Presurgical Therapy Research Articles

Response of malignant scalp dermatofibrosarcoma to presurgical targeted growth factor inhibition

Dermatofibrosarcoma protuberans (DFSP) is an uncommon, locally aggressive, malignant cutaneous tumor that sparingly presents on the scalp. Dermatofibrosarcomas often result from the formation of a fusion oncogene on translocated or supernumerary ring chromosomes 17 and 22, causing the overexpression of PDGFRbeta driven by the COL1A1 promoter. Because of uncertainty surrounding appropriate treatment of aggressive scalp DFSP, the authors performed an extensive review of the available data from a MEDLINE (Ovid) search to describe the clinical presentation and treatment options for this rare tumor. Their search identified 39 different cases, including the illustrative case presented in this study. Adjuvant therapy for this malignant lesion is not universally established in the literature. In the present case, the authors successfully treated a locally invasive scalp DFSP with presurgical therapy that specifically inhibited the PDGFbeta receptor. Imatinib significantly shrank the DFSP tumor mass, reduced hypervascularity, reduced metabolic activity on PET scanning, and permitted a safe gross-total resection. Although wide excision and Mohs micrographic surgery remain the standard surgical treatments for DFSP, the authors illustrate that presurgical chemotherapeutic treatment by imatinib provides a critical adjunct to traditional therapy.

Surgical downstaging and neo-adjuvant therapy in metastatic colorectal carcinoma with irinotecan drug-eluting beads: a multi-institutional study

BackgroundNeoadjuvant chemotherapy for potentially resectable metastatic colorectal cancer (MCC) is becoming a more common treatment algorithm. The aim of the present study was to evaluate the efficacy of precision hepatic arterial Irinotecan therapy in unresectable MCC. MethodsAn open-label, multi-centre, multi-national single arm study of MCC patients, who received hepatic arterial irinotecan. Primary endpoints were safety, tolerance and metastatic tumour resection. ResultsFifty-five patients with metastatic colorectal to the liver underwent a total of 90 hepatic arterial irinotecan treatments. The extent of liver involvement was <25% in 75% of the patients (n= 41), between 26 and 50% in 15% of the patients (n= 11) and >50% in 10% of the patients (n= 24). The median number of hepatic lesions was four (range 1–20), with a median total size of all target lesions of 9cm (range 5.5–28cm) with 50% of patients having bilobar tumour distribution. The median number of irinotecan treatments was two (range 1–5). The median treatment dose was 100mg (range 100–200) with a median total hepatic treatment of 200mg (range 200–650). The majority of treatments (86%) were performed as lobar infusion treatments, and 30% of patients were treated with concurrent simultaneous chemotherapy. Eleven (20%) patients demonstrated significant response and downstage of their disease or demonstrated stable disease without extra-hepatic disease progression allowing resection, ablation or resection and ablation. There were no post-operative deaths. Post-operative complications morbidity occurred in 18% of patients, with none of them hepatic related. Non-tumorous liver resected demonstrated no evidence of steatohepatitis from the irinotecan arterial infusion. ConclusionsHepatic arterial infusion irinotecan drug-eluting beads is safe and effective in pre-surgical therapy and helpful in evaluating the biology of metastatic colorectal cancer to the liver prior to planned hepatic resection.

Neoadjuvant treatment for resectable pancreatic cancer: Time for phase III testing?

This paper discusses the rationale for phase III testing of neoadjuvant therapy in patients affected by resectable pancreatic adenocarcinoma. The therapeutic management of patients affected by resectable pancreatic cancer is particularly troublesome due to the aggressiveness of the disease and to the limited efficacy and sometimes unfavourable risk-benefit ratio of the available therapeutic tools. Conflicting data on the role of adjuvant chemoradiation have been reported, while adjuvant single-agent chemotherapy significantly improved overall survival (OS) when compared to surgery alone. However, the OS figures for adjuvant chemotherapy remain disappointing. In effect, pancreatic cancer exhibits a prominent tendency to recur after a brief median time interval from surgery and extra-pancreatic dissemination represents the predominant pattern of disease failure. Neoadjuvant treatment has a strong rationale in this disease but limited information on the efficacy of this approach is available from single arm trials with low levels of evidence. Thus, in spite of two decades of investigation there is currently no evidence to support the routine use of pre-surgical therapy in clinical practice. To foster knowledge on the optimal management of this disease, and to produce evidence-based treatment guidelines, there is no alternative to well designed randomized trials. Systemic chemotherapy is a candidate for testing because it is supported by a more robust rationale than chemoradiation. Combination chemotherapy regimens with elevated activity in advanced disease warrant investigation. Caution would suggest the running of an exploratory phase II randomized trial before embarking on a large phase III study.

