Clinical Downstaging Research Articles

Concurrent radiotherapy (RT) and chemotherapy (CT) with oxaliplatin as primary treatment of advanced rectal cancer: a phase II study

13507 Background: Combined pre-operative RT and CT increase the possibility for conservative surgery in locally advanced rectal cancer. Most clinical trials show that responding patients could obtain a reduction of local relapse and an improvement of overall survival, especially when a complete pathological response is obtained (pCR 9–29%). The aim of our study was to determine the activity of RT concomitant to oxaliplatin (OHP) in combination with c.i. 5-fluorouracil (5FU). Methods: Primary endpoint was pCR. Sample size was defined according to Simon Two-Stage phase II design (planned sample size: 29 evaluable patients). From May 2002 to November 2005, 33 patients (15 males, 18 females) were enrolled: median age was 64 years (range 21–74); clinical stage was cT3/cT4 cN0 or cTany cN+ M0. In 24 patients rectal cancer was ≤ 5 cm from anal verge. Weekly OHP 60 mg/m2 was administered in combination with c.i. 5FU 225 mg/ m2 for 5 days per week. Twelve patients received conventional RT (CRT): 25 fractions with 1.8 Gy, total dose 50.4 Gy on the pelvis and a boost on tumor bed with 3 fractions of 1.8 Gy. 21 patients received hyperfractionated RT (HRT): 1.2 Gy b.i.d. for 5 days per week for 4 weeks and a concomitant boost on tumor bed with daily 3 Gy (total dose 54–56 Gy on tumor bed, 48–50 Gy on the pelvis). Patients underwent surgery after 6–8 weeks from the end of treatment. Results: All patients were evaluable for pathological response. Sphincter preservation was obtained in 30 patients (=90.9%), a clinical down-staging in 30 patients (=90.9%). Overall, 12 patients (=36.4%) experienced a pCR: 9 of 21 patients (=42.8%) who received HRT obtained a pCR; 3 of 12 patients (=25%) who received CRT showed a pCR. Treatment was well tolerated. No G3–4 toxicity was observed. Conclusions: The results of our study are promising in terms of sphincter preservation, clinical down-staging and pCR. Moreover in this trial patients who received HRT obtained an encouraging outcome. No significant financial relationships to disclose.

Laboratory based low dose combination chemotherapy + bevacizumab for recurrent refractory and unresectable gastric cancer

14133 Twenty consecutive prospectively registered patients with refractory or Stage IV gastric cancer were treated with GFLIP (Bruckner el al ASCO 2002;2005). The last 10 upon relapse were treated with GFL[OX]T and Bevacizumab, substituting oxaliplatin (OX) 30→40 mg/M2, taxotere (T) 30→40 mg/M2 for cisplatin in the q2wk schedule. One or both regimens produced; objective responses for 15 patients including 5 complete (radiologic, tumor markers, PET responses) and 2 surgical downstaging resulting in resection or successful completion surgery; 3 patients had stable disease greater than 4 months with subjective benefit, gemcitabine was given at 400→500 mg/M2 as tolerated (→), 2 failed both regimens. One-year actuarial survival was 75%, two-year survival was 25%. All 20 lived more than six months. The level of activity, multiple crossover responses, responses with both regimens, a number of long remissions (long survival after 5FU cisplatin and GFLIP failed) and clinical downstaging allowing further surgery identify both regimens either individually or in sequence as deserving systematic investigation. The utility of low doses (responses), unusual clinical benefits, quality of life and safety offer possible advantages compared to standard dose regimens.This strategy appears to reduce and delay the limiting toxicity of the irinotecan (I) 80 mg/M2, cisplatin (P) 40 mg/M2 OX/T which are conventionally treatment limiting drugs. The regimens were designed based on laboratory evidence of low dose drug interaction including reversal of resistance to conventional drugs (applicable to both pancreatic and gastric cancer (Janat et al, Amer Asso Cancer Res 1999). After clinical demonstrations of high response rates and reversal of resistance against refractory pancreatic cancer (Bruckner et al, AntiCancer Res and ASCO 2005). The regimens were offered to patients with recurrent previously treated and refractory gastric cancer and then based on initial exceptional responses to high risk patients with poor prognosis due to clinical complications of their gastric cancer. No significant financial relationships to disclose.

