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1.  Prognosis after salvage treatment for unselected male patients with germ cell tumours. 
British Journal of Cancer  1995;72(4):1026-1032.
Long-term outcome of salvage treatment was reviewed in 67 unselected male patients relapsing during or after their primary cisplatin-based chemotherapy for metastatic germ cell tumours. Seven patients underwent only surgery and/or radiotherapy as curatively intended salvage treatment. Thirty-five patients (52%) had a complete or partial response to salvage treatment, 20 (57%) of whom relapsed again. With a median follow-up of 90 months (range 3-143 months) 20 patients (30%) are alive with no evidence of disease, 15 continuously disease-free and five currently disease-free. The 5 year survival from start of salvage treatment is 37% for the group as a whole. Multivariate analysis identified age < or = 35 years, complete response to primary treatment and a relapse-free interval > 3 months as independent predictors of favourable outcome of salvage treatment. A group of patients with these good-risk factors (42%) had a 5 year survival of 72% compared with the remaining patients (58%) with a 5 year survival of only 11%. Whereas patients with good-risk features may be adequately managed by conventional salvage treatment, the remaining patients carry a very poor prognosis and require innovative and more aggressive approaches.
PMCID: PMC2034042  PMID: 7547217
2.  Optimal chemotherapy treatment for women with recurrent ovarian cancer 
Current Oncology  2007;14(5):195-208.
Question
What is the optimal chemotherapy treatment for women with recurrent ovarian cancer who have previously received platinum-based chemotherapy?
Perspectives
Currently, standard primary therapy for advanced disease involves a combination of maximal cytoreductive surgery and chemotherapy with carboplatin plus paclitaxel or with carboplatin alone. Despite initial high response rates, a large proportion of patients relapse, resulting in a therapeutic challenge. Because these patients are not curable, the goal of therapy becomes improvement in both quality and length of life. The search has therefore been to find active agents for women with recurrent disease following platinum-based chemotherapy.
Outcomes
Outcomes of interest included any combination of tumour response rate, progression-free survival, overall survival, adverse events, and quality of life.
Methodology
The medline, embase, and Cochrane Library databases were systematically searched for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. The systematic review and recommendations were approved by the Report Approval Panel of the Program in Evidence-Based Care, and by the Gynecology Cancer Disease Site Group (dsg). The practice guideline was externally reviewed by a sample of practitioners from Ontario, Canada.
Results
Thirteen randomized trials compared various chemotherapy regimens for patients with recurrent ovarian cancer.
In five of the thirteen trials in which 100% of patients were considered sensitive to platinum-containing chemotherapy, further platinum-based combination chemotherapy significantly improved response rates (two trials), progression-free survival (four trials), and overall survival (three trials) when compared with single-agent chemotherapy involving carboplatin or paclitaxel. Only two of these randomized trials compared the same chemotherapy regimens: carboplatin alone versus the combination of carboplatin and paclitaxel. Both trials were consistent in reporting improved survival outcomes with the combination of carboplatin and paclitaxel. In one trial, the combination of carboplatin and gemcitabine resulted in significantly higher response rates and improved progression-free survival when compared with carboplatin alone. Median survival with carboplatin alone ranged from 17 months to 24 months in four trials.
In eight of the thirteen trials in which 35%–100% of patients had platinum-refractory or -resistant disease, one trial reported a statistically significant 2-month improvement in overall survival with liposomal doxorubicin as compared with topotecan (15 months vs. 13 months, p = 0.038; hazard ratio: 1.23; 95% confidence interval: 1.01 to 1.50). In that trial, because of the limited clinical benefit and the unusual finding that a survival difference emerged only after a year of treatment with no corresponding improvement in the rate of response or of progression-free survival, the authors concluded that further confirmation by results from randomized trials were needed to establish the superiority of one agent over another in their trial. In one trial, topotecan was superior to treosulphan in patient progression-free survival by a span of approximately 2 months (5.4 months vs. 3.0 months, p < 0.001).
Toxicity was reported in all of the randomized trials, and although data on adverse events varied by treatment regimen, the observed adverse events correlated with known toxicity profiles. As expected, combination chemotherapy was associated with higher rates of adverse events.
Practice Guideline
Target Population
This clinical recommendation applies to women with recurrent epithelial ovarian cancer who have previously received platinum-based chemotherapy. Of specific interest are women who have previously shown sensitivity to platinum therapy and those who previously were refractory or resistant to platinum-based chemotherapy. As a general categorization within what is actually a continuum, “platinum sensitivity” refers to disease recurrence 6 months or more after prior platinum-containing chemotherapy, and “platinum resistance” refers to a response to platinum-based chemotherapy followed by relapse less than 6 months after chemotherapy is stopped. “Platinum-refractory disease” refers to a lack of response or to progression while on platinum-based chemotherapy.
Recommendations
Although the body of evidence that informs the clinical recommendations is based on randomized trial data, those data are incomplete. Based on the available data and expert consensus opinion, the Gynecology Cancer dsg makes these recommendations:
Systemic therapy for recurrent ovarian cancer is not curative. It is therefore recognized that each patient must be individually assessed to determine optimal therapy in terms of recurrence, sensitivity to platinum, toxicity, ease of administration, and patient preference. All suitable patients should be offered the opportunity to participate in randomized trials, if available.
In the absence of contraindications, combination platinum-based chemotherapy should be considered for patients with prior sensitivity to platinum-containing chemotherapy. As compared with carboplatin alone, the combination of carboplatin and paclitaxel significantly improved both progression-free and overall survival.
If combination platinum-based chemotherapy is not indicated, then a single platinum agent should be considered. Carboplatin has demonstrated efficacy across trials and has a manageable toxicity profile.
If a single platinum agent is not being considered, then monotherapy with paclitaxel, topotecan, or pegylated liposomal doxorubicin are seen as reasonable treatment options.
Some patients may be repeatedly sensitive to treatment and may benefit from multiple lines of chemotherapy.
For patients with platinum-refractory or platinum-resistant disease, the goals of treatment should be to improve quality of life by extending the symptom-free interval, by reducing symptom intensity, and by increasing progression-free interval, and, if possible, to prolong life.
With non-platinum agents, monotherapy should be considered because no advantage appears to accrue to the use of non-platinum-containing combination chemotherapy in this group of patients. Single-agent paclitaxel, topotecan, or pegylated liposomal doxorubicin have demonstrated activity in this patient population and are reasonable treatment options.
No evidence either supports or refutes the use of more than one line of chemotherapy in patients with platinum-refractory or platinum-resistant recurrence. Many treatment options have shown modest response rates, but their benefits over best supportive care have not been studied in clinical trials.
PMCID: PMC2002482  PMID: 17938703
Chemotherapy; drug therapy; ovarian cancer; ovarian neoplasms; practice guideline; systematic review
3.  Consolidative high-dose chemotherapy after conventional-dose chemotherapy as first salvage treatment for male patients with metastatic germ cell tumours 
Introduction:
Some men with metastatic germ cell tumours that have progressed after response to initial cisplatin-based combination chemotherapy are cured with conventional dose first salvage chemotherapy (CDCT) – however, many are not. High-dose chemotherapy with autologous stem cell rescue (HDCT) may be of value in these patients. Prognosis has recently been better defined by International Prognostic Factor Study Group (IPFSG) prognostic factors. HDCT after response to CDCT has been offered at our institution over the past two decades. We retrospectively assessed the validity of the IPFSG prognostic factors in our patients and evaluated the value of HDCT.
Methods:
We identified eligible men with metastatic germ cell tumour progressed after at least 3 cycles of cisplatin-based chemotherapy and treated with cisplatin-based CDCT alone or with carboplatin-based HDCT. We also collected their clinical data. Patients were classified into risk groups using IPFSG factors, and progression-free and overall survival factors were analyzed and compared in patients treated with CDCT alone and with HDCT.
Results:
We identified 38 eligible first salvage patients who had received a median of 4 cycles (range, 1 to 7 cycles) of CDCT. Twenty patients received CDCT alone and 18 patients received CDCT plus HDCT. The overall median progression- free survival was 24.6 months (95%CI, 7.3 to 28.7 months) and overall median overall survival was 34.6 months (95%CI, 17.2 to 51.3 months). Distribution by IPFSG category and 2-year progression- free survival and 3-year overall survival rates within each risk category were very similar to the IPFSG results. There were two toxic deaths with CDCT and none with HDCT. Overall, patients treated with CDCT plus HDCT had improved progression- free survival and overall survival.
