Intraperitoneal chemotherapy for ovarian cancer: where are we now?

Patients with advanced epithelial ovarian cancer are conventionally treated with intravenous (IV) platinum- and taxane-based chemotherapy to try to eradicate residual disease after optimal cytoreductive surgery, resulting in a median overall survival of 49 months. The Gynecologic Oncology Group (GOG) conducted 3 large randomized, phase III clinical trials of intraperitoneal (IP) chemotherapy (GOG 104, 114, and 172) that clearly showed superior progression-free and overall survival with IP chemotherapy compared with IV chemotherapy. All 3 clinical trials investigated IP cisplatin, with the last one adding IP paclitaxel. The most recent study (GOG 172) resulted in a median survival of 66 months for patients in the IP arm versus 50 months for those in the IV arm. Fewer patients in the IP arm than in the IV arm completed all 6 treatment cycles (42% vs. 83%, respectively) because of the toxic effects of chemotherapy and IP catheter-related complications. Initially, patients in the IP arm reported significantly worse quality of life than those in the IV arm. However, at 12-month follow-up, the groups experienced no difference in quality of life, except that paresthesias were more likely to persist at moderate levels among patients in the IP arm. Based on these clinical trials, the National Cancer Institute issued a clinical announcement recommending that women with stage III ovarian cancer who undergo optimal surgical cytoreduction be considered for IP chemotherapy.     

Intraperitoneal chemotherapy for frontline ovarian cancer therapy: Vindicated or vilified?

Conclusions A regimen of IV paclitaxel plus IP cisplatin and paclitaxel improves both PFS and OS in patients with optimally cytoreduced stage III ovarian cancer relative to IV cisplatin and paclitaxel.     

Intraperitoneal drug delivery for ovarian cancer: why, how, who, what, and when?

In 1996, intraperitoneal (IP) administration of cisplatin plus intravenous (i.v.) cyclophosphamide proved superior to both drugs given intravenously at the same doses--which, at the time, was the standard treatment in the United States. The IP 'option' was not adopted, however, because the standard treatment had shifted to i.v. cisplatin plus paclitaxel.Two additional phase III trials by the Gynecologic Oncology Group (GOG) comparing IP versus i.v. cisplatin, but including other variables, have shown similar superior effects of the IP route on outcome, but with toxicities-particularly local tolerance and neuropathy--increased. An ongoing trial by the GOG is again looking into an IP versus i.v. comparison, and introducing in one of the IP arms the substitution of IP carboplatin for IP cisplatin. All three arms of this trial contain bevacizumab (Avastin). Two other trials comparing i.v. versus IP administration of platinums or platinums and paclitaxel have just been launched, led by Japanese and Canadian investigators, respectively. While awaiting additional data on the ongoing debate over IP versus i.v. therapy, it is important that we consider issues concerning why the IP route may be relevant, how can one increase the safety of this route, and who should be treated and with what drugs, particularly when faced with a patient outside the clinical trials setting. The underlying hypothesis for use of IP therapy is based on the existence of a dose-effect relationship for platinum drugs in ovarian cancer. We review the known data on this relationship, and explore why interest in platinum drugs has become the central focus of ovarian cancer treatment.     

Intraperitoneal chemotherapy: standard of care for patients with minimal residual stage III ovarian cancer?

Epithelial ovarian cancer is the leading cause of death from gynecological cancer in most of the Western world, and long-term survival remains poor despite good initial response to systemic therapy after debulking surgery. Even after complete pathological response, the risk of recurrence in the first few years is substantial. The peritoneum is the predominant site of failure and the disease remains confined to the peritoneal cavity for much of its course. Efforts to improve clinical outcomes in this group of patients included investigation of intraperitoneal administration of active agents to expose the low-volume postoperative residual disease in the peritoneum to high concentrations of these drugs. In spite of three National Cancer Institute-sponsored randomized trials demonstrating clinical benefit with intraperitoneal therapy in patients with advanced ovarian cancer, the fact remains that it is not uniformly accepted by the gynecologic oncology community in the USA and is rarely used by clinicians in Europe. Intraperitoneal regimens are perceived to be too toxic for administration, although most of the toxicity is reversible. In this article we discuss the available evidence for intraperitoneal chemotherapy, challenges facing the gynecologic oncology community to make this modality more widely acceptable, the selection of patients most likely to tolerate intraperitoneal therapy and ongoing research in this field.     

Intraperitoneal chemotherapy: standard of care for patients with minimal residual stage III ovarian cancer?