Neoadjuvant XELOX vs. XELIRI in combination with concomitant boost 3D-conformal radiotherapy in locally advanced rectal cancer (LARC)

3570 Background: While several randomized trials have shown that preoperative chemoradiation reduces local recurrence in LARC, there is no standard chemoradiation schedule. The aim of this study was to compare capecitabine + oxaliplatin (XELOX) vs. capecitabine + irinotecan (XELIRI) in association with high-dose radiotherapy. Methods: Patients (pts) with histologically proven uT3–4 N-/+ or uT2 N+ LARC were randomized to receive capecitabine 1250mg/m2 bid d1–14 before chemoradiation and then 825mg/m2 bid d22–55 plus either oxaliplatin 130mg/m2 d1,22&43 (18 pts) or irinotecan 180mg/m2 d1,22&43 (18 pts). On d22 pts also received radiotherapy administered to the whole pelvis (maximum 45Gy; 1.8Gy/fraction), with a concomitant boost to the CTV (maximum 9Gy; 1.5Gy/fraction) during the last 6d of treatment with a 6h inter-fraction interval. Surgery was carried out 6–8w after chemoradiation by the same surgical team. Results: 36 pts (23M/13F, median age 59 years, ECOG PS 0–1) were enrolled between Jan03 and Jun05. No pt had systemic disease at the time of diagnosis. One pt in the XELIRI group discontinued chemoradiation because of GI toxicity; the other 35 pts (18 XELOX, 17 XELIRI) received 95% and 92% of the planned chemotherapy doses, respectively. The most common adverse event was grade 3/4 diarrhea (6% XELOX, 18% XELIRI). There was no relevant neurotoxicity. 12 pts (67%) on XELOX and 12 pts (71%) on XELIRI had clinical and pathological downstaging. There were no treatment-related deaths. A complete pathological remission was seen in 4 pts (22%) on XELOX and 5 pts (29%) on XELIRI. 25 pts (71%; 13 XELOX, 12 XELIRI) underwent sphincter-saving surgery and 10 pts had Miles abdomino-perineal resection. All pts are alive after a median follow-up of 20 months (range 7–36 months), but 4 (2 in each group) have developed distant metastases. Conclusions: XELOX and XELIRI are feasible and effective, with high efficacy comparable to that observed with other neoadjuvant regimens. XELOX was better tolerated, as diarrhea was seen more frequently in the XELIRI arm. Further studies of these regimens are warranted in this setting. No significant financial relationships to disclose.

Complementary use of local excision and transanal endoscopic microsurgery for rectal cancer after neoadjuvant chemoradiation

Neoadjuvant therapies have significantly improved local control and survival of patients with rectal cancer. Nevertheless, although a complete pathologic response can be achieved in 30% of cases, a transabdominal surgical resection is always required. This study aimed, for the first time, to test in the literature the feasibility of local excision combined with transanal endoscopic microsurgery (TEM) as a surgical option for patients treated with neoadjuvant chemoradiation. Between July 1997 and December 2002, 30 patients with rectal cancer affected by an extraperitoneal tumor entered a protocol consisting of neoadjuvant chemoradiation followed by surgery. The surgical treatment, consisting of open surgery, local excision, or TEM, was planned according to the patient's clinical response after chemoradiation and distance from the anal verge. A significant clinical downstaging was observed in eight patients. Five of these patients underwent TEM, and three had local excision. Consequently, open surgery was performed for 22 patients. Histology showed six cases of complete pathologic response: three in the open surgery group and three in the transanal excision group. After a mean follow-up period of 47 months, the disease-free survival rate was 77% in the open surgery group and 100% in TEM or local excision group. The findings suggest the complementary feasibility of TEM and local excision after neoadjuvant chemoradiation. However, randomized trials are needed to confirm the oncologic safety of this approach.

Anemia may influence the outcome of patients undergoing neo-adjuvant treatment of rectal cancer

We hypothesized that anemia could represent one of the major factors influencing the outcome of patients undergoing neo-adjuvant treatment of rectal cancer. This analysis included all the consecutive patients who underwent neo-adjuvant treatment (chemotherapy and/or radiotherapy) before surgery for rectal cancer in three oncology/radiotherapy departments from June 1996 to December 2003. Three hundred and seventeen patients were eligible for our analysis. Median age at diagnosis was 64 years (range 26-88 years); male/female ratio was 184/133. Two hundred and eighty-five patients (89.9%) were diagnosed with adenocarcinoma, while 32/317 (10.1%) with mucinous adenocarcinoma. Neo-adjuvant treatments carried out were as follows: radiotherapy alone in 75/317 patients (23.7%), radiotherapy plus chemotherapy in 242/317 patients (76.3%). At univariate and multivariate analysis, only the hemoglobin (Hb) level (group 1: < or=12 g/dl versus group 2: >12 g/dl) resulted in a significant factor for disease-free survival. The role of the Hb level seemed to be confirmed further by the clinical downstaging obtained in approximately 55% of patients in group 2, in comparison with 35% of the patients achieving a significant downstaging in group 1. Our results indicated that anemia could represent an important parameter able to influence the outcome in patients receiving neo-adjuvant treatment of rectal cancer.

