From daemon Tue Oct 5 11:29:04 1999 Received: (from daemon@localhost) by net.bio.net (8.9.1a/8.9.1) id LAA23109; Tue, 5 Oct 1999 11:29:04 -0700 (PDT) Message-Id: <199910051829.LAA23109@net.bio.net> To: radoncjc@net.bio.net Date: Tue, 5 Oct 1999 06:39:55 -1000 Reply-To: radoncjc@net.bio.net From: Brian J Goldsmith Subject: October 1999 Internet Radiation Oncology Journal Club (IROJC) October 1999 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 53rdd collection of references suggested for attention and discussion by the IROJC's Board of Editors: Sarah Donaldson, M.D. Editor, Pediatric Radiation Oncology Robert Foote, M.D. Editor, Head and Neck / Skin Radiation Oncology Abram Recht, M.D. Editor, Breast Radiation Oncology Rich Hoppe, M.D. Editor, Reticuloendothelial System Radiation Oncology Dan Petereit, M.D. Editor, Gynecological Radiation Oncology Andrew Turrisi, M.D. Editor, Lung and Mediastinum Radiation Oncology Joel Tepper, M.D. Editor, Gastrointestinal and Soft Tissue Sarcoma Radiation Oncology Mack Roach, M.D. Editor, Genitourinary Radiation Oncology Glenn Bauman, M.D. Ph.D. Editor, Central Nervous System Radiation Oncology Rod Withers, M.D., D.Sc. Editor, Radiobiology ----------------------------------------------------- You're encouraged to critically review this set of references and respond by posting your comments to the IROJC readership at radoncjc@net.bio.net. Comments should be in compliance with IROJC commentary rules (see below). In the month that follows this posting of references, submitted comments will be delivered to the e-mail boxes of the IROJC readership, with the goal of stimulating a professional discussion of these references and their subjects. ------------------------------------------------------------ ARCHIVED IROJC POSTINGS and commentary are available on the World Wide Web! Look for them on http://www.bio.net/ Click on the "Access the BIOSCI/bionet Newsgroups" hyperlink, and then go to "RADIATION-ONCOLOGY/Prototype". Or directly access the RADIATION-ONCOLOGY folder at http://www.bio.net/hypermail/RADIATION-ONCOLOGY/ There's also a freeWAIS search tool at the website, for searching archived postings for keywords or phrases! ------------------------------------------------------------ Commentary Rules: (1) Please cite the subject category in the header of your e-mail message, e.g., Subject: CNS 10/99. (2) Address the readership at large - not the Editor who suggested the reference. The Editor is under no obligation to respond to questions posed by the IROJC readership. (3) The Editor's selection is not necessarily an endorsement of the authors' conclusions. In fact, articles may be selected for criticism. (4) Comments posted to the Internet are public. Professional wording is prudent. (5) Comment only on journal articles that you have read recently, and please keep comments specific. (6) In order to minimize confusion, limit comments to the current month's list of references. (7) Please sign all comments and questions to the IROJC. By identifying yourself, you promote a more collegial and friendly environment! (8) Address to the Moderator (briandeb@bellatlantic.net) private questions and comments which are not intended for IROJC posting and public reading. ****************** Peds: Donaldson 10/99 AU: Martelli H, Oberlin O, Rey A, Godzinski J, Spicer RD, Bouvet N, Haie-Meder C, Terrier-Lacombe M-J, Sanchez de Toledo J, Spooner D, Sommelet D, Flamant F, Stevens MCG. TI: Conservative treatment for girls with nonmetastatic rhabdomyosarcoma of the genital tract: a report from the Study Committee of the International Society of Pediatric Oncology. SO: J Clin Oncol 1999, 17(7): 2117-22 URL: http://www.jco.org/cgi/reprint/17/7/2117 Abstract: PURPOSE: To report the results of a conservative multimodal approach in girls with nonmetastatic rhabdomyosarcoma (RMS) of the genital tract, treated in International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumors 84 and 89 protocols. PATIENTS AND METHODS: From 1984 to 1994, 38 girls with RMS of the genital tract (vulva, vagina, uterus) were treated in SIOP protocols. With the exception of patients with rare small tumors, which were resected at the start of the studies, all patients received initial chemotherapy (CHT) (ifosfamide, vincristine, and actinomycin D). Local treatment including surgery, brachytherapy (BT), and external-beam radiotherapy (ERT) was given only to girls who did not achieve complete remission (CR) with CHT or who subsequently relapsed. RESULTS: The primary tumor originated in the vulva or vagina in 27 girls and in the uterus in 11. The overall survival rate (+/- SE) was 91% 6% at 5 years, and the event-free survival rate was 78% 7%. At a median follow-up of 5 years, 30 girls were alive and in first CR and five were alive and in second CR. Four patients treated with complete resection of the tumor at diagnosis received less CHT. Thirteen patients were treated with CHT alone. In 17 patients, local treatment was necessary to achieve complete local control, for a residual mass after initial CHT (10 patients), for viable tumor on biopsy (three patients), or for local relapse (four patients). The local treatment used was radiotherapy (RT) (ERT in three patients, BT in seven), radical surgery with uterine ablation (three patients), RT and radical surgery (three patients), and conservative surgery with RT (one patient). CONCLUSION: Girls with nonmetastatic RMS of the genital tract have an excellent prognosis. We found no difference in outcome between uterine and vulvovaginal RMS. Local treatment does not seem necessary in patients who have a complete response to CHT. When a local treatment is needed, BT may be an alternative to radical surgery or ERT. Editor's comments: The SIOP investigators have long recommended chemotherapy and conservative local therapy, oftentimes brachytherapy, as optimal treatment for young girls with genitourinary rhabdomyosarcoma. This report updates their previous publications and reports a large experience of 38 girls. Following from the SIOP experience, the Intergroup Rhabdomyosarcoma (IRSG) investigators recommend a similar approach with a few important differences. 1. The SIOP studies include all girls with vulva, vagina, and uterine primary tumors, and make the point that they see no difference in outcome beetween those with uterine tumors and those with vulvovaginal tumors. For girls with vaginal primary tumors, the new IRSG V protocols recommend primary chemotherapy, with interval biopsy, and if biopsy is positive, continue chemotheapy until week 28, and then local therapy with external beam or brachytherapy, but avoiding hysterectomy-cystectomy. Radical surgery is to be avoided. However for girls with vulva and uterine primary tumors, the decision for local therapy is not delayed to week 28, but is at week 3 for Clinical Group I and II, and at week 12 for those with Cl Group III. Response to chemotherapy is less good in this group than in those with vaginal tumors. Radiotherapy is used for all patients excepting those with complete resection at time of diagnosis. Patients with nodal disease receive slightly higher radiation doses, and patients with alveolar histology also receive more aggressive treatment than those with embryonal/botryoid histology. Thus, while the SIOP investigators conclude that local therapy is not necessary for patients with a complete response to chemotherapy, the IRSG investigators are more selective in coming to this conclusion based upon histology, time of second look surgery, site of primary tumor and nodal status. 2. Radical surgery should be avoided. 3. Nodal involvement requires nodal radiotherapy. 4. Brachytherapy is most useful for patients with localized vaginal tumors, but external beam is needed for those with uterine tumors. 5. Pathology following treatment may show maturing rhabdomyoblasts, which should not be mistaken for clonogenic tumor, and can be followed without major intervention. ****************** Head/Neck/Skin: Foote 10/99 AU: Nowak PJ, Wijers OB, Lagerwaard FJ, Levendag PC. TI: A three-dimensional CT-based target definition for elective irradiation of the neck. SO: Int J Radiat Oncol Biol Phys 1999 Aug 1;45(1):33-9. Abstract: INTRODUCTION: Elective treatment of the clinically node-negative neck by radiation results in excellent control rates. However, radiation therapy with its organ-preserving properties is not without morbidity. Side effects of elective neck irradiation are mainly due to damage of the major and minor salivary glands, resulting in the dry mouth syndrome. Given that RT is the preferred treatment modality in case of elective treatment of the neck in many institutions, it is of utmost importance to try and reduce the associated sequelae of RT. MATERIAL AND METHODS: With the introduction of CT-planning systems and the development of 3D conformal radiation therapy (3D CRT) techniques, it has become feasible to deliver adequate doses of radiation to the target (neck) and at the same time saving (parts of) the salivary glands from doses beyond tolerance. A prerequisite for these techniques is that they require a precise knowledge of the target (i.e., of the elective neck) on CT. To be able to correlate borders of the surgical levels in the neck (I-VI) with structures seen on CT, an anatomical study, using two fixed (phenol, formaldehyde) human cadavers, was performed. Subsequently, the 6 potential lymph node regions in the neck on CT were defined. RESULTS AND DISCUSSION: The reference for the current 3D CT-based definition of the lymph node regions in the neck is the official report of the American Academy of Otolaryngology, describing, based on surgical anatomy, the lymph node groups in the neck by Levels I-VI. The present investigation depicts reproducible landmarks on transversal CT images, corresponding to anatomical reference structures known from surgical levels (I-VI) and, this way, CT-based lymph node regions (1-6) were constructed. ****************** GYN: Petereit 10/99 No Reference Selected ****************** GI / Soft Tissue Sarcoma: Tepper 10/99 AU: Zhang ZX; Gu XZ; Yin WB; Huang GJ; Zhang DW; Zhang RG. TI: Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients. SO: Int J Radiat Oncol Biol Phys 1998 Dec 1;42(5):929-34. Abstract: PURPOSE: An attempt was made to define the role of radiotherapy before operation for AGC. METHODS AND MATERIALS: From January 1978 to May 1989, a prospective randomized trial on preoperative radiotherapy (R+S) vs. surgery alone (S) for AGC was carried out in 370 patients. Patients were randomized into a combined group (R+S, 171 patients) or a surgery alone group (S, 199 patients) by the envelope method. 