Conclusions:
The IPFSG prognostic risk factors appeared valid in our patient population. The safety of HDCT with etoposide and carboplatin was confirmed. HDCT was associated with improved progression- free survival and overall survival outcomes, consistent with observations of the IPFSG group. Ideally, the value of optimal HDCT should be determined in comparison to optimal CDCT as first salvage therapy in men with metastatic germ cell tumour with a randomized trial.
doi:10.5489/cuaj.11233
PMCID: PMC3328550  PMID: 22511417
4.  Primary malignant mediastinal germ cell tumours: improved prognosis with platinum-based chemotherapy and surgery. 
British Journal of Cancer  1993;67(5):1098-1101.
A retrospective analysis was performed of 18 patients with primary malignant germ cell tumours of the mediastinum treated with platinum-based chemotherapy between 1977 and 1990. All seven patients with pure seminoma were treated initially with chemotherapy and four of these patients received additional mediastinal radiotherapy. Only one patient relapsed; his initial therapy had included radiotherapy and single-agent carboplatin and he was successfully salvaged with combination chemotherapy. With a follow-up of 11 to 117 months (median 41 months) all seven patients with seminoma remain alive and disease free giving an overall survival of 100%. Eleven patients had malignant non seminoma; following chemotherapy eight of these had elective surgical resection of residual mediastinal masses. Complete remission was achieved in nine (82%) patients, however, one of these patients died from bleomycin pneumonitis. With a follow-up of 12 to 113 months (median 55 months) eight of 11 (73%) patients with malignant mediastinal teratoma remain alive and disease free.
PMCID: PMC1968447  PMID: 8494705
5.  Prognostic factors in patients progressing after cisplatin-based chemotherapy for malignant non-seminomatous germ cell tumours 
British Journal of Cancer  1999;80(9):1392-1399.
The aim of this study was to define prognostic parameters for survival in patients with malignant germ cell tumours progressing after platinum-based induction chemotherapy with or without surgery. A total of 164 progressing patients (testicular: 83%, extragonadal: 17%) were identified out of 795 patients treated with platinum-based induction chemotherapy for metastatic germ cell malignancy with or without surgery. ‘Progressive disease’ included patients who had progressed after a previous partial or complete remission as well as patients who failed primary therapy. Salvage chemotherapy consisted of ‘conventional’ platinum-based chemotherapy. Prognostic factors for survival were assessed by uni- and multivariate analyses. The resulting prognostic model was validated in an independent data set of 66 similar patients. For all 164 patients the median time from start of induction chemotherapy to progression was 10 months (range: 0–99). Thirty-eight (23%) patients relapsed after 2 years. The 5-year survival rate for all progressing patients was 30% (95% confidence interval 23–38%). In the univariate analysis the following factors most importantly predicted a poor prognosis: progression-free interval < 2 years: initial poor prognosis category (MRC criteria), < CR to induction chemotherapy, initial treatment early in the 1980s and treatment given at a ‘small’ centre. Three prognostic factors remained in the multivariate analysis: progression-free interval, response to induction treatment and the level of serum human chronic gonadotrophin (hCG) and alpha fetoprotein (AFP) at relapse. One hundred and twenty-four patients could be classified on the basis of these characteristics, Those patients with progression-free interval < 2 years, < CR to induction chemotherapy and high markers at relapse (AFP >100 kU l−1 or hCG >100 IU l−1) formed a poor prognosis group of 30 patients, none of whom survived after 3 years. Patients with at most two of these three risk factors formed a good prognosis group of 94 patients (76%) with a 47% (37–56%) 5-year survival. Thirty-eight patients from the good prognosis group with a progression-free interval of >2 years had a 2-year survival of 74% (60–88%) and 5-year survival of 61%. These prognostic groups were validated in the independent data set, in which 5-year survival rates in the good and poor risk groups were 51% and 0% respectively. One-third of patients progressing during or after platinum-based induction chemotherapy for metastatic germ cell malignancy may be cured by repeated ‘conventional’ platinum-based chemotherapy. Good prognosis parameters are: progression-free interval of > 2 years, CR to induction treatment and normal or low serum markers at relapse (hCG < 100 IU l−1 and AFP < 100 kU l−1). The results of high-dose salvage chemotherapy should be interpreted on the background of these prognostic factors. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690534
PMCID: PMC2363071  PMID: 10424741
germ cell malignancy; relapse; cisplatin-based chemotherapy; survival
6.  Late Relapse and Follow-up Protocols in Testicular Germ Cell Tumours: The Edinburgh Cancer Centre Experience and Review of the Literature 
Aims
To identify clinicopathological features and outcomes in patients with late relapse (LR) of testicular germ cell tumours (GCTs) in order to guide follow-up policy.
Materials and Methods
The Edinburgh Cancer Centre (ECC) database identified all patients diagnosed with testicular GCT between 1988 and 2002. Of 703 patients, six relapsed more than 24 months after their initial treatment. A retrospective casenote review was performed to extract clinical, pathological, treatment and outcome data.
Results
Six patients (0.85%) underwent late relapse. All patients presented initially with stage I disease and five were classified as good risk (International Germ Cell Consensus Classification, IGCCC). Median time to LR was 31 months. Two patients had previously relapsed less than 24 months from initial diagnosis. Markers at the time of relapse were normal in all patients. In all cases of late relapse disease was confined to axial lymphadenopathy. Three patients were treated with chemotherapy alone, two patients underwent surgical resection and one patient received combined treatment. All patients obtained a complete response and all remain disease free with a median follow-up of 52 months.
Conclusions
The incidence of late relapse in this series is low. Chemo-naive patients with LR were successfully salvaged with chemotherapy alone and patients previously exposed to cisplatin-based chemotherapy were salvaged with complete surgical excision. The optimal length of follow-up in patients with testicular germ cell tumours is not known and practice varies widely. In this cohort of 703 patients, only one patient who relapsed was picked up by additional clinic follow-up between 5 and 10 years. Thus, on the basis of this small series, the authors suggest that follow-up after five years may not be justified.
PMCID: PMC3161629  PMID: 21892262
follow-up; germ cell tumors; late relapse
7.  Testicular cancer: seminoma 
Clinical Evidence  2011;2011:1807.
Introduction
More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 25 to 35 years. Most testicular cancers are germ cell tumours and half of these are seminomas, which tend to affect older men and have a good prognosis.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in men with stage 1 seminoma (confined to testis) who have undergone orchidectomy? What are the effects of treatments in men with good-prognosis non-stage 1 seminoma who have undergone orchidectomy? What are the effects of maintenance chemotherapy in men who are in remission after orchidectomy and chemotherapy for good-prognosis non-stage 1 seminoma? What are the effects of treatments in men with intermediate-prognosis seminoma who have undergone orchidectomy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 29 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: chemotherapy (maintenance, adjuvant, single-agent carboplatin, 3 or 4 cycles, different number of cycles of adjuvant, using bleomycin added to vinblastine plus cisplatin, using etoposide plus cisplatin with or without bleomycin, adding higher doses to a 2-drug chemotherapy regimen using cisplatin or vinblastine); radiotherapy (different adjuvant regimens [20 Gy in 10 fractions to para-aortic area, 30 Gy in 15 fractions to para-aortic area and iliac nodes], different drug combinations, 30–36 Gy in 15–18 fractions); and surveillance.
Key Points
More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 25 to 35 years. Most testicular cancers are germ cell tumours and about half of these are seminomas, which tend to affect older men and have a good prognosis.
In men with seminoma confined to the testis (stage 1), standard treatment is orchidectomy followed by radiotherapy, chemotherapy, or surveillance. All 3 management options are associated with cure rates approaching 100% because of successful salvage therapy. Adjuvant chemotherapy reduces the risk of relapse after orchidectomy compared with surveillance, but is associated with short-term adverse effects (nausea, diarrhoea, and indigestion) and possible long-term risks of reduced fertility and development of second malignancies.We don't know which is the most effective chemotherapy regimen, or the optimum number of cycles to use. The high cure rate with standard therapy makes it difficult to show which alternative therapy is superior.Toxicity is lower, but efficacy the same, with adjuvant irradiation of 20 Gy in 10 fractions compared with 30 Gy in 15 fractions, or with irradiation to para-aortic nodes compared with ipsilateral iliac nodes.
In men with good-prognosis non-stage 1 seminoma who have had orchidectomy, radiotherapy may improve survival and be less toxic than chemotherapy, except in men with large-volume disease, in whom chemotherapy may be more effective. Combined chemotherapy may be more effective than single agents, but 3 cycles seem to be as effective as 4 and with less toxicity.A standard radiotherapy treatment comprises 30 to 36 Gy in 15 to 18 fractions (2 Gy per fraction), although we don't know whether this is more effective than other regimens.