Chemotherapy-related steatohepatitis: Proceed with caution

Chemotherapy-related steatohepatitis: Proceed with caution

Reply

As noted in the commentary by Cesario et al. (1), an evidence-based consensus on the role of surgery in multimodality treatment for stage IIIB non-small cell lung cancer (NSCLC) (excluding patients with pleural effusion) is indeed needed. These authors point out that several studies that have examined outcomes of patients with IIIB disease treated with neoadjuvant therapy followed by surgery, including our Phase I study, typically considered surgery only in patients with clinical downstaging from neoadjuvant therapy (2, 3). The best evidence for this approach is provided by the Phase II Southwest Oncology Group (SWOG) 8805 study, in which 126 patients with stage IIIA or B NSCLC received induction cisplatin and etoposide plus concurrent thoracic radiotherapy (2). Resection was attempted in patients without progressive disease. Fifty-one patients (40%) had stage IIIB (T4 primary or N3 nodes) disease. In this subset, resectability was 80%, and 3-year survival was 24%, similar to results for the stage IIIA group. The strongest predictor of survival after surgery was nodal status at the time of resection. In patients with pN0 disease at resection, 3-year survival was 44%, versus 18% in patients with involved nodes (P = 0.0005). The fact that this survival difference was seen in patients with both IIIA and IIIB disease suggests that treatment decisions should not only take anatomic staging into account but should also consider tumor biology and response to therapy. Thus, some patients with stage IIIB disease, for whom guidelines typically recommend combined chemoradiotherapy without surgical resection (4), may, by virtue of an excellent response to neoadjuvant treatment, be able to enjoy the benefits of resection, as would a patient with similarly responsive stage IIIA disease. The final report of the randomized intergroup trial 0139 (RTOG 93-09), investigating the outcomes of patients with stage IIIA NSCLC from combined chemoradiotherapy alone versus chemoradiotherapy followed by surgery, is pending (5). Preliminary data suggest similar overall survival in both groups of patients but improved progression-free survival in the surgical arm. Further analysis may shed light on who will benefit from the full trimodality approach to therapy for locally advanced NSCLC.Based on our results, in which 3 of 12 IIIB patients were deemed resectable, and the SWOG 8805 data, we agree with Cesario et al. (1) that surgical resection after neoadjuvant therapy can be considered in selected patients with stage IIIB (T4 primary or N3 nodes) after neoadjuvant therapy. The patient in question with T4 disease had radiographic evidence of invasion into the mediastinum on presentation, not a satellite nodule or carinal involvement that might meet the more typical guidelines for resectability. The question remains how to best identify patients who may benefit from surgery. In our Phase I study, all patients were restaged by computed tomography (CT) alone after both induction chemotherapy and chemoradiotherapy. Of the 14 patients eligible for surgery based on restaging CTs showing the equivalence of stage IIIA disease or better, 7 of the preoperative CT scans did not accurately predict the postoperative pathological stage. Of these, six patients were downstaged to N0 status or had a pathological complete response to neoadjuvant therapy, indicating that restaging by CT alone is not fully reliable.Alternative approaches to restaging include positron emission tomography (PET) and repeat mediastinoscopy. PET restaging is attractive because it offers the possibility of both characterizing locoregional response to neoadjuvant therapy and identifying clinically unrecognized distant metastatic disease, thereby sparing those patients unnecessary treatment (6). Unfortunately, the data available to date include unacceptable numbers of false positives and false negatives for PET restaging alone to be considered a standard approach to determining resectability of stage III NSCLC after neoadjuvant therapy (7, 8). Repeat mediastinoscopy, as Cesario et al. (1) have observed, can be technically challenging in the postchemoradiotherapy setting and is therefore not routinely performed. As a result, it is difficult to recommend a standardized approach to restaging after neoadjuvant therapy in patients with stage IIIB NSCLC to determine resectability. Nevertheless, the favorable outcomes that can be seen in selected stage IIIB NSCLC patients in response to trimodality therapy do indicate that further study in identifying appropriate surgical candidates is clearly needed.