8-MV photon or telecobalt was used for the preoperative radiation therapy, using anterior-posterior opposing parallel fields to deliver 40 Gy to the cardia, lower segment of the esophagus, fundus, lesser curvature, and hepatogastric ligament. Surgery was performed after 2 to 4 weeks rest. RESULTS: The 5- and 10-year survival rates of the R+S Group and the S Alone Group were 30.10% and 19.75%, 20.26% and 13.30%, respectively. The survival curves of these two groups diverged right from the beginning after the operation over the ninth year. Statistics by Kaplan- Meier log rank test proves that the difference is significant (chi2 equals 6.74, p equals 0.0094). The immediate results were: resection rate 89.5% and 79.4% (p less than 0.01); pathologic stage after resection T2 12.9% and 4.5% (p less than 0.01), T4 40.3% and 51.3% (p less than 0.05), lymph node metastasis rates 64.3% and 84.9% (p less than 0.001); operative mortality rates 0.6% and 2.5%; intrathoracic leak rates 1.8% and 4.0%, respectively. The causes of failure were: local uncontrol and recurrence 38.6% vs. 51.7% (p less than 0.025), regional lymph node metastasis 38.6% vs. 54.6% (p less than 0.005), distant metastasis 24.3% vs. 24.7%. CONCLUSION: Preoperative radiation therapy is able to improve the results of surgery for adenocarcinoma of the gastric cardia. Editor's comments: Although the incidence of gastric cancer has been decreasing in the United States, the incidence of adenocarcinoma of the gastric cardia has been increasing in conjunction with the increasing incidence of esophageal adenocarcinoma. The epidemiology of these two diseases seem similar. Since both diseases are increasing this is not just a matter of definition. However, it is possible that both of these diseases have similar biological characteristics, even though the esophageal cancers tend to arise in Barret's esophagus. This paper indirectly raises the interesting question of whether we should be managing patients with gastric cardia lesions the same way we are managing esophageal cancers, which for many institutions is preoperative radiation plus chemotherapy. The data from this Chinese report show improved survival and local control after preoperative irradiation in a relatively large cohort of patients. Of note is that the radiation fields were more akin to a standard esophageal field than to what many people in the US use for gastric cancer (in the circumstances when it is used). The fact that no chemotherapy was used in this trial makes it difficult to directly apply the results to US practice since there have been a few studies of postoperative adjuvant RT for gastric cancer that have shown improved local control but no survival difference. This study again emphasizes the fact that local failure is a substantial problem in gastric cancer and that improved local therapy could be of value. We are still awaiting the results of the Intergroup trial that tested postoperative RT + FU based chemotherapy in all gastric cancers. However, because of the epidemiology issues, it would not be surprising if the cardia lesions behave differently than mid and distal gastric cancers. ****************** CNS: Bauman 10/99 AU: Fitzek MM; Thornton AF; Rabinov JD; Lev MH; Pardo FS; Munzenrider JE; Okunieff P; Bussiere M; Braun I; Hochberg FH; Hedley-Whyte ET; Liebsch NJ; Harsh GR 4th. TI: Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial. SO: J Neurosurg 1999 Aug;91(2):251-60. Abstract OBJECT: After conventional doses of 55 to 65 Gy of fractionated irradiation, glioblastoma multiforme (GBM) usually recurs at its original location. This institutional phase II study was designed to assess whether dose escalation to 90 cobalt gray equivalent (CGE) with conformal protons and photons in accelerated fractionation would improve local tumor control and patient survival. METHODS: Twenty-three patients were enrolled in this study. Eligibility criteria included age between 18 and 70 years, Karnofsky Performance Scale score of greater than or equal to 70, residual tumor volume of less than 60 ml, and a supratentorial, unilateral tumor. Actuarial survival rates at 2 and 3 years were 34% and 18%, respectively. The median survival time was 20 months, with four patients alive 22 to 60 months postdiagnosis. Analysis by Radiation Therapy Oncology Group prognostic criteria or Medical Research Council indices showed a 5- to 11-month increase in median survival time over those of comparable conventionally treated patients. All patients developed new areas of gadolinium enhancement during the follow-up period. Histological examination of tissues obtained at biopsy, resection, or autopsy was conducted in 15 of 23 patients. Radiation necrosis only was demonstrated in seven patients, and their survival was significantly longer than that of patients with recurrent tumor (p equals 0.01). Tumor regrowth occurred most commonly in areas that received doses of 60 to 70 CGE or less; recurrent tumor was found in only one case in the 90-CGE volume. CONCLUSIONS: A dose of 90 CGE in accelerated fractionation prevented central recurrence in almost all cases. The median survival time was extended to 20 months, likely as a result of central control. Tumors will usually recur in areas immediately peripheral to this 90-CGE volume, but attempts to extend local control by enlarging the central volume are likely to be limited by difficulties with radiation necrosis. Editor's comments: This is a well designed, meticulously documented prospective protocol evaluating the value of dose escalation using combined conformal photon and proton beam radiation. All patients received PCV chemotherapy subsequent to total radiation doses of 90 Cobalt Gray Equivalent delivered by shrinking fields to initially the MRI T2 volume +2 cm (50.4 Gy), then the T1 enhanced volume + 2cm (64.8Gy), and finally to the T1 enhanced volume alone (90Gy). ****************** Breast: Recht 10/99 AU: Ballo MT; Strom EA; Prost H; Singletary SE; Theriault RL; Buchholz TA; McNeese MD. TI: Local-regional control of recurrent breast carcinoma after mastectomy: does hyperfractionated accelerated radiotherapy improve local control? SO: Int J Radiat Oncol Biol Phys 1999 Apr 1;44(1):105-12. Abstract: PURPOSE: Hyperfractionated, accelerated radiotherapy (HART) has been advocated for patients with local-regionally recurrent breast cancer because it is believed to enhance treatment effects in rapidly proliferating or chemoresistant tumors. This report examines the value of HART in patients with local-regionally recurrent breast cancer treated with multimodality therapy. METHODS AND MATERIALS: The study included 148 patients with local-regionally recurrent breast cancer after mastectomy, who were treated with definitive local irradiation and systemic therapy consisting of either tamoxifen, cytotoxic chemotherapy, or both, along with excision of the recurrent tumor when possible. Patients with distant metastases were excluded, except for two patients with ipsilateral supraclavicular nodal metastases. Patients received comprehensive irradiation to the chest wall and regional lymphatics to a median dose of 45 Gy, with a boost to 60 Gy to areas of recurrence. Sixty-eight patients (46%) were treated once daily at 2 Gy/fraction (fx), and 80 (54%) were treated twice daily at 1.5 Gy/fx. Forty-eight patients (32%), who had palpable gross disease that was unresponsive to systemic therapy and/or unresectable, were irradiated. The median follow-up time of surviving patients was 78 months. RESULTS: Overall actuarial local-regional control (LRC) rates at 5 and 10 years were 68% and 55%, respectively. Five- and ten-year actuarial overall survival (OS) and disease-free survival (DFS) rates were 50% and 35%, 39% and 29%, respectively. Univariate analysis revealed that LRC was adversely affected by 1. advanced initial American Joint Committee on Cancer (AJCC) stage (p equals 0.001), 2. clinically evident residual disease at time of treatment (p less than 0.0001), 3. more than three positive nodes at initial mastectomy (p equals 0.014), 4. short interval from mastectomy to recurrence (less than 24 months, p equals 0.0007), 5. nuclear grade (III vs. I or II, p equals 0.045), and 6. number of recurrent nodules (1 vs. greater than 1, p equals 0.02). Patient age at time of recurrence (less than 40 vs. greater than or equal to 40 years), recurrence location on the chest wall, estrogen receptor status, progesterone receptor status or menopausal status did not adversely affect LRC. On multivariate analysis, only clinically evident residual disease at the time of treatment and short interval from mastectomy to recurrence remained significant. When once-a-day irradiation was compared to the twice-a- day schedule, no significant differences were seen in LRC (67% vs. 68%), OS (47% vs. 52%), or DFS (42% vs. 36%) for the entire group of patients at 5 years. Pairwise comparison of the two fractionation schedules in each of the adverse outcome subgroups identified above showed no clinically significant differences in LRC at 5 years. For the 48 patients who began radiotherapy with measurable gross local recurrence, the complete response rate to radiotherapy was 73%, with no difference seen between the two fractionation schedules. The incidence of acute and chronic radiation-related complications was similar in both treatment groups. CONCLUSIONS: Hyperfractionated accelerated radiotherapy, although well tolerated by patients with local-regionally recurrent breast cancer, did not result in superior local-regional control rates when compared to daily fractionated regimens. Alternative strategies, such as dose escalation or chemoradiation, may be required to improve control. Editor's comments: There have been few studies of "altered" fractionation schemes for the local-regional treatment of breast cancer patients. This article is an important contribution to this small literature. Although fractionation schemes were not randomly allocated, the patients treated with accelerated hyperfractionation and conventional fractionation were quite comparable. The results of treatment for these two groups were nearly identical. The interpretation of these results is not so clear, as they could mean that: a) the kinetics of breast cancer growth are such (i.e., fairly slowly proliferating) that acceleration of treatment time will have little or no impact); b) tumors that are sensitive to radiation are equally sensitive, regardless of the overall time to complete treatment, and tumors that are resistant will be resistant similarly; c) the "wrong" fractionation scheme or total dose was chosen for the acceleration; or d) all of the above. (I would tend to favor explanation "a", although this is speculation.) This study is also an important benchmark for the results that can be achieved for patients with local-regional failure following mastectomy in the current era. Note that all patients received systemic therapy; this may be one reason why they have a 10-year disease-free survival rate of 35%, which is better than any other reported series. ****************** RES: Hoppe 10/99 AU: Tondini C, Ferreri AJM, Siracusano L, Valagussa P, Giardini R, Rampinelli I, Bonadonna G. TI: Diffuse large-cell lymphoma of the testis SO: J Clin Oncol 1999, 17(9): 2854-58. Abstract: PURPOSE: To evaluate clinical outcome of patients with testicular diffuse large-cell lymphoma treated with conventional-dose systemic chemotherapy. PATIENTS AND METHODS: This study is a retrospective analysis of adult patients with testicular diffuse large-cell lymphoma who were treated with a doxorubicin-based chemotherapy regimen at our institution, the Istituto Nazionale Tumori of Milan. Twenty-nine assessable patients, with a median age of 61 years, were identified. Sixteen patients had limited