Epithelial ovarian cancer is the leading cause of death from gynecological cancer in most of the Western world, and long-term survival remains poor despite good initial response to systemic therapy after debulking surgery. Even after complete pathological response, the risk of recurrence in the first few years is substantial. The peritoneum is the predominant site of failure and the disease remains confined to the peritoneal cavity for much of its course. Efforts to improve clinical outcomes in this group of patients included investigation of intraperitoneal administration of active agents to expose the low-volume postoperative residual disease in the peritoneum to high concentrations of these drugs. In spite of three National Cancer Institute-sponsored randomized trials demonstrating clinical benefit with intraperitoneal therapy in patients with advanced ovarian cancer, the fact remains that it is not uniformly accepted by the gynecologic oncology community in the USA and is rarely used by clinicians in Europe. Intraperitoneal regimens are perceived to be too toxic for administration, although most of the toxicity is reversible. In this article we discuss the available evidence for intraperitoneal chemotherapy, challenges facing the gynecologic oncology community to make this modality more widely acceptable, the selection of patients most likely to tolerate intraperitoneal therapy and ongoing research in this field.     

Regional chemotherapy in the treatment of advanced pancreatic cancer--is it relevant?

The treatment of pancreatic cancer is still problematic for physicians. Only 15% of patients present with resectable tumours, and systemic chemotherapy is of limited effectiveness. In order to achieve higher local drug concentrations in the tumour without causing the side-effects of a comparable level of systemic treatment, regional chemotherapy has been introduced as an alternative treatment. Several techniques have been developed over recent years, these include: celiac axis infusion (CAI), CAI with microspheres or haemofiltration, aortic stop flow (ASF) and isolated hypoxic perfusion (IHP). Whilst several authors have reported improved response rates and a prolongation of median survival time, these results have not been confirmed by others. In addition, the incidence of side-effects and the rate of technical complications have been reported to be high during regional chemotherapy. Except for a single trial containing 14 patients, no randomised trial comparing systemic and regional chemotherapy has been conducted. For these reasons, none of the reported treatment regimens can be considered to be standard treatment and in order to evaluate, if regional chemotherapy is indeed superior to systemic chemotherapy, randomised trials must be conducted.     

Cytotoxic chemotherapy for prostate cancer: Who and when?

The survival benefit demonstrated by docetaxel-based therapy in two randomized trials, Southwest Oncology Group (SWOG) 99-16 and TAX 327, has changed the perception of chemotherapy in men with hormone-refractory prostate cancer from nihilism to optimism. These survival improvements are of similar magnitude to those found in trials that established chemotherapeutic regimens for metastatic breast, lung, or colorectal cancer. The timing of chemotherapy in the aforementioned solid tumors is much more clearly defined than in men with metastatic prostate cancer. Traditionally, chemotherapy in men with hormone-resistant prostate cancer was reserved for symptomatic patients only; the inclusion of symptomatic and asymptomatic patients in SWOG 99-16 and TAX 327 has raised several questions regarding the optimal use of chemotherapy in these patients. When is the best time to initiate docetaxel-based chemotherapy? Is it appropriate to use chemotherapy in high-risk patients as adjuvant therapy? Although retrospective analysis of current trials may provide hypothesis, only properly designed randomized clinical trials will answer these questions.     

Induction chemotherapy and larynx preservation: is such practice useful?

BACKGROUND: Surgery followed by irradiation is considered to be the standard treatment but require frequently a total laryngectomy. Chemotherapy followed by irradiation is available in larynx and hypopharynx squamous cell carcinoma (SCC) treatment. Are results obtained in daily induction chemotherapy usefulness identical to results obtained in larynx preservation studies? PATIENTS AND METHOD: We conducted a retrospective study on patients treated at centre Oscar-Lambret, Lille, from 1986 to 1995, by chemotherapy followed by definitive radiotherapy or by surgery and radiotherapy for laryngeal or hypopharyngeal cancer treatment. All patients were naive of previous head and neck SCC and a surgical treatment, requiring total laryngectomy, should be proposed with curative intent. Induction chemotherapy associated cisplatin (100 mg/m2) on day 1 and 5-fluorouracil (5FU)(1,000 mg/m2) on days 1-4 or 1-5. Irradiation was performed for responders (complete or partial > 50%). If case of non-responder, patients underwent surgical treatment followed by irradiation. We compared results obtained with patients enrolled in clinical trial and with patients whom benefited from this protocol out of trial. RESULTS: Hundred-eight patients were evaluable for purposes of this study. Fifty-two patients were included in clinical trial (group 1) while 56 patients (group 2) were not. There was no statistical difference as regard neither to sex nor to node (palpable or not palpable) and metastasis status between the groups. We found a higher frequency of laryngeal tumour in group 2 (31 vs 17; p =.03). We observed more stage III and less stage IV in group 1. For chemotherapy-related toxic reactions, the exclusive statistical difference observed was haematological toxicity grade III and IV after the second cycle (0 pt in group 1 vs 8 pts in group 2; p =.02). After initial treatment, complete response was achieved without statistical difference between the groups (88.2% vs 78%; p =.27). A surgical procedure was performed in 46 cases without difference according to the reference group and functional larynx preservation was 55.8% (29/52) in group 1 and 53.6% (30/56) in group 2. Whatever the group, causes of death were similarly distributed. Cancer was the first cause of death in both groups. The overall survival of the population (108 patients) was 81.5% at one year, 49.6% at 3 years and 35.3% at 5 years with a median survival of 3 years. There was no statistical difference between both groups. Some parameters influenced the overall survival like T (p =.04), response to chemotherapy (p=.006), extra capsular spread (p = 0.03) and response after completion treatment. CONCLUSION: Induction chemotherapy is available for larynx preservation but cannot be considered as a standard treatment. Nevertheless, results should be reproduced in daily practice with experimented teams as found with non included patient's results. The long-term side effects of such protocols should be evaluated. Recent publication, on increase postoperative infection after chemotherapy, should be evaluated in clinical trial. If confirmed, cost effectiveness of such complication must be integrated in larynx preservation protocols. Larynx preservation remains an interesting point of view for patients but stay an optional procedure and not a reference.     