Efficacy of Neoadjuvant Chemoradiotherapy in Resectable Esophageal Squamous Cell Carcinoma

A prospective phase II study of neoadjuvant chemoradiotherapy (CRT) for resectable esophageal squamous cell carcinoma was conducted from May 1993 to March 1996. A total of 88 patients fitted the eligibility criteria and were treated with two courses of induction chemotherapy (cisplatin 60 mg/m2/day on day 1 and 5-fluorouracil (5-FU) 1 000 mg/m2/day on days 2-6) with concurrent hyperfractionated radiotherapy (48 Gy/40 fractions/4 weeks) followed by esophagectomy or definitive CRT comprising 4 cycles of cisplatin/5-FU and hyperfractionated radiotherapy (additional 12 Gy) with intracavitary brachytherapy (9 Gy). Clinical response and downstaging were achieved in 83% and 42% of the patients, respectively. With a median follow-up of 77 months, median survival time was 18 months with a 5-year survival rate of 23%. The clinical responses to CRT and surgery were independent prognostic factors for overall survival. Among the intended surgery group (n=52), 41 (79%) patients underwent surgery and 36 had a resection with a pathologic complete response rate of 43%. When compared with a matched historical control (n=40), there was a significant survival benefit in the multimodality arm (p=0.04). This multimodality therapy was feasible and its efficacy was promising, especially when surgical resection was performed. The therapeutic benefit of neoadjuvant CRT remains to be assessed in large well-designed randomized trials, one of which is ongoing at our institution.

Long-term outcome of neoadjuvant therapy for locally advanced breast carcinoma: effective clinical downstaging allows breast preservation and predicts outstanding local control and survival.

To review the long-term follow-up data from the authors' institutional experience of 62 patients with locally advanced breast cancer (LABC) treated with a uniform multimodality regimen. The authors determined the rate of breast preservation, the disease-free and overall survival, and the factors associated with locoregional and distant recurrent disease. It remains a challenge to achieve local and distant control of LABC. Over the last decade, preoperative or neoadjuvant chemotherapy has emerged as the standard of care for these patients. Successful tumor downstaging has been associated with increased rates of breast-conserving therapy (BCT), but the overall effect on long-term survival remains to be seen. This study examines a cohort of 62 patients with LABC treated at the authors' institution from 1992 to 1998. The uniform treatment regimen consisted of neoadjuvant doxorubicin (Adriamycin), followed by operation (BCT if sufficient clinical downstaging), followed by non-cross-resistant cyclophosphamide/methotrexate/5-fluorouracil, followed by radiation therapy. Treatment was both dose-intensive and time-intensive, with a total treatment time of 32 to 35 weeks. In this patient population, the median age was 44 years, with approximately two thirds white patients and one third African American. Eighty-two percent of patients were clinical stage III at presentation, 13 patients had T4d inflammatory cancers, and 3 patients were stage IV at diagnosis. Eighty-four percent of patients demonstrated a significant clinical response to doxorubicin. Twenty-eight patients had sufficient clinical downstaging to attempt BCT, and 22 (45%) of 49 noninflammatory patients underwent successful BCT. Pathologic complete response was seen in 15% of patients. Median follow-up for the cohort was 70 months. The local recurrence rate was 14%, including two ipsilateral breast tumor recurrences (10%) in the BCT patients. Seven (12%) patients developed a new primary cancer in the contralateral breast. Distant metastases occurred in 18 (31%) patients, and the 5-year overall survival rate for the cohort was 76%. Furthermore, in the patients who underwent an attempt at BCT, the survival rate was 96% at 5 years. Dose-intensive and time-intensive multimodality neoadjuvant therapy was successfully administered to a mixed racial group over shortened times. Patients who had sufficient clinical downstaging to allow BCT have the best long-term outcome. Patients who required mastectomy are at a higher risk of relapse, as well as the development of new contralateral cancers, yet have 5-year survival rates of over 50%.