stage (Ann Arbor stage I/II) disease, whereas 13 patients had a testicular mass and distant organ involvement (Ann Arbor stage IV). Patients were retrospectively classified according to the International Prognostic Index. RESULTS: After a median follow-up of 82 months, 22 patients presented disease progression and 22 patients had died. Actuarial median time to treatment failure and overall survival were 44 and 41 months for patients with limited stage and 9 and 16 months for patients with advanced stage, respectively. Eight patients failed initial treatment, and 14 patients relapsed from clinical remission after a median disease-free time of 17 months (range, 6 to 98 months). Median survival time after progression of lymphoma was 5 months (range, 0 to 22 months). In nine (41%) of the 22 failing patients, the initial site of relapse was either the CNS or the contralateral testis; the remaining patients experienced relapse in multiple extranodal sites. CONCLUSION: Poor prognosis of patients with diffuse large-cell lymphoma calls for more effective treatment strategies, such as high-dose chemotherapy programs for younger patients or specifically designed chemotherapy regimens for patients not suitable for high-dose treatment, with the purpose to provide control of both systemic disease and disease of the CNS and contralateral testis. The potential benefit of contralateral testicular irradiation has to be taken into account in the treatment planning. Editor's comments: Primary testicular lymphoma is uncommon, but you may hear about one at next week's tumor board! This series included early (stage I-II) and advanced (Stage IV) patients, treated with chemo. Some had RT to retroperitoneal nodes, some had RT to ipsilateral scrotum (if original testicular mass was greater than 10 cm). None had CNS prophylaxis or contralateral testicular RT. In general, the outcome of treatment for these patients was much worse than would be expected for equivalent stage extra-testicular presentations of DLC lymphoma. A good analysis of failure pattern was completed. Overall, 22/29 (76%) patients suffered a relapse. Fourteen of these patients (64%) had a component of failure that included the CNS or contralateral testis and in 9 (41%) failure was limited to the CNS/contralateral testis. This study once again confirms the importance of CNS prophylaxis (usually with IT MTX) and contralateral testicular irradiation for patients who present with testicular lymphoma. ****************** Lung/Mediastinum: Turrisi 10/99 AU: Furuse K, Kawahara M, Nishiwaki Y, Fukuoka M, Takada M, Miyashita M, Ohashi Y. TI: Phase I/II study of vinorelbine, mitomycin, and cisplatin for stage IIIB or IV non-small-cell lung cancer. SO: J Clin Oncol 1999, 17(10): 3195-3200 URL: http://www.jco.org/cgi/content/abstract/17/10/3195 Abstract: PURPOSE: To determine the maximum-tolerated doses (MTDs) of vinorelbine (VRB), mitomycin (MMC), and cisplatin (P), given in two courses every 28 days to previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: At least three or four patients were entered at each dose level. The starting dose was 20 mg/m2 for VRB on days 1 and 8 and 4 mg/m2 for MMC on day 1, with a fixed dose of P 80 mg/m2 on day 1 every 4 weeks. MMC was increased to 6 mg/m2 at dose level 2 and subsequently to 8 mg/m2 at dose level 4. At dose level 3, VRB was increased to 25 mg/m2. Twenty-five patients were entered onto the phase I study and 19 patients were entered onto phase II study. RESULTS: Nadir leukocyte and platelet counts decreased at each dose level. At dose levels 1 and 2, the dose-limiting toxicity (DLT) was not seen, but at dose levels 3 and 4, DLT was encountered in two patients. Nearly half the patients at dose level 4 had dose reduction due to grade 4 leukopenia. A mathematic model of all toxicity suggested that dose level 4 (VRB 25 mg/m2 on days 1 and 8 and MMC 8 mg/m2 and P 80 mg/m2 on day 1, every 4 weeks) would be the recommended dose for phase II study at which grade 4 toxicity is expected in 25% of patients over two courses. Of the 25 assessable patients in the phase I study, 13 achieved a partial response and one had a complete response for a response rate of 56.0%. Of the 19 assessable patients in the phase II study, 12 had a partial response (63.2%; 95% confidence interval, 38.4% to 83.7%). Grade 3 and 4 leukopenia was observed in 19 (100%), and grade 3 thrombocytopenia was seen in seven (36.8%). Median survival time was 10.7 months and the 1-year survival rate was 43.2% in the 44 assessable patients. CONCLUSION: The VRB/MMC/P regimen is effective against NSCLC, and its efficacy should be confirmed through a randomized study. Editor's comments: There are a series of very important lung papers that I want to deliver to your attention over the next few months, including issues about SCLC BID treatment, extensive disease treatment with thoracic radiotherapy, and prophylactic cranial radiotherapy in NSCLC. This will bring us to the year 2000 literally, but the answers to these issues will take many more years. The paper I've selected is seminal. It questions the established norm that sequential therapy is better because it causes less toxicity. Our practitioners ask and the most oft asked question at conferences is what is standard therapy and what do you do off protocol. Radiotherapy alone for stage III NSCLC is inferior treatment, at least with doses of 60 Gy QD to 69.6 Gy BID in a hyperfractionated scheme. The basis for the chemo followed by 60 Gy as our current benchmark is the hallowed CALGB 8433 - truly a trend setter. However, the drugs used then, as in the important study reported by Dr. Furuse, are dated, and infrequently used today. It is crucial to explore whether the benefits of a mere two cycles of chemotherapy, vinblastine and cisPlatin, can be re-confirmed with other drugs -- mitomycin in this case, or the current trend of a taxane and carboplatin or any other "new" drug combination (gemcitabine; vinorelbine, the topoisomerase inhibitory drugs both I and II). Many have criticized the use of cisplatin/etoposide in NSCLC -- criticism not based on survival observations or randomized data, but on the fact that etoposide is not a very active drug against NSCLC in phase II studies. The Memorial group of the 80's led us to an "MVP" like combination; our Japanese colleagues have adopted it for the randomized trial. Are these observations applicable if we use Other drugs? I don't know. The question of sequence is important. This study suggests that there is a benefit to concurrent therapy even when we use radiotherapy in a less effective but potentially less toxic way. Some have editorialized that the toxicity of concurrent therapy isn't worth it. This study confronts that assertion and says that it is incorrect. However, we must live in the real world, and the oncologists are not using vinblastine or vindesine. I've argued that mitomycin is associated with increased toxicity and should not be used. Interestingly, Ohe at ASCO this year educated me that, in a retrospective study from Japan, they actually found no excess toxicity in their mitomycin treated group, and as much or more with etoposide - cisplatin. North American toxicity reports do not always line up with observations from Japanese populations. We have different frequencies of esophageal toxicity all the time, and I'm not yet convinced that we should bring back mitomycin. On the other hand, I'm not sure how to apply these data to the drugs now in popular use around the world. RTOG 9410 asks a similar question, uses vinblastine and cisplatin in two arms and oral etoposide and cisplatin with the continuous contender, 69.6 BID. We need results from that study to help us understand. The immoderate assertions that sequential is king is now tottering. The wholesale substitution of carboplatin is not data but market driven. The fact that concurrent is indeed better is also not secure. However, the practice of too many cycles of systemic therapy before radiotherapy is not bolstered by data. The current practice of concurrent therapy is the control in many trials, frequently associated with two cycles first. The CALGB 8433 -- cisplatin-vinblastine before 60 Gy -- standard is just not used very much. We need to see the RTOG results to further interpret what to do with the Furuse data. We need a little more data to be secure that whatever the increased toxicity in North American patients, that this price is worth the survival benefit. Until then we rely on the phase II reports of the new drugs, the over-excitement about response rates, and the hypoerventilated ehthusiasms of pharmaceutical industry sponsored trials and pundits that see the future clearer than I do. ****************** GU: Roach 10/99 AU: Akakura K; Isaka S; Akimoto S; Ito H; Okada K; Hachiya T; Yoshida O; Arai Y; Usami M; Kotake T; Tobisu K; Ohashi Y; Sumiyoshi Y; Kakizoe T; Shimazaki J TI: Long-term results of a randomized trial for the treatment of Stages B2 and C prostate cancer: radical prostatectomy versus external beam radiation therapy with a common endocrine therapy in both modalities. SO: Urology 1999 Aug;54(2):313-8. Abstract: OBJECTIVES: To improve the treatment of locally advanced prostate cancer (Stages B2 and C), a prospective randomized trial was conducted to compare radical prostatectomy versus external beam radiotherapy with the combination of endocrine therapy in both modalities. METHODS: One hundred patients were enrolled and 95 were evaluated. Forty-six patients underwent radical prostatectomy with pelvic lymph node dissection, and 49 were treated with radiation by linear accelerator with 40 to 50 Gy to the whole pelvis and a 20-Gy boost to the prostatic area. For all patients, endocrine therapy was initiated 8 weeks before surgery or radiation, and continued thereafter. The living patients were asked to respond to a quality-of-life questionnaire. RESULTS: The follow-up period ranged from 6.0 to 94.4 months (median 58.5). The progression-free and cause-specific survival rates at 5 years were 90.5% and 96.6% in the surgery group and 81.2% and 84.6% in the radiation group, respectively. The surgery group had better progression- free and cause-specific survival rates (P equals 0.044 and 0.024, respectively). More patients in the surgery group complained of urinary incontinence. The questionnaire revealed that quality of life was less disturbed in the radiation group. CONCLUSIONS: Radical prostatectomy combined with endocrine therapy may contribute to the survival benefit of patients with locally advanced prostate cancer. External beam radiotherapy in combination with endocrine therapy can be used in selected patients because of its low morbidity. Editor's comments: It is frequently stated that there are no prospective randomized trials in the modern era comparing surgery vs radiation in the treatment of prostate cancer. Unfortunately, this is not true. In fact, a recently published series from Japan suggests the surgery combined with endocrine therapy may be more effective than radiation in the treatment of prostate cancer. However, this study is so flawed as to be interpretable and thus, does not help to resolve this question. In the brief there are several major flaws worth