relapse-free survival of 74% and overall survival of 91%. Because of superior results in treating stage III B patients with combined modality treatment, we fell that a relapse-free survival of 51% may not justify continuation of TNI as the only modality of treatment for patients with stage III A disease, and we have initiated a trial of combined radiation therapy and MOPP chemotherapy in these patients. The most effective treatment of stage III A Hodgkin's disease, however, remains uncertain and depends both on the ultimate risk of combined modality treatment and the success of retreatment following relapse after radiation.

Between January, 1969 and December, 1975, 20 patients with Stage I and 8 with Stage II pure seminoma of the testes were treated at the Joint Center for Radiation Therapy. Six of these patients had elevated human chorionic gonadotropin (HCG) levels prior to orchiectomy. In addition, 2 of the 6 patients presented with pre-orchiectomy gynecomastia. Patients were treated with radiation therapy to the retroperitoneum; additional mediastinal irradiation was given in some patients. In 4 of the 6 patients, post-orchiectomy HCG titers were measured and were normal. At this writing, all patients were alive without disease 20–98 months following initiation of treatment. The prognosis of patients with pure seminoma and positive pre-orchiectomy HCG titers does not appear to differ from that of pure seminoma patients without elevated HCG levels.