Incidental surgical findings of a phase I trial of weekly gemcitabine and concurrent radiotherapy in patients with unresectable non-small cell lung cancer

Objective: to report the surgical facts of unresectable patients with locally advanced non-small cell lung cancer (NSCLC) treated in a phase I trial with concurrent weekly gemcitabine and radiotherapy who achieved a clinical downstaging so as to re-enter resectability. Materials and methods: from 3/99 to 11/00, 30 patients (ten stage IIIa, 16 IIIb and four IV) with histologically proven, unresectable NSCLC, were enrolled in this phase I trial. Gemcitabine was given weekly for 5 consecutive weeks as a 30-min intravenous infusion, at least 4 h before radiotherapy. Starting dose: 100 mg/m 2. Maximum tolerated dose (MTD): 350 mg/m 2. Radiotherapy total dose: 50.4 Gy (1.8 Gy/day) on primitive tumour and involved lymph nodes. Results: 27 out of 30 patients (90%) were evaluable for clinical restaging (three patients who decided to continue their treatment elsewhere have been excluded). A major clinical response (partial+complete response) was observed in 17 out of 27 cases (62.9%). Clinical complete response rate was 3.7% (1/27) while partial response rate was 59.2% (16/27). Nine patients (33.4%) showed a clinical stable disease and one a disease progression (3.7%). Fourteen patients re-entered resectability and were operated upon: seven lobectomies; four bilobectomies; two pneumonectomies and one explorative thoracotomy. Mean operation duration time was 112 min; mean blood loss was 390 cc. Thirty-day morbidity and mortality were nil. Mean post-operative hospital stay was 6.8 days. A slight increase in operational technical difficulty was encountered. Definitive histology showed a pathologic downstaging of 71.4% (10/14). In four patients, only microscopic neoplastic remnants were found. Conclusions: combined treatment with weekly gemcitabine and concurrent radiotherapy is feasible. In patients with advanced NSCLC who achieved a good clinical response and therefore were judged to be resectable, surgery was possible without any increase in thirty-day morbidity and mortality. Satisfactory pathologic results were obtained.

Long-Term Outcome of Neoadjuvant Therapy for Locally Advanced Breast Carcinoma: Effective Clinical Downstaging Allows Breast Preservation and Predicts Outstanding Local Control and Survival

Long-Term Outcome of Neoadjuvant Therapy for Locally Advanced Breast Carcinoma: Effective Clinical Downstaging Allows Breast Preservation and Predicts Outstanding Local Control and Survival

4–Year Follow–Up Results of a European Prospective Randomized Study on Neoadjuvant Hormonal Therapy prior to Radical Prostatectomy in T2–3N0M0 Prostate Cancer

Objectives: To evaluate the long–term effects of 3–month neoadjuvant hormonal treatment in patients treated by radical prostatectomy for locally confined prostate cancer.Methods: We report the results of 402 patients (220 with a clinical T2 tumor and 182 with a clinical T3 tumor) of whom 192 randomly received neoadjuvant total androgen deprivation using a LHRH analogue (goserelin) plus flutamide for a period of 3 months and 210 underwent radical prostatectomy only.Results: ‘Clinical downstaging’ was seen in 30% of cases in the neoadjuvantly treated group (NEO). ‘Pathological downstaging’ occurred in 7 and 15% of cases in the direct radical prostatectomy (DP) group and the NEO group, respectively (p<0.01). In patients with clinical T2 as well as in patients with clinical T3 tumors, a significant difference in the number of positive margins was shown in favor of the NEO group (cT2, p<0.01; cT3, p = 0.01). This advantage, although there was a trend in favor of the NEO group, specifically in cT2 tumors, did not translate in a significantly better PSA progression rate (p = 0.18). However, when evaluating the local control rate in cT2 tumors, we observed local recurrence in 3 of 102 (3%) patients in the NEO group versus 12 of 114 (11%) patients in the DP group. The difference is statistically significant (p = 0.03). In the cT3 group, this difference was not statistically significant (NEO group: 15 of 87 (17%), and DP group: 21 of 95 (22%) patients; p = 0.41).Conclusions: In this study, the clinical revelance of pathological downstaging and the lower percentage of patients with positive margins in the neoadjuvantly treated group with a clinical T2 tumor is not confirmed by a lower PSA progression rate. However, this study indicates that there may be a trend that this advantage in favor of the NEO group directly translates into a better local control rate in clinical T2 tumors. Better local control in cT2 tumors is only going to be of relevance if subsequently you can show that there is a better survival for these patients. Unfortunately, this article reports a study which is not yet mature enough to show relevant information. Presently, neoadjuvant therapy should not be given outside clinical research settings.