In men who are in remission after orchidectomy plus chemotherapy for good-prognosis, non-stage 1 seminoma, further chemotherapy is unlikely to reduce relapse rates or increase survival. Chemotherapy increases survival in men with intermediate-prognosis seminomas who have had orchidectomy; although evidence for this is derived mostly from treatment of intermediate-prognosis non-seminoma, it is likely to be generalisable to intermediate-prognosis seminoma.
PMCID: PMC3217763  PMID: 21477387
8.  Extracorporeal Photophoresis 
Executive Summary
Objective
To assess the effectiveness, safety and cost-effectiveness of extracorporeal photophoresis (ECP) for the treatment of refractory erythrodermic cutaneous T cell lymphoma (CTCL) and refractory chronic graft versus host disease (cGvHD).
Background
Cutaneous T Cell Lymphoma
Cutaneous T cell lymphoma (CTCL) is a general name for a group of skin affecting disorders caused by malignant white blood cells (T lymphocytes). Cutaneous T cell lymphoma is relatively uncommon and represents slightly more than 2% of all lymphomas in the United States. The most frequently diagnosed form of CTCL is mycosis fungoides (MF) and its leukemic variant Sezary syndrome (SS). The relative frequency and disease-specific 5-year survival of 1,905 primary cutaneous lymphomas classified according to the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification (Appendix 1). Mycosis fungoides had a frequency of 44% and a disease specific 5-year survival of 88%. Sezary syndrome had a frequency of 3% and a disease specific 5-year survival of 24%.
Cutaneous T cell lymphoma has an annual incidence of approximately 0.4 per 100,000 and it mainly occurs in the 5th to 6th decade of life, with a male/female ratio of 2:1. Mycosis fungoides is an indolent lymphoma with patients often having several years of eczematous or dermatitic skin lesions before the diagnosis is finally established. Mycosis fungoides commonly presents as chronic eczematous patches or plaques and can remain stable for many years. Early in the disease biopsies are often difficult to interpret and the diagnosis may only become apparent by observing the patient over time.
The clinical course of MF is unpredictable. Most patients will live normal lives and experience skin symptoms without serious complications. Approximately 10% of MF patients will experience progressive disease involving lymph nodes, peripheral blood, bone marrow and visceral organs. A particular syndrome in these patients involves erythroderma (intense and usually widespread reddening of the skin from dilation of blood vessels, often preceding or associated with exfoliation), and circulating tumour cells. This is known as SS. It has been estimated that approximately 5-10% of CTCL patients have SS. Patients with SS have a median survival of approximately 30 months.
Chronic Graft Versus Host Disease
Allogeneic hematopoietic cell transplantation (HCT) is a treatment used for a variety of malignant and nonmalignant disease of the bone marrow and immune system. The procedure is often associated with serious immunological complications, particularly graft versus host disease (GvHD). A chronic form of GvHD (cGvHD) afflicts many allogeneic HCT recipients, which results in dysfunction of numerous organ systems or even a profound state of immunodeficiency. Chronic GVHD is the most frequent cause of poor long-term outcome and quality of life after allogeneic HCT. The syndrome typically develops several months after transplantation, when the patient may no longer be under the direct care of the transplant team.
Approximately 50% of patients with cGvHD have limited disease and a good prognosis. Of the patients with extensive disease, approximately 60% will respond to treatment and eventually be able to discontinue immunosuppressive therapy. The remaining patients will develop opportunistic infection, or require prolonged treatment with immunosuppressive agents.
Chronic GvHD occurs in at least 30% to 50% of recipients of transplants from human leukocyte antigen matched siblings and at least 60% to 70% of recipients of transplants from unrelated donors. Risk factors include older age of patient or donor, higher degree of histoincompatibility, unrelated versus related donor, use of hematopoietic cells obtained from the blood rather than the marrow, and previous acute GvHD. Bhushan and Collins estimated that the incidence of severe cGvHD has probably increased in recent years because of the use of more unrelated transplants, donor leukocyte infusions, nonmyeloablative transplants and stem cells obtained from the blood rather than the marrow. The syndrome typically occurs 4 to 7 months after transplantation but may begin as early as 2 months or as late as 2 or more years after transplantation. Chronic GvHD may occur by itself, evolve from acute GvHD, or occur after resolution of acute GvHD.
The onset of the syndrome may be abrupt but is frequently insidious with manifestations evolving gradually for several weeks. The extent of involvement varies significantly from mild involvement limited to a few patches of skin to severe involvement of numerous organ systems and profound immunodeficiency. The most commonly involved tissues are the skin, liver, mouth, and eyes. Patients with limited disease have localized skin involvement, evidence of liver dysfunction, or both, whereas those with more involvement of the skin or involvement of other organs have extensive disease.
Treatment
 
Cutaneous T Cell Lymphoma
The optimal management of MF is undetermined because of its low prevalence, and its highly variable natural history, with frequent spontaneous remissions and exacerbations and often prolonged survival.
Nonaggressive approaches to therapy are usually warranted with treatment aimed at improving symptoms and physical appearance while limiting toxicity. Given that multiple skin sites are usually involved, the initial treatment choices are usually topical or intralesional corticosteroids or phototherapy using psoralen (a compound found in plants which make the skin temporarily sensitive to ultraviolet A) (PUVA). PUVA is not curative and its influence on disease progression remains uncertain. Repeated courses are usually required which may lead to an increased risk of both melanoma and nonmelanoma skin cancer. For thicker plaques, particularly if localized, radiotherapy with superficial electrons is an option.
“Second line” therapy for early stage disease is often topical chemotherapy, radiotherapy or total skin electron beam radiation (TSEB).
Treatment of advanced stage (IIB-IV) MF usually consists of topical or systemic therapy in refractory or rapidly progressive SS.
Bone marrow transplantation and peripheral blood stem cell transplantation have been used to treat many malignant hematologic disorders (e.g., leukemias) that are refractory to conventional treatment. Reports on the use of these procedures for the treatment of CTCL are limited and mostly consist of case reports or small case series.
Chronic Graft Versus Host Disease
Patients who develop cGvHD require reinstitution of immunosuppressive medication (if already discontinued) or an increase in dosage and possibly addition of other agents. The current literature regarding cGvHD therapy is less than optimal and many recommendations about therapy are based on common practices that await definitive testing. Patients with disease that is extensive by definition but is indolent in clinical appearance may respond to prednisone. However, patients with more aggressive disease are treated with higher doses of corticosteroids and/or cyclosporine.
Numerous salvage therapies have been considered in patients with refractory cGvHD, including ECP. Due to uncertainty around salvage therapies, Bhushan and Collins suggested that ideally, patients with refractory cGvHD should be entered into clinical trials.
Two Ontario expert consultants jointly estimated that there may be approximately 30 new erythrodermic treatment resistant CTCL patients and 30 new treatment resistant cGvHD patients per year who are unresponsive to other forms of therapy and may be candidates for ECP.
Extracorporeal photopheresis is a procedure that was initially developed as a treatment for CTCL, particularly SS.
Current Technique
Extracorporeal photopheresis is an immunomodulatory technique based on pheresis of light sensitive cells. Whole blood is removed from patients followed by pheresis. Lymphocytes are separated by centrifugation to create a concentrated layer of white blood cells. The lymphocyte layer is treated with methoxsalen (a drug that sensitizes the lymphocytes to light) and exposed to UVA, following which the lymphocytes are returned to the patient. Red blood cells and plasma are returned to the patient between each cycle.
Photosensitization is achieved by administering methoxsalen to the patient orally 2 hours before the procedure, or by injecting methoxsalen directly ino the leucocyte rich fraction. The latter approach avoids potential side effects such as nausea, and provides a more consistent drug level within the machine.
In general, from the time the intravenous line is inserted until the white blood cells are returned to the patient takes approximately 2.5-3.5 hours.
For CTCL, the treatment schedule is generally 2 consecutive days every 4 weeks for a median of 6 months. For cGvHD, an expert in the field estimated that the treatment schedule would be 3 times a week for the 1st month, then 2 consecutive days every 2 weeks after that (i.e., 4 treatments a month) for a median of 6 to 9 months.
Regulatory Status
The UVAR XTS Photopheresis System is licensed by Health Canada as a Class 3 medical device (license # 7703) for the “palliative treatment of skin manifestations of CTCL.” It is not licensed for the treatment of cGvHD.