special comment. First, it is a very small study being composed of 46 men who underwent radical prostatectomy and 49 treated with radiotherapy. The dose of radiotherapy is said to have been 40 to 50 gray to the whole pelvis, with a 20 gray boost to the prostate area. No information is provided as to how many men received 60Gy and how many 70Gy. None of the co-authors are described as being members of a department of radiation oncology. There are no specific details are given regarding the specific treatment techniques used, where the doses prescribed or the field sizes used. Also, of concern, a slightly higher percentage of patients had poorly differentiated tumors in the radiotherapy group (33% compared to 25% in the surgery arm) and a higher percentage of patients had clinical T3 disease (73% compared to 63% in the surgery arm). The most glaring difficulty, however, was the definition of progression free survival, which was defined as local regrowth of tumor and/or appearance of distant metastasis including bone mets. Elevation of PSA alone was not used as a sign of progression. Therefore, a patient who was treated with radical prostatectomy but a rising PSA would not be considered a failure. However a patient who was treated with radiotherapy was considered a failure, if the urologist who did a digital exam and believed that there was evidence of progressive disease locally. Patients who died of any cause who had progression, defined in this manner were considered to have died of prostate cancer. Other problems with this reports includes the fact that among the patients developing recurrences, one in the surgical series and three in the radiation therapy series had local regrowth of tumor. However, two additional patients treated in the radiotherapy series had "unknown" modes of progression. So, five of the twelve patients either had local regrowth or unknown modes of growth, both of which are unreliable endpoints for defining the control rate with surgery or radiation. With a median follow-up time of less than five years, six patients had metastasis in the radiotherapy arm, compared to two in the surgical arm despite the continued use of hormonal therapy. There was no statistically significant difference in overall survival between the two arms however. Because cause-specific survival depended upon the definition of progression free survival, the definition for progression free survival is critical to the evaluation of the study. Ignoring biochemical failure as a valid endpoint for determining control of disease leaves too many questions unanswered. Perceptions about persistent and local disease after radical prostatectomy have been shown to be inaccurate, just as they have been after radiation. For these reasons, it is important that future studies design endpoints that are likely to be more accurate than digital rectal exams. Beware of the small prospective randomized trial which finds no difference in overall survival, which fails to use the most sensitive determinant of failure and fails to give adequate radiotherapy ****************** Radiobiology: Withers 10/99 No Reference Selected ****************** Brian J. Goldsmith, M.D. Moderator, IROJC From daemon Wed Oct 6 09:43:07 1999 Received: (from daemon@localhost) by net.bio.net (8.9.1a/8.9.1) id JAA05752; Wed, 6 Oct 1999 09:43:07 -0700 (PDT) To: radoncjc@net.bio.net Date: Tue, 5 Oct 1999 06:39:55 -1000 Reply-To: radoncjc@net.bio.net From: Brian J Goldsmith Subject: October 1999 Internet Radiation Oncology Journal Club (IROJC) Message-ID: ****************************************************************** ****************************************************************** Dear Readers: Our apologies if you have already received this message. We had a system failure in the midst of yesterday's posting, and many of you on the mailing list failed to receive a copy. Serge Taylor BioSci Administrator ****************************************************************** ****************************************************************** October 1999 Internet Radiation Oncology Journal Club (IROJC) ------------------------------------------------------- Posting of references for review and discussion ------------------------------------------------------- The 53rdd collection of references suggested for attention and discussion by the IROJC's Board of Editors: Sarah Donaldson, M.D. Editor, Pediatric Radiation Oncology Robert Foote, M.D. Editor, Head and Neck / Skin Radiation Oncology Abram Recht, M.D. Editor, Breast Radiation Oncology Rich Hoppe, M.D. Editor, Reticuloendothelial System Radiation Oncology Dan Petereit, M.D. Editor, Gynecological Radiation Oncology Andrew Turrisi, M.D. Editor, Lung and Mediastinum Radiation Oncology Joel Tepper, M.D. Editor, Gastrointestinal and Soft Tissue Sarcoma Radiation Oncology Mack Roach, M.D. Editor, Genitourinary Radiation Oncology Glenn Bauman, M.D. Ph.D. Editor, Central Nervous System Radiation Oncology Rod Withers, M.D., D.Sc. Editor, Radiobiology ----------------------------------------------------- You're encouraged to critically review this set of references and respond by posting your comments to the IROJC readership at radoncjc@net.bio.net. Comments should be in compliance with IROJC commentary rules (see below). In the month that follows this posting of references, submitted comments will be delivered to the e-mail boxes of the IROJC readership, with the goal of stimulating a professional discussion of these references and their subjects. ------------------------------------------------------------ ARCHIVED IROJC POSTINGS and commentary are available on the World Wide Web! Look for them on http://www.bio.net/ Click on the "Access the BIOSCI/bionet Newsgroups" hyperlink, and then go to "RADIATION-ONCOLOGY/Prototype". Or directly access the RADIATION-ONCOLOGY folder at http://www.bio.net/hypermail/RADIATION-ONCOLOGY/ There's also a freeWAIS search tool at the website, for searching archived postings for keywords or phrases! ------------------------------------------------------------ Commentary Rules: (1) Please cite the subject category in the header of your e-mail message, e.g., Subject: CNS 10/99. (2) Address the readership at large - not the Editor who suggested the reference. The Editor is under no obligation to respond to questions posed by the IROJC readership. (3) The Editor's selection is not necessarily an endorsement of the authors' conclusions. In fact, articles may be selected for criticism. (4) Comments posted to the Internet are public. Professional wording is prudent. (5) Comment only on journal articles that you have read recently, and please keep comments specific. (6) In order to minimize confusion, limit comments to the current month's list of references. (7) Please sign all comments and questions to the IROJC. By identifying yourself, you promote a more collegial and friendly environment! (8) Address to the Moderator (briandeb@bellatlantic.net) private questions and comments which are not intended for IROJC posting and public reading. ****************** Peds: Donaldson 10/99 AU: Martelli H, Oberlin O, Rey A, Godzinski J, Spicer RD, Bouvet N, Haie-Meder C, Terrier-Lacombe M-J, Sanchez de Toledo J, Spooner D, Sommelet D, Flamant F, Stevens MCG. TI: Conservative treatment for girls with nonmetastatic rhabdomyosarcoma of the genital tract: a report from the Study Committee of the International Society of Pediatric Oncology. SO: J Clin Oncol 1999, 17(7): 2117-22 URL: http://www.jco.org/cgi/reprint/17/7/2117 Abstract: PURPOSE: To report the results of a conservative multimodal approach in girls with nonmetastatic rhabdomyosarcoma (RMS) of the genital tract, treated in International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumors 84 and 89 protocols. PATIENTS AND METHODS: From 1984 to 1994, 38 girls with RMS of the genital tract (vulva, vagina, uterus) were treated in SIOP protocols. With the exception of patients with rare small tumors, which were resected at the start of the studies, all patients received initial chemotherapy (CHT) (ifosfamide, vincristine, and actinomycin D). Local treatment including surgery, brachytherapy (BT), and external-beam radiotherapy (ERT) was given only to girls who did not achieve complete remission (CR) with CHT or who subsequently relapsed. RESULTS: The primary tumor originated in the vulva or vagina in 27 girls and in the uterus in 11. The overall survival rate (+/- SE) was 91% 6% at 5 years, and the event-free survival rate was 78% 7%. At a median follow-up of 5 years, 30 girls were alive and in first CR and five were alive and in second CR. Four patients treated with complete resection of the tumor at diagnosis received less CHT. Thirteen patients were treated with CHT alone. In 17 patients, local treatment was necessary to achieve complete local control, for a residual mass after initial CHT (10 patients), for viable tumor on biopsy (three patients), or for local relapse (four patients). The local treatment used was radiotherapy (RT) (ERT in three patients, BT in seven), radical surgery with uterine ablation (three patients), RT and radical surgery (three patients), and conservative surgery with RT (one patient). CONCLUSION: Girls with nonmetastatic RMS of the genital tract have an excellent prognosis. We found no difference in outcome between uterine and vulvovaginal RMS. Local treatment does not seem necessary in patients who have a complete response to CHT. When a local treatment is needed, BT may be an alternative to radical surgery or ERT. Editor's comments: The SIOP investigators have long recommended chemotherapy and conservative local therapy, oftentimes brachytherapy, as optimal treatment for young girls with genitourinary rhabdomyosarcoma. This report updates their previous publications and reports a large experience of 38 girls. Following from the SIOP experience, the Intergroup Rhabdomyosarcoma (IRSG) investigators recommend a similar approach with a few important differences. 1. The SIOP studies include all girls with vulva, vagina, and uterine primary tumors, and make the point that they see no difference in outcome beetween those with uterine tumors and those with vulvovaginal tumors. For girls with vaginal primary tumors, the new IRSG V protocols recommend primary chemotherapy, with interval biopsy, and if biopsy is positive, continue chemotheapy until week 28, and then local therapy with external beam or brachytherapy, but avoiding hysterectomy-cystectomy. Radical surgery is to be avoided. However for girls with vulva and uterine primary tumors, the decision for local therapy is not delayed to week 28, but is at week 3 for Clinical Group I and II, and at week 12 for those with Cl Group III. Response to chemotherapy is less good in this group than in those with vaginal tumors. Radiotherapy is used for all patients excepting those with complete resection at time of diagnosis. Patients with nodal disease receive slightly higher radiation doses, and patients with alveolar histology also receive more aggressive treatment than those with embryonal/botryoid histology. Thus, while the SIOP investigators conclude that local therapy is not necessary for patients with a complete response to chemotherapy, the IRSG investigators are more selective in coming to this conclusion based upon histology, time of second look surgery, site of primary tumor and nodal status. 