Editorial on combined therapy for squamous cell carcinoma of the esophagus

T he next two articles in this issue of the Journal are two important Studies On Combined therapy for squamous cell carcinoma of the esophagus. In the Japan Clinical Onco!ogy Group study, 1 postoperative chemotherapy with cisplatin and vindesine are compared with surgery alone for patients having undergone a transthoracic esophagectomy with extensive lymphadenectomy for cancer of the thoracic esophagus. Surgical survivors were randomized to receive postoperative chemotherapy or no further therapy. The sample size was sufficient to show a clinical difference if such occurred. No difference in long-term survival was detected between those treated by surgery alone and those treated by similar operations plus postoperative chemotherapy. Survival was slightly better in those with diseased lymph nodes treated by chemotherapy compared with the no treatment group, but the difference was not significant. In the Hong Kong prospective randomized trial, 2 preoperative chemotherapy with cisplatin and 5-fluorouracil followed by resection was compared with the results of surgery alone for squamous cell carcinoma of the esophagus. This study was not limited to patients with potentially curable disease, and 11% in the chemotherapy and 5% in the control group did not undergo surgical treatment. Again, the long-term survival data showed no significant difference between the group randomized to receive chemotherapy versus the surgery-alone group. As in several other recent publications, 3' 4 those patients

Preliminary results of a prospective randomized study comparing radical prostatectomy versus radical prostatectomy associated with neoadjuvant hormonal combination therapy in T 2–3 N 0 M 0 prostatic carcinoma

Objectives To evaluate the short- and long-term effects of neoadjuvant hormonal treatment in locally confined prostate cancer. Methods We report the preliminary results of 354 patients (199 with a clinical T2 tumor and 155 with a clinical T3 tumor) of whom 164 randomly received neoadjuvant total androgen deprivation using a luteinizinghormone-releasing hormone (LHRH) analog (goserelin) plus flutamide for a period of 3 months. Results Serum prostate-specific antigen (PSA) levels and prostatic volume decreased from a mean of 19.9 ng/ mL and 37.7 cm 3 to a mean of 0.8 ng/mL and 26.5 cm 3 after 3 months of neoadjuvant therapy. “Clinical downstaging” was seen in 32% in the neoadjuvantly treated group. “Pathological downstaging” percentages were 6% and 16% in the direct radical prostatectomy group and neoadjuvantly-treated group, respectively ( P <0.01). In patients with clinical T2 tumors, a significant difference in number of positive margins was shown in favor of the neoadjuvantly treated group ( P <0.01). In patients with clinical T3 tumors, a significant difference could not be detected ( P = 0.14). In 215 patients with a mean follow-up time of 15 months, the calculated 95% confidence intervals of mean time of PSA progression-free survival were 26 to 35 months in the neoadjuvantly-treated group and 28 to 37 months in the direct radical prostatectomy group, indicating no significant differences between treatment groups. However, follow-up time is currently too short to draw definite conclusions. Conclusions These early data confirm high understaging percentages in clinical staging. The clinical relevance of the statistically significant smaller numbers of patients with positive margins in the neoadjuvantly treated group with a clinical T2 tumor will have to be confirmed when further follow-up allows an accurate evaluation of time to PSA progression, local recurrence, and distant metastases. Presently, neoadjuvant therapy is not advisable outside clinical research settings.

Concurrent chemoradiotherapy followed by surgery for advanced stage III non-small cell lung cancer (NSCLC): Katakami N. Matsumoto H. Tomioka H. Okazaki M. Hasegawa T. Sakamoto H. Pulmonary Unit, Kobe City General Hospital, Kobe. Jpn J Cancer Chemother 1995;22:531–537

Forty-two patients with stage IIIA (bronchoscopically T3 and/or bulky N2) and stage IIIB NSCLC were treated with concurrent chemoradiotherapy (CRT). Treatment consisted of CDDP, 20 mg/m2 and etoposide, 40 mg/m2 by continuous infusion (day 1-5) of weeks 1 and 5 simultaneously with chest radiotherapy (RT), 50 Gy, 2 Gy/Fx, 5 Fx/week. Surgery was attempted 3-5 weeks after RT in pts clinically downstaged. Between 10/90 and 12/92, 43 previously untreated pts were enrolled and 42 were eligible. Pts characteristics were: male/female = 37/5; mean age, 61 yrs (range, 31-74 yrs); stage IIIA/IIIB = 10/32; 15 adenocarcinoma, 24 squamous cell, 2 large cell, 1 unclassified; PS 0/1/2 = 11/24/7. Excluding 1 ineligible pts, 42 pts were evaluated for CRT response. The response rate was 81% (1 CR, 33 PR, 5 NC, 1 PD, 2 NE). Clinical downstaging was achieved in 20 pts (48%). Twenty-one pts (50%) received surgery and 19 of them were completely resected. In 7 resection specimens, no tumor was observed. Toxicity of CRT was well tolerable (Grade 4 leukopenia, 15%; Grade 2-3 esophagitis, 15%). We conclude that this intensive combined modality therapy is acceptable and appears to increase the response rate as well as resectability. Prospective randomized studies should be conducted for further evaluation of this treatment modality.