Pre-, peri-, and postoperative chemotherapy for breast cancer: Is one better than the other?

The purpose of the present study was to determine the relative efficacy of pre-, peri-, and postoperative chemotherapy in the prevention of breast cancer relapse and prolongation of host survival. The studies were performed using an experimental mouse breast cancer model. TA3Ha mouse mammary adenocarcinoma was transplanted into the mammary fat pad of syngeneic mice to obtain tumors in their natural organ. The tumors were surgically excised with a “curative” intent. A single treatment with 10 mg/kg doxorubicin was given intravenously pre-, peri-, or postoperatively. Among 74 mice whose tumors were resected but no doxorubicin was given, local recurrence, axillary metastasis, and lung metastasis were seen in 43%, 37%, and 16% of the mice, respectively. Seventeen (23%) mice had no evidence of disease. Doxorubicin given 4 days preoperatively reduced the rate of growth of primary tumor. Local recurrence was reduced in these mice by 30% and metastasis to the axillary lymph nodes and lung was completely prevented. Disease-free survival was increased to 70% (P < 0.01). Similar beneficial effects were obtained when chemotherapy was administered 2 days prior to surgery. The peri-operative chemotherapy group showed 8% (2/26) local recurrence, 4% axillary metastasis, and 0% lung metastasis. Proportion of mice without any evidence of disease increased to 92% (P < 0.00001). Chemotherapy given 4 days postoperatively resulted in 63% (10/16) local recurrence, 38% axillary metastasis, and 6.3% lung metastasis. Only 38% of the mice were disease-free. Thus in the model studied, perioperative chemotherapy offers the best chance for reduced recurrence and for improved disease-free survival. © 1996 Wiley-Liss, Inc.     

Treatment of recurrent head and neck cancer: re-irradiation or chemotherapy?

For most patients with head and neck cancer, locoregional disease recurrence carries an extremely poor prognosis and has severe adverse effects on quality of life. Only a few patients are suitable for salvage surgery and, even in selected cases, the success rate is low. Most patients are managed by supportive palliative care, or with palliative chemotherapy. In the UK, re-irradiation is rarely used because of concerns about treatment-related toxicity and lack of efficacy. Despite this, a significant body of evidence suggests that re-irradiation may have a higher probability of achieving local control than other treatments. In this review, we discuss the use of re-irradiation in patients with locally recurrent head and neck cancer, and present the pertinent data.     

Senescence: a companion in chemotherapy?

Mouse lymphoma model points to an unsuspected role of drug-induced "senescence."     

The immune system--is it relevant to cancer development, progression and treatment?

The ability of the immune system to effectively respond to human tumours is a matter of long-term controversy. There is an increasing body of recent evidence to support a role for the immune system in eliminating pre-clinical cancers, an old concept termed 'immunosurveillance'. 'Immunoediting' is an updated hypothesis, in which selection pressures applied by the immune response to tumours modulate tumour immunogenicity and growth. Tumour infiltration by immune cells has been shown to have powerful prognostic significance in a host of cancer types. Paradoxically, in some circumstances the immune system can promote tumour development. Cytotoxic therapies, including radiotherapy and chemotherapy, induce potentially immunogenic cell death, releasing tumour-associated antigens in the context of a 'danger' signal to the immune system. An understanding of the interaction between immune cells, tumour cells and treatment modalities will therefore guide the future combination of immunotherapy with conventional therapy to achieve optimal anti-tumour effects.