2. Radical surgery should be avoided. 3. Nodal involvement requires nodal radiotherapy. 4. Brachytherapy is most useful for patients with localized vaginal tumors, but external beam is needed for those with uterine tumors. 5. Pathology following treatment may show maturing rhabdomyoblasts, which should not be mistaken for clonogenic tumor, and can be followed without major intervention. ****************** Head/Neck/Skin: Foote 10/99 AU: Nowak PJ, Wijers OB, Lagerwaard FJ, Levendag PC. TI: A three-dimensional CT-based target definition for elective irradiation of the neck. SO: Int J Radiat Oncol Biol Phys 1999 Aug 1;45(1):33-9. Abstract: INTRODUCTION: Elective treatment of the clinically node-negative neck by radiation results in excellent control rates. However, radiation therapy with its organ-preserving properties is not without morbidity. Side effects of elective neck irradiation are mainly due to damage of the major and minor salivary glands, resulting in the dry mouth syndrome. Given that RT is the preferred treatment modality in case of elective treatment of the neck in many institutions, it is of utmost importance to try and reduce the associated sequelae of RT. MATERIAL AND METHODS: With the introduction of CT-planning systems and the development of 3D conformal radiation therapy (3D CRT) techniques, it has become feasible to deliver adequate doses of radiation to the target (neck) and at the same time saving (parts of) the salivary glands from doses beyond tolerance. A prerequisite for these techniques is that they require a precise knowledge of the target (i.e., of the elective neck) on CT. To be able to correlate borders of the surgical levels in the neck (I-VI) with structures seen on CT, an anatomical study, using two fixed (phenol, formaldehyde) human cadavers, was performed. Subsequently, the 6 potential lymph node regions in the neck on CT were defined. RESULTS AND DISCUSSION: The reference for the current 3D CT-based definition of the lymph node regions in the neck is the official report of the American Academy of Otolaryngology, describing, based on surgical anatomy, the lymph node groups in the neck by Levels I-VI. The present investigation depicts reproducible landmarks on transversal CT images, corresponding to anatomical reference structures known from surgical levels (I-VI) and, this way, CT-based lymph node regions (1-6) were constructed. ****************** GYN: Petereit 10/99 No Reference Selected ****************** GI / Soft Tissue Sarcoma: Tepper 10/99 AU: Zhang ZX; Gu XZ; Yin WB; Huang GJ; Zhang DW; Zhang RG. TI: Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients. SO: Int J Radiat Oncol Biol Phys 1998 Dec 1;42(5):929-34. Abstract: PURPOSE: An attempt was made to define the role of radiotherapy before operation for AGC. METHODS AND MATERIALS: From January 1978 to May 1989, a prospective randomized trial on preoperative radiotherapy (R+S) vs. surgery alone (S) for AGC was carried out in 370 patients. Patients were randomized into a combined group (R+S, 171 patients) or a surgery alone group (S, 199 patients) by the envelope method. 8-MV photon or telecobalt was used for the preoperative radiation therapy, using anterior-posterior opposing parallel fields to deliver 40 Gy to the cardia, lower segment of the esophagus, fundus, lesser curvature, and hepatogastric ligament. Surgery was performed after 2 to 4 weeks rest. RESULTS: The 5- and 10-year survival rates of the R+S Group and the S Alone Group were 30.10% and 19.75%, 20.26% and 13.30%, respectively. The survival curves of these two groups diverged right from the beginning after the operation over the ninth year. Statistics by Kaplan- Meier log rank test proves that the difference is significant (chi2 equals 6.74, p equals 0.0094). The immediate results were: resection rate 89.5% and 79.4% (p less than 0.01); pathologic stage after resection T2 12.9% and 4.5% (p less than 0.01), T4 40.3% and 51.3% (p less than 0.05), lymph node metastasis rates 64.3% and 84.9% (p less than 0.001); operative mortality rates 0.6% and 2.5%; intrathoracic leak rates 1.8% and 4.0%, respectively. The causes of failure were: local uncontrol and recurrence 38.6% vs. 51.7% (p less than 0.025), regional lymph node metastasis 38.6% vs. 54.6% (p less than 0.005), distant metastasis 24.3% vs. 24.7%. CONCLUSION: Preoperative radiation therapy is able to improve the results of surgery for adenocarcinoma of the gastric cardia. Editor's comments: Although the incidence of gastric cancer has been decreasing in the United States, the incidence of adenocarcinoma of the gastric cardia has been increasing in conjunction with the increasing incidence of esophageal adenocarcinoma. The epidemiology of these two diseases seem similar. Since both diseases are increasing this is not just a matter of definition. However, it is possible that both of these diseases have similar biological characteristics, even though the esophageal cancers tend to arise in Barret's esophagus. This paper indirectly raises the interesting question of whether we should be managing patients with gastric cardia lesions the same way we are managing esophageal cancers, which for many institutions is preoperative radiation plus chemotherapy. The data from this Chinese report show improved survival and local control after preoperative irradiation in a relatively large cohort of patients. Of note is that the radiation fields were more akin to a standard esophageal field than to what many people in the US use for gastric cancer (in the circumstances when it is used). The fact that no chemotherapy was used in this trial makes it difficult to directly apply the results to US practice since there have been a few studies of postoperative adjuvant RT for gastric cancer that have shown improved local control but no survival difference. This study again emphasizes the fact that local failure is a substantial problem in gastric cancer and that improved local therapy could be of value. We are still awaiting the results of the Intergroup trial that tested postoperative RT + FU based chemotherapy in all gastric cancers. However, because of the epidemiology issues, it would not be surprising if the cardia lesions behave differently than mid and distal gastric cancers. ****************** CNS: Bauman 10/99 AU: Fitzek MM; Thornton AF; Rabinov JD; Lev MH; Pardo FS; Munzenrider JE; Okunieff P; Bussiere M; Braun I; Hochberg FH; Hedley-Whyte ET; Liebsch NJ; Harsh GR 4th. TI: Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial. SO: J Neurosurg 1999 Aug;91(2):251-60. Abstract OBJECT: After conventional doses of 55 to 65 Gy of fractionated irradiation, glioblastoma multiforme (GBM) usually recurs at its original location. This institutional phase II study was designed to assess whether dose escalation to 90 cobalt gray equivalent (CGE) with conformal protons and photons in accelerated fractionation would improve local tumor control and patient survival. METHODS: Twenty-three patients were enrolled in this study. Eligibility criteria included age between 18 and 70 years, Karnofsky Performance Scale score of greater than or equal to 70, residual tumor volume of less than 60 ml, and a supratentorial, unilateral tumor. Actuarial survival rates at 2 and 3 years were 34% and 18%, respectively. The median survival time was 20 months, with four patients alive 22 to 60 months postdiagnosis. Analysis by Radiation Therapy Oncology Group prognostic criteria or Medical Research Council indices showed a 5- to 11-month increase in median survival time over those of comparable conventionally treated patients. All patients developed new areas of gadolinium enhancement during the follow-up period. Histological examination of tissues obtained at biopsy, resection, or autopsy was conducted in 15 of 23 patients. Radiation necrosis only was demonstrated in seven patients, and their survival was significantly longer than that of patients with recurrent tumor (p equals 0.01). Tumor regrowth occurred most commonly in areas that received doses of 60 to 70 CGE or less; recurrent tumor was found in only one case in the 90-CGE volume. CONCLUSIONS: A dose of 90 CGE in accelerated fractionation prevented central recurrence in almost all cases. The median survival time was extended to 20 months, likely as a result of central control. Tumors will usually recur in areas immediately peripheral to this 90-CGE volume, but attempts to extend local control by enlarging the central volume are likely to be limited by difficulties with radiation necrosis. Editor's comments: This is a well designed, meticulously documented prospective protocol evaluating the value of dose escalation using combined conformal photon and proton beam radiation. All patients received PCV chemotherapy subsequent to total radiation doses of 90 Cobalt Gray Equivalent delivered by shrinking fields to initially the MRI T2 volume +2 cm (50.4 Gy), then the T1 enhanced volume + 2cm (64.8Gy), and finally to the T1 enhanced volume alone (90Gy). ****************** Breast: Recht 10/99 AU: Ballo MT; Strom EA; Prost H; Singletary SE; Theriault RL; Buchholz TA; McNeese MD. TI: Local-regional control of recurrent breast carcinoma after mastectomy: does hyperfractionated accelerated radiotherapy improve local control? SO: Int J Radiat Oncol Biol Phys 1999 Apr 1;44(1):105-12. Abstract: PURPOSE: Hyperfractionated, accelerated radiotherapy (HART) has been advocated for patients with local-regionally recurrent breast cancer because it is believed to enhance treatment effects in rapidly proliferating or chemoresistant tumors. This report examines the value of HART in patients with local-regionally recurrent breast cancer treated with multimodality therapy. METHODS AND MATERIALS: The study included 148 patients with local-regionally recurrent breast cancer after mastectomy, who were treated with definitive local irradiation and systemic therapy consisting of either tamoxifen, cytotoxic chemotherapy, or both, along with excision of the recurrent tumor when possible. Patients with distant metastases were excluded, except for two patients with ipsilateral supraclavicular nodal metastases. Patients received comprehensive irradiation to the chest wall and regional lymphatics to a median dose of 45 Gy, with a boost to 60 Gy to areas of recurrence. Sixty-eight patients (46%) were treated once daily at 2 Gy/fraction (fx), and 80 (54%) were treated twice daily at 1.5 Gy/fx. Forty-eight patients (32%), who had palpable gross disease that was unresponsive to systemic therapy and/or unresectable, were irradiated. The median follow-up time of surviving patients was 78 months. RESULTS: Overall actuarial local-regional control (LRC) rates at 5 and 10 years were 68% and 55%, respectively. Five- and ten-year actuarial overall survival (OS) and disease-free survival (DFS) rates were 50% and 35%, 39% and 29%, respectively. Univariate analysis revealed that LRC was adversely affected by 1. advanced initial American Joint Committee on Cancer (AJCC) stage (p equals 0.001), 2. clinically evident residual disease at time of treatment (p less than 0.0001), 