Phase II Presurgical Feasibility Study of Bevacizumab in Untreated Patients With Metastatic Renal Cell Carcinoma

To assess safety and efficacy of presurgical bevacizumab in patients with metastatic renal cell carcinoma (mRCC), and to explore the hypothesis that pretreatment of patients with antiangiogenic therapy will select patients who benefit most from cytoreductive nephrectomy. Patients with newly diagnosed, clear cell mRCC whose primary tumors were considered resectable were enrolled. In this single-arm, phase II trial, patients received bevacizumab plus erlotinib (first patients, n = 23) or bevacizumab alone (n = 27 patients) for 8 weeks followed by restaging. If patients demonstrated progressive disease and had declining performance statuses after 8 weeks, nephrectomy procedures were deferred. Postoperatively, patients continued on the study drug or drugs if disease stabilization or regression had occurred. Between March 2005 and March 2008, 52 patients were enrolled on study, and 50 were included in the analysis. By Memorial Sloan-Kettering Cancer Center criteria, 82% of patients had intermediate-risk, and 18% had poor-risk, features. Forty-two patients underwent nephrectomy. Median progression-free survival was 11.0 months (95% CI, 5.5 to 15.6 months). Median overall survival was 25.4 months (95% CI, 11.4 months to not estimable). Two perioperative deaths occurred; neither was attributable to study drug. Wound dehiscence resulted in treatment discontinuation for three patients and treatment delay for two others. Presurgical treatment with bevacizumab therapy yields clinical outcomes comparable to post-surgical treatment with antiangiogenic therapy in patients with mRCC, but it may result in wound-healing delays. Prospective, randomized trials to test the use of presurgical therapy as a method to select appropriate patients for cytoreductive nephrectomy are warranted.

Phase II presurgical study of bevacizumab plus erlotinib in untreated patients with metastatic renal cell carcinoma

5004 Background: The safety and efficacy of presurgical bevacizumab in patients with metastatic renal cell carcinoma (mRCC) is not known. The current study was designed to answer these clinical questions, and to define predictive tissue biomarkers using nephrectomy specimens from patients on trial. Methods: Patients with newly diagnosed clear cell mRCC whose primary tumor was considered resectable were enrolled. In this single arm phase II trial, patients received bevacizumab plus erlotinib or bevacizumab alone for 8 weeks, followed by restaging. Primary endpoint was progression free survival (PFS). If patients demonstrated progressive disease and had a declining performance status after eight weeks, nephrectomy was deferred. Postoperatively, patients continued on study drug(s) if disease stabilization or regression had occurred. Reverse phase protein arrays (RPPAs) were generated from nephrectomy specimens. Results: Between March 2005 and March 2008, 52 patients were enrolled on the study, and 50 were included in the analysis. By the Memorial Sloan-Kettering Cancer Center criteria, 82% of patients had intermediate-risk, and 18% had poor-risk features. Twenty-three patients received bevacizumab plus erlotinib, and 27 received bevacizumab alone. Forty-two patients underwent nephrectomy. Median progression-free survival was 11.0 months (95% CI: 5.5, 15.6 months). Median overall survival was 25.4 months (95% CI 11.4, not estimable). Two perioperative deaths occurred, and neither was attributable to study drug. Wound dehiscence resulted in treatment discontinuation for three patients. RPPA analysis demonstrated a clear separation of better versus worse responding patients. Conclusions: Presurgical treatment with bevacizumab therapy is relatively safe and yields clinical outcomes comparable to post surgical treatment with antivascular therapy in patients with mRCC. Prospective randomized trials testing the use of presurgical therapy to select appropriate patients for cytoreductive nephrectomy are warranted. [Table: see text]