UVADEX (sterile solution methoxsalen) is not licensed by Health Canada, but can be used in Canada via the Special Access Program. (Personal communication, Therakos, February 16, 2006)
According to the manufacturer, the UVAR XTS photopheresis system licensed by Health Canada can also be used with oral methoxsalen. (Personal communication, Therakos, February 16, 2006) However, oral methoxsalen is associated with side effects, must be taken by the patient in advance of ECP, and has variable absorption in the gastrointestinal tract.
According to Health Canada, UVADEX is not approved for use in Canada. In addition, a review of the Product Monographs of the methoxsalen products that have been approved in Canada showed that none of them have been approved for oral administration in combination with the UVAR XTS photophoresis system for “the palliative treatment of the skin manifestations of cutaneous T-cell Lymphoma”.
In the United States, the UVAR XTS Photopheresis System is approved by the Food and Drug Administration (FDA) for “use in the ultraviolet-A (UVA) irradiation in the presence of the photoactive drug methoxsalen of extracorporeally circulating leukocyte-enriched blood in the palliative treatment of the skin manifestations of CTCL in persons who have not been responsive to other therapy.”
UVADEX is approved by the FDA for use in conjunction with UVR XTS photopheresis system for “use in the ultraviolet-A (UVA) irradiation in the presence of the photoactive drug methoxsalen of extracorporeally circulating leukocyte-enriched blood in the palliative treatment of the skin manifestations of CTCL in persons who have not been responsive to other therapy.”
The use of the UVAR XTS photopheresis system or UVADEX for cGvHD is an off-label use of a FDA approved device/drug.
Summary of Findings
The quality of the trials was examined.
As stated by the GRADE Working Group, the following definitions were used in grading the quality of the evidence.
Cutaneous T Cell Lymphoma
Overall, there is low-quality evidence that ECP improves response rates and survival in patients with refractory erythrodermic CTCL (Table 1).
Limitations in the literature related to ECP for the treatment of refractory erythrodermic CTCL include the following:
Different treatment regimens.
Variety of forms of CTCL (and not necessarily treatment resistant) - MF, erythrodermic MF, SS.
SS with peripheral blood involvement → role of T cell clonality reporting?
Case series (1 small crossover RCT with several limitations)
Small sample sizes.
Retrospective.
Response criteria not clearly defined/consistent.
Unclear how concomitant therapy contributed to responses.
Variation in definitions of concomitant therapy
Comparison to historical controls.
Some patients were excluded from analysis because of progression of disease, toxicity and other reasons.
Unclear/strange statistics
Quality of life not reported as an outcome of interest.
The reported CR range is ~ 16% to 23% and the overall reported CR/PR range is ~ 33% to 80%.
The wide range in reported responses to ECP appears to be due to the variability of the patients treated and the way in which the data were presented and analyzed.
Many patients, in mostly retrospective case series, were concurrently on other therapies and were not assessed for comparability of diagnosis or disease stage (MF versus SS; erythrodermic versus not erythrodermic). Blood involvement in patients receiving ECP (e.g., T cell clonality) was not consistently reported, especially in earlier studies. The definitions of partial and complete response also are not standardized or consistent between studies.
Quality of life was reported in one study; however, the scale was developed by the authors and is not a standard validated scale.
Adverse events associated with ECP appear to be uncommon and most involve catheter related infections and hypotension caused by volume depletion.
GRADE Quality of Studies – Extracorporeal Photopheresis for Refractory Erythrodermic Cutaneous T-Cell Lymphoma
Chronic Graft-Versus-Host Disease
Overall, there is low-quality evidence that ECP improves response rates and survival in patients with refractory cGvHD (Table 2).
Patients in the studies had stem cell transplants due to a variety of hematological disorders (e.g., leukemias, aplastic anemia, thalassemia major, Hodgkin’s lymphoma, non Hodgkin’s lymphoma).
In 2001, The Blue Cross Blue Shield Technology Evaluation Centre concluded that ECP meets the TEC criteria as treatment of cGvHD that is refractory to established therapy.
The Catalan health technology assessment (also published in 2001) concluded that ECP is a new but experimental therapeutic alternative for the treatment of the erythrodermal phase of CTCL and cGvHD in allogenic HPTC and that this therapy should be evaluated in the framework of a RCT.
Quality of life (Lansky/Karnofsky play performance score) was reported in 1 study.
The patients in the studies were all refractory to steroids and other immunosuppressive agents, and these drugs were frequently continued concomitantly with ECP.
Criteria for assessment of organ improvement in cGvHD are variable, but PR was typically defined as >50% improvement from baseline parameters and CR as complete resolution of organ involvement.
Followup was variable and incomplete among the studies.
GRADE Quality of Studies – ECP for Refractory cGvHD
Conclusion
As per the GRADE Working Group, overall recommendations consider 4 main factors.
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates and the relative value placed on the outcome.
The quality of the evidence (Tables 1 and 2).
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise.
Uncertainty about the baseline risk for the population of interest.
The GRADE Working Group also recommends that incremental costs of healthcare alternatives should be considered explicitly alongside the expected health benefits and harms. Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 3 is the overall trade-off between benefits and harms and incorporates any risk/uncertainty.
For refractory erythrodermic CTCL, the overall GRADE and strength of the recommendation is “weak” – the quality of the evidence is “low” (uncertainties due to methodological limitations in the study design in terms of study quality and directness), and the corresponding risk/uncertainty is increased due to an annual budget impact of approximately $1.5M Cdn (based on 30 patients) while the cost-effectiveness of ECP is unknown and difficult to estimate considering that there are no high quality studies of effectiveness. The device is licensed by Health Canada, but the sterile solution of methoxsalen is not licensed.
With an annual budget impact of $1.5 M Cdn (based on 30 patients), and the current expenditure is $1.3M Cdn (for out of country for 7 patients), the potential cost savings based on 30 patients with refractory erythrodermic CTCL is about $3.8 M Cdn (annual).
For refractory cGvHD, the overall GRADE and strength of the recommendation is “weak” – the quality of the evidence is “low” (uncertainties due to methodological limitations in the study design in terms of study quality and directness), and the corresponding risk/uncertainty is increased due to a budget impact of approximately $1.5M Cdn while the cost-effectiveness of ECP is unknown and difficult to estimate considering that there are no high quality studies of effectiveness. Both the device and sterile solution are not licensed by Health Canada for the treatment of cGvHD.
If all the ECP procedures for patients with refractory erythrodermic CTCL and refractory cGvHD were performed in Ontario, the annual budget impact would be approximately $3M Cdn.
Overall GRADE and Strength of Recommendation (Including Uncertainty)
PMCID: PMC3379535  PMID: 23074497
9.  Residual tumor after the salvage surgery is the major risk factors for primary treatment failure in malignant ovarian germ cell tumors: A retrospective study of single institution 
Background
Malignant ovarian germ cell tumors are rare, and knowledge of their prognostic factors is limited, with little available randomized data. This study was conducted to evaluate the clinicopathologic characteristics of malignant ovarian germ cell tumors and to determine the association of their prognostic factors to primary treatment failure.
Methods
The medical records of 57 patients with stages I to IV malignant ovarian germ cell tumor were retrospectively reviewed, and their clinicopathologic and treatment-related data were collected and analyzed.
Results
The median age at the diagnosis was 23.3 years (range: 8-65 years), and the median follow-up period was 108 months (range: 48-205 months). The histological types of the tumors were immature teratoma (n = 24), dysgerminoma (n = 20), endodermal sinus tumor (n = 8), mixed germ cell tumor (n = 4), and choriocarcinoma (n = 1). 66.7% of the patients had stage I disease; 5.2%, stage II; 26.3%, stage III; and 1.8%, stage IV. After the initial surgery, 49 patients (86%) received cisplatin-based chemotherapy. The five-year survival rate was 96.5%. There were six primary treatment failures, with two of the patients dying of the disease, and the median time to the recurrence was 8 months. The histological diagnosis (P < 0.0001), tumor stage (P = 0.0052), elevation of beta-hCG (P = 0.0134), operation methods (P = 0.0006), and residual tumor after the salvage surgery (P < 0.0001) were significantly associated with the risk of primary treatment failure in the univariate analysis. In the multivariate analysis, the residual tumor after the salvage surgery was the only significant variable associated with primary treatment failure (P = 0.0011, Hazard ratio = 29.046, 95% Confidence interval 3.832-220.181).