3. more than three positive nodes at initial mastectomy (p equals 0.014), 4. short interval from mastectomy to recurrence (less than 24 months, p equals 0.0007), 5. nuclear grade (III vs. I or II, p equals 0.045), and 6. number of recurrent nodules (1 vs. greater than 1, p equals 0.02). Patient age at time of recurrence (less than 40 vs. greater than or equal to 40 years), recurrence location on the chest wall, estrogen receptor status, progesterone receptor status or menopausal status did not adversely affect LRC. On multivariate analysis, only clinically evident residual disease at the time of treatment and short interval from mastectomy to recurrence remained significant. When once-a-day irradiation was compared to the twice-a- day schedule, no significant differences were seen in LRC (67% vs. 68%), OS (47% vs. 52%), or DFS (42% vs. 36%) for the entire group of patients at 5 years. Pairwise comparison of the two fractionation schedules in each of the adverse outcome subgroups identified above showed no clinically significant differences in LRC at 5 years. For the 48 patients who began radiotherapy with measurable gross local recurrence, the complete response rate to radiotherapy was 73%, with no difference seen between the two fractionation schedules. The incidence of acute and chronic radiation-related complications was similar in both treatment groups. CONCLUSIONS: Hyperfractionated accelerated radiotherapy, although well tolerated by patients with local-regionally recurrent breast cancer, did not result in superior local-regional control rates when compared to daily fractionated regimens. Alternative strategies, such as dose escalation or chemoradiation, may be required to improve control. Editor's comments: There have been few studies of "altered" fractionation schemes for the local-regional treatment of breast cancer patients. This article is an important contribution to this small literature. Although fractionation schemes were not randomly allocated, the patients treated with accelerated hyperfractionation and conventional fractionation were quite comparable. The results of treatment for these two groups were nearly identical. The interpretation of these results is not so clear, as they could mean that: a) the kinetics of breast cancer growth are such (i.e., fairly slowly proliferating) that acceleration of treatment time will have little or no impact); b) tumors that are sensitive to radiation are equally sensitive, regardless of the overall time to complete treatment, and tumors that are resistant will be resistant similarly; c) the "wrong" fractionation scheme or total dose was chosen for the acceleration; or d) all of the above. (I would tend to favor explanation "a", although this is speculation.) This study is also an important benchmark for the results that can be achieved for patients with local-regional failure following mastectomy in the current era. Note that all patients received systemic therapy; this may be one reason why they have a 10-year disease-free survival rate of 35%, which is better than any other reported series. ****************** RES: Hoppe 10/99 AU: Tondini C, Ferreri AJM, Siracusano L, Valagussa P, Giardini R, Rampinelli I, Bonadonna G. TI: Diffuse large-cell lymphoma of the testis SO: J Clin Oncol 1999, 17(9): 2854-58. Abstract: PURPOSE: To evaluate clinical outcome of patients with testicular diffuse large-cell lymphoma treated with conventional-dose systemic chemotherapy. PATIENTS AND METHODS: This study is a retrospective analysis of adult patients with testicular diffuse large-cell lymphoma who were treated with a doxorubicin-based chemotherapy regimen at our institution, the Istituto Nazionale Tumori of Milan. Twenty-nine assessable patients, with a median age of 61 years, were identified. Sixteen patients had limited stage (Ann Arbor stage I/II) disease, whereas 13 patients had a testicular mass and distant organ involvement (Ann Arbor stage IV). Patients were retrospectively classified according to the International Prognostic Index. RESULTS: After a median follow-up of 82 months, 22 patients presented disease progression and 22 patients had died. Actuarial median time to treatment failure and overall survival were 44 and 41 months for patients with limited stage and 9 and 16 months for patients with advanced stage, respectively. Eight patients failed initial treatment, and 14 patients relapsed from clinical remission after a median disease-free time of 17 months (range, 6 to 98 months). Median survival time after progression of lymphoma was 5 months (range, 0 to 22 months). In nine (41%) of the 22 failing patients, the initial site of relapse was either the CNS or the contralateral testis; the remaining patients experienced relapse in multiple extranodal sites. CONCLUSION: Poor prognosis of patients with diffuse large-cell lymphoma calls for more effective treatment strategies, such as high-dose chemotherapy programs for younger patients or specifically designed chemotherapy regimens for patients not suitable for high-dose treatment, with the purpose to provide control of both systemic disease and disease of the CNS and contralateral testis. The potential benefit of contralateral testicular irradiation has to be taken into account in the treatment planning. Editor's comments: Primary testicular lymphoma is uncommon, but you may hear about one at next week's tumor board! This series included early (stage I-II) and advanced (Stage IV) patients, treated with chemo. Some had RT to retroperitoneal nodes, some had RT to ipsilateral scrotum (if original testicular mass was greater than 10 cm). None had CNS prophylaxis or contralateral testicular RT. In general, the outcome of treatment for these patients was much worse than would be expected for equivalent stage extra-testicular presentations of DLC lymphoma. A good analysis of failure pattern was completed. Overall, 22/29 (76%) patients suffered a relapse. Fourteen of these patients (64%) had a component of failure that included the CNS or contralateral testis and in 9 (41%) failure was limited to the CNS/contralateral testis. This study once again confirms the importance of CNS prophylaxis (usually with IT MTX) and contralateral testicular irradiation for patients who present with testicular lymphoma. ****************** Lung/Mediastinum: Turrisi 10/99 AU: Furuse K, Kawahara M, Nishiwaki Y, Fukuoka M, Takada M, Miyashita M, Ohashi Y. TI: Phase I/II study of vinorelbine, mitomycin, and cisplatin for stage IIIB or IV non-small-cell lung cancer. SO: J Clin Oncol 1999, 17(10): 3195-3200 URL: http://www.jco.org/cgi/content/abstract/17/10/3195 Abstract: PURPOSE: To determine the maximum-tolerated doses (MTDs) of vinorelbine (VRB), mitomycin (MMC), and cisplatin (P), given in two courses every 28 days to previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: At least three or four patients were entered at each dose level. The starting dose was 20 mg/m2 for VRB on days 1 and 8 and 4 mg/m2 for MMC on day 1, with a fixed dose of P 80 mg/m2 on day 1 every 4 weeks. MMC was increased to 6 mg/m2 at dose level 2 and subsequently to 8 mg/m2 at dose level 4. At dose level 3, VRB was increased to 25 mg/m2. Twenty-five patients were entered onto the phase I study and 19 patients were entered onto phase II study. RESULTS: Nadir leukocyte and platelet counts decreased at each dose level. At dose levels 1 and 2, the dose-limiting toxicity (DLT) was not seen, but at dose levels 3 and 4, DLT was encountered in two patients. Nearly half the patients at dose level 4 had dose reduction due to grade 4 leukopenia. A mathematic model of all toxicity suggested that dose level 4 (VRB 25 mg/m2 on days 1 and 8 and MMC 8 mg/m2 and P 80 mg/m2 on day 1, every 4 weeks) would be the recommended dose for phase II study at which grade 4 toxicity is expected in 25% of patients over two courses. Of the 25 assessable patients in the phase I study, 13 achieved a partial response and one had a complete response for a response rate of 56.0%. Of the 19 assessable patients in the phase II study, 12 had a partial response (63.2%; 95% confidence interval, 38.4% to 83.7%). Grade 3 and 4 leukopenia was observed in 19 (100%), and grade 3 thrombocytopenia was seen in seven (36.8%). Median survival time was 10.7 months and the 1-year survival rate was 43.2% in the 44 assessable patients. CONCLUSION: The VRB/MMC/P regimen is effective against NSCLC, and its efficacy should be confirmed through a randomized study. Editor's comments: There are a series of very important lung papers that I want to deliver to your attention over the next few months, including issues about SCLC BID treatment, extensive disease treatment with thoracic radiotherapy, and prophylactic cranial radiotherapy in NSCLC. This will bring us to the year 2000 literally, but the answers to these issues will take many more years. The paper I've selected is seminal. It questions the established norm that sequential therapy is better because it causes less toxicity. Our practitioners ask and the most oft asked question at conferences is what is standard therapy and what do you do off protocol. Radiotherapy alone for stage III NSCLC is inferior treatment, at least with doses of 60 Gy QD to 69.6 Gy BID in a hyperfractionated scheme. The basis for the chemo followed by 60 Gy as our current benchmark is the hallowed CALGB 8433 - truly a trend setter. However, the drugs used then, as in the important study reported by Dr. Furuse, are dated, and infrequently used today. It is crucial to explore whether the benefits of a mere two cycles of chemotherapy, vinblastine and cisPlatin, can be re-confirmed with other drugs -- mitomycin in this case, or the current trend of a taxane and carboplatin or any other "new" drug combination (gemcitabine; vinorelbine, the topoisomerase inhibitory drugs both I and II). Many have criticized the use of cisplatin/etoposide in NSCLC -- criticism not based on survival observations or randomized data, but on the fact that etoposide is not a very active drug against NSCLC in phase II studies. The Memorial group of the 80's led us to an "MVP" like combination; our Japanese colleagues have adopted it for the randomized trial. Are these observations applicable if we use Other drugs? I don't know. The question of sequence is important. This study suggests that there is a benefit to concurrent therapy even when we use radiotherapy in a less effective but potentially less toxic way. Some have editorialized that the toxicity of concurrent therapy isn't worth it. This study confronts that assertion and says that it is incorrect. However, we must live in the real world, and the oncologists are not using vinblastine or vindesine. I've argued that mitomycin is associated with increased toxicity and should not be used. Interestingly, Ohe at ASCO this year educated me that, in a retrospective study from Japan, they actually found no excess toxicity in their mitomycin treated group, and as much or more with etoposide - cisplatin. North American toxicity reports do not always line up with observations from Japanese populations. We have different frequencies of esophageal toxicity all the time, and I'm not yet convinced that we should bring back mitomycin. On the other