Neoadjuvant/presurgical treatments

In this article the term 'neoadjuvant' is used to describe pre-operative treatment for 3 months or more for large (usually ≥ 3 cm) operable cancers before surgery. Clinical response and pathological response are important end-points. The term 'presurgical' refers to treatment of short duration (around 2 weeks) before surgery, sometimes referred to as a 'window of opportunity' study. This approach can be used for any size of cancer provided it can be core biopsied, and the endpoints are molecular markers. Traditional goals of neoadjuvant therapy include the following: • to improve survival; • to downstage so that inoperable cancers become operable or so that conservative surgery can replace mastectomy; • to identify short-term clinical or molecular markers of response to predict long-term outcome as a prelude to (or as a substitute for) adjuvant trials; • to predict outcome and plan further treatment in the individual patient; and • to identify the molecular mechanisms that underlie response and resistance to treatment. Short-term presurgical therapies can have similar aims with the proviso being that this treatment will not lead to downstaging and that clinical and pathological response rates are unrealistic end-points. Current evidence suggests that there is no survival benefit from neoadjuvant chemotherapy [1]. The question has not thus far been addressed in a large neoadjuvant endocrine therapy trial. Neoadjuvant chemotherapy has been shown to downstage and reduce the need for mastectomy in some but by no means all women [1]. The same is true for neoadjuvant endocrine therapy; about 40% of mastectomies can be avoided with preoperative aromatase inhibitor therapy [2].

The benefit using an integrated electronical study platform for a presurgical therapy trial (HEDON) in primary breast cancer

The benefit using an integrated electronical study platform for a presurgical therapy trial (HEDON) in primary breast cancer

Presurgical Nasoalveolar Molding Therapy for the Treatment of Unilateral Cleft Lip and Palate: A Preliminary Study

Presurgical Nasoalveolar Molding Therapy for the Treatment of Unilateral Cleft Lip and Palate: A Preliminary Study

88 INVITED Biological lessons from pre-surgical endocrine therapy

88 INVITED Biological lessons from pre-surgical endocrine therapy

Response: Re: Prognostic Value of Ki67 Expression After Short-Term Presurgical Endocrine Therapy for Primary Breast Cancer

Response: Re: Prognostic Value of Ki67 Expression After Short-Term Presurgical Endocrine Therapy for Primary Breast Cancer

Re: Prognostic Value of Ki67 Expression After Short-Term Presurgical Endocrine Therapy for Primary Breast Cancer

Re: Prognostic Value of Ki67 Expression After Short-Term Presurgical Endocrine Therapy for Primary Breast Cancer

Presurgical therapy in metastatic renal cell carcinoma

The standard approach for managing patients with metastatic renal cell carcinoma consists of a cytoreductive nephrectomy followed by immunotherapy, chemotherapy or a targeted agent. Optimal timing of surgery and systemic therapy is not known, and has not been researched. A number of questions arise. First, in the era of antivascular therapy, is cytoreductive nephrectomy a necessity? Second, is it possible that pretreatment with systemic therapy prior to cytoreductive nephrectomy improves surgical outcome and survival? Third, which agents are best suited for an integration of surgery with systemic therapy, both in the metastatic and the nonmetastatic setting? This review will address each of these questions and summarize ongoing trials that are designed to provide some of the answers.

Presurgical promestriene therapy in postmenopausal women with stress urinary incontinence

Objective. Our study was aimed at evaluating the efficacy of therapy with promestriene, a synthetic diethyl-ether of estradiol with no distal hormonal effects, in patients undergoing surgical correction for stress urinary incontinence (SUI).Materials and methods. Ninety-eight healthy, postmenopausal women, non-users of hormone replacement therapy, with a diagnosis of SUI and vulvovaginal dystrophy, were recruited and openly randomized into two main groups. Group I (48 patients) received promestriene 10 mg daily, by vaginal capsule, for 21 days before the operation. Group II (50 patients) underwent the surgical procedure with TVT (Tension-free Vaginal Tape) directly, without pharmacological preparation. The results were collected and analyzed using SAS software (version 8).Results. The two groups were homogeneous in terms of age, parity and body mass index. There were no significant differences between the two groups with respect to the time required to accomplish the TVT, blood loss, length of hospital stay, blood component measurements and postoperative subjective symptoms. There were slight differences postoperatively in problems during intercourse and the appearance of new genital symptoms, but again they were not shown to be statistically significant.Conclusions. Our results, although preliminary and subjective, confirm the efficacy of remedial surgical treatment of SUI with TVT. Preoperative administration of promestriene seems to favor trophism and vascularization of the whole muscular and fascial support of the pelvic floor and facilitates performance of the operation, but is not supported statistically.