Neoadjuvant androgen blockade prior to prostatectomy: a retrospective study and critical review.

The treatment of locally advanced prostatic cancer is controversial, as there are several possible treatment options. The aims of temporary androgen deprivation prior to radical prostatectomy are to achieve downgrading and downstaging of the tumor, an increase in local control, a decrease in morbidity and operative sequelae, a decrease in the time to progression, and an improvement in survival. A retrospective study has been carried out on 100 patients who underwent radical prostatectomy between 1988 and 1992. Forty patients received androgen deprivation therapy followed by prostatectomy, while the remaining 60 acted as controls, undergoing prostatectomy alone. Treated patients had a 40-50% reduction in prostate volume after 3 months, facilitating dissection of the prostate, reducing intraoperative blood loss, and reducing operation time. Of these 40 treated patients, one third showed clinical downstaging; one patient staged initially as T2/B was downstaged to PT0. The proportion of patients with positive surgical margins was 32% in the group treated preoperatively, compared with 57% in untreated patients. Treated patients also recovered full continence more rapidly after the operation than patients who underwent prostatectomy alone. After androgen blockade, serum PSA levels returned to normal (< 4 ng/ml) in 37 of the 40 patients. Of these patients, 22 had undetectable serum PSA levels (< 0.25 ng/ml), showing a definite reduction in tumor activity. PSA levels after 3 months of neoadjuvant hormonal treatment might play a useful predictive role in selecting patients before radical prostatectomy, since 86% with undetectable PSA had tumors confined to the gland (T2/B2), while patients who still had PSA > 4 ng/ml all had stage T3-T4 tumors. Although downstaging was confirmed pathologically in only 13% of patients, this is of significance when the total number of patients with locally advanced prostate cancer is considered and, therefore, may have implications for survival in the future. Prospective randomized studies should provide conclusive information on the potential benefit of this approach.

Report of phase ii trial of concurrent chemoradiotherapy with radical thoracic irradiation (60 gy), infusional fluorouracil, bolus cisplatin and etoposide for clinical stage IIIB and bulky iiia non-small cell lung cancer

Purpose : To assess the response rate, median and long-term survival of patients (pts) with locally advanced, initially inoperable non-small cell lung cancer (NSCLC) treated on a phase II study of radical thoracic radiotherapy (TRT) and concurrent radiosensitizing chemotherapy. Methods and Materials : From 3/87 to 7/90, 41 previously untreated patients at Fox Chase Cancer Center with locally advanced non-small cell lung cancer, 24 with bulky clinical Stage IIIA, and 17 with IIIB disease, received concurrent thoracic radiotherapy (60 Gy/2.0 Gy/d in 6 weeks) and 2 cycles of infusional 5FU (640–800 mg/m 2/24 hrs × 5 d); cisplatin (20 mg/m 2 qd × 5); and etoposide (50 mg/m 2 d 1, 2, 5) administered days 1 and 28 of TRT. Results : Forty of 41 were evaluable. Response rate was 90%, with radiographic CR in 20%. Thirteen pts (33%) underwent thoracotomy and complete resection with clinical downstaging in 10, including three pathologic CR's. Overall median survival was 14 months and 2-year survival was 38% with no difference between CS IIIA and IIIB pts ( p = 0.2224). At median potential follow-up of 42 months, 8/40 pts. (20%) are alive and progression-free, including 4 of 13 resected pts. The chief toxicity was esophagitis, occurring in 32 pts. (80%), Grade 3–4 in 21 (52%), with 13 (33%) requiring hospitalization and 7 (18%) needing TPN. Grade 3–4 granulocytopenia was noted in 20 pts. (50%) with ten episodes of fever mandating intravenous antibiotics. Cardiac ischemia was documented in 2 (5%). Of 13 thoracotomy pts, six underwent lobectomy without perioperative mortality; 3 of 7 pneumonectomy pts died post-operatively, two from broncopleural fistula, and one from ARDS. Conclusion : This aggressive regimen produced a 2-year survival (38%) comparable to the best arm of cancer and leukemia groups B study 8433, which administered radical thoracic radiotherapy after protoadjuvant vinblastine and cisplatin in similar and earlier stage non-small cell lung cancer patients. Toxicity, particularly esophagitis, was severe, but of short duration. An unacceptably high complication rate was seen following pneumonectomy, but not lobectomy.