hand, I'm not sure how to apply these data to the drugs now in popular use around the world. RTOG 9410 asks a similar question, uses vinblastine and cisplatin in two arms and oral etoposide and cisplatin with the continuous contender, 69.6 BID. We need results from that study to help us understand. The immoderate assertions that sequential is king is now tottering. The wholesale substitution of carboplatin is not data but market driven. The fact that concurrent is indeed better is also not secure. However, the practice of too many cycles of systemic therapy before radiotherapy is not bolstered by data. The current practice of concurrent therapy is the control in many trials, frequently associated with two cycles first. The CALGB 8433 -- cisplatin-vinblastine before 60 Gy -- standard is just not used very much. We need to see the RTOG results to further interpret what to do with the Furuse data. We need a little more data to be secure that whatever the increased toxicity in North American patients, that this price is worth the survival benefit. Until then we rely on the phase II reports of the new drugs, the over-excitement about response rates, and the hypoerventilated ehthusiasms of pharmaceutical industry sponsored trials and pundits that see the future clearer than I do. ****************** GU: Roach 10/99 AU: Akakura K; Isaka S; Akimoto S; Ito H; Okada K; Hachiya T; Yoshida O; Arai Y; Usami M; Kotake T; Tobisu K; Ohashi Y; Sumiyoshi Y; Kakizoe T; Shimazaki J TI: Long-term results of a randomized trial for the treatment of Stages B2 and C prostate cancer: radical prostatectomy versus external beam radiation therapy with a common endocrine therapy in both modalities. SO: Urology 1999 Aug;54(2):313-8. Abstract: OBJECTIVES: To improve the treatment of locally advanced prostate cancer (Stages B2 and C), a prospective randomized trial was conducted to compare radical prostatectomy versus external beam radiotherapy with the combination of endocrine therapy in both modalities. METHODS: One hundred patients were enrolled and 95 were evaluated. Forty-six patients underwent radical prostatectomy with pelvic lymph node dissection, and 49 were treated with radiation by linear accelerator with 40 to 50 Gy to the whole pelvis and a 20-Gy boost to the prostatic area. For all patients, endocrine therapy was initiated 8 weeks before surgery or radiation, and continued thereafter. The living patients were asked to respond to a quality-of-life questionnaire. RESULTS: The follow-up period ranged from 6.0 to 94.4 months (median 58.5). The progression-free and cause-specific survival rates at 5 years were 90.5% and 96.6% in the surgery group and 81.2% and 84.6% in the radiation group, respectively. The surgery group had better progression- free and cause-specific survival rates (P equals 0.044 and 0.024, respectively). More patients in the surgery group complained of urinary incontinence. The questionnaire revealed that quality of life was less disturbed in the radiation group. CONCLUSIONS: Radical prostatectomy combined with endocrine therapy may contribute to the survival benefit of patients with locally advanced prostate cancer. External beam radiotherapy in combination with endocrine therapy can be used in selected patients because of its low morbidity. Editor's comments: It is frequently stated that there are no prospective randomized trials in the modern era comparing surgery vs radiation in the treatment of prostate cancer. Unfortunately, this is not true. In fact, a recently published series from Japan suggests the surgery combined with endocrine therapy may be more effective than radiation in the treatment of prostate cancer. However, this study is so flawed as to be interpretable and thus, does not help to resolve this question. In the brief there are several major flaws worth special comment. First, it is a very small study being composed of 46 men who underwent radical prostatectomy and 49 treated with radiotherapy. The dose of radiotherapy is said to have been 40 to 50 gray to the whole pelvis, with a 20 gray boost to the prostate area. No information is provided as to how many men received 60Gy and how many 70Gy. None of the co-authors are described as being members of a department of radiation oncology. There are no specific details are given regarding the specific treatment techniques used, where the doses prescribed or the field sizes used. Also, of concern, a slightly higher percentage of patients had poorly differentiated tumors in the radiotherapy group (33% compared to 25% in the surgery arm) and a higher percentage of patients had clinical T3 disease (73% compared to 63% in the surgery arm). The most glaring difficulty, however, was the definition of progression free survival, which was defined as local regrowth of tumor and/or appearance of distant metastasis including bone mets. Elevation of PSA alone was not used as a sign of progression. Therefore, a patient who was treated with radical prostatectomy but a rising PSA would not be considered a failure. However a patient who was treated with radiotherapy was considered a failure, if the urologist who did a digital exam and believed that there was evidence of progressive disease locally. Patients who died of any cause who had progression, defined in this manner were considered to have died of prostate cancer. Other problems with this reports includes the fact that among the patients developing recurrences, one in the surgical series and three in the radiation therapy series had local regrowth of tumor. However, two additional patients treated in the radiotherapy series had "unknown" modes of progression. So, five of the twelve patients either had local regrowth or unknown modes of growth, both of which are unreliable endpoints for defining the control rate with surgery or radiation. With a median follow-up time of less than five years, six patients had metastasis in the radiotherapy arm, compared to two in the surgical arm despite the continued use of hormonal therapy. There was no statistically significant difference in overall survival between the two arms however. Because cause-specific survival depended upon the definition of progression free survival, the definition for progression free survival is critical to the evaluation of the study. Ignoring biochemical failure as a valid endpoint for determining control of disease leaves too many questions unanswered. Perceptions about persistent and local disease after radical prostatectomy have been shown to be inaccurate, just as they have been after radiation. For these reasons, it is important that future studies design endpoints that are likely to be more accurate than digital rectal exams. Beware of the small prospective randomized trial which finds no difference in overall survival, which fails to use the most sensitive determinant of failure and fails to give adequate radiotherapy ****************** Radiobiology: Withers 10/99 No Reference Selected ****************** Brian J. Goldsmith, M.D. Moderator, IROJC --- End Forwarded Message --- ---------------------- Serge Taylor jstaylor@sulmail.stanford.edu From daemon Thu Oct 7 10:43:26 1999 Received: (from daemon@localhost) by net.bio.net (8.9.1a/8.9.1) id KAA02118; Thu, 7 Oct 1999 10:43:26 -0700 (PDT) Message-Id: <199910071743.KAA02118@net.bio.net> To: radoncjc@net.bio.net Subject: ERRATUM October 1999 IROJC: Lung/Mediastinum Reply-To: radoncjc@net.bio.net Date: Thu, 07 Oct 1999 13:17:29 -0400 From: Brian Goldsmith ERRATUM October 1999 IROJC: Lung/Mediastinum ****************** The Oct99 IROJC initial posting erroneously appended the wrong reference and abstract to Dr. Turrisi's commentary. The correct reference and abstract, with comments, are attached below. Please amend your archives. I sincerely apologize for the inconvenience. Also supplied are links to the JCO website for the correct abstract and full text article (in PDF format). Brian Goldsmith, M.D. Moderator, IROJC ****************** Lung/Mediastinum: Turrisi 10/99 AU: Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, Katagami N, Ariyoshi Y, for the West Japan Lung Cancer Group. TI: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non–small-cell lung cancer. SO: J Clin Oncol 1999, 17(9): 2692-99 URL: http://www.jco.org/cgi/content/abstract/17/9/2692 Full Text Article (PDF): http://www.jco.org/cgi/reprint/17/9/2692.pdf Abstract: PURPOSE: A phase III study was performed to determine whether concurrent or sequential treatment with radiotherapy (RT) and chemotherapy (CT) improvessurvival in unresectable stage III non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were assigned to the two treatment arms. In the concurrent arm, chemotherapy consisted of cisplatin (80 mg/m2 on days 1 and 29), vindesine (3 mg/m2 on days 1, 8, 29, and 36), and mitomycin (8 mg/m2 on days 1 and 29). RT began on day 2 at a dose of 28 Gy (2 Gy per fraction and 5 fractions per week for a total of 14 fractions) followed by a rest period of 10 days, and then repeated. In the sequential arm, the same CT was given, but RT was initiated after completing CT and consisted of 56 Gy (2 Gy per fraction and 5 fractions per week for a total of 28 fractions). RESULTS: Three hundred twenty patients were entered onto the study. Pretreatment characteristics were well balanced between the treatment arms. The response rate for the concurrent arm was significantly higher(84.0%) than that of the sequential arm (66%) (P equals .0002). The median survival duration was significantly superior in patients receiving concurrent therapy (16.5 months), as compared with those receiving sequential therapy (13.3 months) (P equals .03998). Two-, 3-, 4-, and 5-year survival rates in the concurrent group (34.6%, 22.3%, 16.9%, and 15.8%, respectively) were better than those in the sequential group (27.4%, 14.7%, 10.1%, and 8.9%, respectively). Myelosuppression was significantly greater among patients on the concurrent arm than on the sequential arm (P equals .0001). CONCLUSION: In selected patients with unresectable stage III NSCLC, the concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach. Editor's comments: There are a series of very important lung papers that I want to deliver to your attention over the next few months, including issues about SCLC BID treatment, extensive disease treatment with thoracic radiotherapy, and prophylactic cranial radiotherapy in NSCLC. This will bring us to the year 2000 literally, but the answers to these issues will take many more years. The paper I've selected is seminal. It questions the established norm that sequential therapy is better because it causes less toxicity. Our practitioners ask and the most oft asked question at conferences is what is standard therapy and what do you do off protocol. Radiotherapy alone for stage III NSCLC is inferior treatment, at least with doses of 60 Gy QD to 69.6 Gy BID in a hyperfractionated scheme. The basis for the chemo followed by 60 Gy as our current benchmark is the hallowed CALGB 8433 - truly a trend setter. However, the drugs used then, as in the important study reported by Dr. Furuse, are dated, and infrequently used today. It is crucial to explore whether the benefits of a mere two cycles of chemotherapy, vinblastine and cisPlatin, can