Presurgical treatment with somatostatin analogs in patients with acromegaly: effects on the remission and complication rates

The question of whether preoperative therapy with somatostatin analogs can improve surgical outcome in acromegaly has not been definitively answered. In this paper, the authors report the effects of preoperative treatment with somatostatin analogs in a large sample of patients with acromegaly. Between 1990 and 2003, 399 consecutive patients with acromegaly underwent surgery at the Istituto Scientifico San Raffaele. Thirty-three patients who had previously undergone surgery or radiation treatment, 48 patients treated with somatostatin analogs for fewer than 3 months, and patients who had stopped therapy for too long a time before surgery were excluded from the study. One hundred forty-three patients who had received somatostatin analogs prior to surgery (Group 1) were randomly matched to 143 patients who had never been treated with somatostatin analogs (Group 2). Matching criteria were tumor size and invasiveness into the cavernous sinus. Before surgery, Group 1 patients showed reduction of growth hormone levels to less than 50% of baseline in 64% of cases, but insulin-like growth factor-I was normalized in only 19.5%. Surgical remission occurred in 81 Group 1 patients (56.6%) and in 91 Group 2 patients (63.6%; p = 0.28). No significant difference in the remission rate was observed when cases were analyzed according to tumor size or invasiveness. Logistic regression analysis confirmed that pretreatment with somatostatin analogs was not associated with surgical outcome. Surgical morbidity was mild and similar in Group 1 and Group 2 patients (7 and 5.6%, respectively; p = 0.81). Surgical remission and complication rates in patients with acromegaly who received treatment with somatostatin analogs prior to surgery were not significantly different from those of matched patients who did not receive these agents. At present, the routine use of presurgical therapy with somatostatin analogs for patients with acromegaly cannot be recommended.

An open label, randomized phase II trial of primary systemic therapy with exemestane (EXE 25 mg/d) plus epirubicin (EPI, 20 vs 30 mg/m2 q1w × 8–12) in breast cancer: An interim analysis of the German Neoadjuvant Aromasin Initiative (GENARI-3)

826 Background: This randomized phase II trial explores the efficacy of EXE, a steroidal aromatase inactivator, in combination with lower doses of EPI, a topoisomerase-II targeted anthracycline, as an alternative presurgical therapy (PST) option for women who may not be eligible for more toxic primary chemotherapy regimens. Methods: Age: ≥ 50 years, postmenopausal hormone receptor (HR) + /−, primary tumors T2, 3, 4a-c, Nx, M0, ECOG PS 0–2. All patients (pts) obtained continuous EXE and were randomized to either 20 mg/m2 (A) or 30 mg/m2 (B) EPI q1w × 8–12. Endpoints (1st/2nd): pathological complete remissions (pCR), rate of breast conserving surgery (BCS), and grade/frequency of toxicity. Results: A total of 23 pts (12 in arm A, 11 in B) with median age of 68 (53–77) and tumor status T2 were enrolled. 28 patients are still under therapy and will be applicable for final analysis at the time of this presentation. All pts were HR+ and were evaluable for toxicity. Four patients (n=3: 20 mg/m2; n=1: 30 mg/m2) had reduced numbers of cycles [5(n=2), 6(n=1), 11(n=1)] after dose delay due to grade (G) 2 toxicity (NCI-CTC): leukopenia (n=2), infection (n=2) or G 3 toxicity: infection (n=1). One patient withdrew consent for pre-operative staging and surgery (arm B, no DLT). Efficacy (22 pts): Clinical responses were as follows: (A/B): clinical partial responses, n= 9/7; clinical stable disease, n= 3/3. Pathological tumor response (A/B): ypT0 (pCR), n=0/1, ypT1a, n=1/0; ypT1c, n=6/2; ypT2, n=4/5; ypT3, n=1/2. BCS: n=19/3. Conclusions: The interim results for 23 of 60 patients suggest good therapeutic efficacy and excellent tolerability of combined EXE and EPI . It has to be shown wether this treatment offers additional benefit for women with hormone- receptor positive breast cancer, who showed lower response to primary chemotherapy when compared to receptor- negative patients. In addition this supports the concept of combination PST as an alternative to hormonal PST in postmenopausal patients. No significant financial relationships to disclose.