Conclusion
Most malignant ovarian germ cell tumors have excellent prognoses with primary treatment, and good reproductive outcomes can be expected. Because primary treatment failure is associated with the residual disease after the salvage surgery, knowledge of the presence or absence of this risk factor may be helpful in risk stratification and individualization of adjuvant therapy in malignant ovarian germ cell tumors. Further large-scale prospective studies to confirm these results should be performed.
doi:10.1186/1477-7819-9-123
PMCID: PMC3214187  PMID: 21988930
Malignant ovarian germ cell tumor; Primary treatment failure; Prognostic factors
10.  Early prediction of treatment response to high-dose salvage chemotherapy in patients with relapsed germ cell cancer using [18F]FDG PET 
British Journal of Cancer  2002;86(4):506-511.
To assess the ability of [18F]fluorodeoxyglucose positron emission tomography for the early prediction of response in patients with relapsed metastatic germ cell tumours undergoing salvage high-dose chemotherapy. The role of positron emission tomography was compared with established means of tumour response assessment such as CT scans/MRI and serum tumour marker changes. In addition, positron emission tomography was compared with a current prognostic score which differentiates three prognostic groups with failure-free survival rates ranging from 5–50%. [18F]fluorodeoxyglucose uptake of metastases from germ cell tumours as well as CT scans and serum tumour marker were acquired after 2–3 cycles of induction chemotherapy but before the start of high-dose chemotherapy and CT scans/serum tumour marker were compared with the baseline examinations in 23 patients with relapsed germ cell tumours. To evaluate the validity of early response prediction by positron emission tomography, radiological monitoring and serum tumour marker decline, histopathologic response after resection of residual masses and/or the clinical course over 6 months after the end of treatment (relapse vs freedom of progression) were used. Overall, 10 patients (43%) achieved a marker-negative partial remission, three (13%) a marker-positive partial remission, five (22%) a disease stabilization and five (22%) progressed during treatment. Nine patients (39%) remained progression-free over 6 months following treatment, whereas 14 (61%) progressed. The outcome of high-dose chemotherapy was correctly predicted by positron emission tomography/CT scan/serum tumour marker in 91/59/48%. Eight patients with a favourably predicted outcome by CT scans plus serum tumour marker but a positive positron emission tomography prior to high-dose chemotherapy, failed treatment. This results in the following sensitivities/specificities for the prediction of failure of high-dose chemotherapy: positron emission tomography 100/78%; radiological monitoring 43/78%; serum tumour marker 15/100%. The positive and negative predictive values of positron emission tomography were 88 and 100%, respectively. As compared with the prognostic score, positron emission tomography was correctly positive in all patients of the three risk groups who failed treatment. In addition, a negative positron emission tomography correctly predicted a favourable outcome in the good and intermediate group. [18F]fluorodeoxyglucose positron emission tomography imaging can be used to assess response to chemotherapy in patients with relapsed germ cell tumours early in the course of treatment and may help to identify patients most likely to achieve a favourable response to subsequent high-dose chemotherapy. In patients with response to induction chemotherapy according to CT scans or serum tumour marker evaluation, positron emission tomography seems to add information to detect patients with an overall unfavourable outcome. It may also be a valuable addition to the prognostic model particularly in the good and intermediate group for further selection of patients who will profit from high-dose chemotherapy.
British Journal of Cancer (2002) 86, 506–511. DOI: 10.1038/sj/bjc/6600122 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600122
PMCID: PMC2375283  PMID: 11870528
germ cell cancer; response monitoring; PET; tumour markers; high-dose chemotherapy
11.  Treatment options in recurrent cervical cancer (Review) 
Oncology Letters  2010;1(1):3-11.
The management of recurrent cervical cancer depends mainly on previous treatment and on the site and extent of recurrence. Concurrent cisplatin-based chemo-radiation is the treatment of choice for patients with pelvic failure after radical hysterectomy alone. However, the safe delivery of high doses of radiotherapy is much more difficult in this clinical setting compared with primary radiotherapy. Pelvic exenteration usually represents the only therapeutic approach with curative intent for women with central pelvic relapse who have previously received irradiation. In a recent series, the 5-year overall survival and operative mortality after pelvic exenteration ranged from 21 to 61% and from 1 to 10%, respectively. Free surgical margins, negative lymph nodes, small tumour size and long disease-free interval were associated with a more favourable prognosis. Currently, pelvic reconstructive procedures (continent urinary conduit, low colorectal anastomosis, vaginal reconstruction with myocutaneous flaps) are strongly recommended after exenteration. Concurrent cisplatin-based chemo-radiation is the treatment of choice for isolated para-aortic lymph node failure, with satisfactory chances of a cure in asymptomatic patients. Chemotherapy is administered with palliative intent to women with distant or loco-regional recurrences not amenable by surgery or radiotherapy. Cisplatin is the most widely used drug, with a response rate of 17–38% and a median overall survival of 6.1–7.1 months. Cisplatin-based combination chemotherapy achieves higher response rates (22–68%) when compared with single-agent cisplatin, but median overall survival is usually less than one year. In a recent Gynecologic Oncology Group (GOG) trial the combination topotecan + cisplatin obtained a significantly longer overall survival than single-agent cisplatin in patients with metastatic or recurrent or persistent cervical cancer. A subsequent GOG study showed a trend in terms of longer overall survival and better quality of life for the doublet cisplatin + paclitaxel vs. the doublets cisplatin + topotecan, cisplatin + vinorelbine, and cisplatin + gemcitabine. Molecularly targeted therapy may represent a novel therapeutic tool, but its use alone or in combination with chemotherapy is still investigational.
doi:10.3892/ol_00000001
PMCID: PMC3436344  PMID: 22966247
recurrence; surgery; pelvic exenteration; radiotherapy; chemo-radiation; cisplatin; combination chemotherapy; molecularly-targeted therapy
12.  TI-CE High-Dose Chemotherapy for Patients With Previously Treated Germ Cell Tumors: Results and Prognostic Factor Analysis 
Journal of Clinical Oncology  2010;28(10):1706-1713.
Purpose
We previously reported a dose-finding and phase II trial of the TI-CE regimen (paclitaxel [T] plus ifosfamide [I] followed by high-dose carboplatin [C] plus etoposide [E] with stem-cell support) in germ cell tumor (GCT) patients predicted to have a poor prognosis with conventional-dose salvage therapy. We now report the efficacy of TI-CE with prognostic factors for disease-free survival (DFS) and overall survival (OS) in our full data set of 107 patients.
Patients and Methods
Eligible patients had advanced GCTs with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, incomplete response [IR] to first-line therapy, or relapse/IR to ifosfamide-cisplatin–based conventional-dose salvage). Univariate and multivariate analyses (MVAs) of prognostic factors were performed. The predictive ability of the Einhorn and Beyer prognostic models was assessed.
Results
Most patients were platinum refractory and had an IR to first-line chemotherapy. There were 54 (5%) complete and eight (8%) partial responses with negative markers; 5-year DFS was 47% and OS was 52% (median follow-up, 61 months). No relapses occurred after 2 years. Five (24%) of 21 primary mediastinal nonseminomatous GCTs are continuously disease free. On MVA, primary mediastinal site (P < .001), two or more lines of prior therapy (P < .001), baseline human chorionic gonadotropin ≥ 1,000 U/L (P = .01), and lung metastases (P = .02) significantly predicted adverse DFS. Poor-risk patients did worse than good- or intermediate-risk patients according to both Beyer (P < .002) and Einhorn (P < .05) models.
Conclusion
TI-CE is effective salvage therapy for GCT patients with poor prognostic features. Mediastinal primary site and two or more lines of prior therapy were most predictive of adverse DFS. Beyer and Einhorn models can assist in predicting outcome.
doi:10.1200/JCO.2009.25.1561
PMCID: PMC3651604  PMID: 20194867
13.  Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours 
British Journal of Cancer  2005;93(4):412-417.