Neoadjuvant hormonal deprivation before radical prostatectomy.

Our experience with 40 patients receiving complete androgen blockade with luteinizing hormone-releasing hormone agonist and flutamide, prior to radical surgery, has shown a definitive decrease in prostate volume of 40-50%. This significant reduction in volume, induced by the neoadjuvant therapy, seems to facilitate the dissection of the prostate from closely vulnerable structures, with a reduction in blood loss (average 400 ml) and in time of surgery (average 135 min). Clinical downstaging was observed in one third of the patients, but the final pathological staging clearly showed that it is difficult to confirm this issue. Downgrading was not observed, but this is difficult to assess since the biopsies are not representative of the entire heterogeneous tumor. Prostate-specific antigen (PSA) dropped to undetectable levels in 59% of the patients 3 months after hormone suppression. Among these, 80% had pT2 and only 13% had pT3 tumors while there was 1 pT0 patient. Patients who still had a PSA of > 4 ng/ml after neoadjuvant therapy all had stage PT3-PT4 disease. Histological changes were observed in both the non-neoplastic tissue and the prostatic carcinoma, with effects being more marked in the latter. PSA, after 3 months of neoadjuvant hormone treatment, might have a useful predictive value in patient selection for radical surgery, since 86% of patients with undetectable PSA had tumors confined to the gland (pT2-B2). Large, prospective, randomized studies, comparing radical prostatectomy against radical prostatectomy with neoadjuvant complete androgen deprivation in locally advanced (T2-T3N0M0) prostatic carcinoma, are needed to assess the true influence of the combined approach on local control, time to progression and overall survival.

Neoadjuvant hormonal deprivation before radical prostatectomy.

Hormonal deprivation before radical prostatectomy remains controversial. The main purpose is to achieve downstaging, downgrading, improvement of the surgical results and increased survival. Experience with the last 100 patients who underwent radical prostatectomy, in whom 40 patients received complete preoperative androgen blockade (luteinizing-hormone-releasing hormone agonist and flutamide) prior to radical surgery, has shown a definitive decrease in volume of 40-50%). The significant reduction of volume seemed to facilitate the dissection of the prostate from closely vulnerable structures. Clinical downstaging was observed in one third of the patients, but the final pathological staging did not confirm the clinical impression and shows that it is difficult to solve this issue. There was one PT0 patient. Histological changes are observed in both the nonneoplastic tissue as well as in the prostatic carcinoma with more marked effects on the latter. Downgrading was not observed, but this is even more difficult to assess since biopsies cannot be considered as representative of the entire heterogeneous tumor. Prostate-specific antigen (PSA) dropped to undetectable levels in 59% of the patients 3 months after hormonal suppression. Among these, 80% had PT2 and only 13% had PT3 tumor. PSA, 3 months after neoadjuvant hormonal treatment, might have a useful predictive value in patient selection for radical surgery since 86% with undetectable PSA had tumors confined to the gland (PT2/B2). On the other hand, patients who still had PSA > 4 ng/ml after neoadjuvant therapy had all stage PT3-PT4 disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Downstaging of Stage C Prostatic Carcinoma by Inductive Chemo-Hormonal Therapy?

One hundred and three patients with clinical stage C prostatic carcinoma (palpable extra-organ extension) underwent inductive chemo-hormonal treatment followed by radical retropubic prostatectomy with pelvic lymphadenectomy. First a careful noninvasive tumor staging was performed, which included a thorough digital rectal palpation, PSA, PAP, chest X-ray, bone scan, IVP, transabdominal and transrectal ultrasonography, CT and MRI. Then inductive chemo-hormonal therapy commenced. It consisted of total androgen deprivation plus the administration of cDDP or 5-FU + calcium folinate + mitomycin. After completion of chemotherapy (i.e. 4 months later), noninvasive staging was repeated. Then radical prostatectomy was carried out, followed by histologic work-up of the specimen. Postinductive, noninvasive examinations showed clinical downstaging in 49 of the original 103 patients (47.5%). Histopathology showed confinement of the tumor to the prostate in 40 specimens (38.8%). These results prove that chemo-hormonal induction is highly effective and suggest strongly but do not prove definitely histological downstaging in a significant percentage of the patients.