An open label, randomized phase II trial of primary systemic therapy with exemestane (EXE 25 mg/d) plus epirubicin (EPI, 20 vs 30 mg/m2 q1w × 8–12) in breast cancer: An interim analysis of the German Neoadjuvant Aromasin Initiative (GENARI-3)

826 Background: This randomized phase II trial explores the efficacy of EXE, a steroidal aromatase inactivator, in combination with lower doses of EPI, a topoisomerase-II targeted anthracycline, as an alternative presurgical therapy (PST) option for women who may not be eligible for more toxic primary chemotherapy regimens. Methods: Age: ≥ 50 years, postmenopausal hormone receptor (HR) + /−, primary tumors T2, 3, 4a-c, Nx, M0, ECOG PS 0–2. All patients (pts) obtained continuous EXE and were randomized to either 20 mg/m2 (A) or 30 mg/m2 (B) EPI q1w × 8–12. Endpoints (1st/2nd): pathological complete remissions (pCR), rate of breast conserving surgery (BCS), and grade/frequency of toxicity. Results: A total of 23 pts (12 in arm A, 11 in B) with median age of 68 (53–77) and tumor status T2 were enrolled. 28 patients are still under therapy and will be applicable for final analysis at the time of this presentation. All pts were HR+ and were evaluable for toxicity. Four patients (n=3: 20 mg/m2; n=1: 30 mg/m2) h...

Blood conservation in patients undergoing non-cardiac surgery

Concerns about the safety, inventory, and cost of allogeneic blood have led to a renewed interest in blood conservation. Autologous blood collection techniques, including preoperative autologous donation, acute normovolemic hemodilution, and perioperative blood recovery are routinely used as alternatives to allogeneic transfusion. In the future, these techniques may be combined with pharmacological strategies, such as presurgical erythropoietin therapy or red cell substitutes, to reduce further the need for allogeneic blood.

Neoadjuvant hormonal therapy for prostate cancer?

Hormonal therapy administered before radical prostatectomy to reduce tumour size in patients with prostate cancer is of little value in preventing relapse, and only serves to ‘confuse the pathology’, experts said at the 92nd Annual Meeting of the American Urological Association [New Orleans, US; April 1997]. A multicentre study presented at the meeting confirmed this view. Results of the study showed that men receiving ‘neoadjuvant’ hormonal therapy before surgery for early prostate cancer had recurrence rates virtually identical to men who received no pre-surgical therapy.

組織学的照射効果からみた直腸癌に対する術前照射療法の評価

直腸癌20例に術前照射療法を施行した.照射効果をEf 0(なし),Ef 1(軽度),Ef 2-3(中等度～強度)に分類し,その有効性について検討した.(1)Ef 2-3症例は扁平上皮癌,高分化腺癌に高率であった.(2)Ef 1やEf 2-3症例は,深達度についてはs(a2),si(ai)が低率であり,リンパ節転移についてはn0やn1が,stageについてはstage 3以下が高率であった.また,Ef 2-3症例ではewの改善が4例に認められた。(3)リンパ管侵襲,静脈侵襲,神経周囲侵襲等の程度については,Ef 1やEf 2-3症例では,軽度以下が高率であった.(4)予後については,Ef 2-3症例では再発は認められていない.したがって,直腸癌に対する術前照射療法は有効と考えられるが,進行度が若い症例や脈管侵襲が軽度の症例に照射効果が期待できる可能性も否定できない.術前照射療法を厳密に評価するためには,照射前の進行度や脈管侵襲等を正確に把握する必要がある.

Etoposide, cyclophosphamide, cisplatin, and doxorubicin as neoadjuvant chemotherapy for osteosarcoma

The authors evaluated the combination of etoposide/cyclophosphamide (VP/CY) as initial, presurgical therapy for patients with osteosarcoma and found an 88% response rate for the primary tumor and any metastases. After definitive, limb-salvage surgery and adjuvant chemotherapy with etoposide, cyclophosphamide, cisplatin, and doxorubicin, patients without metastases at diagnosis whose cases were followed for a median of 2 years from diagnosis achieved a relapse-free survival (RFS) probability of 78% +/- 9%. This result is equivalent to the best adjuvant chemotherapy results reported to date. Patients without metastases at diagnosis had significantly better RFS probability (78% +/- 9%) than those with metastases at diagnosis (0%). Transient, severe myelosuppression has been the only major toxicity of the VP/CY courses. No irreversible organ damage or toxic deaths have been seen in patients enrolled in this study. The authors conclude that the combination of VP/CY is effective treatment for osteosarcoma, and when combined with cisplatin/doxorubicin (CIS/DOX), is as effective as any previously reported chemotherapy for osteosarcoma.