We reviewed the European Group for Blood and Marrow Transplantation (EBMT) experience with salvage high-dose chemotherapy (HDC) in paediatric patients with extragonadal germ-cell tumour (GCT). A total of 23 children with extragonadal GCT, median age 12 years (range 1–20), were treated with salvage HDC with haematopoietic progenitor cell support. The GCT primary location was intracranial site in nine cases, sacrococcyx in eight, retroperitoneum in four, and mediastinum in two. In all, 22 patients had a nongerminomatous GCT and one germinoma. Nine patients received HDC in first- and 14 in second- or third-relapse situation. No toxic deaths occurred. Overall, 16 of 23 patients (70%) achieved a complete remission. With a median follow-up of 66 months (range 31–173 months), 10 (43%) are continuously disease-free. Of six patients who had a disease recurrence after HDC, one achieved a disease-free status with surgical resection followed by chemotherapy and radiotherapy. In total, 11 patients (48%) are currently disease-free. Eight of 14 patients (57%) with extracranial primary and three of nine patients (33%) with intracranial primary GCT are currently disease-free. HDC induced impressive long-term remissions as salvage treatment in children with extragonadal extracranial GCTs. Salvage HDC should be investigated in prospective trials in these patients.
doi:10.1038/sj.bjc.6602724
PMCID: PMC2361583  PMID: 16106248
extragonadal germ cell tumour; high-dose chemotherapy; salvage therapy; children
14.  Salvage chemoradiotherapy after primary chemotherapy for locally advanced pancreatic cancer: a single-institution retrospective analysis 
BMC Cancer  2012;12:609.
Background
There is no consensus on the indication for salvage chemoradiotherapy (CRT) after failure of primary chemotherapy for locally advanced pancreatic cancer (LAPC). Here we report on the retrospective analysis of patients who received salvage CRT after primary chemotherapy for LAPC. The primary objective of this study was to evaluate the efficacy and safety of salvage CRT after primary chemotherapy for LAPC.
Methods
Thirty patients who underwent salvage CRT, after the failure of primary chemotherapy for LAPC, were retrospectively enrolled from 2004 to 2011 at the authors’ institution. All the patients had histologically confirmed pancreatic adenocarcinoma.
Results
Primary chemotherapy was continued until progression or emergence of unacceptable toxicity. Eventually, 26 patients (87%) discontinued primary chemotherapy because of local tumor progression, whereas four patients (13%) discontinued chemotherapy because of interstitial pneumonitis caused by gemcitabine. After a median period of 7.9 months from starting chemotherapy, 30 patients underwent salvage CRT combined with either S-1 or 5-FU. Toxicities were generally mild and self-limiting. Median survival time (MST) from the start of salvage CRT was 8.8 months. The 6 month, 1-year and 2-year survival rates from the start of CRT were 77%, 33% and 26%, respectively. Multivariate analysis revealed that a lower pre-CRT serum CA 19–9 level (≤ 1000 U/ml; p = 0.009) and a single regimen of primary chemotherapy (p = 0.004) were independent prognostic factors for survival after salvage CRT. The MST for the entire patient population from the start of primary chemotherapy was 17.8 months, with 2- and 3-year overall survival rates of 39% and 22%, respectively.
Conclusions
CRT had moderate anti-tumor activity and an acceptable toxicity profile in patients with LAPC, even after failure of gemcitabine-based primary chemotherapy. If there are any signs of failure of primary chemotherapy without distant metastasis, salvage CRT could be a treatment of choice as a second-line therapy. Patients with relatively low serum CA19-9 levels after primary chemotherapy may achieve higher survival rates after salvage CRT. The strategy of using chemotherapy alone as a primary treatment for LAPC, followed-by CRT with salvage intent should be further investigated in prospective clinical trials.
Trial registration
2011–136
doi:10.1186/1471-2407-12-609
PMCID: PMC3546942  PMID: 23256481
Pancreatic cancer; Locally advanced pancreatic cancer; Induction chemotherapy; Salvage therapy; Chemoradiotherapy; Prognostic factor
15.  Treatment and outcome of patients with extragonadal germ cell tumours--the Norwegian Radium Hospital's experience 1979-94. 
British Journal of Cancer  1998;77(2):329-335.
This report reviews 48 patients who from 1979 to 1994 were treated at the Norwegian Radium Hospital for newly diagnosed noncerebral extragonadal malignant germ cell tumour (EGGCT). Based on histology and/or serum tumour markers, 12 patients had a seminoma and 36 a non-seminoma. At diagnosis, 33 and 15 patients were classified as having abdominal and mediastinal EGGCT respectively. At the time of diagnosis 13 patients, all with non-seminomatous tumours, had metastases to bone, liver or brain. One patient with abdominal seminoma was cured by radiotherapy alone, whereas cisplatin-based chemotherapy (with or without surgery) was planned in the 47 remaining patients. Twenty-seven out of 42 patients receiving four or more chemotherapy cycles were rendered tumour free by induction chemotherapy, including 5 of the 13 patients with extralymphatic non-pulmonal disease. An additional tumour-free patient died of septicaemia after only two cycles of chemotherapy. Late relapses (after > 2 years) were observed in three patients, and a testicular primary was diagnosed during follow-up in three cases. Seven patients died of treatment-related complications, five of these because of neutropenic septicaemia. The median age of these patients was 52 years compared with 35 years in the remaining 41 patients (P < 0.05). The 5-year overall survival for all 48 patients was 60% (95% CI 46-74%) [cancer-specific 5-year survival 71% (95% CI 50-92%)]. EGGCT is a potentially curable disease, even in patients with very advanced disease. Special attention should, however, be devoted to patients above the age of 40 years because of an increased risk of treatment-related side-effects. Late relapses and the subsequent development of testicular tumours indicate the need for long-term follow-up.
PMCID: PMC2151244  PMID: 9461006
16.  High incidence of metastatic disease in primary high grade and large extremity soft tissue sarcomas treated without chemotherapy 
BMC Cancer  2006;6:160.
Background
The risk of metastasis and the survival in patients with primary extremity soft tissue sarcomas is worse when tumour size is large and the grade of malignancy is high. Such tumours may receive chemotherapy and/or radiation therapy (RTX) for optimising local control. Irradiation can either be applied preoperatively or after tumour resection. The question arises if the kind of RTX in the absence of chemotherapy influences the outcome concerning local control, metastatic disease, survival and complications.
Methods
We retrospectively reviewed the clinical outcome of 233 patients with a primary extremity soft tissue sarcoma treated between 1990 – 2000 with a mean follow-up of 35.8 (4–120) months in our institute. 41 patients had high grade, deep and large tumours (>8 cm), an AJCC stage III (no evidence of metastasis prior to treatment) and were treated with limb salvage surgery and irradiation but stayed without additional chemotherapy. Two groups of patients were compared: the first group received postoperative RTX after tumour resection (n = 33); the second group was treated with preoperative RTX (n = 8). Both groups did not differ concerning clinical parameters. We analysed primary and secondary outcomes.
Results
56% (23/41) of the population developed metastatic disease, 24% (10/41) local recurrence. The risk of metastasis was higher in the group with preoperative irradiation (p = 0.046). The overall (p = 0.0248) and relapse free survival (p = 0.104) were worse in this group. The delay to tumour resection amounted 8 weeks on average in the preoperative group. Local control was not different (p = 0.38) in both study groups. Wound infections and other combined therapy related complications were equally distributed (p = 0.22).
Conclusion
Without chemotherapy there remains a high risk of metastasis in AJCC grade 3 patients. In high risk patients treated without chemotherapy the elapsed time to tumour resection after preoperative radiation might contribute to the development of metastasis. This outcome may support the thesis that a combination of RTX and offensive multimodal treatment protocols is advantageous in such a subset of patients
doi:10.1186/1471-2407-6-160
PMCID: PMC1550254  PMID: 16780601
17.  Intensive chemotherapy as salvage treatment for solid tumors: focus on germ cell cancer 
Germ cell tumors present contrasting biological and molecular features compared to many solid tumors, which may partially explain their unusual sensitivity to chemotherapy. Reduced DNA repair capacity and enhanced induction of apoptosis appear to be key factors in the sensitivity of germ cell tumors to cisplatin. Despite substantial cure rates, some patients relapse and subsequently die of their disease. Intensive doses of chemotherapy are used to counter mechanisms of drug resistance. So far, high-dose chemotherapy with hematopoietic stem cell support for solid tumors is used only in the setting of testicular germ cell tumors. In that indication, high-dose chemotherapy is given as the first or late salvage treatment for patients with either relapsed or progressive tumors after initial conventional salvage chemotherapy. High-dose chemotherapy is usually given as two or three sequential cycles using carboplatin and etoposide with or without ifosfamide. The administration of intensive therapy carries significant side effects and can only be efficiently and safely conducted in specialized referral centers to assure optimum patient care outcomes. In breast and ovarian cancer, most studies have demonstrated improvement in progression-free survival (PFS), but overall survival remained unchanged. Therefore, most of these approaches have been dropped. In germ cell tumors, clinical trials are currently investigating novel therapeutic combinations and active treatments. In particular, the integration of targeted therapies constitutes an important area of research for patients with a poor prognosis.
doi:10.1590/1414-431X20144214
PMCID: PMC4288488  PMID: 25493378
High-dose chemotherapy; Germ cell tumors; Stem cell transplantation; Solid tumors; Breast cancer; Ovarian cancer
18.  Ovarian metastases from primary gastrointestinal malignancies: the Royal Marsden Hospital experience and implications for adjuvant treatment. 