be re-confirmed with other drugs -- mitomycin in this case, or the current trend of a taxane and carboplatin or any other "new" drug combination (gemcitabine; vinorelbine, the topoisomerase inhibitory drugs both I and II). Many have criticized the use of cisplatin/etoposide in NSCLC -- criticism not based on survival observations or randomized data, but on the fact that etoposide is not a very active drug against NSCLC in phase II studies. The Memorial group of the 80's led us to an "MVP" like combination; our Japanese colleagues have adopted it for the randomized trial. Are these observations applicable if we use Other drugs? I don't know. The question of sequence is important. This study suggests that there is a benefit to concurrent therapy even when we use radiotherapy in a less effective but potentially less toxic way. Some have editorialized that the toxicity of concurrent therapy isn't worth it. This study confronts that assertion and says that it is incorrect. However, we must live in the real world, and the oncologists are not using vinblastine or vindesine. I've argued that mitomycin is associated with increased toxicity and should not be used. Interestingly, Ohe at ASCO this year educated me that, in a retrospective study from Japan, they actually found no excess toxicity in their mitomycin treated group, and as much or more with etoposide - cisplatin. North American toxicity reports do not always line up with observations from Japanese populations. We have different frequencies of esophageal toxicity all the time, and I'm not yet convinced that we should bring back mitomycin. On the other hand, I'm not sure how to apply these data to the drugs now in popular use around the world. RTOG 9410 asks a similar question, uses vinblastine and cisplatin in two arms and oral etoposide and cisplatin with the continuous contender, 69.6 BID. We need results from that study to help us understand. The immoderate assertions that sequential is king is now tottering. The wholesale substitution of carboplatin is not data but market driven. The fact that concurrent is indeed better is also not secure. However, the practice of too many cycles of systemic therapy before radiotherapy is not bolstered by data. The current practice of concurrent therapy is the control in many trials, frequently associated with two cycles first. The CALGB 8433 -- cisplatin-vinblastine before 60 Gy -- standard is just not used very much. We need to see the RTOG results to further interpret what to do with the Furuse data. We need a little more data to be secure that whatever the increased toxicity in North American patients, that this price is worth the survival benefit. Until then we rely on the phase II reports of the new drugs, the over-excitement about response rates, and the hypoerventilated ehthusiasms of pharmaceutical industry sponsored trials and pundits that see the future clearer than I do. From daemon Thu Oct 7 10:57:07 1999 Received: by net.bio.net (8.9.1a/8.9.1) id KAA04588; Thu, 7 Oct 1999 10:57:07 -0700 (PDT) Message-Id: <199910071757.KAA04588@net.bio.net> To: radoncjc@net.bio.net Subject: ERRATUM October 1999 IROJC: CNS Reply-To: radoncjc@net.bio.net Date: Thu, 07 Oct 1999 13:33:59 -0400 From: Brian Goldsmith ERRATUM October 1999 IROJC: CNS ****************** Dr. Bauman's CNS editorial comments were inadvertantly truncated. The reference and abstract, with complete commentary, are attached below. Please amend your archives. I sincerely apologize for the inconvenience. Brian Goldsmith, M.D. Moderator, IROJC ****************** CNS: Bauman 10/99 AU: Fitzek MM; Thornton AF; Rabinov JD; Lev MH; Pardo FS; Munzenrider JE; Okunieff P; Bussiere M; Braun I; Hochberg FH; Hedley-Whyte ET; Liebsch NJ; Harsh GR 4th. TI: Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial. SO: J Neurosurg 1999 Aug;91(2):251-60. Abstract OBJECT: After conventional doses of 55 to 65 Gy of fractionated irradiation, glioblastoma multiforme (GBM) usually recurs at its original location. This institutional phase II study was designed to assess whether dose escalation to 90 cobalt gray equivalent (CGE) with conformal protons and photons in accelerated fractionation would improve local tumor control and patient survival. METHODS: Twenty-three patients were enrolled in this study. Eligibility criteria included age between 18 and 70 years, Karnofsky Performance Scale score of greater than or equal to 70, residual tumor volume of less than 60 ml, and a supratentorial, unilateral tumor. Actuarial survival rates at 2 and 3 years were 34% and 18% respectively. The median survival time was 20 months, with four patients alive 22 to 60 months postdiagnosis. Analysis by Radiation Therapy Oncology Group prognostic criteria or Medical Research Council indices showed a 5- to 11-month increase in median survival time over those of comparable conventionally treated patients. All patients developed new areas of gadolinium enhancement during the follow-up period. Histological examination of tissues obtained at biopsy, resection, or autopsy was conducted in 15 of 23 patients. Radiation necrosis only was demonstrated in seven patients, and their survival was significantly longer than that of patients with recurrent tumor (p equals 0.01). Tumor regrowth occurred most commonly in areas that received doses of 60 to 70 CGE or less; recurrent tumor was found in only one case in the 90-CGE volume. CONCLUSIONS: A dose of 90 CGE in accelerated fractionation prevented central recurrence in almost all cases. The median survival time was extended to 20 months, likely as a result of central control. Tumors will usually recur in areas immediately peripheral to this 90-CGE volume, but attempts to extend local control by enlarging the central volume are likely to be limited by difficulties with radiation necrosis. Editor's comments: This is a well designed, meticulously documented prospective protocol evaluating the value of dose escalation using combined conformal photon and proton beam radiation. All patients received PCV chemotherapy subsequent to total radiation doses of 90 Cobalt Gray Equivalent delivered by shrinking fields to initially the MRI T2 volume +2 cm (50.4 Gy), then the T1 enhanced volume + 2cm (64.8Gy), and finally to the T1 enhanced volume alone (90Gy). Like other conformal, dose escalated treatments (radiosurgery, brachytherapy boost, conformal photon dose escalation), modest (5-6 mo, within RTOG RPA strata) improvements in survival were noted at a cost of considerable toxicity (re-operation for necrosis, steroid dependancy etc). Novel strategies to address the invasive component (beyond modest dose RT to areas at risk and standard chemotherapy agents) of high grade gliomas are likely necessary before the benefit of improved central control with dose escalation will be translated into improved patient outcome. From daemon Tue Oct 26 10:01:24 1999 Received: by net.bio.net (8.9.1a/8.9.1) id KAA29888; Tue, 26 Oct 1999 10:01:24 -0700 (PDT) Message-Id: <199910261701.KAA29888@net.bio.net> To: radoncjc@net.bio.net Subject: October 1999 IROJC: Lung/Mediastinum (re Furuse et al, JCO Reply-To: radoncjc@net.bio.net Date: Tue, 26 Oct 1999 08:31:21 -0700 (PDT) From: Tim Sawyer I agree with Dr. Turrisi's comments regarding the recently published lung cancer manuscript by Furuse et al, and definitely agree that the manuscript provides yet another hint regarding the advantages of concurrent (as opposed to sequential) therapy for non-small cell lung cancer (NSCLC). I am writing this, though, because I am hearing some physicians say that this now establishes the standard of care. I disagree, and I don't think I'm being overly picky when I say that the Furuse trial design has some major limitations. I'll describe the most significant one. Although the authors downplay this in the discussion, I don't think it's possible to overstate the significance of the fact that patients in the concurrent arm of this trial received more chemotherapy. Specifically, 59 % of the concurrent patients, versus 25 % of the sequential patients, received 3-4 cycles! Could the additional chemotherapy have made the difference? I don't know - but there is plenty of evidence in the lung cancer literature that says maybe. Although the comparison is admittedly rough, one could say that the sequential (control) arm of the Furuse study - 2 cycles of cisplatin, vindesine, and mitomycin followed by 56 Gy - is approximately equivalent to the sequential (positive) arm in CALGB 8433, namely 2 cycles of cisplatin and vinblastine followed by 60 Gy. If so, one may become convinced that - by establishing that Dr. Furuse's concurrent chemo-XRT regimen is superior to a regimen which is very similar to the sequential (positive) CALGB arm - the Furuse study has established a new standard of care. However, even if I believed in the validity of making inter-study comparisons such as these (which I don't), I would have no way of knowing whether Furuse's concurrent regimen is superior because it is concurrent, or because additional chemotherapy was given to a significant percentage of the concurrent patients. My guess is that concurrent chemoradiation will become the standard of care, if it hasn't already. But my bias toward concurrent therapy arises more from extrapolation from other disease sites, promising phase II data, and (yes, I admit it) gestalt than from the Furuse data. I look forward to more definitive data, using more modern chemotherapy. Tim Sawyer, MD From daemon Wed Oct 27 12:08:24 1999 Received: by net.bio.net (8.9.1a/8.9.1) id MAA25343; Wed, 27 Oct 1999 12:08:24 -0700 (PDT) Message-Id: <199910271908.MAA25343@net.bio.net> To: radoncjc@net.bio.net Date: Tue, 26 Oct 1999 17:10:34-0400 Reply-To: radoncjc@net.bio.net From: "Turrisi, Andrew" Subject: RE: October 1999 IROJC: Lung/Mediastinum (re Furuse et al) Just a quick note to this -- the search for standards is a bit off-putting. We do so marginally in NSCLC that it is impossible to say that one is clearly better than the other. Perhaps getting two more cycles of MVP makes a difference; perhaps it is more the timing. But one study does not set a standard. And clinical practice is influenced by more than clinical research -- not too many people are using MVP in the US, a lot are using carboplatinum taxol despite a number of studies showing equivalence to the old studies and vinorelbine platinum (or carboplatinum if you have left platinum for the more silver lining of carbo!) or even gemcitabine platinum as used in Europe. These cannot be used interchangeably with radiotherapy to the chest. And Japanese esophageal toxicity seems to be very different from what is seen in North America. The RTOG 9410 study uses vinorelbine-platinum just like the CALGB study. It should be reported soon, as well as a BID to 69.6 Gy and platinum etoposide. Although some still hail MVP as a standard and despite a paucity of lung toxicity with the addition of mitomycin C in Japan, mitomycin improves response but has no proven value in survival, and has been associated with more toxicity in US trials. Saying all this merely underscores that we have too much uncertainties to expect "standards" so the control arm will need to be negotiated -- it's far from clear. Drew Turrisi