British Journal of Cancer  1995;71(1):92-96.
We investigated the pattern and frequency of ovarian metastases in patients with primary gastrointestinal malignancies and evaluated the response to surgery, chemotherapy and in three cases radiotherapy. The literature reports that this group of patients have a poor prognosis, but no report has specifically addressed the response to chemotherapy. Using a database which is generated prospectively, we analysed 51 patients with primary gastrointestinal malignancies and ovarian metastases. All patients received chemotherapy but only 36 were evaluable for response; five had adjuvant treatment and ten had non-measurable disease. Seventeen patients had surgical oophorectomy and three patients received radiotherapy. The overall response rate to chemotherapy was 22%; eight partial responses and no complete responses. When stratified according to site of response, 11 (31%) patients had a partial response at sites of extraovarian metastases and only five (14%) had a partial response in the ovaries. Seven patients with primary colorectal cancer had a differential response in favour of extraovarian sites. The median survival was 9 months for the 51 patients. Three premenopausal women with resected gastric carcinoma received adjuvant chemotherapy and relapsed only in the ovaries. In primary colorectal tumours the response of ovarian metastases to chemotherapy is less than that for other sites. Therefore, the ovary may be a sanctuary site for metastases which has important implications for adjuvant chemotherapy in women. These women could be followed up regularly by transvaginal ultrasonography to detect such metastases at an early stage when they would be amenable to surgical resection. Surgery should be considered for selected patients who develop metachronous metastases, as patients may be rendered disease free for several months.
PMCID: PMC2033445  PMID: 7819057
19.  SAFETY AND EFFICACY OF STEREOTACTIC RADIOSURGERYAND ADJUVANT BEVACIZUMAB IN PATIENTS WITH RECURRENT MALIGNANT GLIOMAS 
Purpose
Patients with recurrent malignant gliomas treated with stereotactic radiosurgery (SRS) and multiagent systemic therapies were reviewed to determine the effects of patient- and treatment-related factors on survival and toxicity.
Methods and Materials
A retrospective analysis was performed on patients with recurrent malignant gliomas treated with salvage SRS from September 2002 to March 2010. All patients had experienced progression after treatment with temozolomide and radiotherapy. Salvage SRS was typically administered only after multiple post-chemoradiation salvage systemic therapies had failed.
Results
63 patients were treated with SRS for recurrent high-grade glioma; 49 patients had World Health Organization (WHO) Grade 4 disease. Median follow-up was 31 months from primary diagnosis and 7 months from SRS. Median overall survival from primary diagnosis was 41 months for all patients. Median progression-free survival (PFS) and overall survival from SRS (OS-SRS) were 6 and 10 months for all patients, respectively. The 1-year OS-SRS for patients with Grade 4 glioma who received adjuvant (concurrent with or after SRS) bevacizumab was 50% vs. 22% for patients not receiving adjuvant bevacizumab (p = 0.005). Median PFS for patients with a WHO Grade 4 glioma who received adjuvant bevacizumab was 5.2 months vs. 2.1 months for patients who did not receive adjuvant bevacizumab (p = 0.014). Karnofsky performance status (KPS) and age were not significantly different between treatment groups. Treatment-related Grade 3/4 toxicity for patients receiving and not receiving adjuvant BVZ was 10% and 14%, respectively (p = 0.58).On multivariate analysis, the relative risk of death and progression with adjuvant bevacizumab was 0.37 (confidence interval [CI] 0.17–0.82) and 0.45 (CI 0.21–0.97). KPS >70 and age <50 years were significantly associated with improved survival.
Conclusions
The combination of salvage radiosurgery and bevacizumab to treat recurrent malignant gliomas is well tolerated and seems to be associated with improved outcomes. Prospective multiinstitutional studies are required to determine efficacy and long-term toxicity with this approach.
doi:10.1016/j.ijrobp.2010.12.074
PMCID: PMC3690566  PMID: 21489708
Stereotactic radiosurgery; Glioma; Bevacizumab; Vascular endothelial growth factor-A
20.  Concurrent radiochemotherapy in locally-regionally advanced oropharyngeal squamous cell carcinoma: analysis of treatment results and prognostic factors 
Background
Concurrent radiochemotherapy is a recommended treatment option for patients with locally advanced squamous cell head and neck carcinomas with recent data showing the most significant absolute overall and event-free survival benefit achieved in patients with oropharyngeal tumours. The aim of this study was to analyse the results of three-dimensional conformal radiotherapy given with concomitant weekly cisplatin in patients with advanced oropharyngeal carcinoma and to identify prognostic factors influencing outcomes of this patients category.
Methods
Sixty-five patients with stage III or IV squamous cell carcinoma of the oropharynx who underwent concurrent radiochemotherapy between January 2005 and December 2010 were retrospectively analyzed. All patients received radiotherapy to 70 Gy/35 fractions/2 Gy per fraction/5 fractions per week. Concurrent chemotherapy consisted of weekly cisplatin (30 mg/m2) started at the first day of radiotherapy.
Results
Median age was 57 years (range, 36 to 69 years) and 59 (90.8%) patients were male. Complete composite response was achieved in 47 patients (72.3%). Local and/or regional recurrence was the most frequent treatment failure present in 19 out of 25 patients (76.0%). At a median follow-up of 14 months (range, 5 to 72 months), 2-year local relapse-free, regional relapse-free, locoregional relapse-free, disease-free, and overall survival rates were 48.8%, 57.8%, 41.7%, 33.2% and 49.7%, respectively.
On multivariate analysis the only significant factor for inferior regional relapse-free survival was the advanced N stage (p = 0.048). Higher overall stage was independent prognostic factor for poorer local relapse-free survival, locoregional relapse-free survival and disease-free survival (p = 0.022, p = 0.003 and p = 0.003, respectively). Pre-treatment haemoglobin concentration was an independent prognostic factor for local relapse-free survival, regional relapse-free survival, locoregional relapse-free survival, disease-free survival, and overall survival (p = 0.002, p = 0.021, p = 0.001, p = 0.002 and p = 0.002, respectively).
Conclusions
Poor treatments results of this study suggested that introduction of intensity-modulated radiotherapy, use of induction chemotherapy followed by concurrent radiochemotherapy, accelerated radiotherapy regimens, and molecular targeted therapies could positively influence treatment outcomes. The incorporation of reversal of anaemia should be also expected to provide further improvement in locoregional control and survival in patients with advanced squamous cell carcinoma of the oropharynx.
doi:10.1186/1748-717X-7-78
PMCID: PMC3404949  PMID: 22640662
Concurrent radiochemotherapy; Oropharyngeal carcinoma; Prognostic factor
21.  Salvage concurrent radio-chemotherapy for post-operative local recurrence of squamous-cell esophageal cancer 
Purpose
To evaluate the treatment outcome of salvage concurrent radio-chemotherapy for patients with loco-recurrent esophageal cancer after surgery.
Methods
50 patients with loco-recurrent squamous-cell cancer after curative esophagectomy were retrospectively analyzed. Patients were treated with radiotherapy (median 60 Gy) combined with chemotherapy consisting of either 5-fluorouracil (5-FU) plus cisplatin (DDP) (R-FP group) or paclitaxel plus DDP (R-TP group).
Results
The median follow-up period was 16.0 months. The 1-year and 3-year survival rates were 56% and 14%, respectively. The median progression-free survival (PFS) and overall survival (OS) time was 9.8 and 13.3 months respectively. There was no statistical significance of the PFS of the two groups. The OS (median 16.3 months) in the R-TP group was superior to that in the R-FP group (median: 9.8 months) (p = 0.012). Among the patients who had received ≥60 Gy irradiation dose, the median PFS (10.6 months) and OS (16.3 months) were significantly superior to the PFS (8.7 months) and OS (11.3 months) among those patients did not (all p < 0.05). Grade 3 treatment-related gastritis were observed in 6 (27.3%) and 7 (25%) patients in the R-FP and R-TP group respectively. By univariate survival analysis, the age (<60 years), TP regimen and higher irradiation dose might improve the OS of such patients in present study.
Conclusions
For those patients with post-operative loco-recurrent squamous-cell esophageal carcinoma, radiotherapy combined with either FP or TP regimen chemotherapy was an effective salvage treatment. Younger age, treatment with the TP regimen and an irradiation dose ≥60 Gy might improve the patients’ treatment outcome.
doi:10.1186/1748-717X-7-93
PMCID: PMC3431241  PMID: 22713587
Squamous-cell esophageal cancer; Post-operative local recurrence; Salvage radio-chemotherapy; Treatment outcomes; Toxicity
22.  Extramedullary plasmacytoma of the head and neck region: clinicopathological correlation in 25 cases. 
British Journal of Cancer  1997;75(6):921-927.
Extramedullary plasmacytomas (EMP) of head and neck are rare tumours. Between 1972 and 1993, 25 cases of EMP of head and neck were seen at our institute. The clinical and pathological features and response to treatment are presented. At initial presentation, 23 (92%) patients presented with disease confined to a single extramedullary site only and two patients had in addition clinical involvement of cervical lymph nodes. All except these two patients received radiotherapy to the primary site only as initial treatment. Initial primary control of local disease was obtained in 16 of 24 (67%) patients treated with radical intent. With salvage treatment of further radiotherapy and/or chemotherapy, local disease control was achieved in 21 of 24 (88%) patients. One patient was treated with palliative intent. Conversion to multiple myeloma was seen in two patients (8%). Pathologically, the tumours were classified into low, intermediate and high grade, which correlated closely with outcome. This classification has been used for the first time in extramedullary plasmacytomas and is based on the multiple myeloma grading criteria devised by Bartl et al (1987). Fifteen of eighteen (83%) low-grade tumours and only one of six (17%) intermediate- and high-grade tumours were locally controlled after primary radiotherapy. This is statistically significant for local control (P= 0.0019) but not for overall survival (P= 0.12). The median survival and 5-year overall survival is 68 months and 58.9% respectively. We recommend consideration of adjuvant chemotherapy in patients with higher grade disease.
Images
PMCID: PMC2063399  PMID: 9062417
23.  Quality of life in advanced non-small cell lung cancer patients receiving palliative chemotherapy: A meta-analysis of randomized controlled trials 
For advanced non-small cell lung cancer (NSCLC) patients, the only treatment option is palliative therapy, with the aim of prolonging overall survival and improving disease-related symptoms and quality of life (QOL). However, to date, the effect of palliative care on QOL has not yet been thoroughly examined, and there has been no meta-analysis of previous studies reporting QOL outcomes following palliative care. We consider that it is important to evaluate not only survival and/or response rates, but also QOL in patients with advanced NSCLC receiving palliative chemotherapy. The aim of the present study was to obtain useful information for the selection of suitable chemotherapy regimens for advanced NSCLC patients, taking into consideration QOL, and to demonstrate the importance of QOL assessments during treatment. We performed a meta-analysis of QOL outcomes following treatments that compared carboplatin- to cisplatin-based chemotherapy. Trials were eligible for analysis if they had compared carboplatin- to cisplatin-based chemotherapy in advanced NSCLC patients who had not received prior chemotherapy, and if these studies reported QOL data. In the six trials eligible for analysis, 2,405 patients were randomized to receive cisplatin-based or carboplatin-based chemotherapy. The patients who received carboplatin-based chemotherapy had higher global QOL and less severe symptoms than those who received cisplatin-based chemotherapy. The survival rate, which was the primary outcome in clinical trials, and the response rate did not differ significantly between the two treatment groups. It is important to evaluate QOL in addition to the survival and response rates for advanced NSCLC, particularly when the treatment is palliative.
doi:10.3892/etm.2011.368
PMCID: PMC3438671  PMID: 22969858
palliative care; quality of life; meta-analysis; advanced non-small cell lung cancer; chemotherapy
24.  Alternating dose-dense chemotherapy in patients with high volume disseminated non-seminomatous germ cell tumours 
British Journal of Cancer  2002;86(10):1555-1560.
Only about half of patients with a poor-prognosis non-seminomatous germ-cell tumours can achieve a cure. The aim of this phase II study was to assess the efficacy and toxicity of a dose-dense alternating chemotherapy regimen in this subset of patients. High volume non-seminomatous germ-cell tumours was defined as follows: at least two sites of non pulmonary metastases, an extragonadal primary tumour, a serum human chorionic gonadotropin level higher than 10 000 mIU ml−1, or a alpha-foetoprotein level higher than 2000 mIU ml−1. Patients who fulfilled these criteria were treated with the so-called BOP-CISCA-POMB-ACE regimen (bleomycin, vincristine, and cisplatin; cisplatin, cyclophosphamide, and doxorubicin; cisplatin, vincristine, methotrexate, and bleomycin; etoposide, dactinomycin, and cyclophosphamide) plus granulocyte colony-stimulating factor. A total of 58 patients were enrolled. Patients were retrospectively classified according to the International Germ-Cell Cancer Consensus Group classification; 38 patients (66%) had poor-prognosis disease and 19 patients (33%) had intermediate-prognosis. Patients received a median of 2.5 courses (range 0.25 to five courses) of the BOP-CISCA-POMB-ACE regimen. Forty-two patients (72.4%) had a complete response to therapy. With a median follow-up time of 31 months, the 3-year progression-free survival rate was 71% (95% confidence interval, 60 to 84%) and the 3-year overall survival rate was 73% (95% confidence interval: 62 to 86%). The 3-year PFS rates were 83% (95% confidence interval: 68 to 100%) in the intermediate-prognosis group and 65% (95% confidence interval: 51 to 82%) in the poor-prognosis group. Early side effects included mainly grade 4 haematologic toxicity (neutropaenia in 79% of patients, thrombocytopaenia in 69%, anaemia in 22%), grade 4 stomatitis (19%), and four early deaths (7% of patients), at least partially related to toxicity. The dose-dense BOP-CISCA-POMB-ACE regimen is highly active in patients with non-seminomatous germ-cell tumours classified as intermediate-prognosis or poor-prognosis according to the International Germ-Cell Cancer Consensus Group. Because outcomes with this regimen compare favourably with outcome after standard therapy, dose-dense chemotherapy should be further investigated in this subset of patients.
British Journal of Cancer (2002) 86, 1555–1560. DOI: 10.1038/sj/bjc/6600272 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600272
PMCID: PMC2746595  PMID: 12085204
chemotherapy; dose-dense chemotherapy; germ-cell tumours; International Germ-Cell Cancer Consensus Group; non-seminomatous germ cell-tumours
25.  Durable Remission With Salvage Second Autotransplants in Patients with Multiple Myeloma 
Cancer  2011;118(14):3549-3555.
Background
High dose chemotherapy with autologous hematopoietic cell transplant (auto-HCT) has been shown to improve survival in patients with newly diagnosed multiple myeloma. However, the role of salvage auto-HCT for relapsed patients, particularly in the era of novel therapeutics, is not well-defined.
Methods
We performed a retrospective analysis of all 44 myeloma patients (24 males, 20 females) who received a second auto-HCT as salvage between 1/3/1992 and 11/4/2008 at M.D. Anderson Cancer Center.
Results
Median interval between the first and salvage auto HCT was 30 months (range 2–78). Median age at salvage HCT was 54 years (38–73) and median number of salvage treatment regimens was 2 (range 0–5). Eleven (25%) patients had high-risk chromosomal abnormalities on conventional cytogenetic studies between diagnosis and salvage auto. Ten patients (23%) experienced grade 3 or higher non-hematologic toxicity after the salvage auto-HCT. One patient died within 100 days for a treatment-related mortality of 2%. Best responses after salvage chemotherapy + salvage auto-HCT were as follows: CR+ near CR 11%, PR 79%, with an overall response rate of 90%. Eighteen (41%) patients received post auto HCT maintenance therapy. Median follow-up from salvage HCT was 41 months. Kaplan-Meier estimates of median progression-free survival and overall survival (OS) from time of salvage auto-HCT were 12.3 and 31.7 months, respectively. Median OS from the time of diagnosis was 75 months. In a fitted Bayesian multivariate model, shorter time to progression (TTP) after first auto HCT, greater number of prior therapies, African-American race, and IgG subtype were significantly associated with worse OS.
Conclusions
In selected myeloma patients, a second auto-HCT for salvage therapy is well tolerated with acceptable toxicity. The ORR and PFS are comparable to other salvage regimens.
doi:10.1002/cncr.26662
PMCID: PMC4038445  PMID: 22086552
myeloma; transplantation; salvage therapy; toxicity

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